Central Nervous System Pharmacology Question And Answers

Central Nervous System Pharmacology

 

General Anesthetics

Question 1. Classify general anesthetics. Explain the pharmacokinetic factors which influence the administration of inhalational anesthetics.
Answer:

Definition General anesthetics: General anesthetics are agents that bring about a reversible loss of sensation and consciousness.

General anesthetics Classification:

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Inhalational Anesthetics:

Pharmacokinetics of Inhalational Anesthetics:

Inhalational anesthetics are administered at a specific concentration. Since the brain is a highly perfused organ, steady state can be achieved quickly.

Factors that influence the partial pressure of the anesthetic attained in the brain are:

1. The partial pressure of the anesthetic in the inspired gas: Higher the partial pressure (PP) of the anesthetic in the inspired air, the greater is its quantity moving into the blood.
2. Pulmonary ventilation: Delivery of the anesthetic into the alveoli is directly proportional to pulmonary ventilation.
3. Alveolar exchange: When ventilation-perfusion is appropriate, volatile anesthetics freely diffuse across the alveoli.
4. Solubility of the anesthetic in the blood: Lower the solubility of the anesthetic in the blood, the faster is the rise of its PP in the blood and the faster is the induction.
5. Solubility of the anesthetic in the tissue: Anestheics which are more soluble in tissues like the adipose tissue requires a longer time to attain equilibrium.
6. Cerebral blood flow: Because the blood flow to the brain is high, GAs reach it rapidly and if other factors are favorable, anesthesia can be rapidly attained.

Nitrous Oxide

Question 2. Write briefly on the role of nitrous oxide in general anesthesia.
Answer:

Nitrous oxide:

Nitrous oxide is a gas with a slightly sweetish odor. It produces light anesthesia without significant depression of respiration or vasomotor center.

Nitrous oxide Advantages:

• Strong analgesic.
• Induction is rapid and smooth.
• Nonirritating and noninflammable.
• Recovery is rapid.
• Postoperative nausea is not significant.
• Little effect on respiration and cardiovascular (CV) functions → ideal for combination.
• Nontoxic to liver, kidney, and brain; quickly removed from the lungs.
• Inexpensive.

Nitrous oxide Disadvantages:

• Less potent—used with other agents.
• Poor muscle relaxant.
• Repeated use can depress the bone marrow.
• Long-term exposure (like in staff of operation theater) to low doses
• Can impair DNA synthesis resulting in fetal abnormalities on conception.
• May cause vitamin B₁₂ deficiency.
• NO₂ displaces nitrogen in the air-filled cavities and it enters the cavities faster, i.e. even before nitrogen escapes.
• This results in the expansion of such cavities leading to pneumothorax and air embolus.

Hence NO₂ should be avoided in such patients:

Nitrous oxide Status in anesthesia:

Adjuvant—nitrous oxide (~50%) with oxygen (30%) is used to provide analgesia and sedation with other anesthetics.

Ether

Ether is a colorless volatile liquid.

Ether Advantages:

• Potent and reliable anesthetic Good analgesic CV and respiratory functions → no significant effects
• Bronchodilator
• Good muscle relaxation
• Does not sensitize the heart to adrenaline
• Easy to administer—complicated equipment not necessary
• Inexpensive

Ether Disadvantages:

• Highly inflammable → diathermy contraindicated
• Highly soluble in body tissues—induction is slow and unpleasant
• Vapors are irritating → respiratory secretions.
• Premedication with atropine is essential
• Postoperative nausea and vomiting are frequent
• Recovery is slow.

Ether  Status in anesthesia:

Ether is not the preferred anesthetic because it is inflammable and has irritant property

Halothane

Question 3. Describe briefly the advantages and disadvantages of halothane as an anesthetic.
Answer:

Halothane is a colorless volatile liquid with a sweet odor.

Halothane Advantages:

• Potent, noninflammable anesthetic.
• Induction is smooth and rapid—surgical anesthesia in 2–5 minutes.
• Nonirritant—no increased secretions.
• Recovery is rapid.
• Less postoperative nausea and vomiting.

Halothane Disadvantages:

• Not a good analgesic and not a muscle relaxant.
• Direct myocardial depressant— ↓ HR, CO, BP. It sensitizes the heart to the arrhythmogenic effects of adrenaline.
• Mild respiratory depression.
• Severe hepatitis may be fatal (1: 50,000).
• Reduces renal blood flow and GFR.
• Malignant hyperthermia a genetically determined reaction is rare but can be fatal → treated with dantrolene.

Halothane Status in Anesthesia:

Halothane was a popular anesthetic but it is toxic to the heart, lungs, kidneys, liver, and brain and therefore its use has largely declined as newer safer derivatives are available.

 Enflurane

Question 4. Write short note on enflurane/isoflurane/disflurane/sevoflurane.
Answer:

Enflurane is similar to halothane except that:

• It is metabolized to a lesser extent than halothane—therefore safe for the liver.
• Does not sensitize the heart to adrenaline.
• May precipitate seizures in epileptics → avoid in them.
• A metabolite of enflurane is nephrotoxic.

Nitrous Oxide Ether And Halothane:

 Isoflurane

Isoflurane differs from halothane in the following ways:

• More potent than halothane.
• Does not sensitize the heart to adrenaline → safer in patients with myocardial ischemia.
• Metabolism is negligible (99% excreted through lungs)—therefore safe for the liver.
• Does not provoke seizures.
• Preferred anesthetic in neurosurgical procedures (less cerebral vasodilation and less increase in intracranial pressure).
• Isoflurane is extensively used now for the maintenance of anesthesia.

Isoflurane Disadvantages:

• It can cause hypotension.
• Requires a skeletal muscle relaxant

Desflurane

• Has all the advantages of isoflurane.
• Rapid and smooth induction and recovery because of low solubility in blood and tissues.

Desflurane Disadvantages:

• Pungent → may induce coughing and sometimes laryngospasm → not preferred for induction.
• Because of low volatility, a special vaporizer is required for administration.
• Can cause transient sympathetic stimulation and tachycardia

Sevoflurane

Sevoflurane has many advantages and is now the preferred anesthetic.

Sevoflurane Advantages:

• Not pungent.
• Rapid and smooth induction and recovery because of low solubility in blood and tissues.
• A good bronchodilator.
• Suitable for daycare surgeries and in children.

Sevoflurane Disadvantages:

• Chemically unstable and is degraded by carbon dioxide adsorbents (soda lime) to a nephrotoxic metabolite.
• Postoperative restlessness is avoided by premedication with midazolam.
• Sevoflurane metabolized (~ 3%) in the liver → fluoride ions released → are nephrotoxic.
• Malignant hyperthermia in genetically susceptible individuals.
• Expensive.

Xenon

Question 5. What are the advantages and disadvantages of xenon?
Answer:

Xenon is an inert gas. It has properties very close to an ideal anesthetic.

Xenon Advantages:

• Rapid induction → insoluble in blood and tissues
• Rapid recovery.
• Good anesthetic.
• No effect on hepatic, renal, or pulmonary function.
• No significant CV effects—no effect on CO, HR, or BP.
• Not metabolized in the body

Xenon Disadvantages:

• Very expensive because xenon cannot be manufactured currently.
• But can only be extracted from the air.

Intravenous Anesthetics

Question 6. Discuss briefly the different intravenous anesthetics.
Answer:

Intravenous Anesthetics:

Intravenous Anesthetics Advantage:

Extremely rapid induction because the blood concentration can be raised rapidly and in one arm brain circulation (~11 sec) there is loss of consciousness.

Intravenous Anesthetics Disadvantages:

• Anesthetics given intravenously have no channel for quick elimination like the lungs.
• Elimination of inhaled anesthetics can be made faster by hyperventilation but not possible with IV anesthetics.
• Hence IV anesthetics are used only for induction because of the rapid onset of action and anesthesia is maintained by an inhalational agent.

Intravenous anesthetics;

Thiopentone Sodium

Question 7. Write a short note on thiopentone sodium.
Answer:

Thiopentone sodium is an ultra-short-acting barbiturate. On IV injection it produces unconsciousness in 20–30 seconds. The duration of action is 4–7 minutes. It is highly lipid-soluble, rapidly crosses the BBB, and gets rapidly redistributed in the body tissues leading to the termination of its action.

Thiopentone Sodium Advantages:

• The quick onset of action
• Induction is smooth, rapid, and pleasant.

Thiopentone Sodium Disadvantages:

• Neither a good analgesic nor a muscle relaxant.
• Cannot be used alone due to respiratory and circulatory depression.
• Severe hypotension and hiccups may occur.
• Should not be mixed with acidic drugs because barbiturates may be precipitated.
• Administered repeatedly, may accumulate in the body fat.
• Extravasation produces intense pain, necrosis, and gangrene. Injection into an artery produces severe vasospasm.

Thiopentone Sodium Uses:

• Induction of anesthesia.
• To control convulsions in status epilepticus.
• Medicolegal use—‘truth serum’ for interrogation of suspects, subanesthetic doses of thiopentone sodium produces altered consciousness when the capacity of a person to concoct stories and lie is lost.

Propofol

Question 8. Discuss the role of propofol in general anesthesia.
Answer:

Propofol is an oily liquid with several advantages and most preferred IV anesthetic.

Propofol Advantages:

• Quick induction and rapid recovery.
• Because of rapid recovery, preferred for ‘day cases’.
• Has antiemetic properties.
• Can be safely used in pregnant women.

Propofol  Disadvantages:

• Respiratory depressants like thiopental.
• Vasodilation → fall in BP.
• Negative inotropic effect—depression of cardiac contractility.
• Pain on injection—prevented by diluting and combining with lignocaine.
• ‘Propofol infusion syndrome’ is characterized by skeletal muscle necrosis, metabolic acidosis, hyperkalemia, renal failure, arrhythmias, and CV collapse—but rare.
• Histamine release and anaphylactoid reactions.

Propofol  Uses:

• For induction and maintenance of general anesthesia (GA) for short procedures of up to 1-hour duration. The effect of a single dose is terminated by redistribution.
• Total IV anesthesia—continuous infusion or intermittent injection for short surgical procedures like endoscopies, and burns dressing in poor-risk patients.
• Postoperative nausea and vomiting in subanesthetic doses.

Fospropofol:

Fospropofol is a prodrug of propofol. It does not cause pain at the injection site (propofol causes pain) but the onset of action and recovery is slow because it is a prodrug.

Ketamine

Question 9. Write a short note on ketamine.
Answer:

Ketamine:

• Ketamine produces a trance-like state known as dissociative anesthesia characterized by intense analgesia, immobility, amnesia, and a feeling of dissociation from the surroundings with or without actual loss of consciousness.
• Ketamine is highly lipid-soluble and gets rapidly distributed
  and then redistributed to less vascular structures.
• Dissociative anesthesia starts within 3–5 minutes and lasts for 10–15 minutes.
• Amnesia lasts for 1–2 hours.

Ketamine Mechanism of action:

Ketamine acts by blocking the NMDA receptor which is an excitatory amino acid receptor.

Ketamine Advantages:

• Good analgesia (only IV anesthetic to provide analgesia) and amnesia.
• No respiratory depression, no hypotension.
• Convenient to use—epidural, IV, IM, and rectal.
• Particularly suitable in children, poor-risk patients, and asthmatics as it may produce bronchodilatation.
• Increases HR, CO, and BP—useful in poor-risk cardiogenic shock.

Mind Map Ketamine:

Ketamine  Disadvantages:

• Hallucinations, delirium, involuntary movements, and nystagmus may occur during recovery.
• Premedication with diazepam helps.
• ↑ ↑ BP, heart rate, and cardiac output—dangerous in hypertensives.
• ↑ ↑ Intracranial pressure.

Ketamine Uses:

• Short surgical and diagnostic procedures particularly in poor-risk patients.
• Topical use for joint pain.

Preanaesthetic Medication

Question 10. Write briefly on pre-anesthetic medication. Give reason: Why glycopyrrolate is used as pre-anesthetic medication.
Answer:

Prior to anesthesia, certain drugs are administered in order to make anesthesia safer and more pleasant, and is known as pre-anesthetic medication.

Preanesthetic medication is given in order to:

• Decrease anxiety
• Provides amnesia for the preoperative period
• Relive preoperative pain
• Making anesthesia safer reduces the side effects of anesthetics
• Reduce gastric acidity.

To achieve the above purpose, more than one drug is required. They are:

1. Sedative hypnotics: Benzodiazepines reduce anxiety, produce sedation, and also amnesia.

2. Antihistamines: Antihistamines for sedative, antiemetic, and anticholinergic properties, for example, P promethazine.

3. Antiemetics and prokinetics:

• Metoclopramide and domperidone are dopamine antagonists that increase gastrointestinal motility, increase the tone of the esophageal end of the stomach and speed up gastric emptying.
• The combination of H₂ blocker + metoclopramide provides the best protection against aspiration. Ondansetron may be used for antiemetic effects.

4. Anticholinergic drugs:

• During anesthesia, the secretions from the oral cavity and trachea may creep into the larynx inducing laryngospasm.
• They may enter into the lungs causing aspiration pneumonia.

Anticholinergics:

• Reduce the secretions—good antisialogogues
• Prevent bradycardia due to vagal stimulation
• Prevent laryngospasm which is due to excessive secretions.
• Atropine, scopolamine, or glycopyrrolate can be used.

Glycopyrrolate:

It is preferred as pre-anesthetic anticholinergic because:

• It is longer acting
• Less likely to cause significant tachycardia
• Produces less sedation than scopolamine
• A good antisialogogue.

Mind Map: Preanesthetic Medication

5. Drugs that reduce acidity:

• General anesthetics may induce vomiting with an increased risk of aspiration into the respiratory tract because normal protective airway reflexes are depressed by anesthetics.
• Aspiration of the acidic gastric contents into the lungs causes damage to the lungs.
• H₂-blockers like ranitidine decrease gastric acid secretion and reduce the damage to the lungs if aspiration occurs while on anesthesia.

Conscious sedation:

• It is a state when the patient has sedation and amnesia without being unconscious. Such a state is attained by a combination of a sedative (midazolam) and an analgesic (fentanyl).
• The patient responds to commands but is drowsy.
• For longer action, diazepam may be combined with pethidine.
• It is reasonably safe as antidotes for both drugs are available (flumazenil and naloxone). Propofol may be used in place of midazolam.
• Indications are minor surgical and diagnostic procedures. In addition, regional blocks with local anesthetics may be used for short surgical procedures.
• Avoided in COPD or psychotic patients and in pregnancy.

Local Anesthetics

Local anesthetics (LA) are drugs that block nerve conduction when supplied locally to nerve tissue in appropriate concentrations. Local anesthesia is loss of sensation without loss of
consciousness.

Local Anesthetics Classification:

Classification Based On Structure:

 Esters And Amides:

Note:

• Esters have single ‘i’ in all names
• Amides have double ‘i’ in all names

Local Anesthetics Mechanism of action:

• Local anesthetics penetrate through the cell membrane and bind to them voltage-sensitive sodium channels from the inner side of the cell membrane.
• They block the voltage-gated sodium channels.
• Local anesthetics prevent the generation and conduction of nerve impulses. The threshold for electrical excitability increases.

Local Anesthetics Pharmacological action:

LAs interfere with the functions of all organs in which the conduction or transmission of impulses occur.

Thus nervous system, autonomic ganglia, NMJ, and all muscles are affected:

1. Peripheral nerves:

• Small nerve fibers are blocked first and then the large fibers.
• Autonomic fibers are blocked first followed by sensory fibers conducting pain, temperature, sense, then touch, pressure, and vibration sensations in the same order
  (differential blockade).
• Small nonmyelinated fibers are blocked faster than the myelinated fibers.

2. Systemic actions:

• CNS: LA depresses the cortical inhibitory pathway and this loss of inhibition results in restlessness, and tremors and may proceed to convulsions. The central stimulation is followed by generalized CNS depression and death may result from respiratory failure.
• CVS:
  • Heart: Heart LA blocks the sodium channels in the myocardium resulting in a decreased force of contraction and conduction rate quinidine-like effects.  Since procaine is short-acting, procainamide is used as an antiarrhythmic.
  • Blood vessels:  Blood vessels LA cause hypotension due to sympathetic blockade and arteriolar dilatation.
• Smooth muscle: LA depresses contractions in the intact bowel and relaxes vascular and bronchial smooth muscles.

Combination Of Adrenaline With A Local Anesthetic:

Question 11. Explain why adrenaline is used with lignocaine/LA.
Answer:

The addition of a vasoconstrictor like adrenaline (1:1,00,000 to 1:2,00,000) or phenylephrine (1:20,000) with lignocaine is often used for infiltration.

Adrenaline LA  Advantages :

• Prolongs the duration of action of LA by slowing the rate of absorption from the site.
• Reduces systemic toxicity of LA because the absorption rate is reduced and as it gets absorbed, it gets metabolized.
• Reduces bleeding at the site.

Adrenaline should not be used:

• Around end arteries to avoid necrosis
• Intracutaneously to avoid sloughing.

Adrenaline LA  Adverse Effects:

Techniques Of Local Anesthesia:

Depending on the site and technique of administration, LA can be

Types/techniques of LA:

EMLA Cream with Eutectic Mixture of Local Anesthetics:

• A eutectic mixture containing 2.5% each of lignocaine and prilocaine at room temperature has a lower melting point than either of the drugs.
• This is emulsified and applied as a cream to anesthetize the intact skin (should not be used on abraded skin) for procedures like venepuncture and skin graft harvesting.

Spinal Anesthesia:

• LA solution is injected into the subarachnoid space between L2–3 or L3–4 below the lower end of the spinal cord and it acts on nerve roots.
• The lower abdomen and lower limbs are anesthetized and paralyzed.
• The level of anesthesia can be altered by the volume of injection, the specific gravity of the
• The level of sympathetic block produced is 2 segments higher and motor paralysis is 2 segments lower than sensory or cutaneous anesthesia.
• Duration depends on the concentration, dose, and the drug itself.
• Lignocaine, tetraine, bupivascaine and ropivacaine are used.

Spinal Anesthesia Advantages:

• Safe, provides good analgesia and muscle relaxation
• There is no loss of consciousness. In cardiac, pulmonary, and renal diseases, Spinal anesthesia (SA) may be preferred over GA.

Spinal Anesthesia Uses:

• Surgical procedures on the lower limb, pelvis, lower abdomen, and obstetric procedures.
• Cesarean sections are done with spinal anesthesia.

Spinal Anesthesia Complications: 

1. Hypotension and bradycardia:
2. Respiratory paralysis: Hypotension and ischemia of the respiratory center result in respiratory failure.
3. Due to paralysis of the abdominal muscles, the cough reflex is less effective resulting in stasis of respiratory secretions, leading to respiratory infections.
4. Headaches due to leakage of CSF may need analgesics.
5. Cauda equina syndrome is loss of control over the bladder and bowel sphincters because of damage to nerve roots.
6. Sepsis results in meningitis.
7. Nausea and vomiting—premedication needed.

Sedative Hypnotics:

Question 12. Classify sedative-hypnotics. Write briefly their mechanism of action, pharmacological actions, and uses.
Answer:

A sedative is a drug that produces a calming or quietening effect. Hypnosis is a drug that produces sleep that resembles natural sleep.

Sedative Hypnotics Classification:

Sedative Hypnotics Pharmacological Actions:

CNS: The most important actions of benzodiazepines (BZDs) are on the CNS:

• Hypnosis: Benzodiazepines reduce the time needed to fall asleep and increase the duration of sleep. Stage 2 NREM is prolonged while the duration of REM and other stages of NREM is decreased. The quality of sleep resembles natural sleep. Tolerance develops in 1–2 weeks.
• Sedation or anxiolytic effects: BZDs reduce anxiety and aggression and produce a calming effect. Alprazolam has additional antidepressant properties.
• Anesthesia: BZDs in higher doses produce general anesthesia up to stage III. Midazolam is used as an IV anesthetic. BZDs are used as adjuvants to general anesthetics.
• Muscle relaxant action: The spinal polysynaptic reflexes maintain the muscle tone.
• BZD → Depress spinal polysynaptic reflexes → ↓ Muscle tone
• Anticonvulsant effects: ↑ ↑ The seizure threshold suppresses the development and spread of seizures.
• Amnesia: BZDs produce anterograde amnesia, i.e. loss of memory for the events happening after the administration of BZDs.  This is useful in surgical procedures as the patient does not remember unpleasant events.

Other actions: In higher doses, decrease ↓ BP, ↑ HR, and depress respiration. They decrease nocturnal gastric acid secretion.

Sedative hypnotics Mechanism of action:

• GABA is the most important inhibitory neurotransmitter of the CNS and it acts through GABA receptors.
• Benzodiazepines bind to the GABAA receptor in the CNS neurons and increase the affinity of GABA for the receptor.
• Increased Cl– ions cause hyperpolarization of the neuronal membrane inhibiting synaptic transmission → CNS depression.

Bzds As Hypnotics:

Question 13. Explain why BZDs are preferred over barbiturates as sedative-hypnotics.
Answer:

When compared to barbiturates:

• BZD induces sleep that closely resembles natural sleep and has less hangover.
• REM suppression is lesser.
• In hypnotic doses, they do not depress respiration or cardiovascular functions.
• BZDs have a higher safety margin → safer even in overdoses.
• Respiratory depression in overdoses is milder and unlikely to be fatal.
• In BZD overdosage, a specific BZD antagonist (flumazenil) is available.
• BZDs are not microsomal enzyme inducers → no related drug interactions.
• BZDs have lower abuse liability—dependence and withdrawal symptoms are mild.
• Because of the above advantages, BZDs are the most preferred sedative-hypnotics.

Bzds As Hypnotics Pharmacokinetics:

• All BZDs are completely absorbed in oral administration.
• IM absorption of diazepam is slow—hence oral route is preferred.
• Triazolam is rapidly absorbed as it has good lipid solubility.
• BZDs are extensively bound to plasma proteins (e.g. diazepam 99%).
• Some metabolites are active—hence prolonged action.

Bzds As Hypnotics Drug Interactions:

• CNS depressants + BZD (alcohol, opioids) → additive effects
• Microsomal enzyme inhibitors + BZD → prolonged action (longer t½)(for example, ketoconazole, omeprazole)

Question 14. List the adverse effects of BZDs.
Answer:

Adverse effects:

BZDs are well-tolerated and are fairly safe drugs.

The common side effects are:

• Drowsiness
• Confusion
• Dizziness
• Amnesia
• Lethargy
• Weakness
• Headache
• Blurred Vision
• Ataxia
• Disorientation
• Daytime sedation
• Nightmares
• Worsening of sleep apnea

Impaired motor coordination:

Impaired motor coordination and judgment, such as driving skills—therefore, while on BZDs driving should be avoided.

• BZDs can impair learning ability due to depressed cognitive functions.
• Given to a pregnant mother during labor → cause hypotonia and respiratory depression in the neonate (floppy-body syndrome). In some patients, BZDs may cause paradoxical irritability and anxiety

Tolerance and dependence:

Tolerance to the sedative effects develops after 1–2 weeks of use.

• Both physiologic and psychological dependence develop on repeated long-term use of BZDs.
• The withdrawal symptoms are mild and slow in onset with long-acting ones. The severity of withdrawal symptoms also depends on the dose and duration of use.
• Withdrawal symptoms include anxiety, nervousness, tremors, anorexia, dizziness, insomnia, restlessness, bad dreams, and may rarely cause convulsions.
• BZDs are ‘Schedule H’ drugs.

Benzodiazepines poisoning:

• Symptom—hypnosis, mild respiratory depression, and cardiovascular depression are common.
• BP and ventilation have to be maintained.
• Specific antagonist flumazenil reverses all the effects of BZDs but constant monitoring is required as it is short-acting.
• Renal function should be watched for.
• Hemodialysis or hemoperfusion may be needed.

BZDs Uses:

1. Insomnia:

Nonpharmacological measures following a regular bedtime, avoiding naps during the daytime, avoiding stimulants like coffee and sentimental discussions at bedtime, adequate exercise or physical activity throughout the day, proper food habits, and following relaxation or meditation techniques before sleeping. When such measures fail, drugs may be needed to induce sleep depending on the category:

• Transient insomnia:
  • <3 days—due to acute stress or air travel to a new time zone, sudden change in place, jet lag, etc. → low dose of a short-acting hypnotic for 2–3 days.
  • Good sleep hygiene and reassurance.
• Short-term insomnia:
  • Lasts for 2–3 weeks; causes stressful situations at work or family life or medical illness.
  • A short-acting hypnotic for a maximum of 2–3 weeks and gradually withdrawn with good sleep hygiene, exercises and other measures.
• Long-term insomnia:
  • Could be secondary to chronic alcoholism, drug dependence, sleep apnea, nocturnal hyperacidity or psychiatric illnesses.
  • Needs proper evaluation to find the cause. Nonpharmacological measures are vital.
  • If required, a hypnotic may be given intermittently once in 2–3 days.

2. Anxiety states:

Any of the BZDs except the ultra-short-acting ones may be used. They (alprazolam) are also useful in panic attacks, in agoraphobia (Agora = marketplace, phobias = fear of being suddenly incapacitated in public and is often associated with panic attacks).

3. Convulsions

•  IV diazepam is the drug of choice in the treatment of status epilepticus. Rectal administration of diazepam is used in febrile convulsions.
• Clonazepam or clobazam are used as adjuncts with other antiepileptic drugs. Nitrazepam and lorazepam also have antiepileptic activity.

4. Muscle relaxation: In chronic muscle spasms and spasticity.

5. Preanesthetic medication: BZDs provide sedation, amnesia, and anxiolytic effects.

6. General anesthesia: IV midazolam or diazepam as IV anesthetics. BZDs are also used to supplement anesthesia.

7. Minor procedures: Endoscopies, fracture reduction, cardiac catheterization, prior to ECT, and in other minor procedures, intravenous diazepam is used.

8. Alcohol withdrawal: During withdrawal of alcohol and opioids sedative hypnotics help.

9. In psychiatry: For the initial control of mania, diazepam is used as an adjuvant.

Benzodiazepine Antagonist:

Flumazenil: Flumazenil is a competitive antagonist at the BZD receptor—competes for the same binding site as BZDs on the GABA receptor and blocks the effects of BZDs, zolpidem, zopiclone, eszopiclone and zaleplon as well as the inverse agonists (beta carbolines)

• Flumazenil is given IV to overcome the effects of BZDs but the disadvantage is its short action and most BZDs are long-acting due to the active metabolites.
• Hence dose needs to be repeated and constant monitoring is needed.
• Adverse effects include nausea, confusion, dizziness, and rarely seizures.

Benzodiazepine Antagonist Uses:

1. To reverse BZD sedation/anesthesia
2. In BZD overdosage.

Newer Sedative Hypnotics:

Question 15 . Write short notes on newer sedative-hypnotics.
Answer:

Melatonin:

• Melatonin is the hormone secreted by the pineal gland and is known to regulate sleep
• . It is secreted at night and plays an important role in the circadian rhythm (chronobiotic).
• Increasing levels are seen in the evening and decrease towards dawn. It acts on two types of melatonin

Receptors:

• MT₁ and MT₂ which are GPCRs. It does not depress the CNS; MT₁ receptors mediate sleep, while MT₂ receptors are involved in circadian rhythm.
• Melatonin improves the quality of sleep and helps in withdrawing benzodiazepines after long-term use.

Dose: 2–10 mg at bedtime.

Newer sedative-hypnotics Advantages: 

• Does not modify the sleep architecture
• No rebound insomnia or other major withdrawal symptoms
• Well-tolerated.

Newer sedative-hypnotics Uses:

• Hypnotic: For short periods and to help withdraw hypnotics in elderly dependents. Chronic insomnia with no known abuse liability—melatonin is considered a natural remedy for
  insomnia and is free from the disadvantages of BZDs.
• Jet lag: To overcome jet lag and other conditions of disturbed biorhythm.
• Aging: The secretion of melatonin decreases with age and therefore, it is supplemented with the hope that it retards aging.
• Ramelteon and Tasimelteon are agonists of the melatonin receptors.

Newer sedative-hypnotics  Adverse effects:

• Including dizziness and fatigue.
• There could be an increase in prolactin levels and a decrease in testosterone.

 Z Hypnotics:

The newer agents zolpidem, zopiclone, eszopiclone, and zaleplon are sedative-hypnotics.

• They are not BZDs but produce their effects by binding to the GABAA receptors and facilitating the inhibitory actions of GABA.
• They are specific hypnotics—do not have antianxiety, anticonvulsant, or muscle relaxant properties, unlike BZDs.
• The modification of sleep patterns is negligible in therapeutic doses.
• Their actions are blocked by flumazenil.
• They are all rapid- and short-acting agents and produce a minimum hangover.
• Dependence and tolerance are lower than with BZDs and withdrawal symptoms are milder.

Z Hypnotics Uses: Used for short periods to treat insomnia.

Barbiturates

Barbiturates are derivatives of barbituric acid and were earlier the largest group of hypnotics in use.

Barbiturates Classification:

Barbiturates Mechanism of action:

• Barbiturates bind to a specific site (different from the BZD binding site) on the GABA
• A receptor Cl–channel complex.
• They facilitate inhibitory neurotransmission by prolonging the duration of the opening of the chloride ion channels by GABA and also hyperpolarizing the neural membrane.

Barbiturates Pharmacological Actions:

1. CNS: Barbiturates cause depression of all excitable tissues and CNS is the most sensitive.

• Hypnosis: Barbiturates induce sleep and prolong the duration of sleep but the quality of sleep is poor with decreased duration of REM. On waking up, there is some hangover
  with headache and residual sedation.
• Antianxiety: Barbiturates reduce anxiety, impair short-term memory and judgment.
• Produce euphoria and are drugs of addiction but some people may experience dysphoria.
• Barbiturates produce hyperalgesia (increased sensitivity to pain) → not preferred as hypnotics in pain.
• Anesthesia: In higher doses, barbiturates produce general anesthesia. IV thiopentone is used for induction of anesthesia.
• Anticonvulsant effects: Phenobarbitone in sub-hypnotic doses is used in epilepsy.

2. Respiratory system: Barbiturates cause significant respiratory depression. High doses can cause direct paralysis of the medullary respiratory center.

3. Cardiovascular system: ↓ BP and ↓ HR. High doses ↓ of myocardial contractility.

4. Skeletal muscles: Higher doses depress the excitability of the neuromuscular junction.

Adverse reactions:

• Hangover due to residual depression of the CNS may be accompanied by nausea, vomiting, vertigo, and diarrhea.
• Distortions of mood, impaired judgment, and fine motor skills may be evident. Barbiturates may cause excitement and irritability in some patients, particularly children.
• Barbiturates cause respiratory depression and in respiratory disorders, even the hypnotic doses of barbiturates can cause serious respiratory depression.
• Hypersensitivity reactions like skin rashes, swelling of the eyelids and lips, and rarely exfoliative dermatitis may be seen
• . Barbiturates are contraindicated in porphyrias because they increase porphyrin synthesis.

Tolerance and dependence:

• Tolerance develops to the effects of barbiturates.
• Development of both psychological and physical dependence → drugs of abuse.
• Withdrawal symptoms include anxiety, restlessness, abdominal cramps, hallucinations, delirium, and convulsions.

Acute Barbiturate Poisoning:

Fatal dose of phenobarbitone: 6–10 g. Manifestations include respiratory depression with slow and shallow breathing, hypotension, skin eruptions, cardiovascular collapse and renal failure.

Treatment: There is no specific antidote. The treatment measures include:

• Gastric lavage followed by administration of activated charcoal to prevent further absorption of barbiturates.
• Artificial ventilation and oxygen administration.
• General supportive measures like maintenance of BP, and airways.
• Forced alkaline diuresis with sodium bicarbonate, a diuretic, and IV fluids will hasten the excretion of barbiturates through the kidneys since they are acidic drugs.
• Hemodialysis may be needed.

Uses of barbiturates:

Because of respiratory depression and abuse liability, barbiturates are generally not preferred.

• Anesthesia: Thiopentone sodium is used in IV for the induction of general anesthesia.
• Neonatal jaundice: Phenobarbitone is used in neonates to clear physiological jaundice.
• Antiepileptic: Phenobarbitone is used as an antiepileptic.
• Sedation and hypnosis: Not preferred

Alcohol

Question 16. List the uses of alcohol.
Answer:

Ethyl alcohol (ethanol) is a colorless, volatile inflammable liquid.

Alcohol Uses:

• Antiseptic: 70% alcohol is applied topically.
• Bedsores: Alcohol is an astringent—when rubbed onto the skin, alcohol precipitates surface proteins—hardens the skin, and prevents bedsores.
• Fever: Alcoholic sponges are used for the reduction of body temperature in fevers.
• Appetite stimulant: About 50 mL of 6–10% alcohol before meals is an appetite stimulant.
• Neuralgias: In severe neuralgias like trigeminal neuralgia, injection of alcohol around the nerve causes permanent loss of transmission and relieves pain.
• In methanol poisoning: Methanol and ethanol are metabolized by alcohol dehydrogenase but ethanol has more affinity for alcohol dehydrogenase. Hence, it competes with methanol and thus, slows down the metabolism of methanol.

Treatment of Alcohol Dependence:

Question  17. Write a short note on alcohol dependence. Give reason: Disulfiram is used in alcohol deaddiction.
Answer:

Alcohol dependence is a common social evil that is difficult to treat.

Drugs tried in chronic alcoholism are:

1. Disulfiram: Disulfiram is used to make alcohol consumption an unpleasant experience so that the person gives up drinking.

• The person develops an aversion to alcohol and often gives up the habit. The effect lasts for 7–14 days after stopping disulfiram.
• The willingness of the person to give up the habit adds to the success.
• The reactions can be severe, and therefore, treatment should be given in a hospital.
• Contraindications: Patients with liver disease, and patients physically dependent on alcohol.

2. Benzodiazepines:

Diazepam relieves symptoms like anxiety and insomnia and should be continued and gradually tapered over months.

3. Clonidine:

Clonidine an a₂-receptor agonist, reduces the release of sympathetic neurotransmitters while propranolol blocks the effects of sympathetic overactivity like tremors and tachycardia.

Naltrexone:

• Naltrexone is an opioid antagonist (50 mg OD or IM inj. once a month)—that reduces alcohol craving and ‘relapse’ of heavy drinking.
• It can cause nausea and should not be given with disulfiram as both can cause hepatotoxicity.
• Nalmefene an alternative to naltrexone.

Acamprosate: Acamprosate an NMDA receptor antagonist, may prevent relapse of heavy drinking.

6. Other drugs:

• Ondansetron, an antiemetic, baclofen, a GABA_B receptor antagonist, and topiramate, an antiepileptic drug are tried.
• Rimonabant, a CB1 cannabinoid receptor antagonist has also been useful in alcohol withdrawal.

7. Counseling: Counseling by a psychologist also helps.

Other drugs that cause antabuse reaction:

• Metronidazole
• Griseofulvin
• Sulfonylureas
• Nitrofurantoin.

Methyl Alcohol (Methanol, Wood Alcohol):

Question 18. Write briefly on the treatment of methanol poisoning.
Answer:

Methanol:

It is used to denature ethyl alcohol and has no therapeutic value. Poisoning needs immediate treatment as it can be fatal.

• Methanol can be absorbed through the skin.
• Toxic effects are due to formic acid which causes vomiting, headache, visual disturbances, vertigo, severe abdominal pain, hypotension, delirium, acidosis, and coma.
• Formic acid has an affinity for the optic nerve and causes retinal damage resulting in blindness. Even 15 mL of methanol can cause blindness.
• Death is due to respiratory failure.

Methyl Alcohol Treatment:

• Correction of acidosis: Because acidosis hastens retinal damage, immediate correction of acidosis with IV sodium bicarbonate infusion helps in preventing blindness.
• Protect eyes: Patients should be kept in a dark room to protect their eyes.
• Gastric lavage: Should be given.
• BP and ventilation: Must be maintained.
• Ethyl alcohol: Should be given IV immediately (loading dose 0.6 g/kg f/b infusion 10 g/hour). It competes with methanol for alcohol dehydrogenase because of its higher affinity for alcohol dehydrogenase.
• Hemodialysis: Should be started at the earliest possible to enhance the removal of methanol.
• Antidote: Fomepizole specifically inhibits the enzyme alcohol dehydrogenase and thereby prevents the formation of toxic metabolites—formaldehyde and formic acid.

Antiepileptic Drugs

Epilepsy:

Epilepsy is a chronic disorder of brain function characterized by recurrent seizures often accompanied by episodes of unconsciousness and/or amnesia.

Seizure:

A seizure is a transient alteration in behavior because of the disordered firing of groups of brain neurons. New nomenclature of seizure types has been recently introduced. Older terminology is given in brackets.

Antiepileptics:

Question 19. Classify antiepileptics and write the pharmacology of phenytoin.
Answer:

Antiepileptics Classification:

• Hydantoins: Phenytoin, mephenytoin
• Barbiturates: Phenobarbitone, mephobarbitone
• Deoxybarbiturate: Primidone
• Iminostilbene: Carbamazepine
• Succinimide: Ethosuximide
• GABA transaminase: Valproic acid, vigabatrin
• Benzodiazepines: Diazepam, clonazepam, lorazepam, clorazepate
• Miscellaneous: Magnesium sulfate, acetazolamide

Newer agents:

• Most commonly used Levetiracetam, lacosamide, lamotrigine, topiramate.
• Others Gabapentin, pregabaline, tiagabine, retigabine, felbamate, zonisamide, rufinamide, parempanel, stiripentol

Mechanism of Action of Antiepileptics:

Antiepileptics act by enhancing GABA-mediated inhibition, reducing excitatory transmission

Modifying the ionic conductances by one or more of the following mechanisms :

Phenytoin:

• Phenytoin has good antiseizure activity and is one of the most effective antiepileptics.
• It has a Selective antiepileptic effect without causing general depression, i.e. without much drowsiness.

Phenytoin Mechanism of Action:

• Phenytoin blocks the voltage-dependent sodium channels and stabilizes the neuronal membrane.
• Phenytoin blocks the Na⁺ channels which are in an inactivated state and delays their recovery from inactivation.
• It decreases the number of channels that are available for the generation of action potentials and inhibits the excitability of these voltage-dependent Na⁺ channels.
• Phenytoin preferentially blocks high-frequency firing (neurons in the normal state have low-frequency firing while in seizures, high-frequency firing occurs).

Phenytoin  Adverse effects:

As phenytoin may be used for a long duration, adverse effects are common.

1. GIT:  Nausea, vomiting, epigastric pain, anorexia.

2. Nystagmus, diplopia, and ataxia.

3. Gingival hyperplasia: Gingival hyperplasia It could be because phenytoin inhibits the enzyme collagenase and alters collagen metabolism.

• It also promotes angiogenesis in the gingival tissue through increased activity of growth factors.
• It is more common in children on prolonged use and good oral hygiene should be followed.

4. Peripheral neuropathy: Peripheral neuropathy on long-term use—with diminished deep tendon reflexes.

5. Endocrine:

• Hirsutism, acne due to increased secretion of androgens and coarsening of facial features.
• Hyperglycemia—as phenytoin inhibits insulin release.
• ↓ Release of ADH.
• Phenytoin also reduces tissue sensitivity to vitamin D.
• Osteomalacia, hypocalcemia—due to altered metabolism of vitamin D and inhibition of intestinal absorption of calcium

6. Hypersensitivity: Rashes, lymphadenopathy, and neutropenia. Idiosyncratic reactions hepatic necrosis, Stevens–Johnson syndrome, and SLE rarely.

7. Megaloblastic anemia:  Phenytoin decreases absorption and increases excretion of folates.

8. Cardiotoxicity:  Can block conduction in the heart.

9. Teratogenicity:  Fetal hydantoin syndrome characterized by hypoplastic phalanges, cleft palate, harelip, and microcephaly in the offspring.

10. Toxicity:

• High doses of IV phenytoins cause cardiac arrhythmias, hypotension, and CNS depression.
• When high doses are given orally, cerebellar and vestibular effects are prominent; vestibular effects include nystagmus, vertigo, diplopia, and ataxia.
• Drowsiness, delirium, confusion, hallucinations, disorientation, altered behavior, and coma follow.

Treatment is symptomatic as there is no antidote.

Phenytoin Uses:

• Generalized tonic-clonic seizures.
• Partial seizures (not useful in absence seizures).
• Status epilepticus—phenytoin is used by slow IV injection.
• Trigeminal neuralgia and other neuralgias—as an alternative to carbamazepine.
• Cardiac arrhythmias—digitalis-induced arrhythmias.

Question 20. What are the advantages of fosphenytoin over phenytoin?
Answer:

Fosphenytoin is a prodrug of phenytoin for parenteral use.

Advantages over phenytoin:

1. It is quickly converted phenytoin in the body
2. More potent
3. Less cardiotoxic
4. Safer on the intestine
5. Can be injected into a glucose drip unlike phenytoin
6. The drip rate can be faster is  phenytoin
7. Can be given IM.
8. Damage to the vessels wall is milder

Because of the above advantages, fosphenytoin is preferred over phenytoin in status epilepticus.

Phenobarbitone:

Question  21. Give a reason for the use of phenobarbitone in epilepsy.
Answer:

Phenobarbitone is a long-acting barbiturate.

Antiepileptic actions:

• Phenobarbitone has specific antiepileptic activity and raises the seizure threshold.
• It is effective in generalized tonic-clonic seizures but is ineffective in generalized absence seizures.

Phenobarbital Mechanism of Action:

• Barbiturates increase the inhibitory neurotransmission in the CNS by increasing the activation of GABAA receptors and thus facilitating the GABA—mediated
• opening of chloride ion channels. Barbiturates also reduce glutamate-mediated excitation.

Phenobarbital Pharmacokinetics:

Oral absorption of phenobarbitone is complete. It is a microsomal enzyme inducer and can result in many drug interactions.

Phenobarbital Adverse effects:

Sedation, nystagmus, ataxia, megaloblastic anemia, osteomalacia, skin rashes, and other hypersensitivity reactions. Tolerance develops after prolonged use.

Uses: Phenobarbitone can be used in:

• Generalized tonic-clonic seizures.
• Focal aware or partial seizures.

Carbamazepine:

Question 22. Discuss briefly the pharmacology of carbamazepine.
Answer:

Carbamazepine is a commonly used antiepileptic drug.

Carbamazepine Mechanism of Action:

• Carbamazepine has good antiseizure activity.
• Its mechanism of action and antiepileptic actions are similar to phenytoin, i.e. it blocks sodium channels and reduces neuronal excitability.
• Carbamazepine has mild antidiuretic effects.

Carbamazepine Pharmacokinetics:

• Absorption is slow and erratic—t½ of 30–36 hours.
• Carbamazepine is a powerful microsomal enzyme inducer and after continuous administration, its t½ reduces to 8– 12 hours due to ‘autoinduction’ (enhances its own metabolism).
• It also reduces the plasma levels of other drugs like phenytoin, valproate, clonazepam, lamotrigine, and topiramate given with it.
• Therefore, patients on carbamazepine need therapeutic drug monitoring.

Dose: 200–400 mg TDS.

Carbamazepine carbamazepinedverse effects:

• Drowsiness, vertigo, ataxia, diplopia, blurring of vision, nausea, vomiting, and dizziness are common.
• Driving is dangerous for patients on carbamazepine. It also causes water retention due to antidiuretic effects.
• Hypersensitivity reactions like skin rashes may occur.
• Bone marrow depression with leukopenia, thrombocytopenia, and rarely agranulocytosis and aplastic anemia is uncommon.
• It is a teratogen.

Drug interactions: Due to enzyme induction, carbamazepine reduces the effects of drugs like phenytoin, valproic acid, and clonazepam. Oral contraceptive failure has been reported.

Uses Carbamazepine:

• Generalized tonic-clonic seizures (grand mal epilepsy) are commonly used drugs.
• Focal awareness and focal impaired awareness (simple and complex partial seizures) especially temporal lobe epilepsy.
• Trigeminal neuralgia and glossopharyngeal neuralgia carbamazepine is the drug of choice
• Hemifacial spasm following facial palsy.
• Chronic neuropathic pain and in tabetic pain.
• Bipolar mood disorder carbamazepine is an alternative to lithium as a mood stabilizer.
• Oxcarbazepine and eslicarbazepine are prodrugs and have the following advantages over carbamazepine fewer hypersensitivity reactions, and milder induction of microsomal enzymes— hence fewer drug interactions. Used as an alternative to carbamazepine.

Ethosuximide:

Ethosuximide is a succinimide used in absence seizures.

Ethosuximide Mechanism of Action:

• Ethosuximide raises the seizure threshold → reduces the T-type calcium currents in the thalamic neurons.
• These T-type calcium currents are thought to be responsible for generalized absence seizures.

Ethosuximide Pharmacokinetics: 

Absorption is complete on oral administration—given twice daily.

Ethosuximide Adverse effects: Nausea, vomiting, epigastric pain, gastric irritation, and anorexia → can be avoided by starting with a low dose and gradually increasing it.

• CNS effects like drowsiness, fatigue, lethargy, euphoria, dizziness, headache, and hiccup are dose-related effects.
• Hypersensitivity reactions like rashes, urticaria, leukopenia, thrombocytopenia, or pancytopenia have been reported.

Ethosuximide Uses:

Ethosuximide is the drug of choice for generalized absence seizures.

Valproic Acid

Question 23. Write a short note on sodium valproate. Write the mechanism of action, uses, and adverse effects of valproic acid.
Answer:

Valproic acid (sodium valproate) is a very effective antiepileptic drug useful in many types of epilepsies including generalized absence seizures, and partial and generalized tonic-clonic seizures— a broad-spectrum antiepileptic.

Divalproex sodium = valproic acid + sodium valproate → better bioavailability and better tolerated.

Valproic acid Mechanism of action: Valproic acid acts by multiple mechanisms.

• Increases levels of GABA by:
  • Increasing the synthesis of GABA—↑ GABA synthetase enzyme.
  • Decreasing the metabolism of GABA—by inhibiting GABA transaminase enzyme.
• Blocks the sodium channels.
• Decreases T-type Ca++ current in the thalamus.

Valproic acid Pharmacokinetics:

Valproate is well absorbed, 90% bound to plasma proteins and is metabolized in the liver.

Valproic acid Adverse effects:

• Gastrointestinal symptoms like nausea, vomiting, and epigastric distress occur initially.
• Weight gain is common.
• Tremors, sedation, ataxia, rashes, and alopecia are rare.

Idiosyncratic response → hepatotoxicity is more common in children below 2 years but, can occur in all age groups and could be fatal.

• Hence careful monitoring of liver functions is mandatory.
• Valproic acid should be avoided in patients with hepatic dysfunction.
• Idiosyncratic thrombocytopenia has also been reported.
• Valproic acid is teratogenic, it can cause neural tube defects including spina bifida

Valproic acid Drug interaction:

Valproic acid  Uses:

• Focal onset (partial) and generalized seizures.
• Generalized absence seizures and myoclonic seizures. In patients with both generalized absence seizures and generalized tonic-clonic attacks, valproate is the drug of choice.
• Effective in juvenile myoclonic seizures.
• As a mood stabilizer in bipolar mood disorder.
• Tried in the prophylaxis of migraine.

Newer Antiepileptics

Question 24. Name the newer antiepileptics. Write the mechanism of action and uses of any 4 of them. Write short note on newer antiepileptics.
Answer:

Most Commonly Used:

1. Levetiracetam

• Analog of piracetam, a commonly used drug
• Binds to a protein in the synapse and modifies the release of glutamate and GABA.

Levetiracetam Advantages:

• Not an enzyme inducer—not related to drug interactions;
• Almost completely absorbed and can be given both orally and IV.

Dose: 250–1,000 mg BD.

Levetiracetam Adverse effects:

Drowsiness, dizziness, weakness, ataxia, and rarely psychosis.

Levetiracetam Uses:

• Add-on drugs in refractory partial seizures, generalized tonic-clonic seizures, and myoclonic seizures.
• As antiepileptic in pregnancy.
• Brivaracetam and seletracetam are analogs with actions similar to levetiracetam.

2. Lamotrigine:

• Broad-spectrum of antiepileptic activity.
• Prolongs the inactivation of sodium channels and also inhibits the release of excitatory amino acids like glutamate.
• Completely absorbed on oral administration, metabolized by glucuronidation.
• Skin rashes, drowsiness, nausea, ataxia, blurred vision, and dizziness.

Lamotrigine Uses:

• Used either alone or with other drugs in focal onset and generalized seizures.
• Generalized absence and myoclonic seizures also respond. Dose: 50–300 mg/day.

Lamotrigine Drug interactions:

• Phenytoin, phenobarbitone and carbamazepine → ↓ t½ of lamotrigine by 6–8 hours.
• Valproic acid inhibits glucuronidation and ↑ t½ of lamotrigine — ↓ 50% lamotrigine dose.

3. Topiramate: Acts by multiple mechanisms:

• Blocks the sodium channels.
• Potentiates the effects of GABA.
• It is effective in focal onset and generalized seizures. Dose: Started with 50 mg/day— gradually increased to 200–600 mg/day.

Topiramate Adverse effects:

• Fatigue, drowsiness, dizziness, and nervousness. It can promote the formation of renal calculi because it inhibits.
• The enzyme carbonic anhydrase; dysgeusia and cognitive dysfunction have been reported. It is teratogenic.

Topiramate Uses:

• Add-on therapy in refractory epilepsy and in Lennox-Gastaut syndrome.
• In focal onset, generalized and generalized absence seizures and infantile spasms.
• In migraine prophylaxis.

4. Lacosamide (LCM):

• Selectively enhances sodium channel slow inactivation.
• Dose: 50–100 mg BD.
• Well-tolerated.
• Nausea, dizziness, sedation, headache, and diplopia were reported.
• Treatment of partial seizures as an adjuvant and as monotherapy in diabetic neuropathic pain.

5. GABA analogs: Gabapentin, pregabalin, vigabatrin (inhibit the enzyme GABA transaminase) and tiagabine are analogs of GABA. They act by increasing GABA levels.

• Used with other antiepileptic drugs in focal onset and generalized tonic-clonic seizures.
• Gabapentin are pregabalin are also used in migraine, and neuropathic pain including postherpetic neuralgia and in bipolar mood disorder.

6. Felbamate:

• Felbamate An analog of meprobamate blocks the NMDA receptors.
• However, felbamate can cause serious adverse effects like aplastic anemia and hepatitis—hence used only in refractory epilepsy.

7. Zonisamide:

• A sulfonamide derivative
• Inhibits T-type Ca⁺⁺ currents and also blocks Na⁺ channels.

Zonisamide Uses:

Refractory focal onset seizures, generalized tonic-clonic seizures, and generalized myoclonic seizures as well as infantile spasms.

Zonisamide Advantages:

• No drug interactions with other antiepileptic drugs.
• Well absorbed, has a long t½ of 1–3 days.

8. Parempanel, retigabine, rufinamide, and stiripentol may be used in refractory seizures.

Febrile Convulsions:

Question 25. Outline the treatment of febrile convulsions.
Answer:

• 2–4% of children experience convulsions during fever; out of them 2–3% become epileptics.
• Children <18 months, those with neurological abnormalities, and those with seizures lasting
• >15 minutes, and complex seizures—all these have a greater risk of recurrence.
• Prevention: Diazepam (0.5 mg/kg) given orally or rectally at the onset of fever prevents convulsions.
• Timely use of paracetamol and tepid sponging prevent high fever.
• If convulsions occur, diazepam (rectally or intravenously) can be used.

Treatment Of Status Epilepticus;

Status epilepticus is a neurological emergency that may be fatal.

Treatment:

• Diazepam: IV 5–10 mg every 10–15 minutes up to 30 mg is the drug of choice.
• Lorazepam: 0.1 mg/kg IV is as effective and longer acting.
• Fosphenytoin: Fosphenytoin is preferred to phenytoin in status epilepticus because phenytoin (even IV), takes 15–20 minutes to act. May combine diazepam with phenytoin/fosphenytoin.
• Ventilatory support may be needed.
• Phenobarbitone (100–200 mg):  Phenobarbitone is an alternative but respiratory depression is expected.
• If seizures continue, general anesthesia with propofol or thiopental is the last resort. Airway maintenance is important. After the control of seizures, long-term antiepileptic therapy is needed.

Absence status going into status epilepticus → IV diazepam/lorazepam is the drug of choice.

Antiepileptics In Pregnancy:

• In pregnancy, antiepileptics should be continued because sudden discontinuation increases the risk of status epilepticus which is hazardous to the fetus.
• Most antiepileptics are teratogenic—phenytoin can cause ‘fetal hydantoin syndrome’ and sodium valproate can cause neural tube defects.
• Though carbamazepine use was associated with major malformations like microcephaly and growth retardation, the incidence was same as in mothers who did not receive antiepileptics.
• Levetiracetam has been found to be a good choice in pregnancy.
• Lamotrigine has also been used though it could increase the risk of cleft lip.
• Epilepsy should be well controlled before pregnancy and the lowest possible doses of antiepileptics—continued in pregnancy.
• Treatment should be restricted to a single drug as far as possible.
• Folic acid supplementation (500 µg daily) should be given during 2nd and 3rd trimesters to avoid neural tube defects.
• Vitamin K₁₂10 mg/day is given for the last 2–4 weeks to avoid vitamin K deficiency and bleeding disorders.

Drugs Used In The Treatment Of Parkinsonism

Parkinsonism is a chronic, progressive, motor disorder characterized by rigidity, tremors, and bradykinesia. Other symptoms are excessive salivation, abnormalities of posture and gait, seborrhea, and mood changes. Drugs used in the treatment of Parkinsonism may be classified as:

Parkinsonism Classification:

1. Drugs that increase dopamine influence:

• DA precursor: Levodopa
• Dopaminergic agonists: Bromocriptine, pergolide, lisuride, ropinirole, pramipexole, rotigotine, apomorphine
• Dopamine metabolism inhibitors:
  • MAO_B inhibitors: Selegiline, rasagiline, safinamide
  • COMT inhibitors: Tolcapone, entacapone
• DA releaser: Amantadine
• Peripheral DOPA decarboxylase Inhibitors: Carbidopa, benserazide

2. Drugs influencing the cholinergic system:

• Central anticholinergics: Benzhexol (trihexyphenidyl), benztropine, piperidine
• Antihistamines: Diphenhydramine, orphenadrine, promethazine

Levodopa:

• Dopamine is of no therapeutic value because it does not cross the blood–brain barrier.
• Levodopa, a prodrug crosses the BBB and is taken up by the surviving nigrostriatal neurons and converted to DA.

Antiparkinsonian effect:

• All the symptoms subside, bradykinesia, rigidity, tremors, sialorrhea, and seborrhea respond.
• There is an improvement in general motor performance and mood as the patient shows more interest in the surroundings.

Levodopa Other actions: Large amounts of levodopa are converted to dopamine in the periphery which brings about other actions.

1. CTZ: Dopamine stimulates the CTZ to induce vomiting.
2. CVS: It causes postural hypotension, tachycardia, and arrhythmias.
3. Endocrine: Dopamine suppresses prolactin secretion.

Levodopa  Adverse reactions:

About 99% of levodopa converted to dopamine in the periphery causes several adverse effects :

1. Nausea, vomiting, anorexia.

2. Postural hypotension, palpitation, and occasionally arrhythmias (stimulation of β₁ receptors).

3. Taste sensation may be altered.

4. Mydriasis and this may raise IOP → avoided in glaucoma.

Above peripheral effects can be prevented by domperidone which is a peripheral dopamine antagonist.

5. Behavioral effects: Behavioral effects like anxiety, depression, hallucinations, mania, confusion, and sometimes psychosis (excessive dopaminergic activity in the limbic system) can occur.

6. Sudden withdrawal:  May precipitate neuroleptic malignant syndrome with confusion, rigidity, and hyperthermia.

7. Abnormal involuntary movements: Like facial tics, grimacing, and choreoathetosis movements of the limbs, may develop after a few months of use → require dose reduction.

8. Fluctuation in response: Fluctuation in response to levodopa can occur after 2–5 years of use—known as the ‘on-off’ phenomenon where the patient swings alternately from periods of good response to severe disabling disease.

Levodopa  Uses:

• Levodopa is useful in idiopathic Parkinsonism but is not useful in drug-induced Parkinsonism.
• On long-term use, there is a ‘wearing-off’ of therapeutic effects.

Levodopa Drug Interactions:

• Pyridoxine + Levodopa
• Pyridoxine → ↑ peripheral conversion (decarboxylation) → ↓ Levodopa available to CNS of levodopa to DA
• Phenothiazines/metoclopramide → DA antagonists → Reverse levodopa effects
• MAO inhibitors → prevent degradation of DA → ↑ ↑ DA in periphery → hypertensive (nonselective) crisis

Combination Of Levodopa + Carbidopa:

Question 26. Give reason: Why pyridoxine should be avoided with levodopa? Why levodopa is combined with carbidopa?
Answer:

Carbidopa and benserazide:

• They are peripheral DOPA decarboxylase inhibitors → when given with levodopa, they prevent the formation of dopamine in the periphery.
• They do not cross the BBB and hence allow levodopa to be converted to DA in the CNS. The combination is
• synergistic, and therefore, levodopa is always given with carbidopa/benserazide

Combination Of Levodopa  Advantages:

• The dose of L-DOPA can be reduced by 75%.
• Response to L-DOPA appears earlier.
• Side effects like vomiting and tachycardia are largely reduced.
• Pyridoxine does not interfere with the use of levodopa.

Dopamine Agonists: Bromocriptine:

• An ergot derivative is a dopaminergic agonist and directly stimulates the DA receptors (D₂ agonist).
• It does not depend on the enzymes for conversion to active metabolites (unlike levodopa).
• DA agonists are less likely to generate free radicals which could damage the dopaminergic neurons.
• They are well absorbed and given orally. Dopamine agonists are all longer acting than levodopa → useful in the treatment of the ‘on-off’ phenomenon and are the first-line drugs in Parkinson’s disease.

The newer agents—ropinirole, and pramipexole are preferred because they are:

• Nonergot derivatives—hence no related side effects
• Selective D₂ and D₃ agonists
• Quickly attain therapeutic levels (hence dose titration can be done faster)
• Adverse effects are milder except for some sleep disorders
• Better tolerated than bromocriptine
• Longer-acting → hence no dyskinesia and ‘on-off’ phenomenon.

Dopamine Agonists Adverse Effects:

• Nausea, vomiting, anorexia, dyspepsia, and skin eruptions.
• Ergot derivatives cause postural hypotension or hypertension initially and first dose phenomenon → sudden cardiovascular collapse. Cardiac arrhythmias can occur.
• Psychiatric disturbances like hallucinations, confusion, and impulsive behavior (betting, gambling, sexual overactivity due to loss of impulse control) are reported but are reversible.
• Sleep disorders with uncontrolled sleep may require the withdrawal of DA agonists.
• Patients should avoid driving.

Dopamine Agonists Uses:

These drugs should be started with a low dose and gradually increased. Ropinirole and pramipexole are used for:

• Initiation of therapy as first-line drugs.
• Treatment of on-off phenomenon.

Rotigotine: Rotigotine another DA agonist, is used as a transdermal patch so that constant dopaminergic stimulation is possible.

MAO_B Inhibitors: Selegiline:

• There are two subtypes of monoamine oxidases MAO_A and MAO_B selectively metabolize dopamine and is present in DA-containing regions of the CNS.
• Selegiline is a selective MAO_B inhibitor in therapeutic doses and prolongs the action of levodopa by preventing its degradation.
• Selegiline may delay the progression of Parkinsonism through a neuroprotective effect.
• Dose: 5 mg at breakfast.
• Rasagiline is more potent than selegiline.

MAO_B Inhibitors Adverse effects:

• Nausea, postural hypotension, confusion, and hallucinations.
• Risk of drug interactions particularly serotonin syndrome if taken with TCA or SSRIs.

MAO_B Inhibitors Uses: 

• Mild cases of Parkinsonism are started on selegiline.
• Also used as an adjunct to levodopa as it prolongs the action of levodopa and the dose of levodopa can be reduced.

Comt Inhibitors

Tolcapone and Entacapone:

• Inhibit the peripheral metabolism of levodopa by inhibiting the enzyme COMT → increase the bioavailability of levodopa.
• Tolcapone also crosses the BBB and increases the availability of levodopa in the brain.
• Levodopa converted to DA in the brain also gets metabolized by COMT. Tolcapone prevents this → hence the duration of action of levodopa is prolonged and the response is smoother with reduced on-off periods.
• Both are rapidly absorbed; entacapone has peripheral effects, whereas tolcapone has both central and peripheral effects.

Comt Inhibitors Adverse effects:

• Nausea, diarrhea, orthostatic hypotension, dyskinesias, sleep disturbances, confusion, and hallucinations mostly due to increased effects of L-DOPA.
• The dose of levodopa should be reduced by 30%.
• Tolcapone can cause hepatotoxicity, and acute hepatic failure which may be fatal—hence entacapone more preferred.

Comt Inhibitors  Uses:

• COMT inhibitors are used as add-on drugs in Parkinsonism.
• A fixed dose combination of levodopa and carbidopa with entacapone is also available.

Dopamine Release

Amantadine is an antiviral drug also useful in Parkinsonism. It increases the release of DA in the brain and also reduces the reuptake of DA.  Amantadine is also an adenosine receptor antagonist and adenosine receptors are found to inhibit the D₂ receptors.  Thus this action may also help patients with Parkinsonism.

Dopamine Advantages:

The response starts early and its adverse effects are minor.

Dopamine Adverse effects:

Large doses produce insomnia, irritability, excitement, headache, constipation, dizziness, vomiting, postural hypotension, hallucinations, ankle edema, and livido reticularis.

Dopamine Uses:

• In mild cases of Parkinsonism (100 mg BD –TDS). It can also be used along with levodopa as an adjunct.
• Amantadine is used for short periods as the response may be blunted after a few weeks. Dyskinesias may also subside.

Anticholinergics

Cholinergic overactivity is overcome by anticholinergics they block the muscarinic receptors in the striatum. Tremors, seborrhea, and sialorrhea are reduced more than rigidity, and bradykinesia.

• Atropine derivatives like benzhexol (trihexyphenidyl) (2–10 mg/day), biperidin, procyclidine, and benztropine are used. Antihistamines like orphenadrine, owe their beneficial effects in
• Parkinsonism to their anticholinergic properties.
• Atropine-like side effects, such as dry mouth, constipation, urinary retention, and blurred vision may be encountered.

Anticholinergics Uses:

1. Adjuncts to levodopa
2. Drugs of choice in drug-induced Parkinsonism.

Drug-Induced Extrapyramidal Reactions/Drug-Induced Parkinsonism

Drugs like reserpine, metoclopramide, and phenothiazines can induce extrapyramidal reactions.

• Reserpine depletes dopamine (catecholamines) stores, while metoclopramide and phenothiazines are dopamine antagonists.
• They induce several types of extrapyramidal reactions and symptoms of drug-induced Parkinsonism are almost similar to idiopathic Parkinsonism.

Treatment:

• Whenever possible the drug responsible for it should be withdrawn this usually reverses the symptoms.
• Low doses of anticholinergics like benzhexol/benztropine (or other anticholinergics) are given along with antipsychotics to prevent and treat EPS.

Dystonias:

• Dystonias which are painless, spasmodic contractions of muscles (e.g. torticollis, trismus) may be seen following metoclopramide or phenothiazines.
• Promethazine inj. 25 mg may be followed by 1–2 oral doses.

Levodopa or other dopamine agonists are not effective in drug-induced Parkinsonism because DA receptors are blocked by drugs like metoclopramide and phenothiazines.

Treatment Of Alzheimer’S Disease

• Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairment of memory and cognitive functions.
• Since there is a loss of cholinergic neurons, drugs that enhance cholinergic function have been tried.
• Many other drugs have also been used to improve cognitive functions with variable results.
• Rivastigmine, donepezil, and galantamine are selective central anticholinesterases hence do not cause GI side effects that are due to peripheral cholinergic activity.
• They increase acetylcholine levels in the surviving neurons and have produced good response cognitive, and function improvement. They all are started at low doses which are gradually increased.
• Donepezil has the advantage of longer action and once-a-day administration.
• Nootropics piracetam and aniracetam have not shown consistent results in AD.
• Memantine is an NMDA receptor antagonist useful in moderate to severe AD.
• The benefit is thought to be due to the blockade of glutamate-induced excitotoxicity.
• Memantine is well-tolerated adverse effects are mild and reversible and may cause dizziness and headache.
• NSAIDs: Small doses of aspirin (and other NSAIDs) have been shown to delay the onset of AD. However, further studies are needed to prove their benefit.

Opioid Analgesics And Antagonists

Pain or algesia is an unpleasant subjective sensation. Pain may be somatic pain (arising from skin, muscles, bones, and joints), visceral pain, and referred pain.

Analgesic is a drug that relieves pain without loss of consciousness:

Analgesics are of 3 classes:

1. Opioid or morphine type
2. Nonopioid or aspirin type
3. Adjuvant analgesics:
   1. Antiepileptics gabapentin, pregabalin
   2. Antidepressants amitriptyline, venlafaxine, citalopram

Opioid Analgesics

Opioid Analgesics Classification:

1. Agonists
   • Morphine, codeine, pethidine, methadone, oxycodone, oxymorphone, fentanyl, diphenoxylate, loperamide, dextropropoxyphene, tramadol, tapentadol
2. Mixed agonist–antagonists
   • Pentazocine, nalbuphine, butorphanol, buprenorphine, nalorphine
3. Antagonists
   • Naloxone, naltrexone, nalmefene, naloxegol
4. Opioids can also be classified depending on their source:
   • Natural opium alkaloids
     • Morphine, codeine, noscapine
   • Semisynthetic and synthetic opioids
     • Heroin, oxymorphone, pholcodine, pethidine, methadone, fentanyl, oxycodone, oxymorphone, diphenoxylate, loperamide, dextropropoxyphene, tramadol, tapentadol

Opioid Morphine

Question 27. Classify opioids. Write the mechanism of action and describe briefly the pharmacological actions of opioids/morphine.
Answer:

Opioid Morphine Mechanism of Action:

• Morphine and other opioids act on specific opioid receptors mu, kappa, and delta which are abundant in the CNS (periaqueductal gray area, substantia gelatinosa, and spinal cord) and other tissues in the body.
• Opioids also stimulate the descending pain control pathway and inhibit the release of neurotransmitters involved in pain transmission viz. DA,

GABA, glutamate, NA, 5HT, and substance P. All opioid receptors are GPCRs:

Opioid Morphine Pharmacological Actions

1. Central nervous system: Opioids have depressant effects on CNS but they also have stimulant effects at some tissues.

Depressant effects:

• Analgesia: Morphine is a potent analgesic and relieves pain without loss of consciousness.
  • Dull aching visceral pain is relieved better than sharp pricking pain.
  • It raises the pain threshold and thus increases the capacity to tolerate pain.
  • Morphine alters both the perception and reaction to pain.
  • It also alters the emotional reaction to pain which is aided by euphoria and sedation.
• Euphoria: Morphine produces a feeling of well-being making it a drug of abuse. Rapid
  • IV injection of morphine produces a warm flushing of the skin and an immensely pleasurable sensation in the lower abdomen lasting for about 45 seconds which is known as ‘high’, ‘rush’, or ‘kick’.
  • The person loses rational thinking and is lost in colorful daydreams.
  • Morphine may produce dysphoria in some.
• Sedation and hypnosis:  It also produces drowsiness, a calming effect, inability to concentrate, feeling of detachment, and indifference to surroundings.
• Respiration:  Morphine directly depresses the respiratory center to produce significant respiratory depression which is dose-dependent.
  • It depresses all phases of respiratory activity—rate, tidal volume, and rhythm to produce irregular and periodic breathing.
  • Morphine suppresses neurogenic (originating in RAS), chemical (hypercapnia), and hypoxic drive in the order.
  • The respiratory center is insensitive to increased plasma CO2 concentration.
  • With toxic doses, breathing is maintained by a hypoxic drive. Sedation adds to the depression, finally resulting in respiratory arrest.
• Cough center:  Morphine directly depresses the cough center—a good antitussive.
• Heat regulation:  Opioids depress the heat-regulating center and produce hypothermia.

Stimulant effects:

• Nausea and emesis:
  • Morphine → Stimulates CTZ → Nausea, vomiting
  • Higher doses → Depress vomiting center
  • Hence there is no vomiting in poisoning and emetics should not even be tried in morphine poisoning.
• Pupils:
  • In high doses, it causes a characteristic pinpoint pupil.
  • Because miosis is a central effect, morphine cannot be used as eye drops to produce miosis.
  • Morphine → Stimulates 3 nerve nuclei (EW) → Miosis
• Vagus:  Morphine stimulates the vagal center causing bradycardia.
• Truncal rigidity:
  • Some opioids like fentanyl increase the tone of the large muscles of the trunk (by acting at the supraspinal levels) and interfere with breathing.
  • A neuromuscular blocker or opioid antagonist may be used to overcome truncal rigidity.
•  Excitatory effect: In high doses, opioids produce convulsions.

2. Peripheral actions:

Cardiovascular system: Morphine produces hypotension by:

Gastrointestinal tract (GIT): Opioids decrease the motility of the gut by stimulating of the µ, δ receptors in the gut.

• Stomach:
  • Gastric motility and gastric acid secretion are reduced and esophageal reflux may increase.
  • The tone of the antrum and first part of the duodenum are increased which contribute to delayed emptying by almost 12 hour and this can retard the absorption of orally given drugs.
• Intestines: ↓ ↓ All intestinal secretions
  • Delays digestion of food in the small intestine
  • Resting tone of the intestine and the sphincters is increased → there can be spasms.
  • Intestinal motility is diminished.

The water content of stool is better absorbed in the large intestine due to prolonged stay, and inattention to the sensory stimuli for the defecation reflex → all lead to constipation.

Other smooth muscles:

• Biliary tract: Spasm of the sphincter of Oddi → intrabiliary pressure rises → may cause biliary colic. Atropine partly antagonizes this.
• Urinary bladder and ureter: ↑ ↑ Tone and amplitude of contractions of the ureter.
• ↑ ↑ The tone of the external sphincter and the volume of the bladder

Urinary voiding reflex → inhibited

Hence, if opioids are used to relieve ureteric colic, they may worsen the pain due to an increase in the tone of the ureters. All these result in urinary retention especially in the elderly male with prostatic hypertrophy.

Bronchi:

Morphine causes the release of histamine from the mast cells leading to bronchospasm. This together with respiratory depression can be dangerous in asthmatics. Histamine release → induces flushing of the skin and itching.

Opioid Morphine  Adverse Effects:

• Nausea, vomiting, constipation
• Drowsiness, dizziness, sedation, mental clouding, dysphoria
• Miosis
• Respiratory depression
• Urinary retention
• Hypotension
• Apnea: Morphine given to the mother in labor can cause apnea in the newborn. Naloxone injection to the umbilical cord reverses this effect.
• Allergic reactions: Skin rashes, pruritus, and wheal at the site of injection due to histamine release and rarely anaphylaxis.
• Tolerance: Develops to most of the effects of opioids including respiratory depression, analgesia, and euphoria but constipation and miosis show no tolerance.
  • Addicts and patients in pain can also tolerate a higher dose of morphine.
  • Cross-tolerance is seen among different opioids.
  • Tolerance is mainly pharmacodynamic, at the receptor level, though pharmacokinetic mechanisms like increased metabolism also contribute.

Question 28. How do you treat an opioid addict?
Answer:

Opioid Dependence:

• The ability to produce euphoria has made opioid drugs of addiction for many centuries. Opioids produce both psychological- and physical dependence.
• Sudden stopping or administration of opioid antagonists produces withdrawal symptoms in dependent individuals.

Withdrawal Symptoms:

• Gooseflesh is due to pilomotor activity; skin resembles that of a plucked turkey.
• Hence the word ‘cold turkey’ is used for symptoms of withdrawal. Abdominal cramps, pain in the bones and muscles of the back and limbs are also characteristic.
• In spite of all these disturbing symptoms, withdrawal symptoms are generally not life-threatening.
• Administration of a suitable opioid dramatically and completely reverses the symptoms of withdrawal. Without treatment, symptoms disappear in 7–10 days.

Treatment of Addiction:

1. Methadone: Morphine is slowly withdrawn over several days and substituted by oral methadone.

Methadone Advantages :

• Effective orally and by this route no ‘kick’ is experienced.
• More potent, long-acting, and prevents withdrawal symptoms because it is slowly released from the tissues.
• The dose is adjusted as per the degree of dependence 1 mg methadone for every 4 mg of morphine (once a day).
• Methadone is then gradually withdrawn.

2. Clonidine: Clonidine a central alpha-2 agonist can suppress some of the autonomic withdrawal symptoms like anxiety, nausea, vomiting, and diarrhea. It is given for 7–10 days and withdrawn over 3–4 days.

3. Night-time sedation with hypnotic-like diazepam is helpful.

• Most addicts can be completely withdrawn from opioids in about 10 days though mild withdrawal symptoms like insomnia, malaise, restlessness, irritability, fatigue and GI hyperactivity may last up to several months.

Withdrawal in the newborn:

• Irritability, excessive crying, tremors, frantic suckling of fists, diarrhea, sneezing, yawning, vomiting and fever.
• A tincture of opium 0.2 mL/kg/3–4 hours is started at birth and gradually withdrawn.

Precautions And Contraindications For Use Of Opioids/Morphine:

Question 29. Mention the precautions and contraindications in using opioids.
Answer:

•  Avoid opioids in patients with respiratory insufficiency, COPD.
• May produce bronchospasm in patients with bronchial asthma.
• Children and elderly people are more susceptible to respiratory depression.
• Head injury morphine is contraindicated because:
  • Causes marked respiratory depression.
  • CO₂ retention due to respiratory depression—↑ CSF pressure → ↑ intracranial tension.
  • Vomiting, miosis, and mental clouding due to morphine interfere with the diagnosis and assessment of progress in head injuries.

• In hypovolemic shock, morphine further reduces BP.
• Opioids potentiate CNS depressants.
• Undiagnosed acute abdomen—opioids relieve pain and may interfere with the diagnosis.
• Most opioids induce vomiting and their spasmogenic effect may add to the drawbacks.
• Hence opioids can be administered only after the diagnosis is established, if necessary.
• Pregnancy—opioids should be avoided.
• Renal and hepatic dysfunction—avoid opioids or reduce the dose.
• Partial agonists (like pentazocine) + pure agonists (like morphine) → ↓ ↓ ↓ analgesic effect.
• Hence avoid such a combination.

Opioids/Morphine Drug Interactions:

• Opioids + CNS depressants → ↑ ↑ CNS depression → ↑ ↑ Respiratory depression (sedatives, hypnotics, may be dangerous alcohol, antipsychotics)
• Opioids + MAO inhibitors → hyperpyrexia, coma and hypertension.

Acute Morphine Poisoning:

Question 30. Outline the treatment of morphine/opioid poisoning.
Answer:

• Poisoning may be accidental, suicidal, or homicidal. The lethal dose in nonaddicts is about 250 mg but addicts can tolerate grams of morphine.
• Signs and symptoms are respiratory depression, pinpoint pupils, hypotension, shock, cyanosis, flaccidity, stupor, hypothermia, coma, and death due to respiratory failure and pulmonary edema.

Morphine/opioid poisoning Treatment:

• Positive pressure respiration.
• Maintenance of BP.
• Gastric lavage with potassium permanganate to remove the unabsorbed drug.
• The specific antidote is naloxone—0.4–0.8 mg IV repeated every 10–15 minutes.

Codeine

Question 31. Write a short note on codeine.
Answer:

Codeine is an opium alkaloid, less potent (one-sixth) than morphine as an analgesic (60 mg codeine = 10 mg morphine).

• Mechanism of action → activates opioid receptors mu, kappa, and delta.
• Codeine depresses the cough center even in subanalgesic doses (10–30 mg).
• Effective orally and is well-absorbed.
• Produces less respiratory depression and is less constipating.
• Codeine has less addiction liability.
• Constipation is the most common side effect.

Codeine Uses: Commonly used antitussive. Also used with paracetamol for analgesia (30–60 mg).

Noscapine

Noscapine is a natural opium alkaloid.

• In therapeutic doses, it has no significant actions on the CNS except for antitussive effects.
• Highly effective and safe. The only adverse effect is nausea.

Noscapine Use:  Cough suppressant.

Dose: 15–30 mg, 3–4 times a day.

Tramadol:

Question 32. Write a short note on tramadol/tapentadol.
Answer:

Tramadol is a synthetic codeine analog. It is an effective analgesic but its mechanism of action is not clear. It is a weak opioid agonist.

• In addition, it blocks the reuptake of serotonin in the
• CNS and inhibits the function of the noradrenaline transporter.
• Nausea is a common side effect. Other adverse effects include drowsiness, dryness of mouth, and sedation. Respiratory depression is mild. It is a drug of dependence. It may precipitate seizures.
• Intravenous administration of tramadol can cause truncal rigidity.
• It should be avoided in patients on MAO inhibitors because tramadol inhibits serotonin uptake and both together increase serotonin levels resulting in ‘serotonin syndrome’.

Tramadol Uses: Tramadol is used in acute and chronic pain like postoperative pain and neuralgias.

Dose: 50–100 mg oral/IM/IV infusion.

Tapentadol:

Tapentadol is similar to tramadol in structure, actions, uses, and adverse effects.

Dose: 50–100 mg. Sustained-release and immediate-release tablets are also available.

Pethidine (Meperidine):

Question 33.  Write a short note on pethidine.
Or
What are the differences between morphine and pethidine?
Or
Pethidine is preferred in obstetric analgesia give a reason.

Pethidine is a derivative of morphine. It was accidentally found to have opioid effects when research was done to obtain anticholinergic drugs.

When compared to morphine:

• Pethidine is 1/10th as potent as morphine (100 mg pethidine = 10 mg morphine). However, efficacy as an analgesic is equal to morphine.
• May produce a negative inotropic effect.
• In toxic doses, pethidine sometimes produces CNS stimulation with tremors, restlessness, and convulsions instead of sedation. This is because of the toxic metabolite norpethidine.

Compare and contrast of morphine and pethidine:

Pethidine Adverse effects:

• Similar to morphine except that constipation and urinary retention are less common.
• Anticholinergic side effects like blurred vision, dry mouth, and tachycardia are common.
• Pethidine may also produce a negative inotropic effect.
• Preparations dose: 25–100 mg IM/SC.

Pethidine Uses:

1. Analgesic: In visceral pain and also for other indications of morphine—because of its better oral efficacy and less spasmogenic effect, pethidine is preferred to morphine.
2. During labor: Pethidine produces less respiratory depression in the newborn when compared to morphine. Moreover, it does not interfere with uterine contractions and labor and is, therefore, preferred to morphine for obstetric analgesia.
3. Preanesthetic medication: Pethidine can be used

Derivatives Of Pethidine:

Fentanyl and its congeners (sufentanil, alfentanil, remifentanil), diphenoxylate, and loperamide are derivatives of pethidine.

Fentanyl:

Fentanyl is a derivative of pethidine.

Fentanyl Advantages:

• 100 times more potent than morphine as an analgesic.
• Highly lipid-soluble and fast-acting (maximum effect within 5 minutes).
• Mild effects on the CVS—slightly reduces HR and BP. Hence safer than other opioids in cardiovascular surgeries.
• Transdermal patches of fentanyl act for 48 hours.
• Unlike morphine, fentanyl does not increase the intracranial pressure.
• Fentanyl is not a histamine liberator.
• Used with droperidol, a neuroleptic agent to produce neuroleptanalgesia.
• Because of the above advantages, fentanyl is a commonly used opioid analgesic.

Dose: 0.05–2 mg inj. transdermal patches act for 2–3 days.

Fentanyl Adverse effects:

• Bolus doses of fentanyl cause muscle rigidity.
• This can be reduced by avoiding bolus doses.
• Other adverse effects include nausea, vomiting, and respiratory depression.

Fentanyl Uses:

1. Neuroleptanalgesia: Fentanyl + droperidol → IV over 10 minutes produces sedation and intense analgesia without loss of consciousness. This state is maintained for 30–40 minutes as both have rapid and short action. The patient is drowsy but responds to commands.
2. Epidural fentanyl with local anesthetics is used for postoperative and obstetric analgesia.
3. Chronic pain: Transdermal fentanyl patch may be used in conditions like terminal cancer pain. Constant watch for respiratory depression is needed. Fentanyl is also available as a lozenge and as a ‘lollipop’ for transmucosal drug delivery.

Congeners of fentanyl:

• Alfentanil and remifentanil are faster acting and recovery is rapid.
• They are used for short surgical procedures.

Methadone:

Question 34. Explain why methadone is used in opioid de-addiction.
Or
|Write a short note on methadone.

Methadone has actions similar to morphine. Its important features are:

• An effective analgesic.
• Effective by many routes—oral, rectal, SC, IV, and spinal routes. Dose: 10 mg oral or 1M.
• Effective in some neuropathic and cancer pain that is not relieved by morphine.
• Methadone is metabolized by microsomal enzymes (CYP3A4) in the liver—microsomal enzyme inhibitors and hepatic failure can ↑ blood levels of methadone.
• Euphoric effects are less intense → abuse potential is less. Tolerance develops more slowly.
• Long duration of action (t½: 24–36 hours).
• Withdrawal symptoms are milder because it is firmly bound to proteins in various tissues including the brain and it gradually accumulates in tissues → is slowly released from the binding sites.

Methadone Uses: 

1. Substilution therapy: In opioid dependence oral methadone is given for 2–3 days. When methadone is stopped, withdrawal symptoms appear but are mild and tolerable.
2. Opioid maintenance: Gradually increasing doses of methadone are given orally to produce a high degree of tolerance (50–100 mg/day). Such subjects do not experience the pleasurable effects of morphine or other opioids and they give up the habit.
3. As an analgesic methadone is effective.
   • Dextropropoxyphene: Dextropropoxyphene produces effects similar to morphine. It is less constipating, longer acting, and has good oral bioavailability but it is an irritant when given parenterally.
   • Levopropoxyphene: Levopropoxyphene is a good antitussive.

Uses Of Morphine And Other Opioids:

Question 35. Write the rationale the use of morphine.
Or
1. Morphine is used in MI give a reason.

2.  Explain why atropine is used with morphine in biliary colic.

3. Explain why morphine is used in acute pulmonary edema/acute LVF.
Answer:

Dose: Morphine 10–20 mg IM/SC; ethylmorphine 20 mg tablet for oral use.

1. Analegesic:

Morphine provides symptomatic relief of pain without affecting the underlying disease. It is an excellent analgesic for severely painful conditions, such as acute myocardial infarction, fractures, burns, pulmonary embolism, terminal stages of cancer, acute pericarditis, spontaneous pneumothorax, and postoperative pain.

In severe pain, morphine can be given IV:

• In myocardial infarction, morphine relieves pain and thereby anxiety. As a result, reflex sympathetic stimulation is reduced and shock is minimized it can be life-saving.
• In renal and biliary colic: Morphine given to relieve pain may cause spasms of the sphincter of Oddi which in turn raises intrabiliary pressure. Hence along with morphine, atropine is given which relieves spasms of the sphincter of Oddi.
• Epidural analgesia: As opioid receptors are present in the spinal cord, small doses of morphine can be used to produce epidural analgesia. Such analgesia is segmental in distribution, there is no interference with motor function or autonomic changes, no systemic adverse effects, and provides good analgesia for 12–24 hours.
• Obstetric analgesia: Pethidine is preferred—causes milder respiratory depression in the newborn.
• Opioids can be freely used to control the pain of terminal illnesses like cancer.
• Opioids should not be freely used in other chronic pain because of addiction liability.

2. Acute Left Ventricular Failure/Acute Pulmonary Edema:

IV morphine is used to relieve the dyspnea of acute LVF and pulmonary edema in which the response may be dramatic. The relief may be due to:

• Alteration in the patient’s reaction to impaired respiratory function.
• Reduced anxiety, decreases sympathetic stimulation which in turn decreases the workload of the heart.
• Cardiovascular effects like decreased PVR lead to the shifting of blood from pulmonary to peripheral circulation, thereby reducing cardiac workload.

Morphine is contraindicated in pulmonary edema due to respiratory irritants.

3. In Anesthesia:

Preanesthetic medication—though opioids reduce anxiety, provide analgesia, allow smoother induction, and reduce the dose of the anesthetic required.

Disadvantages are:

• Depress respiration
• May cause bronchospasm
• Vasomotor depression
• May induce vomiting
• Miosis may interfere with pupillary response to anesthesia
• Postoperative urinary retention and constipation may be troublesome.
• Special anesthesia high doses of morphine are used to produce general anesthesia.
• Neuroleptanalgesia fentanyl + droperidol—can be used in minor procedures.
• Epidural analgesia for labor pain, postoperative and chronic pain.

4. Diarrhea: Diphenoxylate and loperamide are used for symptomatic treatment of diarrhea.

Eluxadoline an agonist at m and k receptors with prominent effects on the gut—is used to overcome abdominal pain and diarrhea associated with inflammatory bowel disease.

5. Cough: Codeine, noscapine and many nonaddictive antitussives are available.

6. Shivering: Pethidine reduces shivering → could be by its action on a2-adrenoceptors.

7. Sedative: Morphine relieves anxiety in threatened abortion without affecting uterine motility.

Mixed Agonists And Antagonists

Question 36. Explain why pentazocine is not a suitable analgesic in MI. Write short note on pentazocine.
Answer:

1. Pentazocine:

• To get an analgesic with less addiction liability and low adverse effects, pentazocine was developed. Pentazocine is a k receptor agonist.
• CNS effects of pentazocine are similar to morphine. 20 mg pentazocine = 10 mg morphine.
• Euphoria only in low doses. Higher doses (>60 mg) → dysphoria due to k stimulation.
• Sedation, respiratory depression, biliary spasm and constipation are less.
• It has weak antagonistic properties at m receptors.
• Tolerance and dependence develop on repeated use.
• CVS: In contrast to morphine, pentazocine increases BP and heart rate and thereby increases cardiac work. It is, therefore, not suitable in myocardial infarction.
• Given both orally and parenterally. Dose: 50–100 mg oral; 30–60 mg IM, SC, IV inj.

Pentazocine  Adverse effects:

Sedation, sweating, dizziness, nausea, dysphoria with anxiety, nightmares, and hallucinations seen above 60 mg. Irritant → IM injection can be painful and cause sterile abscesses.

Pentazocine Uses: Analgesic in postoperative and chronic pain—abuse liability less than morphine.

2. Cyclazocine: Cyclazocine is similar to pentazocine.

3. Nalbuphine:

• Nalbuphine is a good analgesic.
• It has a ceiling effect for respiratory depression at 30 mg, i.e. an increase in dose beyond 30 mg does not increase respiratory depression further.
• Higher doses produce dysphoria.
• Used as an analgesic 10–20 mg IM.

4. Buprenorphine:

• Buprenorphine a highly lipid-soluble synthetic opioid, is 25 times as potent as morphine.
• Though the onset of action is slow, the duration of analgesia is long.
• Respiratory depression is milder and has a lower degree of tolerance and dependence liability. Withdrawal syndrome appears late and is mild.

Dose: 0.3-0.6 mg SC, IM or sublingual.

Uses:

• Chronic pain is like in terminal cancer patients.
• Maintenance drug in opioid addicts—as the withdrawal symptoms are mild.

5. Butorphanol: Butorphanol is similar to pentazocine. Intranasal spray is available. Dose: 1–2 mg.

6. Nalorphine:

• At low doses, it is a good analgesic but with an increase in dose, there is no increase in analgesia.
• It causes dysphoria (k agonist) and respiratory depression even in low doses.
• Hence it cannot be used as an analgesic. At high doses, it acts as an antagonist and counters all the actions of opioids.

Uses: Opioid poisoning (but pure antagonist preferred) and diagnosis of opioid addiction.

Opioid Antagonists

Question 37. Write a short note on naloxone/opioid antagonists.
Answer:

Naloxone:

• Naloxone a pure opioid antagonist acts as a competitive antagonist to all types of opioid receptors.
• In normal subjects, it does not produce any significant actions, but in opium addicts, it blocks all the actions of morphine including respiratory depression, sedation, and precipitates withdrawal syndrome.
• It also blocks the actions of endogenous opioid peptides—endorphins, enkephalins, and dynorphins.
• It blocks the analgesia produced by placebo and acupuncture. This suggests that endogenous opioid peptides are responsible for analgesia by these techniques.
• Given intravenously duration of action is 1–2 hours; metabolized by glucuronide conjugation.

Naloxone Uses:

• Drug of choice for morphine poisoning. (0.1–0.4 mg IV). The dose should be repeated after every 1–2 hours as naloxone is short-acting.
• To reverse neonatal asphyxia due to opioids used in labor.
• Diagnosis of opioid dependence—it precipitates withdrawal symptoms.
• Hypotension seen during shock could be due to endogenous opioids released during such stress. Naloxone has been found to be beneficial in reversing hypotension.

Naltrexone is another pure opioid antagonist. It is:

• More potent than naloxone
• Orally effective. Dose: 50–100 mg/day.
• Has a longer duration of action of 1–2 days.

Naltrexone  Uses:

• Opioid blockade therapy in post-addicts—(50–100 mg/day orally OD on alternate days) so that even if the addict takes an opioid, he does not experience the pleasurable effects and therefore, loses the craving.
• Alcohol craving is also reduced by naltrexone and is used to prevent relapse of heavy drinking.

Nalmefene:

Nalmefene a derivative of naltrexone is effective orally (but only an IV preparation is available) and longer-acting. It has better bioavailability and is not hepatotoxic. It is used in opioid overdosage.

Peripheral opioid antagonists:

Methylnaltrexone, naloxegol, and alvimopan block m opioid receptors in the gut and reverse opioid-induced constipation in terminally ill cancer patients.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammation drugs are aspirin-type or non-narcotic analgesics. In addition, they have anti-inflammatory, antipyretic and uricosuric properties without addiction potential.

Mechanism Of Action Of Nsaids:

During inflammation, arachidonic acid liberated from membrane phospholipids is converted to prostaglandins (PGs), catalyzed by the enzyme cyclo-oxygenase (COX).

• These prostaglandins produce hyperalgesia they sensitize the nerve endings to pain caused by other mediators of inflammation like bradykinin and histamine.
• NSAIDs inhibit PG synthesis by inhibiting the enzyme cyclo-oxygenase. There are two forms of cyclo-oxygenase, viz. COX-1 and COX-2.
• COX-1 found in most of the normal cells (constitutive) is involved in maintaining tissue homeostasis, particularly in the gut, kidney, and platelets.
• COX-2 is induced in the inflammatory cells by cytokines and other mediators of inflammation.
• This COX-2 catalyzes the synthesis of prostanoids which are the mediators of inflammation. Most NSAIDs inhibit both COX-1 and
• COX-2, while some newer agents like celecoxib and rofecoxib selectively inhibit only COX-2.

NSAIDs Classification:

• Nonselective COX inhibitors:
  1. Salicylates: Aspirin
  2. Para-aminophenol derivatives: Paracetamol
  3. Propionic acid derivatives: Ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, naproxen
  4. Acetic acid derivatives: Ketorolac, tolmetin, indomethacin, sulindac
  5. Fenamates (anthranilic acids): Mefenamic acid, meclofenamic acid
  6. Pyrazolone derivatives: Phenylbutazone, azapropazone
  7. Oxicams (enolic acid derivatives): Piroxicam, tenoxicam
• Preferential COX-2 inhibitors: Diclofenac, aceclofenac, etodolac, meloxicam, nabumetone, nimesulide
• Selective COX-2 inhibitors: Celecoxib, parecoxib, etoricoxib

NSAIDs Salicylates:

Salicylates are salts of salicylic acid and aspirin is the prototype.

Pharmacological Actions:

1. Analgesia:

• Aspirin is a good analgesic and relieves pain of inflammatory origin.
• PGs are formed during inflammation and they sensitize the tissues to pain and aspirin inhibits PG synthesis and reduces pain.
• Somatic pain originating from the integumental structures like muscles, bones, joints, and pain in connective tissues is relieved.

2. Antipyretic action:

• In the presence of fever, salicylates bring down the temperature to a normal level but in normal individuals, there is no change in temperature.
• In fever, pyrogen, a protein, circulates in the body and increases the synthesis of PGs in the hypothalamus, thereby raising its temperature set point.
• The thermostatic mechanism in the hypothalamus is thus disturbed.
• Aspirin inhibits PG synthesis in the hypothalamus and resets the thermostat to the normal level bringing down the temperature.
• Increased sweating and cutaneous vasodilatation promote heat loss and help in the antipyretic action.

3. Anti-inflammatory action:

At higher doses of 4–6 g/day, aspirin has anti-inflammatory action. Signs of inflammation like tenderness, swelling, erythema, and pain are all reduced to provide symptomatic relief.

• Once again the mechanism involved is PG synthesis inhibition
• PGs present in inflammatory tissues are responsible for edema, erythema, and pain.
• In addition, aspirin also interferes with the formation of chemical mediators of the kallikrein system.
• As a result, it decreases the adherence of granulocytes to the damaged vasculature, stabilizes lysosomes, and decreases the migration of the leukocytes and macrophages into the site of inflammation.

Respiration, acid-base, and electrolyte balance: In therapeutic doses of 4–6 g/day, salicylates increase the consumption of oxygen by skeletal muscles.

• As a result, there is increased CO₂ production which stimulates the respiratory center. Salicylates also directly stimulate the respiratory center.
• Both these actions increase the rate and depth of respiration so that plasma CO₂ is washed out leading to respiratory alkalosis.
• In anti-inflammatory doses, salicylates produce respiratory alkalosis as given above; pH becomes alkaline which is compensated by increased excretion of HCO^–₃ in the urine accompanied by Na⁺, K^+, and water. This stage is known as compensated respiratory alkalosis.
• With toxic doses, salicylates depress the respiratory center directly and CO₂ accumulates and pH decreases.
• Since the concentration of HCO^–₃ is already low due to enhanced renal excretion, the change results in uncompensated respiratory acidosis.
• This is superimposed by metabolic acidosis caused by the accumulation of acids.

The above effects are accompanied by dehydration due to:

• Water lost in urine with HCO^–₃, Na^+, and K⁺
• Increased sweating
• Water lost during hyperventilation
• Thus there is severe dehydration with acidosis.

5. Gastrointestinal tract:

• Aspirin is a gastric irritant. Irritation of the gastric mucosa leads to epigastric distress, nausea and vomiting.
• Aspirin also stimulates the CTZ to produce vomiting.
• In higher doses → erosive gastritis, mucosal congestion, gastric ulceration, and GI
  bleeding resulting in melena and hematemesis can occur.

Mechanism:

• In the acidic pH of the stomach, salicylates remain unionized.
• These drug particles produce irritation of the mucosa.
• These particles also promote local back diffusion of acid.

• Aspirin inhibits prostaglandin synthesis. PGs inhibit gastric acid secretion, increase mucosal production, and act as cytoprotectives in gastric mucosa.
• This defense mechanism is lost due to PG inhibition.
• The above actions make aspirin ulcerogenic. In addition, it decreases platelet aggregation which also increases the tendency to bleed. With soluble aspirin, gastric irritation is less.
• The selective COX-2 inhibitors cause less gastric irritation because gastric epithelial cells have COX-1.

6. CVS: Prolonged use may cause salt-and water retention → worsen CCF and hypertension.

7. Immunological effects:

• In higher doses, salicylates suppress many antigen-antibody reactions → inhibit antibody production, Ag–Ab aggregation and antigen-induced release of histamine.
• These effects also help in rheumatic fever.

8. Uric acid excretion:

• 1–2 g/day → ↓ urate secretion by distal tubules → urate retention >5 g/day → ↓ urate reabsorption by proximal tubules → uricosuric effect
• But, its uricosuric effect cannot be used therapeutically because high doses are required.

9. Platelet function:

• In small doses, aspirin irreversibly inhibits platelet cyclo-oxygenase and thereby TXA2 synthesis by the platelets. It, therefore, inhibits platelet aggregation and prolongs the bleeding time.
• Even a single dose can irreversibly inhibit TXA2 synthesis which is for the life of the platelets (8–11 days). Fresh platelets have to be formed to restore
• TXA2 activity because platelets cannot synthesize proteins as they have no nuclei— which means COX cannot be regenerated in platelets.
• Moreover, aspirin inhibits platelet COX in the portal circulation itself, and therefore, even small doses (50 mg daily) of aspirin are adequate for its antiplatelet effects.
• Other NSAIDs are reversible inhibitors of platelet cyclo-oxygenase.

Local effects: Salicylic acid when applied locally is a keratolytic. It also has mild antiseptic and fungistatic properties. Salicylic acid is also an irritant for the broken skin.

NSAIDs Adverse effects: Analgesic doses are generally well-tolerated but anti-inflammatory doses are usually associated with adverse effects especially when used over a long period.

• GI tract: Nausea, epigastric distress, vomiting, erosive gastritis, peptic ulcer, melena.
• Nephrotoxicity: NSAIDs can cause nephrotoxicity after long-term use (analgesic nephropathy). Salt-and-water retention with hypertension and impaired renal function with
  acute interstitial nephritis and acute papillary necrosis can occur.
• CNS: Headache, dizziness, and confusion.
• Allergic reactions:  Include rashes, urticaria, pruritus, photosensitivity, rhinorrhea, angioedema, and asthma, especially in those with a history of allergies.
• Respiratory system: As aspirin inhibits the cyclo-oxygenase pathway more arachidonic acid is available for conversion by lipoxygenase pathway into leukotrienes. Leukotrienes are
  powerful bronchoconstrictors. Hence aspirin can precipitate bronchial asthma.
• Hemolysis: Salicylates can cause hemolysis in patients with G6PD deficiency. NSAIDs can also cause thrombocytopenia and neutropenia.

• Hepatotoxicity: Hepatotoxicity with hepatic necrosis and cholestatic jaundice can also occur when high doses are used over a long period. Plasma levels of liver enzymes are raised.
• Reye’s syndrome:
  • Reye’s syndrome seen in children is a type of hepatic encephalopathy that may be fatal. It develops a few days after a viral infection, especially influenza and varicella.
  • An increased incidence of this syndrome has been noted when aspirin is used to treat fever. Hence aspirin and other salicylates are contraindicated in children and young adults < 20 years old with viral fever. Paracetamol may be used to treat fever in such children.
• Pregnancy: Aspirin given at term delays labor and may increase bleeding (PPH). The newborn may develop portal hypertension.
• Salicylism: Higher doses given for a long time may cause ‘salicylism’. The syndrome is characterized by headache, vertigo, dizziness, tinnitus, vomiting, mental confusion, diarrhea, sweating, difficulty in hearing, thirst, and dehydration. These symptoms are reversible on the withdrawal of salicylates.

Acute Salicylate Intoxication:

Poisoning may be accidental or suicidal—is more common in children. The fatal dose of aspirin is 15–30 g.

Symptoms and signs: Dehydration, hyperpyrexia, GI irritation, vomiting, sometimes hematemesis, acid-base imbalance, metabolic acidosis, restlessness, delirium, hallucinations, tremors, convulsions, coma and death due to respiratory failure and CV collapse.

Treatment: Treatment is symptomatic:

• Gastric lavage to eliminate unabsorbed drugs.
• IV fluids to correct acid-base imbalance and dehydration.
• Temperature is brought down by external cooling with alcohol or cold water sponges.
• If hemorrhagic complications are seen, blood transfusion and vitamin K are needed.
• IV fluids should contain Na+, K+, HCO^–₃
• , and glucose (to treat hypokalemia and acidosis).
• Blood pH should be monitored.
• In severe cases, forced alkaline diuresis—sodium bicarbonate + a diuretic (frusemide) + IV fluids.
• Sodium bicarbonate ionizes salicylates making them water-soluble and increasing their excretion through the kidneys.

Acute Salicylate Intoxication Uses:

1. Analgesic:

• For headache, backache, myalgias, arthralgias, neuralgias, toothache, and dysmenorrhea. In headaches, PGs may be responsible for cerebral vasodilatation.
• NSAIDs inhibit PG synthesis and relieve headaches. PG synthesis is responsible for dysmenorrhea aspirin effectively relieves pain.
• Painful conditions of somatic origin are associated with PG synthesis hence, NSAIDs help.

2. Fever: NSAIDs are useful for the symptomatic relief of fever.

3. Inflammatory conditions: NSAIDs are effective in inflammatory conditions, such as arthritis and fibromyositis.

4. Rheumatic fever:

• Aspirin 4–6 g/day (100 mg/kg/day) in 4–6 divided doses, brings about a dramatic relief of signs and symptoms in 24–48 hours.
• The dose is reduced after 4–7 days to 50 mg/kg/day for 2–3 weeks.

5. Rheumatoid arthritis (RA): Aspirin relieves pain, reduces swelling and redness of joints in RA. Joint mobility improves and there is a reduction in morning stiffness but the relief is
symptomatic.

6. Osteoarthritis: NSAIDs provide symptomatic relief.

7. Antiplatelet uses: ↓ Incidence of reinfarction in post–MI patients
↓ Incidence of TIA, stroke

• Prevent MI in angina patients
• Prevent recurrence in deep vein thrombosis.

Aspirin inhibits platelet aggregation (low dose of 50–300 mg/day).

8. Inflammatory bowel disease: Mesalamine and sulfasalazine are given orally for local effects in ulcerative colitis because both are not well absorbed and act on the colon.

9. Other uses:

• To delay labor: Aspirin delays labor but has the risk of increased bleeding and premature closure of the ductus arteriosus.
• Colon cancer prevention: In familial adenomatous polyposis, polyps develop in the colon at a younger age and then cancer colon in an older age. Chemoprophylaxis with
  aspirin may reduce the risk of colon cancers in such patients.
• Patent ductus arteriosus: For closure of PDA in the newborn—indomethacin is preferred.
• Bartter’s syndrome (PDA): Excess production of renal PGs may be responsible for
• Bartter’s syndrome is characterized by raised plasma renin and aldosterone with hypokalemia. NSAIDs are useful in such patients.
• Eclampsia: As PGs are involved in the genesis of eclampsia and hypertension, NSAIDs (aspirin 60–100 mg daily) are useful in lowering BP in such pregnant women.
• Niacin flush: Niacin (hypolipidemic) often causes intense flushing due to the release of PGD2 from the skin. NSAIDs can be used to prevent flushing.

10. Local: Salicylic acid is used as a keratolytic, fungistatic, and mild antiseptic.

Methylsalicylate is a counterirritant used in myalgias.

Other Nsaids:

• Paracetamol (Acetaminophen): Paracetamol is a relatively safe and effective analgesic.
• Actions: Paracetamol has analgesic, good antipyretic, and weak anti-inflammatory properties.
• Reason: The inflammatory sites are rich in peroxides generated by the leukocytes. In the presence of peroxides, paracetamol is a weak inhibitor of COX and thereby PG synthesis. Hence paracetamol has poor anti-inflammatory actions.

Paracetamol is active on cyclo-oxygenase in the brain—hence a good antipyretic. It does not stimulate respiration, and has no actions on acid-base balance, cellular metabolism, cardiovascular system, and platelet function; it is not a uricosuric agent and gastric irritation is mild.

Adverse effects: Antipyretic doses → safe and well-tolerated. Nausea and rashes may occur.

Higher doses → hepatotoxic

Question 38. Outline the treatment of acute paracetamol poisoning.
Answer:

Acute paracetamol poisoning:

• Children are more affected because their ability to conjugate by glucuronidation is poor. 10–15 g in adults causes serious toxicity.
• Symptoms—nausea, vomiting, anorexia, and abdominal pain during the first 24 hours. Nephrotoxicity may result in acute renal failure.

Hepatotoxicity:

• Paracetamol is hepatotoxic and the effects are seen within 2–4 days → raised liver enzymes, jaundice, liver tenderness, and prolonged prothrombin time which may progress to liver failure.
• Hepatic lesions are reversible when promptly treated.

Mechanism of toxicity:

• A small portion of paracetamol is metabolized to a highly reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI) which is detoxified generally by conjugation with glutathione.
• However, when large doses of paracetamol are taken, hepatic glutathione is depleted and the toxic metabolite binds to sulfydryl groups in hepatic proteins resulting in hepatic necrosis.

Chronic alcoholics and infants are more prone to hepatotoxicity.

Toxicity Treatment:

• Stomach wash—activated charcoal prevents further absorption.
• The antidote is N-acetylcysteine more effective when given early.
• It partly replenishes the glutathione stores in the liver and prevents the binding of toxic metabolites to the cellular constituents.

Toxicity Uses:

• Analgesic in painful conditions like toothache, headache, and myalgia
• Antipyretic.

Ibuprofen

Question 39. Write a short note on ibuprofen.
Answer:

• Ibuprofen is better tolerated than aspirin—analgesic, antipyretic, and anti-inflammatory efficacy is slightly lower than aspirin.
• Ibuprofen is well absorbed, >99% bound to plasma proteins, crosses
  the BBB, and also reaches the synovial fluid. It is metabolized in the liver and excreted both in bile and through the kidneys.
• Ibuprofen is available for oral, parenteral, and topical use (gel, cream).

Dose: 400–800 mg TDS.

Ibuprofen’s Adverse effects:

• Milder when compared to other NSAIDs and the incidence is low.
• Nausea, vomiting, gastric discomfort, CNS effects, hypersensitivity reactions, and fluid retention are all similar but less severe.

Ibuprofen Uses: 

• Analgesic—soft tissue injuries, and fractures, to relieve postoperative pain, dysmenorrhea, and osteoarthritis.
• In fever.
• Gout.

Indomethacin

Indomethacin is a potent anti-inflammatory agent, antipyretic and good analgesic.

Indomethacin Adverse effects: 

High Gastrointestinal irritation with nausea, GI bleeding, vomiting, diarrhea, peptic ulcers, and pancreatitis can occur.

Indomethacin CNS effects: 

• Headache, dizziness, ataxia, confusion, hallucinations, depression, and psychosis.
• Hypersensitivity reactions like skin rashes, leukopenia, and asthma.
• Edema due to salt and water retention.

Indomethacin Uses 

• For closure of PDA in premature infants.
• Though indomethacin is effective in reducing pain and inflammation in
• RA, ankylosing spondylitis, gout, and psoriatic arthritis, a wide range of adverse effects have made it the least preferred of the NSAIDs.
• Dose: 25–50 mg BD-TDS.
• Epidural indomethacin is tried for pain relief in patients who have undergone laminectomy.
• Topical:
  • Eye drops in inflammation.
  • As mouth rinse—to suppress gingival inflammation.

Piroxicam

• Piroxicam an oxicam derivative, has good anti-inflammatory, analgesic, and antipyretic activity.
• Better tolerated as it is less ulcerogenic.
• Almost completely absorbed, 99% bound to plasma proteins.
• It has a slow onset of action and is longer acting—given once daily (20 mg OD).

Piroxicam Uses:

Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal pain, and postoperative pain.

Preferential Cox-2 Inhibitors

Diclofenac: Diclofenac is an analgesic, antipyretic and anti-inflammatory agent.

• Its tissue penetrability is good and attains good concentration in the synovial fluid which is maintained for a long time.
• Selectively inhibits COX-2 as a result of which it is more ‘gastric-friendly’ and also has poor antiplatelet activity (COX-1 mediated).
• Adverse effects are similar to other NSAIDs but are milder.

Aceclofenac: Aceclofenac is more gastric-friendly as it is more COX-2 selective and is also longer acting.

Aceclofenac Uses:

Diclofenac and aceclofenac are the most commonly used NSAIDs.

• Chronic inflammatory conditions like rheumatoid arthritis and osteoarthritis.
• Acute musculoskeletal pain.
• Postoperatively for relief of pain and inflammation.
• Eye: To reduce ocular inflammation.

Selective Cox-2 Inhibitors

Question 40. Write a short note on selective COX-2 inhibitors.
Or
Discuss the advantages and disadvantages of selective COX-2 inhibitors.
Or
Compare and contrast aspirin and celecoxib/selective COX-2 and nonselective COX inhibitors.

COXIBS:

• Though NSAIDs are extremely useful drugs, they are poorly tolerated particularly due to gastric irritation when they are used for long periods.
• Selective inhibition of COX-2 was found to be advantageous because COX-2 is involved in inflammation and COX-1 which is protective on gastroduodenal mucosa is spared.
• Selective COX-2 inhibitors have been synthesized—like the
• COXIBs celecoxib, parecexib and etoricoxib. These drugs have analgesic, anti-inflammatory, and antipyretic effects like nonselective NSAIDs but with much less gastric ulcerogenic effects.
• They also do not inhibit platelet aggregation because COX-1 is involved in platelet function.

However, many of the COXIBs have been withdrawn due to the adverse effects.

Note: PGI₂ → Inhibits platelet aggregation TXA2 → Promotes platelet aggregation

COXIBS Adverse effects:

• Studies have shown that use of selective COX-2 inhibitors increases the risk of cardiovascular and cerebrovascular thrombotic events—may increase the risk of myocardial infarction and stroke.
• Hence most of them were withdrawn from the market and the others are under supervision. They are used only in patients who cannot tolerate NSAIDs and are at a high-risk of developing peptic ulcer.
• Celecoxib can cause hypertension and edema which can be troublesome in patients with cardiovascular problems. Anti-inflammatory 100–200 mg
• OD/BD.

COXIBS Uses:

Acute painful conditions like postoperative pain, dysmenorrhea, osteoarthritis, and rheumatoid arthritis—in patients who cannot tolerate other NSAIDs.

• Etoricoxib: Etoricoxib is highly selective for COX-2 and long-acting to be given once daily (60–120 mg tab).
• Parecoxib: Parecoxib prodrug of valdecoxib, can be given parenterally

Topical Nsaid Preparations

Some of the NSAIDs like diclofenac, ibuprofen, and paracetamol are available for topical use as ointment sprays and transdermal patches. They may be applied to the site of pain to avoid systemic toxicity. Many NSAIDs are also available as eye drops.

Aspirin and cetecoxib (nonselective and selective COX-2 inhibitors);

Drugs Used In Rheumatoid Arthritis

Question 41. Classify/name the drugs used in RA. Write briefly the role of any 3 of them in the treatment of RA.
Answer:

Rheumatoid arthritis is a chronic, progressive, autoimmune, inflammatory disease, that mainly affects the joints and the periarticular tissues. Antigen–antibody complexes trigger the pathological process.

Mediators of inflammation released in the joints initiate the inflammatory process. The inflammatory cells release lysosomal enzymes which cause damage to bones and cartilage.

Drugs used in the treatment of rheumatoid arthritis are:

• Disease-modifying antirheumatic drugs (DMARDs).
• Anti-inflammatory drugs to suppress the inflammation.

RA Classification:

1. DMARDs:

• Immunosuppressants: Methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide, chloroquine, hydroxychloroquine, gold salts, penicillamine, sulfasalazine
• Biologics:
  • TNF-alpha blockers—etanercept, infliximab, adalimumab, certolizumab, golimumab
  • T cell activation inhibitor: Abatacept
  • Anti-B lymphocyte antibody: Rituximab
  • IL-1B antibody: Kanakinumab
  • IL-6 antagonist: Tocilizumab

2. Antiinflammatory agents:

• NSAIDs
• Glucocorticoids

DMARDs

DMARDs could delay the progression of the disease in addition to symptomatic relief in RA patients. The onset of action is however slow and could range from few weeks to few months.

Immunosuppressants:

In lower doses than that used in cancers, methotrexate provides benefits in patients with rheumatoid arthritis. The mechanism of action of methotrexate in RA could be:

• It increases adenosine levels which is a potent inhibitor of inflammation.
• Also inhibits cytokines, directly suppresses the cells involved in inflammation and immunological diseases, and stimulates apoptosis of these cells.
• Inhibition of DHFR could influence macrophage and lymphocyte function.

Methotrexate is now the most commonly used drug in autoimmune disorders. Leucovorin rescue with folinic acid may be given to reduce toxicity.

Methotrexate Adverse effects:

• Including nausea, mucosal ulcers, bone marrow suppression, and hepatotoxicity.
• Weekly regimens of low oral doses are better tolerated.

Azathioprine:

• A purine analog is a prodrug converted to 6-thioguanine in the body.
• It suppresses cell-mediated immunity and inhibits T- and B-cell function. It is used as an alternative to methotrexate.

Cyclophosphamide:

An alkylating agent (see Page 396) also inhibits T cell and B cell function and cyclosporine, an immunosuppressant may be used as alternatives.

Leflunomide:

• It is a prodrug and the active metabolite inhibits autoimmune T cell proliferation and production of autoantibodies by B cells.
• Leflunomide has a long t½ of 5–40 days.

Leflunomide Adverse effects:

• Including diarrhea, raised hepatic enzymes, weight gain, hypertension, and sometimes alopecia.
• Leflunomide is used with methotrexate in rheumatoid arthritis patients not responding to methotrexate alone.

Hydroxychloroquine and chloroquine: These antimalarial drugs are found to be useful in mild non-erosive rheumatoid arthritis. They induce remission in 50% of patients. Mechanism of action is not exactly understood but they are known to depress cell-mediated immunity.

Hydroxychloroquine and chloroquine Adverse effects:

• Chloroquine and hydroxychloroquine accumulate in tissues leading to toxicity like retinopathy on long-term use.
• This toxicity is less common and reversible with hydroxychloroquine which is, therefore, preferred over chloroquine in rheumatoid arthritis.
• Every 3 months eyes should be tested. Other adverse effects include myopathy, neuropathy, and irritable bowel syndrome.

Gold salts:

• Aurothiomalate and auranofin are no more preferred because of their toxicity and the availability of safer agents.
• Gold depresses cell-mediated immunity (CMI). On treatment with gold salts, a gradual reduction of the signs and symptoms are seen.

Gold salts Adverse effects:

Dermatitis and a gray-blue pigmentation on exposed parts of the skin, hepatotoxicity, nephrotoxicity, encephalitis, peripheral neuritis, pulmonary fibrosis, and bone marrow suppression can occur.

Biologics

Question 42. Role of biologics in RA/short note on biologics in RA.
Answer:

Biologics are agents obtained from biological sources including microbes animals or humans.

Biological agents used in RA are:

TNF-α blocking agents:

• Cytokines, particularly tumor necrosis factor-alpha (TNF-α) play an important role in the process of inflammation.
• TNF-α produced by macrophages and activated T cells, acts through TNF-α receptors to stimulate the release of other cytokines.

Infliximab:

• Infliximab is a monoclonal antibody that specifically binds with high affinity to human TNF-a.
• When given in combination with methotrexate, it slows the progression of rheumatoid arthritis.

Biologics Adverse effects of the combination:

• Increased risk of upper respiratory infections; dormant tuberculosis may become active.
• Nausea, headache, cough, sinusitis, skin rashes, and allergic reactions can occur. Rarely hepatitis and activation of viral hepatitis have been reported.
• Antinuclear and anti-DNA antibodies may develop and this can be largely avoided by giving methotrexate along with infliximab.

Biologics Uses:

• Autoimmune diseases like ankylosing spondylitis, Crohn’s disease, psoriasis, ulcerative colitis, and sarcoidosis.
• RA along with methotrexate or one of the other DMARDs.

Etanercept:

• It is a recombinant fusion protein that binds to TNF-a molecules. Etanercept is also given with methotrexate and the combination has a higher efficacy.
• Pain, itching, and allergic reactions at the site of injection, anti-etanercept antibodies, and anti-DNA antibodies have been detected.
• Dose: 50 mg weekly SC.

Inhibitor Of T-Cell Activation

Abatacept:

• Abatacept inhibits the activation of T-cells. It has a long t½ of 13–16 days. Given as IV infusion of 800–1,000 mg and repeated after 2 and 4 weeks provides symptomatic improvement.
• The infusion is then repeated at monthly intervals. It is well-tolerated but may cause hypersensitivity reactions on infusion.

Abatacept + TNF-a blockers → ↑ ↑ Upper respiratory infections → Avoid combination.

IL-1 antagonist:

Anakinra is a recombinant IL-1 receptor antagonist tried in patients not responding to other DMARDs.

Anti-B lymphocyte antibody:

• Rituximab is a monoclonal antibody against B cells and is used in lymphomas
• Reduction in B cells suppresses the inflammatory process and
  inhibits the release of cytokines.
• It has been approved for use in moderate to severe active RA along with methotrexate.

IL-6 antagonist:

• Tocilizumab is an IL-6 antibody that binds to IL-6 receptors and blocks its action.
• Tocilizumab may be used (IV once in 4 weeks) as monotherapy or with a DMARD in moderate to severe RA not responding to other DMARDs.
• Increased susceptibility to infection is a limiting factor.

Anti-Inflammatory Drugs

NSAIDs: Diclofenace and other NSAIDs are used for symptomatic relief in RA.

Glucocorticoids: Glucocorticoids have anti-inflammatory and immunosuppressant activity.

• They produce prompt and dramatic relief of symptoms but do not arrest the progress of the disease.
• However, long-term use of these drugs leads to several adverse effects.
• Moreover, on withdrawal of glucocorticoids, there may be an exacerbation of the disease. Therefore, glucocorticoids are used only as adjuvants. They may be used to treat exacerbations.
• Low-dose long-term treatment with prednisolone (5–10 mg/day) or IM depot methylprednisolone 80–160 mg are used in some patients. Intra-articular corticosteroids are helpful to relieve pain in severely inflamed joints.

Diet and inflammation:

Diet rich in unsaturated fatty acids (such as marine fish), brings about a decrease in morning stiffness, pain, and swelling of the joints.

Sulfasalazine:

On oral administration, when it reaches the colon, it is split by the bacteria, and sulfapyridine gets absorbed which has anti-inflammatory actions.

Pharmacotherapy Of Gout

Gout is a familial metabolic disorder characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in the joints and cartilage.

Gout Classification:

Colchicine:

Colchicine an alkaloid of Colchicum autumnale, is a unique anti-inflammatory agent effective only against gouty arthritis. It is not an analgesic and also does not alter the production of uric acid.

Colchicine Actions:

Colchicine is highly effective in acute attacks of gout and it dramatically relieves pain within a few hours.

Colchicine Mechanism of Action:

• Colchicine inhibits the migration of granulocytes into the inflamed area and the release of glycoprotein by them.
• It binds to the protein tubulin, prevents microtubule formation, and arrests cell division in metaphase.
• It inhibits the migration of leukocytes and also their phagocytosis.

Other actions: Colchicine increases gut motility by neurogenic stimulation.

Colchicine Pharmacokinetics:

• Colchicine is rapidly absorbed orally, metabolized in the liver, and undergoes enterohepatic circulation.
• Dose: 0.5 mg.

Colchicine Adverse effects:   

• Dose-related nausea, vomiting, diarrhea, and abdominal pain are the earliest side effects.
• Though these GI effects may be avoided by giving colchicine intravenously, it can cause serious toxicity and hence IV colchicine should be avoided.
• Anemia, leukopenia, and alopecia may be seen.
• In high doses, hemorrhagic gastroenteritis, nephrotoxicity, muscular paralysis, acute renal failure, respiratory failure, shock and fatal CNS depression can occur.

Colchicine Uses:

1. Acute gout: Colchicine 1 mg orally initially, followed by 0.5 mg every 2–3 hours relieves pain and swelling within 12 hours but diarrhea limits its use.
2. Prophylaxis: Colchicine may also be used for the prophylaxis of recurrent episodes of gouty arthritis 0.6 mg OD/TDS.

Allopurinol: 

Allopurinol is an analog of hypoxanthine and inhibits the biosynthesis of uric acid.

Allopurinol Mechanism of Action:

• Purine nucleotides are degraded to hypoxanthine. Uric acid is produced from hypoxanthine.
• Allopurinol and its metabolite alloxanthine both inhibit the enzyme xanthine oxidase and thereby prevent the synthesis of uric acid.
• The plasma concentration of uric acid is reduced.

Allopurinol Pharmacokinetics:

Allopurinol is absorbed orally; t½ 2–3 hours; and t½ of alloxanthine—24 hours.

Allopurinol Adverse effects are mild: Hypersensitivity reactions include fever and rashes.

• Gastrointestinal irritation, headache, nausea, and dizziness may occur during the initial months of treatment with allopurinol.
• Attacks of acute gouty arthritis may be seen frequently.

Allopurinol Drug interactions:

• The anticancer drugs, 6-mercaptopurine and azathioprine are metabolized by xanthine oxidase.
• Hence when allopurinol is used concurrently, the dose of these anticancer drugs should be reduced.

Allopurinol Uses:

• Chronic gout and secondary hyperuricemia—initial dose is 100 mg/day and may be gradually increased to 300 mg/day depending on the response.
• Colchicine or an NSAID should be given during the first few weeks of allopurinol therapy to prevent acute attacks of gouty arthritis (gout flares).
• On treatment with allopurinol, tophi are gradually resorbed and the formation of renal stones is prevented. In patients with large tophaceous deposits, both allopurinol and uricosuric drugs can be given.

Febuxostat:

• It is another xanthine oxidase inhibitor but is not a purine. It reduces the formation of xanthine and uric acid.
• Like allopurinol, treatment with febuxostat can cause gout flares.
• It can also cause nausea, diarrhea, headache, and altered liver function.
• Febuxostat is well absorbed and is used in a dose of 80–120 mg for the treatment of chronic gout.

Rasburicase:

• Urate oxidase is an enzyme present in mammals but absent in human beings.
• It converts uric acid to allantoin which is a highly soluble product easily excreted by the kidneys.
• Rasburicase is recombinant urate oxidase (pegloticase is pegylated recombinant urate oxidase).
• Given intravenously (4–12 mg) it rapidly reduces uric acid levels in 1–3 days, maintaining it up to 21 days.

Rasburicase Adverse effects:

Allergic reactions, gout flare, nausea, anemia, and methemoglobinemia. They are to be avoided in G6PD deficiency.

Rasburicase Uses Tumor lysis syndrome and refractory chronic gout.

Antipsychotics (Neuroleptics)

Psychiatric disorders may be psychoses, neuroses, personality disorders, and organic mental disorders.

• Psychoses involve a major impairment of behavior, and inability to think appropriately and to understand (comprehend) reality.
• There is no organic cause in these, for example, Schizophrenia

Neuroleptic is a drug that produces emotional quietening and induces drowsiness.

Antipsychotics Classification: 

Chlorpromazine:

Chlorpromazine (CPZ) has a wide variety of actions and adverse effects because it blocks the actions of several neurotransmitters including adrenaline, dopamine (DA), histamine,
acetylcholine and serotonin.

Chlorpromazine Mechanism of action:

• Typical or first-generation neuroleptics act by blocking the dopamine D2 receptors in the CNS.
• There are 5 subtypes of dopamine receptors D₁ to D₅. They are all G protein-coupled receptors.
• As proposed in DA hypothesis, dopaminergic overactivity in the limbic area is thought to be responsible for schizophrenia, and typical antipsychotics block dopamine D₂ receptors in the CNS particularly in the mesolimbic area.
• Some drugs like phenothiazines also block D₁, D_3, and D₅ receptors. However, antipsychotic efficacy correlates with D₂ blocking ability.

Chlorpromazine Pharmacological Actions

CNS: Behavioral effects—in normal subjects, CPZ reduces motor activity, and produces drowsiness and indifference to surroundings.

• In psychotic agitated patients, CPZ induces neuroleptics syndrome, reduces aggression, initiative, impulsiveness, and motor activity, relieves anxiety, and brings about emotional quietening and drowsiness.
• Hallucinations, delusions, and disordered thoughts gradually subside.
• They normalize the sleep disturbances characteristic of psychoses.

Other CNS Actions:

• Cortex: CPZ lowers the seizure threshold and can precipitate convulsions in untreated epileptics.
• Hypothalamus:
  • ↓ Gonadotrophin secretion → amenorrhea in women
  • ↑ Prolactin secretion → galactorrhea and gynecomastia.
• Basal ganglia: CPZ is a dopamine antagonist → results in extrapyramidal motor symptoms and drug-induced Parkinsonism.
• Brainstem: Vasomotor reflexes are depressed → fall in BP.
• CTZ: Block the DA receptors in the CTZ—hence are antiemetics.

Autonomic nervous system:

The actions of the ANS are complex. CPZ blocks alpha-adrenergic and cholinergic muscarinic receptors which lead to side effects. The degree of a blocking and anticholinergic activity varies with each drug.

• CVS: a-blockade → postural hypotension, reflex tachycardia.
• Local anesthetic: CPZ has local anesthetic properties.
• Kidney: CPZ depresses ADH secretion → weak diuretic effects.

Tolerance develops to the sedative and hypotensive actions while no tolerance is seen to the antipsychotic actions.

Adverse Reactions:

Question 43. Write a short note on the adverse effects of antipsychotics/chlorpromazine.
Answer:

Antipsychotics have a high therapeutic index and are fairly safe drugs.

1. CNS effects: Drowsiness and mental confusion are common. Extrapyramidal symptoms are the prominent side effects.

Extrapyramidal symptoms:

• Acute dystonias: Facial grimacing, tics, muscle spasms, protruding tongue, and similar involuntary movements can occur in the first few days of starting antipsychotics. They respond to anticholinergics.
• Parkinsonism: Bradykinesia, tremors, and rigidity including the typical ‘Parkinsonian face’ may be noticed in the first few weeks. It responds to anticholinergic antiparkinsonian drugs.
• Perioral tremors: Also called ‘rabbit syndrome’ may occur after several months of antipsychotic therapy—anticholinergics are useful.
• Akathesia: It is a feeling of intense discomfort which compels the person to be continuously moving like constantly walking. It necessitates a reduction in antipsychotic dosage and treatment with propranolol or other antianxiety drugs.
• Tardive dyskinesia: Appears after months or years of therapy—involuntary movements of the face, tongue, eyelids, trunk, and limbs. A changed over to typical antipsychotics like clozapine because of the lower EPS.
• Malignant neuroleptic syndrome: Immobility, rigidity, tremors, fever, dysphagia, stupor, or coma with autonomic effects like fluctuating blood pressure and heart rate—can be fatal and could be due to sudden reduction of dopaminergic activity or increase in cholinergic activity.
• Treatment: Stop Neuroleptic. Tepid water sponging to reduce the body temperature, skeletal muscle relaxants like dantrolene or diazepam; bromocriptine may help to increase central dopaminergic activity.

2. Cardiovascular and autonomic effects:

• Antipsychotics can cause postural hypotension and palpitation both due to alpha receptor blockade and central effects.
• \Some of the antipsychotics in higher doses can cause QT prolongation and arrhythmias in overdosage.
• Nasal stuffiness is due to a blockade; blurred vision, dry mouth, reduced sweating, decreased gastric motility, constipation, and urinary retention result from the blockade of muscarinic receptors.

3. Endocrine disturbances: Gynecomastia, galactorrhea, and amenorrhea.

4. Ocular toxicity: Long-term use of some antipsychotics can cause corneal and lenticular opacities as well as retinal pigmentation and degeneration.

5. Hypersensitivity reactions: Jaundice, agranulocytosis, and skin rashes.

Drug interactions:

Antipsychotics/Chlorpromazine Uses:

Neuroleptics are given orally (chlorpromazine: 100–800 mg). In acute psychosis, they may be given intramuscularly and the response is seen in 24 hours, while in chronic psychosis it takes 2–3 weeks of treatment for response:

1. Psychiatric conditions: Psychoses including schizophrenia and organic brain syndromes like delirium and dementia all respond to antipsychotics. The manic phase of bipolar mood disorder responds to antipsychotics and generally atypical antipsychotics are used.
2. Other neuropsychiatric syndromes: Syndromes with psychiatric features like psychoses associated with chronic alcoholism, Huntington’s disease, and Gilles de La Tourette’s syndrome may respond.
3. Hiccups: CPZ can control intractable hiccups but the mechanism of action is not known.
4. Vomiting: Prochlorperazine is used in vomiting due to radiation sickness and drug-induced vomiting.
5. Pruritus: Promethazine blocks H1 receptors and is useful in pruritus.
6. Neuroleptanalgesia: Droperidol is used with fentanyl for neuroleptanalgesia.

Haloperidol:

Haloperidol a butyrophenone, is a potent antipsychotic with actions similar to chlorpromazine.

Compared to chlorpromazine:

• It has a lesser incidence of autonomic side effects hence preferred in older patients
• Epileptogenic property is less
• It has a long t½ of 24 hours.

Haloperidol Uses:

• Useful in acute schizophrenia
• Drug of choice in Gilles de la Tourette’s syndrome and Huntington’s disease.
• Dose: 2–20 mg

Penfluridol:

Penfluridol is a long-acting neuroleptic given once a week 20–60 mg orally.

Thioxanthenes:

Thioxanthines are chemically related to phenothiazines and are similar to them.

Flupenthixol:

• Flupenthixol has additional antidepressant properties.
• It is available as depot preparation for injection and is suitable for maintenance therapy of schizophrenia.
• Dose: 3–5 mg daily

Atypical Second-Generation Antipsychotics:

• The atypical antipsychotics have weak D₂ blocking properties but prominent 5-HT₂ antagonistic actions.
• They also block a-adrenergic and H₁ histamine receptors. Some of them also block muscarinic receptors.

Advantages over first-generation agents:

• Extrapyramidal side effects are absent or low
• Low endocrine side effects—particularly no raised prolactin levels, hence no galactorrhea and no gynecomastia.
• Effective in suppressing both positive and negative symptoms of schizophrenia
• Effective in resistant cases of psychosis.
• Atypical antipsychotics are used as first-line drugs in newly diagnosed patients and in patients having troublesome EPS with conventional antipsychotics.
• However, their efficacy is not superior to conventional antipsychotics.

Clozapine:

Clozapine blocks the dopamine D₁ and D₄ receptors but has a low affinity for D₂ receptors hence a very low incidence of EPS.

Clozapine Adverse effects:

• Clozapine can cause agranulocytosis in some patients which can be fatal— hence not preferred.
• Clozapine can also cause sedation, weight gain, hyperglycemia, urinary incontinence, hypotension, and tachycardia. Clozapine is epileptogenic.

Olanzapine: It is similar to clozapine but it does not cause agranulocytosis. It has a t½ of 24– 30 hours—given once daily.

Olanzapine Adverse effects:

• Anticholinergic side effects—weight gain, hyperglycemia, and hypertriglyceridemia can occur.
• These side effects are particularly of concern in diabetics.

Olanzapine Uses:

It is used in mania, schizoaffective disorders, and in Tourette’s syndrome.

Risperidone:

• Risperidone blocks 5HT and dopamine D₂ receptors.
• Dose: 1–3 mg twice daily.

Risperidone Adverse effects:

• Including nausea, anorexia, agitation, and drowsiness.
• Increased incidence of cerebrovascular disease is reported.

Risperidone Uses:

• Mania, schizoaffective disorders, schizophrenia, and other psychotic conditions.
• The salient features of antipsychotics are given in the Table

Salient features of antipsychotics:

Antianxiety Drugs (Anxiolytics)

Question 44. Write a short note on antianxiety drugs. Explain why buspirone is used as an anxiolytic. List the differences between BZD and buspirone.
Answer:

Anxiety is a universal human emotion. However, when it becomes excessive and disproportionate to the situation, it becomes disabling and needs treatment.

Benzodiazepines:

Benzodiazepines have good antianxiety actions and are the most commonly used drugs for anxiety. They are CNS depressants. Alprazolam in addition has antidepressant properties.

Buspirone:

Buspirone is an azapirone with good anxiolytic properties but differs from BZDs.

• It is a selective 5 – HT_IA partial agonist. 5 – HT_IA receptors are inhibitory autoreceptors and binding of buspirone inhibits the release of 5-HT. Buspirone is also a weak D₂ antagonist.
• Unlike diazepam, it is not a muscle relaxant, nor an anticonvulsant, does not produce significant sedation, tolerance or dependence, and is not much useful in panic attacks.

Buspirone is rapidly absorbed and metabolized in the liver and undergoes extensive first-pass metabolism. Microsomal enzyme inducers like rifampicin shorten the t½, while enzyme inhibitors like erythromycin prolong its t½.

Dose: 5–15 mg OD/TDS.

Buspirone Adverse effects:

Adverse effects are mild headache, dizziness, nausea, tachycardia, nervousness, paraesthesias, and rarely, restlessness.

Buspirone Uses:

Mild to moderate anxiety the antianxiety effect develops over 2 weeks. It is particularly useful when sedation is to be avoided.

Ipsapirone and gepirone are similar to buspirone.

Diazepam And Buspirone:

Beta-blockers:

• In patients with prominent autonomic symptoms of anxiety like tremors, palpitation, and hypertension, propranolol may be useful.
• b-blockers are also useful in anxiety-inducing states like public speaking and stage performance. They can be used as adjuvants to benzodiazepines.

Sedative antihistamine:

Hydroxyzine is an antihistaminic with anxiolytic actions but due to high sedation, it is not used.

Antidepressants And Mood Stabilizers

Depression is a common psychiatric disorder but the etiology of it is not clear.

Depression could be:

• Unipolar:
  • Reactive depression
  • Endogenous depression
• Bipolar mood disorder or manic depressive illness.

Mood Stabilizers Classification:

1. Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine, fluvoxamine, paroxetine, citalopram, escitalopram, sertraline
2. Tricyclic antidepressants (TCAs): Imipramine, desipramine, clomipramine, amitriptyline, nortriptyline, doxepin
3. Serotonin-norepinephrine reuptake inhibitors (SNRIs): Venlafaxine, desvenlafaxine, duloxetine, milnacipran
4. Atypical antidepressants: Mianserine, amineptine, tianeptine, bupropion, reboxetine, mirtazapine, amoxapine, atomoxetine, maprotiline, trazodone, nefazodone, vortioxetine
5. Monoamine oxidase (MAO) inhibitors: Phenelzine, tranylcypromine, moclobemide, selegiline.

Selective Serotonin Reuptake Inhibitors:

SSRIs are now considered the first-line drugs in depression.

SSRIs Mechanism of action:

• SSRIs block the reuptake of serotonin from the synapse into the serotonergic nerve endings by inhibiting the serotonin transporter (SERT).
• About 80% reuptake is inhibited and more serotonin is available at the synapse which in turn results in the production of related proteins like brain-derived neurotrophic factor (BDNF) responsible for the
  effects of SSRIs.
• Hence they enhance serotonin levels in these synapses

TCAs were earlier the first-line drugs but presently, SSRIs have taken over the place to a large extent because of several advantages over TCAs (see Compare and Contrast).

Advantages of SSRIs Over TCAs:

• Low cardiovascular side effects.
• Anticholinergic side effects are negligible.
• Less sedation.
• Preferred in the elderly because of lower anticholinergic effects (anticholinergic effects like constipation and urinary retention may be troublesome in the elderly).
• Safer in overdose (particularly advantageous in patients with depression who may have suicidal tendencies).
• Due to the low side effect profile, SSRIs are generally well tolerated and accepted by patients.

Imiramine And fluoxetine:

SSRIs Pharmacokinetics:

• SSRIs are well absorbed when given orally, most are bound to plasma proteins.
• SSRIs are microsomal enzyme inhibitors—though each of them inhibits different isoforms.
• Fluoxetine is converted to active metabolite norfluoxetine prolonging the action to 7–10 days.

Therapeutic dose and unique features of SSRIs:

SSRIs  Adverse effects:

• Include nausea, vomiting, insomnia, headache, restlessness, anxiety, and sexual dysfunction may interfere with ejaculation.
• Inhibition of platelet function may result in ecchymosis. Serotonin syndrome—when given with MAOI.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) like imipramine have been extensively used in the treatment of depression for a few decades. Though adverse effects are more common with TCAs, they are less expensive than SSRIs and are, therefore, still in use.

Tricyclic Antidepressants Pharmacological Actions:

1. CNS:

In normal subjects, TCAs cause dizziness, drowsiness, confusion, and difficulty in thinking. In depressed patients, after 2–3 weeks of treatment, the elevation of mood occurs; the patient shows more interest in the surroundings and the sleep pattern becomes normal.

CNS Mechanism of action:

• TCAs block the reuptake of both NA and serotonin into the presynaptic terminals by binding to the transporters, viz. SERT and norepinephrine transporter (NET).
• The synaptic levels of these monoamines increase and thereby prolong their action on the receptors.
• Thus TCAs potentiate amine neurotransmission in the CNS. The extent of binding and selectivity for SERT and NET varies with each TCA.

2. CVS and ANS:

Blockade of a 1-adrenergic and muscarinic receptors results in postural hypotension, tachycardia, and anticholinergic effects.

Tricyclic Antidepressants Pharmacokinetics:

• TCAs are rapidly absorbed, extensively protein bound, and metabolized in the liver.
• Microsomal enzymes are involved in the metabolism of TCAs and can result in drug interactions.
• TCAs have a long t½—given once daily. On prolonged administration, accumulation can occur resulting in cumulative toxicity.

Tricyclic Antidepressants Adverse Effects:

• H₁ blockade—sedation, confusion
•  α-blockade—postural hypotension, tachycardia and sweating.
• Anticholinergic side effects—dry mouth, blurred vision, constipation, and urinary retention.
•  Lower the seizure threshold → may precipitate convulsions in epileptics; hallucinations and mania in some patients.
• ↑ Appetite→ weight gain.
• Cardiac arrhythmias.

Acute toxicity:

Acute toxicity (mimic symptoms of atropine poisoning) delirium, excitement, hypotension, convulsions, fever, arrhythmias, respiratory depression, and coma.

Treatment:

• Physostigmine given to overcome atropine-like effects.
• Sodium bicarbonate for acidosis, diazepam or phenytoin for seizures, and lignocaine/propranolol for arrhythmias—with other supportive measures.
• Gastric lavage, IV fluids, and respiratory support are needed.

Tolerance and dependence:

• Tolerance develops gradually to the sedative and anticholinergic effects over 2–3 weeks.
• Starting with a low dose and gradually increasing the dose minimizes the side effects.
• Withdrawal symptoms like headache, anxiety, and chills can occur due to physical dependence. Hence, TCAs should be gradually withdrawn.

Drug Interactions:

• TCA + sympathomimetics → ↑ BP
• TCA + highly protein-bound drugs (phenytoin, aspirin) → TCA displaced → toxicity
• TCA + anticholinergic drug → ↑ anticholinergic side effects
• TCA + alcohol/CNS depressants → ↑ ↑ CNS depression

Serotonin Norepinephrine Reuptake Inhibitors (Snris)

Question 45. Write a short note on venlafaxine.
Answer:

Venlafaxine:

Venlafaxine (and desvenlafaxine, duloxetine, and milnacipran) inhibit the reuptake of both serotonin and norepinephrine at the presynaptic neurons by binding to SERT and NET-like TCA.

Venlafaxine  Advantages: 

• Unlike TCA, SNRIs do not have anticholinergic, α-blocking or antihistaminic effects—hence fewer side effects → therefore better tolerated.
• Venlafaxine is faster-acting and may be useful in patients not responding to other antidepressants.
• Venlafaxine has a short t½ (~5 hours), given twice daily; it is safe in overdosage. If abruptly stopped, withdrawal symptoms are common.

Atypical Antidepressants

Question 46. Write a short note about Atypical antidepressants.
Answer:
Atypical antidepressants.

• Bupropion, mianserin, mirtazapine, amoxapine, maprotiline, trazodone and nefazodone.
• Act by increasing monoamine levels in the brain either by inhibiting their reuptake or preventing their degradation.
• Mirtazapine blocks 5-HT₂, 5-HT_3, and a₂-receptors → increases the release of NA and 5-HT.
• It is faster acting action that starts in a week; causes sedation but other side effects are negligible.
• Bupropion is a weak DA reuptake inhibitor and has CNS stimulant effects. It is used in depression with anxiety and also to help cessation of smoking (along with nicotine patch).
• It can cause insomnia, agitation but does not cause sexual side effects.
• Mianserin: Acts by blocking presynaptic a₂ -receptors but toxicity including blood, dyscrasias, seizures, and liver dysfunction has limited its use.
• Trazodone: It is a serotonin antagonist and also weak serotonin reuptake inhibitor.
• Vortioxetine: It is a newly introduced antidepressant with complex actions on serotonin receptors. Antagonist at 5-HT₃, 5-HT₇, and 5- HT_IA
• receptors, an agonist at 5 – HT_IA receptors, and partial agonist at 5-HT_IB receptors.
• Dose: 10–20 mg OD.

Mao Inhibitors (MAOIs)

Monoamine oxidase (MAO) is an enzyme that metabolizes NA, serotonin, and DA. Drugs that inhibit this enzyme, enhance the neuronal levels of monoamines like NA, DA, and serotonin. Two isozymes of MAO are—MAO_A and MAO_B. MAO_A is selective for serotonin.

Irreversible and nonselective MAO inhibitors:

• Irreversibly inhibit the enzyme MAO and enhance neuronal levels of NA, DA, and serotonin.
• Antidepressant actions develop slowly over weeks of treatment.
• Side effects—orthostatic hypotension, weight gain, restlessness, insomnia (due to CNS stimulation), anticholinergic effects, and rarely liver dysfunction.
• Abrupt stopping → withdrawal syndrome (confusion, excitement, psychosis).

MAO inhibitors Drug Interactions

Question 47. What is serotonin syndrome?
Or
What are the drug interactions of MAO inhibitors?
Answer:

MAOI interacts with many drugs and food;

1. Food-drug interaction: 

• Patients on MAOi receiving tyramine-containing food—develop severe hypertension known as ‘cheese reaction’.
• Tyramine is normally metabolized by MAO in the gut wall.
• On the inhibition of MAO by drugs, tyramine escapes metabolism and displaces
• NA from nerve endings leading to hypertension.

2. Serotonin syndrome:

• When an SSRI and an MAO inhibitor are administered at the same time, there could be an increase in serotonin levels in the synapses—because of both reduced
  reuptake and inhibition of metabolism.
• Raised serotonin levels can result in hyperthermia, restlessness, sweating, muscle rigidity, aggressive behavior, tremors, seizures and coma. It can be fatal.
• This pharmacodynamic interaction can also occur when there is potentiation of serotonergic activity with drugs like amphetamines, cocaine (5-HT release), tryptophan (5- HT synthesis), buspirone, and sumatriptan (5-HT agonists). Hence such combinations should be avoided.

Because of side effects and drug interactions, MAO inhibitors are not preferred.

Reversible Inhibitor Of MAO_A (RIMA)

• Moclobemide: Moclobemide is a reversible, competitive, selective MAOA inhibitor.
• Short-acting → MAO activity recovers within 1–2 days after stopping.
• Adverse effects include nausea, insomnia, headache, dizziness, and liver dysfunction.

Of MAO_A Advantages:

• An effective antidepressant, not a sedative
• Does not produce cardiovascular and anticholinergic side effects → well-tolerated.
• No significant drug interactions are seen.

Of MAO_A Uses:

• Mild to moderate depression as an alternative to TCA.
• Dose: 150 mg BD-TDS.
• In anxiety-related mood disorders.

Uses Of Antidepressants

Question 48. Write briefly the uses of antidepressants.
Answer:

1. Endogenous depression: Response to antidepressants is seen after 2–3 weeks of treatment. The choice of drug depends on the side effects and patient factors like age. SSRIs are the most commonly used antidepressants.
2. Panic attacks: Acute, recurrent, brief episodes of anxiety are known as panic attacks. Posttraumatic stress disorders, panic attacks, and other anxiety disorders—all respond.
3. Obsessive-compulsive disorders (OCDs): OCDs are characterized by repeated anxiety-provoking thoughts and compulsive behavior to overcome such anxiety. OCDs respond to SSRIs/clomipramine along with counseling.
4. Other anxiety disorders: SSRIs are effective in several anxiety states like post-traumatic stress disorders, phobias, and social anxiety. They may be preferred over BZDs in many of these conditions.
5. Chronic pain: SSRIs and SNRIs influence ascending pain pathway and are effective in chronic pain including diabetic neuropathy, backache, postherpetic neuralgia and
   fibromyalgia.
6. Psychosomatic disorders: Newer antidepressants are tried in irritable bowel syndrome, chronic fatigue, tics, and sleep apnea.
7. Bulimia nervosa: An eating disorder with episodic excessive eating responds to SSRIs.
8. Premenstrual syndrome: SSRIs may be given for 2 weeks prior to menstruation and the cycles may be repeated. Flushing and other vasomotor symptoms seen in perimenopausal
   women also respond to SSRIs.
9. Smoking withdrawal: Bupropion reduces the urge in people who need to quit smoking.
10. Nocturnal enuresis: Nocturnal enuresis in children may need SSRIs only when other measures fail.
11. Premature ejaculation: SSRIs are effective. Dapoxetine has a faster effect and should be taken 1 hour before intercourse.
12. Other indications: Migraine, attention deficit hyperactivity disorder, chronic fatigue, urinary stress incontinence, and chronic alcoholism—may result in depression—
    antidepressants are tried.

Drugs Used In Bipolar Mood Disorder

Question 49. Write short notes on lithium/mood stabilizers.
Answer:

Mood stabilizers control the mood swings that are seen in bipolar mood disorders. They are also called antimanic drugs.

Mood stabilizers include:

• Lithium
• Valproic acid
• Carbamazepine
• Lamotrigine
• Topiramate
• Gabapentin
• Risperidone
• Olanzapine

Lithium

• Lithium is a monovalent cation. (Cade in 1949 discovered its use). On prophylactic use in bipolar mood disorder (manic-depressive illness), lithium acts as a mood stabilizer.
• It prevents swings of mood and thus reduces both the depressive and manic phases of the illness.
• Given in acute mania, it gradually suppresses the episode over weeks.

Lithium Mechanism of action:

Lithium is complex and not fully understood. It is thought that lithium acts by the following mechanisms.

1. Inositol pathway:

• Lithium interferes with the regeneration of inositol. It inhibits the conversion of IP₃ to inositol, leading to a depletion of phosphatidyl inositol biphosphate (PIP₂).
• This results in a reduction in the formation of the second messengers IP and DAG leading to a reduction in the receptor activity.
• Lithium selectively inhibits signal transduction in the hyperfunctioning neurons as seen in mania. Lithium inhibits monophosphatases that convert IP to inositol

Other modes of action: Effect on electrolytes—lithium can compete with and replace sodium at many sites including neurons.

Neurotransmitters:

Lithium inhibits the release of NA and DA from the nerve terminals and prevents the supersensitivity of the receptors induced by dopamine antagonists
(antipsychotics).

Lithium  Pharmacokinetics:

• Lithium is a small ion and mimics the role of sodium in excitable tissues.
• Given orally it is well-absorbed. It is filtered at the glomerulus but reabsorbed like sodium. Since lithium has low safety margin, plasma lithium concentration needs to be monitored (0.5–1mEq is the therapeutic plasma concentration) 3–5 mEq can cause fatal toxicity.

Lithium  Adverse effects:

Lithium is a drug of a low therapeutic index and side effects are common.

• Nausea, vomiting, mild diarrhea, and edema occur in most patients.
• Tremors are common with therapeutic doses and it responds to propranolol.
• Hypothyroidism is due to reversible inhibition of thyroid function—monitor TSH.
• Polyuria, thirst due to inhibition of ADH (nephrogenic diabetes insipidus)—should avoid dehydration while on lithium.
• Weight gain can also occur.
• CNS: Include coarse tremors, drowsiness, giddiness, confusion, ataxia, blurred vision, and nystagmus.
• In overdosage, delirium, muscle twitchings, convulsions, arrhythmias, and renal failure develop.

Lithium Precautions:

• The minimum effective dose should be used.
• Always use the same formulation in a patient.
• Patients should be told of the first symptom of toxicity.
• Lithium is contraindicated in pregnancy.

Lithium Drug Interactions:

1. Lithium + diuretics

Diuretic → ↑ Na+ excretion → ↑ Li+ reabsorption (in place of Na+) → ↑ Li+ levels → Toxicity

2. NSAIDs decrease lithium elimination and increase toxicity.

Lithium Uses:

• Prophylaxis of bipolar mood disorder: Reduce frequency and severity of mania and depression.
• Acute mania: Since the response to lithium is slow, neuroleptics are preferred.
• Recurrent depression: Lithium is tried with other antidepressants as an add-on drug.
• Leukopenia: Lithium increases leukocyte count and has been used in leukopenia following cancer chemotherapy.
• Other uses: Lithium is tried in recurrent neuropsychiatric disorders, childhood mood disorders, hyperthyroidism and inappropriate ADH secretion syndrome.

Other Mood Stabilizers

Because of the difficulty in using lithium like the need for monitoring plasma levels, risk of toxicity, and potential for drug interactions, other drugs are being tried.

Carbamazepine:

• Carbamazepine is effective in preventing the relapses of bipolar mood disorder and in the treatment of acute mania.
• It can be combined with lithium for better therapeutic effects but
  lithium can increase the toxicity of carbamazepine.
• Mechanism of action is not understood. Carbamazepine may be used alone in mild cases as a mood stabilizer.

Sodium valproate has several advantages:

• It is almost as effective as lithium as a mood stabilizer
• May be effective in patients not responding to lithium
• Safer
• Better tolerated
• Dose can be rapidly titrated upwards
• Well-tolerated and adverse effects are milder (occasional nausea) as compared to lithium
• It can be combined with other antipsychotics and the combination is well-tolerated.
• Valproic acid is now considered the first-line drug in the initial treatment of mania.
• Dose: Started with 750 mg/day—may be increased to 1,500–2,000 mg/day.

Other antiepileptics: Lamotrigine, gabapentin, topiramate, and other newer antiepileptics are tried in the prophylaxis of bipolar mood disorder as alternatives to lithium.

Antipsychotics like risperidone, olanzapine, quetiapine, and aripiprazole are used to control acute mania. Riluzole, a neuroprotective agent is also tried in mood disorders.

Cns Stimulants

CNS stimulants include:

• Respiratory stimulants: Doxapram, nikethamide
• Psychomotor stimulants: Amphetamine, cocaine, methylxanthines
• Convulsants: Leptazol, strychnine

Respiratory Stimulants (Analeptics)

• They stimulate respiration and are sometimes used to treat respiratory failure.
• Though they may bring about temporary improvement in respiration, the mortality is not reduced.
• They have a low safety margin and may produce convulsions. The availability of ventilators has reduced the need for analeptics.

Doxapram:

• Doxapram appears to act mainly on the brainstem and spinal cord and increase the activity of medullary respiratory and vasomotor centers.
• Doxapram in low doses can selectively stimulate respiration. Given intravenously as an infusion. 1–2 mg/kg/hr or 40–80 mg IM.

Respiratory Stimulants Adverse effects:

Nausea, cough, restlessness, muscle twitching, hypertension, tachycardia, arrhythmias, and convulsions.

Respiratory Stimulants Uses:

• Acute respiratory failure occasionally used IV as an analeptic.
• Apnea in premature infants not responding to theophylline.

Methylxanthines

Caffeine, theophylline, and theobromine are naturally occurring xanthine alkaloids.

1. CNS:

• Caffeine and theophylline are CNS stimulants—they increase mental alertness, reduce fatigue, produce a sense of well-being, and improve motor activity and performance with a clearer flow of thought.
• Caffeine stimulates the respiratory center.
• Higher doses produce irritability, nervousness, restlessness, insomnia, excitement, and headache. High doses can resultin convulsions.

2 . CVS:

• Increase the force of contraction of the myocardium and heart rate, and therefore, increase the cardiac output. But they also produce peripheral vasodilatation which tends to decrease the BP.
• The changes in BP are, therefore, not consistent. Caffeine causes vasoconstriction of cerebral blood vessels.

3. Kidneys: The xanthines have a diuretic effect.

4. Smooth muscle: Relax the smooth muscles, particularly the bronchial smooth muscle.

5. Skeletal muscle: Xanthines increase the power of muscle contraction and thereby increase the capacity to do muscular work by both central stimulant effect and the peripheral actions.

6. GI tract: Xanthines increase acid and pepsin secretion in the stomach and gastric irritants.

Methylxanthines Adverse effects:

Nervousness, insomnia, tremors, tachycardia, hypotension, arrhythmias, headache, gastritis, nausea, vomiting, epigastric pain and diuresis. High doses produce
convulsions. Tolerance develops after some time. Habituation to caffeine is common.

Methylxanthines Uses:

• Headache: Caffeine causes vasoconstriction of cerebral blood vessels, hence it is combined with ergotamine for the relief of migraine headache. Caffeine is also combined with aspirin/paracetamol for the treatment of headaches.
• Bronchial asthma: Theophylline is used as a bronchodilator.
• Apnea in premature infants: Episodes of prolonged apnea (>15–20 seconds) may be seen in premature infants which if too frequent may result in neurologic and other tissue damage due to hypoxia. When no primary cause can be detected, theophylline or caffeine may be used for 1–3 weeks to reduce the duration of episodes of apnea.

Nootropics

Nootropics are drugs that improve memory and cognition. They are also called cognition enhancers.

Piracetam:

• Piracetam is thought to protect the cerebral cortex from hypoxia and improve learning and memory.
• In higher doses, it also inhibits platelet aggregation. Adverse effects include insomnia, weight gain, nervousness, depression, and gastrointestinal disturbances.
• Piracetam and aniracetam have been tried in dementia, myoclonus, stroke, and other cerebrovascular accidents; alcoholism, Alzheimer’s disease, behavioral disorders, and learning problems in children and in vertigo.
• The beneficial effects in all these are not proven.

Drugs Of Abuse

Several drugs have been used for recreational purposes—for their pleasurable effects. Repeated use of such drugs may result in drug dependence or drug addiction. Dependence may be physical or psychological. Sudden withdrawal of such drug of dependence can result in withdrawal symptoms that are difficult to tolerate.

All drugs of abuse increase dopamine levels at different sites of the mesolimbic projections

Cns Stimulants:

Cocaine, amphetamines, and their analogs are CNS stimulants that produce euphoria and psychotomimetic effects, loss of inhibitions, and a feeling of being energized. Long-term abuse of these stimulants can result in changes in personality, paranoid behavior, depression, irritability, and even psychosis.

• Caffeine: Long-term intake of caffeine can cause dependence. Withdrawal symptoms like headache and lethargy can occur.
• Nicotine: It is an alkaloid present in tobacco and is a commonly used drug of dependence.
• Tobacco is used for smoking (as cigarettes) as well as by other routes (like nasal insufflation of snuff) and by chewing.