Drugs Acting On Central Nervous System Notes

Neurotransmitters And Central Nervous System

Neurotransmitters in the central nervous system (CNS) could be inhibitory, excitatory or both.

 

Read And Learn More: Pharmacology for Dentistry Notes

Neurotransmitters in central nervous system (CNS)

1. Inhibitory postsynaptic potential (IPSP) When an inhibitory transmitter binds and interacts with specific receptors on the postjunctional membrane, the membrane permeability to K⁺ or Cl^– increases.
2. Excitatory postsynaptic potential (EPSP) When an excitatory neurotransmitter binds and interacts with the specific receptors on the postjunctional membrane, the membrane permeability to cations increases.
3. Manifestations of CNS depression and stimulation

Sedatives And Hypnotics

A sedative is a drug that reduces excitement and calms the person. Hypnotic is a drug that produces sleep resembling normal sleep.

1. Sleep: The phases of sleep include nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is divided into stage 0, 1, 2, 3 and 4. Normally, about 50% of sleep time is spent in stage 2. Slow-wave sleep includes stage 3 and 4. REM sleep constitutes about 30% of the sleep time and lasts for 5–30 min in each cycle of sleep. Types of sleep disorders and their treatment are depicted in Table. Types of Sleep Disorders and Their Treatment
2. Classification of sedatives and hypnotics
   • Benzodiazepines (BZDs): Diazepam, lorazepam, clonazepam, clobazam, chlordiazepoxide, oxazepam, temazepam, midazolam, alprazolam, triazolam, flurazepam, nitrazepam
   • Barbiturates:
     • Long-acting: Phenobarbitone
     • Short-acting: Pentobarbitone
     • Ultra-short acting: Thiopentone
   • Nonbenzodiazepine hypnotics: Zolpidem, zopiclone, eszopiclone, zaleplon
   • Others: Melatonin, ramelteon

Benzodiazepines

All BZDs have a benzene ring fused to a seven-membered diazepine ring.

1. Sites of action Midbrain (ascending reticular formation), limbic system, brain stem, etc.
2. Mechanism of action BZDs facilitate action of gamma-aminobutyric acid (GABA) – they potentiate the inhibitory effects of GABA. BZDs have no GABA-mimetic action.
3. Pharmacological actions and therapeutic uses
   • Sedation and hypnosis: BZDs decrease the time required to fall asleep (sleep latency). The total sleep time is increased. They shorten all stages of NREM sleep except stage 2, which is prolonged. The duration of REM sleep is usually decreased. BZDs reduce night awakenings and produce refreshing sleep. At present, BZDs are preferred to barbiturates for treatment of short-term insomnia because:
     • They have a wide therapeutic index.
     • They cause near-normal sleep; and less rebound phenomena on withdrawal.
     • They produce minimal hangover effects (headache and residual drowsiness on waking).
     • They cause minimal respiratory depression.
     • They are less likely to cause tolerance and dependence when used for a short period.
     • They have no enzyme-inducing property; hence drug interactions are less.
     • They have a specific BZD receptor antagonist, flumazenil, for the treatment of overdosage.
     • Long-term use of BZDs for insomnia is not recommended because of the development of tolerance, dependence and hangover effects; but these drugs are ideal for occasional use by air travellers, shift workers, etc.
   • Anticonvulsant: Diazepam, lorazepam, clonazepam, clobazam, etc. have selective anticonvulsant effect. Intravenous (i.v.) diazepam/lorazepam is used to control life-threatening seizures in status epilepticus, tetanus, drug-induced convulsions, febrile convulsions, etc. Clonazepam is used in the treatment of absence seizures.
   • Diagnostic (endoscopies) and minor operative procedures: Intravenous BZDs are used because of their sedative–amnesic–analgesic and muscle-relaxant properties.
   • Preanaesthetic medication and general anaesthesia: These drugs are used as pre-anaesthetic medication because of their sedative–amnesic and anxiolytic effects. Hence, the patient cannot recall the perioperative events later. Intravenous diazepam, lorazepam, midazolam, etc. are combined with other CNS depressants to produce general anaesthesia.
   • Antianxiety (anxiolytic) effect: Some of the BZDs (diazepam, oxazepam, alprazolam, lorazepam, chlordiazepoxide, etc.) have selective antianxiety action at low doses. The anxiolytic effect is due to their action on the limbic system. Tolerance to the antianxiety action of BZDs develops only on prolonged use.
   • Muscle relaxants (centrally acting): They reduce skeletal muscle tone by inhibiting polysynaptic reflexes in the spinal cord. The relaxant effect of BZDs is useful in spinal injuries, tetanus, and cerebral palsy and to reduce spasms due to joint injury or sprain.
   • To treat alcohol-withdrawal symptoms: Long-acting BZDs, such as chlordiazepoxide and diazepam are used.
   • Conscious sedation
4. Pharmacokinetics BZDs are usually given orally or intravenously and occasionally by rectal route (diazepam) in children. The rate of absorption following oral administration is variable; absorption is erratic from the intramuscular (i.m.) site of administration; hence rarely used.
   1. They have a large volume of distribution. They have a short duration of action on occasional use because of rapid redistribution and, hence are free of residual (hangover) effects, even though the elimination half-life is long.
   2. BZDs are metabolized in the liver. Some of them produce active metabolites that have long half-lives; hence cumulative effects may be seen. The metabolites are excreted in urine. BZDs cross the placental barrier.
5. Adverse effects BZDs have a wide margin of safety. They are generally well tolerated. The common side effects are drowsiness, confusion, blurred vision, amnesia, disorientation, tolerance and drug dependence.
   1. Withdrawal after chronic use causes symptoms like tremors, insomnia, restlessness, nervousness and loss of appetite.
   2. Use of BZDs during labour may cause respiratory depression and hypotonia in newborns (floppy baby syndrome). In some patients, these drugs may produce paradoxical effects, i.e. convulsions and anxiety.

Important features of BZDs are given in Table.

Inverse Agonist (β-Carboline)

Its interaction with BZD receptors will produce anxiety and convulsions.

Benzodiazepine Antagonist (Flumazenil)

Flumazenil competitively reverses the effects of both BZD agonists (CNS depression) and BZD-inverse agonists (CNS stimulation). Flumazenil is not used orally because of its high first-pass metabolism. It is given by i.v. route and has a rapid onset of action.

Flumazenil is used in the treatment of BZD overdosage and to reverse the sedative effects of BZDs during general anaesthesia. It can also be used to reverse the hypnotic effect of zolpidem, zaleplon and eszopiclone. Adverse effects include confusion, dizziness and nausea. It may precipitate withdrawal symptoms (anxiety and convulsions) in independent subjects.

Barbiturates

All barbiturates are derivatives of barbituric acid. They are nonselective CNS depressants and act at many sites, the ascending reticular activating system (ARAS) being the main site.

1. Mechanism of action Barbiturates have GABA-facilitatory action – they potentiate the inhibitory effects of GABA. At high concentrations, barbiturates have a GABA-mimetic effect (i.e. barbiturates can directly increase Cl^– conductance into the neuron).

1. Pharmacological actions and uses
   • Sedation and hypnosis: Barbiturates were used in the treatment of insomnia. They decrease sleep latency, duration of REM sleep, and stages 3 and 4 of NREM sleep. They cause marked alteration of sleep architecture. At present, barbiturates are not recommended because:
     • They have a low therapeutic index.
     • They cause a rebound increase in REM sleep on stoppage of therapy.
     • They cause marked respiratory depression.
     • They produce marked hangover effects (headache and drowsiness the next day morning).
     • They cause a high degree of tolerance and drug dependence.
     • They are potent enzyme inducers and cause many drug interactions.
     • They have no specific antidote.
2. General anaesthesia (GA): Ultra-short-acting barbiturate (thiopentone) may be used for the induction of GA.
3. Anticonvulsant: Phenobarbitone has an anticonvulsant effect and is used in the treatment of status epilepticus and generalized tonic-clonic seizures (GTCS).
4. Adverse effects
   • The common side effects are drowsiness, confusion, headache, ataxia, hypotension and respiratory depression.
   • Hypersensitivity reactions like skin rashes, itching and swelling of the face may occur.
   • Tolerance develops to their sedative and hypnotic actions on repeated use.
   • Physical and psychological dependence develops on repeated use.
   • Prolonged use of phenobarbitone may cause megaloblastic anaemia by interfering with the absorption of folic acid from the gut.
   • They may precipitate attacks of acute intermittent porphyria; hence, barbiturates are contraindicated in porphyria.
   • Acute barbiturate poisoning: The signs and symptoms are drowsiness, restlessness, hallucinations, hypotension, respiratory depression, convulsions, coma and death.
     • Treatment of acute barbiturate poisoning
       1. Maintain airway, breathing and circulation.
       2. Maintain electrolyte balance.
       3. Gastric lavage – after stomach wash, administer activated charcoal that may enhance the elimination of phenobarbitone. Endotracheal intubation is performed before gastric lavage to protect the airway in unconscious patients.
       4. Alkaline diuresis – there is no specific antidote for barbiturates; the main treatment is alkaline diuresis. Intravenous sodium bicarbonate alkalinizes urine.
       5. Barbiturates are weakly acidic drugs. In alkaline urine, barbiturates exist in ionized form; so, they are not reabsorbed while passing through renal tubules and are rapidly excreted in urine.
       6. Haemodialysis is employed in severe cases.
5. Drug interactions Barbiturates are potent inducers of hepatic microsomal enzymes and reduce the effectiveness of coadministered drugs (for example oral contraceptives, oral anticoagulants, and oral hypoglycaemics).

Nonbenzodiazepine Hypnotics

They include zolpidem, zopiclone, zaleplon and eszopiclone. They have less potential for abuse than BZDs. They have less antianxiety, anticonvulsant and muscle-relaxant effects than BZDs. The effect on REM sleep is less as compared to BZDs.

1. Zolpidem: Zolpidem mainly produces a hypnotic effect – decreases sleep latency and increases duration of sleep time in insomnia.
   1. It produces near-normal sleep-like BZDs with minimal alteration in REM sleep; causes minimal hangover effects and rebound insomnia; less likely to produce tolerance and drug dependence; lacks anticonvulsant, antianxiety and muscle-relaxant effects.
   2. It is given orally, well absorbed, metabolized in the liver and excreted in the urine. It has a short duration of action and is used for short-term insomnia.
   3. The actions of zolpidem are antagonized by flumazenil. The common side effects are headache, confusion, nausea and vomiting.
2. Zopiclone: Zopiclone is orally effective and is used for short-term treatment of insomnia. It produces near-normal sleep like BZDs. The side effects are headache, drowsiness, GI disturbances and metallic taste.
   • Mechanism of action

• • • Zaleplon: It is useful in sleep-onset insomnia. It is the shortest-acting non-BZD hypnotic.
    • Eszopiclone: It is used orally for short- and long-term treatment of insomnia.
    • Melatonin: It is the hormone secreted by the pineal gland; involved in the maintenance of the sleep-wake cycle and circadian rhythm.
    • Ramelteon: It is a melatonin-receptor (MT₁ and MT₂) agonist, which can be used orally for the treatment of sleep-onset insomnia. It reduces sleep latency and prolongs the total duration of sleep. There is no rebound insomnia on withdrawal; it does not cause tolerance on chronic use. The important adverse effects are fatigue and dizziness.

General Anaesthetics

General anaesthesia refers to drug-induced reversible loss of consciousness and all sensations. The features of GA are:

1. Reversible loss of consciousness.
2. Reversible loss of sensation.
3. Analgesia and amnesia.
4. Muscle relaxation and the abolition of reflexes.

There is no single anaesthetic agent that can produce all the above effects. Hence, an anaesthetic protocol includes:

1. Premedication.
2. Induction of anaesthesia (for example propofol).
3. Maintenance of anaesthesia (N₂O⁺ isoflurane/halothane).
4. Skeletal muscle relaxation.
5. Analgesia – as premedication, during and after the operation.
6. Use of other drugs:
   • To reverse neuromuscular blockade.
   • To reverse the residual effects of opioids (naloxone) and BZDs (flumazenil).

Minimal alveolar concentration (MAC) is the minimum concentration of an anaesthetic in alveoli required to produce immobility in response to a painful stimulus in 50% of patients. It indicates the potency of inhalational general anaesthetics (N₂O > 100%; halothane 0.75%).

1. Mechanism of action of general anaesthetics The main site of action of anaesthetics is reticular formation, which normally maintains a state of consciousness. Most anaesthetics depress reticular formation by enhancing the activity of inhibitory transmitters like GABA (for example BZDs, barbiturates and propofol) and blocking the activity of excitatory transmitters (for example blockade of N-methyl-D-aspartate [NMDA] glutamate receptors by ketamine and nitrous oxide). Stages of general anaesthesia: Stages 1-4 are seen mainly with ether because of its slow action. Stage 2 is the most dangerous period. Surgical procedures are performed in stage 3. Induction aims to reach stage 3 as early as possible followed by maintenance anaesthesia and muscle relaxation.
   • Stages of Anaesthesia
2. Indications for general anaesthesia in dentistry In dental practice, the need for general anaesthesia is determined on an individual basis. It is indicated in:
   • Acute dentoalveolar abscess and severe pulpitis: It may be difficult to achieve adequate local anaesthesia in these conditions. Management of these conditions may require general anaesthesia.
   • Mentally challenged patients: In these patients, the conduct of dental procedures safely under local anaesthesia could be difficult.
   • Children: In small children where attempts to use local anaesthesia alone or with conscious sedation have been unsuccessful or the child does not cooperate, dental procedures need to be carried out under general anaesthesia.
   • Patients are allergic to local anaesthetics.
   • Extensive dental procedures.
3. General anaesthesia in dental practice Depending on the health status of the individual and the nature of the dental procedure to be undertaken, general anaesthesia when indicated can be administered as:
   • Dental chair anaesthesia (on an outpatient basis).
   • Daycare anaesthesia (patient is admitted and discharged on the same day) for oral surgical procedures lasting not more than 1 h.
   • Inpatient anaesthesia for extensive procedures.

Classification

Inhalational Anaesthetics

These are discussed under the following headings.

1. Gas/volatile liquid
2. Noninflammable/inflammable
3. Margin of safety
4. Induction and recovery
5. Skeletal-muscle relaxation
6. Analgesia
7. Sensitization of myocardium
8. Hepatotoxicity
9. Irritation of respiratory passages
10. Postoperative nausea and vomiting
11. Other points
    • The use of ether is obsolete.
    • Halothane sensitizes the myocardium to the arrhythmogenic effect of catecholamines.
    • The speed of induction and recovery depends on the solubility of the anaesthetic agent in blood and fat.
    • Anaesthetics with low blood solubility produce rapid induction and recovery (for example N₂O and desflurane).
    • Anaesthetics with high solubility in the blood produce slow induction and recovery (for example ether).
    • Desflurane, isoflurane and ether irritate respiratory passages and can induce cough.
    • The basis for combining halothane/isoflurane/sevoflurane and nitrous oxide:
      • The concentration (MAC) of halothane/isoflurane required to produce anaesthesia is reduced when given with N₂O because of the second gas effect. As the concentration of halothane/isoflurane required is reduced, the side effects of halothane/isoflurane (hypotension and respiratory depression) are reduced.
        • Second gas effect: N₂O rapidly diffuses, whereas halothane/isoflurane diffuses poorly (alveoli ↔ blood ↔ brain) into the blood. When these (halothane/isoflurane and N₂O) anaesthetics are administered simultaneously, halothane/isoflurane also enters the blood rapidly along with rapidly diffusible gas (N₂O). This is known as the ‘second gas effect’.
      • Because of the reduction in the dosage, recovery will be faster.
      • Halothane/isoflurane is a potent anaesthetic and poor analgesic, whereas N ₂O is a good analgesic and poor anaesthetic; hence, the combined effect of these two results in potent anaesthesia and good analgesia.
    • Comparative Features of Ether, Halothane and Nitrous Oxide
    • Comparative Features of Halogenated Anaesthetics (Fluorinated Anaesthetics)
    • Diffusion hypoxia: Nitrous oxide has low blood solubility – when the administration of N₂O is discontinued, it rapidly diffuses from the blood into alveoli and causes a marked reduction of PaO₂ in the alveoli resulting in hypoxia, which is known as diffusion hypoxia. It can be avoided by giving 100% O₂ for a few minutes immediately after N₂O is discontinued. Comparative features of halogenated anaesthetics are depicted in Table.

Parenteral General Anaesthetics

1. Inducing drugs
   • Propofol is available as a 1% emulsion for intravenous administration. Propofol is a commonly used, popular, rapidly-acting anaesthetic. Propofol acts on GABA receptors to increase chloride conductance and hyperpolarization of neurons thus producing CNS depression. It has a rapid onset and short duration of action; for long procedures, it can be given in repeated doses or as continuous i.v. infusion. It is highly bound to plasma protein; it crosses the placental barrier and can be used in pregnant women. It is metabolized in the liver and excreted rapidly in urine.
     • Induction of anaesthesia and recovery are rapid. Residual symptoms are less.
     • Most suitable for outpatient surgical procedures
     • No irritation of air passages; suitable for use in asthmatics.
     • Has an antiemetic effect, hence postoperative nausea and vomiting are rare.
     • Can be used for both induction and maintenance of anaesthesia.
     • Frequently used to sedate patients in intensive care unit (ICU) who are intubated.
     • Used in status epilepticus when not controlled by other drugs.
     • Causes respiratory depression and fall in BP.
     • Pain on injection occurs – can be reduced with lignocaine.
     • In high doses, can cause acidosis and a rise in blood lipid levels.
   • Thiopentone sodium is an ultra-short-acting barbiturate. It is a commonly used i.v. anaesthetic for induction of anaesthesia. It is highly lipid soluble, hence has a rapid onset and short duration (5–8 min) of action.
   • It is highly alkaline (pH 10.5–11), hence highly irritant. It should be prepared as a fresh solution before injection. It is injected as a 2.5% solution. After a single i.v. dose, it rapidly enters highly perfused organs like the brain, liver and heart and produces anaesthesia.
   • As the blood level of the drug falls rapidly, it diffuses out of the CNS into the blood and then to less-perfused organs like skeletal muscle and adipose tissue. This redistribution results in the termination of drug action. Repeated doses will result in accumulation and delayed recovery.
     • Uses
       1. Thiopentone sodium can be used for induction of anaesthesia.
       2. It is occasionally used as an anticonvulsant in cases not controlled by other drugs.
     • Advantages of thiopentone
       1. Rapid induction of anaesthesia and rapid recovery.
       2. Does not sensitize the myocardium to circulating catecholamines.
     • Disadvantages/adverse effects of thiopentone
       1. Depresses the respiratory centre.
       2. Depresses the vasomotor centre and myocardium.
       3. Poor analgesic.
       4. Poor muscle relaxant.
       5. Causes laryngospasm
       6. Accidental intra-arterial injection causes vasospasm and gangrene of the arm.
       7. It can precipitate acute intermittent porphyria, hence contraindicated in susceptible individuals (absolute contraindication).
   • Etomidate It is an i.v. anaesthetic used for induction – has a rapid onset and short duration of action. It causes minimal cardiovascular and respiratory depression.
2. Slow-acting drugs
   • Ketamine It produces ‘dissociative anaesthesia’, which is characterized by sedation, amnesia, marked analgesia, unresponsiveness to commands and dissociation from the surroundings.
   • It acts by blocking n-methyl-d-aspartate (NMDA) type of glutamate receptors. It is commonly given by i.v. route; other routes are i.m., oral and rectal. Ketamine has good analgesic effect. It causes bronchodilation, suitable for use in asthmatics.
   • Ketamine causes sympathetic stimulation – heart rate, BP, cardiac output and skeletal muscle tone are usually increased. It is used in patients with hypovolaemia. It is well tolerated by children.
     • Site of action: Cortex and subcortical areas. Ketamine is highly lipid soluble, and rapidly enters highly perfused organs like the brain, liver and heart; later it redistributes to less perfused organs. It is metabolized in the liver, and excreted in urine and bile.
     • Uses
       1. For operations on the head, neck and face.
       2. For dressing burn wounds.
       3. Well suited for children/asthmatics undergoing short procedures.
     • Adverse effects and contraindications
       1. Increases BP and heart rate, hence is contraindicated in patients with hypertension and ischaemic heart disease.
       2. Increases intracranial pressure.
       3. Causes the emergence of delirium and hallucinations.
3. Benzodiazepines BZDs are slow-acting parenteral anaesthetics. They include diazepam, lorazepam and midazolam. The use of large doses delays recovery and prolongs amnesia. They have a poor analgesic effects. They do not cause postoperative nausea and vomiting. The effects of BZDs can be reversed by flumazenil. They are useful for angiography, endoscopies, fracture reduction, etc.
4. Opioid analgesics These include fentanyl, alfentanil, sufentanil and remifentanil. They are potent analgesics and can be used along with anaesthetics – to decrease the requirement of anaesthetic.
   • Complications of general anaesthesia
     • CVS: Hypotension, cardiac arrhythmias, cardiac arrest
     • Respiratory depression, aspiration pneumonia, apnoea
     • CNS: Convulsions, persistent sedation
     • GIT: Nausea, vomiting, hepatotoxicity
     • Nephrotoxicity
     • Malignant hyperthermia

Preanaesthetic Medication

It is the use of drugs before administration of anaesthetics to make anaesthesia more pleasant and safe.

1. Objectives/aims of premedication
   • To reduce anxiety and apprehension: BZDs like diazepam, lorazepam or midazolam are preferred because of their sedative, amnesic, calming, anxiolytic effects and a wide margin of safety. They reduce anxiety by acting on the limbic system.
   • To prevent vagal bradycardia and to reduce salivary secretions caused by anaesthetics: Antimuscarinic agents such as atropine or glycopyrrolate are used to prevent vagal bradycardia and hypotension. They also prevent laryngospasm by reducing respiratory secretions. Glycopyrrolate is preferred because it is potent, does not cause CNS effects and causes less tachycardia.
   • To relieve pre- and postoperative pain: Opioid analgesics such as morphine, pethidine or fentanyl may be used to relieve pain. The limitations of opioids are respiratory depression, hypotension, nausea, vomiting, constipation, biliary spasm, and bronchospasm in asthmatics. NSAIDs like diclofenac can also be used.
   • For antiemetic effect: Metoclopramide, domperidone or ondansetron may be used to control vomiting. Acute dystonias and extrapyramidal symptoms (EPS) are the main side effects of metoclopramide; domperidone rarely produces EPS. 5-HT₃ antagonists like ondansetron are the preferred antiemetic as they rarely cause adverse effects and are well tolerated.
   • To prevent acid secretion and stress ulcers: H₂-Blocker such as ranitidine or proton-pump inhibitors like omeprazole may be used to reduce gastric acid secretion, especially before prolonged surgery.
   • To hasten gastric emptying before emergency surgery: Metoclopramide or domperidone may be used. These are prokinetic drugs – that increase the tone of the lower oesophageal sphincter and accelerate gastric emptying, thus preventing aspiration pneumonia.

Conscious Sedation

Conscious sedation is a level of CNS depression where a patient does not lose consciousness but can communicate and cooperate during the procedure/treatment.

1. Indications
   • Uncooperative patients.
   • Anxious patients.
   • Emotionally compromised patients.
2. Conscious sedation should be avoided in:
   • Chronic obstructive pulmonary disease.
   • Pregnancy.
   • Prolonged surgery.
   • Psychoses.
3. Drugs used
   • Benzodiazepines
     • Diazepam is the most commonly used drug for conscious sedation. Small doses (1–2 mg) of diazepam is administered intravenously slowly. It can also be administered orally.
     • Midazolam is a short-acting BZD given intravenously.
     • Temazepam is given orally. It is safe and has better patient compliance.
   • Nitrous oxide + oxygen: Nitrous oxide is given by inhalational route along with 100% oxygen.
   • Propofol (i.v. infusion), fentanyl (i.v.), etc. can also be used for conscious sedation.
4. Precautions
   • Written informed consent should be obtained from the patient prior to the procedure.
   • Conscious sedation should be administered by trained personnel.
   • Constant monitoring of the vital signs should be done during and after the procedure.
   • The procedure should be documented. Postoperative instructions should be in written form.
   • Equipment and emergency drugs should be kept ready to tackle any emergency.
   • The patient should be escorted by an attendant.

Local Anaesthetics

Local anaesthetics (LAs) are the drugs that, when applied topically or injected locally, block nerve conduction and cause reversible loss of all sensation in the part supplied by the nerve. The order of blockade of nerve function proceeds in the following manner – pain, temperature, touch, pressure and finally skeletal muscle power.

Chemistry

LAs are weak bases. They consist of three parts:

1. hydrophilic amino group,
2. lipophilic aromatic group and
3. intermediate ester or amide linkage.

• Classification of local anaesthetics

1. According to clinical use
   • Surface anaesthetics
     • Cocaine, lignocaine, tetracaine, benzocaine, oxethazaine, proparacaine, butylaminobenzoate, dyclonine.
   • Injectable anaesthetics
     • Short-acting with low potency: Procaine, chloroprocaine.
     • Intermediate-acting with intermediate potency: Lignocaine, mepivacaine, prilocaine, articaine.
     • Long-acting with high potency: Tetracaine, bupivacaine, dibucaine, ropivacaine.
2. According to structure
   • Esters: Cocaine, procaine, chloroprocaine, benzocaine, tetracaine.
   • Amides: Lignocaine, mepivacaine, bupivacaine, prilocaine, articaine, ropivacaine.

1. Mechanism of action LAs act on voltage-sensitive Na⁺ channels. Sodium channels exist in resting, open and inactivated states (resting → open → inactivated state). The channels have to recover from the inactivated state to the resting state before they can be opened in response to an impulse. The LAs in ‘unionized’ form easily penetrate the nerve sheath and axon membrane. Within the axoplasm, the molecules become ‘ionized’ and block the voltage-gated Na⁺ channels.

1. • A blockade is frequency-dependent.
   • The action of local anaesthetic is pH dependent and the penetrability of LA is increased at alkaline pH (i.e. when the unionized form is more). Penetrability is very poor at the acidic pH of tissues.
   • In infected tissues, there is a low pH, which causes ionization of the drug. This reduces penetration of LA through the cell membrane, thus decreasing the effectiveness of LAs. Therefore, LAs are less effective in inflamed and infected areas.
   • Diameter of nerve fibres: LAs block small fibres first followed by larger fibres.
   • Myelinated fibres are blocked earlier than nonmyelinated nerves of the same diameter.
   • Sensory fibres are blocked earlier than motor fibres because of their high firing rate and longer duration of action potential.
   • Fibres in the centre are blocked later than ones located in the circumference of the nerve bundle.
2. Factors affecting LA action
   • pK_a: Higher the pK_a, more is the ionized fraction of the drug at physiological pH. Hence, onset of action is slow and vice versa; e.g. the pKa of procaine is 9.1 – it has slow onset of action, whereas the pKa of lignocaine is 7.7 – it has rapid onset of action. Although pK_a of chloroprocaine is 9.1, it has a rapid onset of action.
   • Degree of plasma protein binding: Higher the plasma protein binding, longer the duration of action of the drug, e.g. procaine is poorly bound to plasma proteins, hence has a short duration of action, whereas bupivacaine is highly plasma protein bound and has longer duration of action.
   • Rate of diffusion from the site of administration: It depends on the initial concentration gradient of the drug. Higher the concentration, rapid is the onset of action.
   • Lipid solubility: Higher the lipid solubility, more is the potency of the drug, e.g. lignocaine is more potent than procaine as it is more lipid soluble.
   • Presence of vasoconstrictor: Prolongs the duration of local anaesthetics. The commonly used vasoconstrictor with local anaesthetics is adrenaline. Others are phenylephrine, felypressin, etc.
3. Combination of vasoconstrictor with local anaesthetic The addition of a vasoconstrictor (for example adrenaline) to the LA has the following advantages:
   • Slow absorption from the local site which results in prolonged duration of action of local anaesthetics.
   • Decreased bleeding in the surgical field.
   • Slow absorption of LA reduces its systemic toxicity.
     • Disadvantages and contraindications of combining vasoconstrictor with LA:
       1. Intense vasospasm and ischaemia in tissues with end arteries may cause gangrene of the part (example use of vasoconstrictors is contraindicated in these sites.
       2. Absorption of adrenaline can cause systemic toxicity – tachycardia, palpitation, rise of BP and precipitation of angina or cardiac arrhythmias. Hence, combined preparation (LA with adrenaline) should be avoided in patients with hypertension, congestive cardiac failure (CCF), arrhythmias, ischaemic heart disease and uncontrolled hyperthyroidism.
       3. May delay wound healing by reducing blood flow to the affected area.
       4. Felypressin: It is a synthetic analogue of vasopressin. It can also be used with local anaesthetic to prolong the duration of action. It may be safely used with a local anaesthetic in patients with hyperthyroidism, cardiovascular diseases and those receiving monoamine oxidase (MAO) inhibitors or tricyclic antidepressants. It is contraindicated in pregnant patients because of its oxytocic (uterine stimulant) action on the uterus.
4. Pharmacological actions
   • Nervous system
     • Peripheral nerves: Autonomic fibres are blocked earlier than somatic fibres. A sensation of pain disappears first followed by temperature, touch, pressure and motor functions.
     • CNS: Most of the LAs cross the blood-brain barrier (BBB) – initially, they cause CNS stimulation and then depression in higher doses. They cause excitement, tremor, twitching, restlessness and convulsions. Large doses can cause respiratory depression, coma and death.
   • Cardiovascular system (CVS)
     • Heart: LAs, by blocking Na+ channels, decrease abnormal pacemaker activity, contractility, conductivity, excitability, heart rate, and cardiac output and increase the effective refractory period.
       1. At higher concentrations, i.v. administration of LAs may precipitate cardiac arrhythmias.
       2. Bupivacaine is more cardiotoxic than other LAs – and may cause cardiovascular collapse and death.
       3. Lignocaine decreases automaticity and is useful in ventricular arrhythmias.
     • Blood vessels: Local anaesthetics produce hypotension due to vasodilatation and myocardial depression.
5. Pharmacokinetics Most of the ester-linked LAs are rapidly metabolized by plasma cholinesterase, whereas amide-linked drugs are metabolized mainly in the liver. LAs (procaine, lignocaine, etc.) are not effective orally because of high first-pass metabolism. In liver diseases, the metabolism of lignocaine may be impaired; hence, the dose must be reduced accordingly.
   • Comparative features of esters and amides are shown in Table.
   • Comparative Features of Procaine and Lignocaine
6. Adverse effects
   • CNS: LAs initially cause CNS stimulation followed by depression. They are restlessness, tremor, headache, drowsiness, confusion and convulsions followed by respiratory depression, coma and death.
   • CVS: Bradycardia, hypotension, cardiac arrhythmias, rarely cardiovascular collapse and death. Bupivacaine is highly cardiotoxic.
   • Allergic reactions: These are skin rashes, itching, erythema, urticaria, wheezing, bronchospasm and rarely anaphylactic reaction. The incidence of allergic reactions is higher with ester-linked LAs than with amide-linked LAs.
   • Mucosal irritation (cocaine) and methaemoglobinaemia (prilocaine) may be seen.
   • Methylparaben, a preservative in LA preparation, may cause allergic reactions.
   • Adverse effects due to vasoconstrictors.

Some Important Local Anaesthetics

1. Cocaine It is an alkaloid that has excellent surface anaesthetic but is rarely used because of its addiction liability.
   • Properties of Local Anaesthetics
     
     
     
     • Chloroprocaine has a pKa of 9.1 but has a rapid onset of action.
     • Procaine is a prototype drug for esters. It is rarely used now because of the availability of better agents.
     • Tetracaine An ester type of LA, it has a long duration but slow onset of action. It is useful for spinal anaesthesia because of its longer duration of action. It is mainly used as a surface anaesthetic for the eye, nose and upper respiratory tract.
     • Lignocaine is a prototype agent for amides. It is a very popular anaesthetic used widely for topical application, infiltration, spinal and conduction block anaesthesia. It is also available as a patch – and can be used to control severe pain of postherpetic neuralgias.
     • Bupivacaine is a widely used LA. It is potent and has a long duration of action. It produces more sensory than motor blockade; hence, it is very popular for obstetric analgesia. It is highly cardiotoxic and may precipitate ventricular arrhythmias.
     • Levobupivacaine: It is similar to bupivacaine but less cardiotoxic and less likely to cause seizures.
     • Ropivacainev cIt is less potent and less cardiotoxic than bupivacaine. Its duration of action is similar to bupivacaine. It is used for both epidural and regional anaesthesia. It is more selective for sensory fibres than motor fibres, hence used for obstetric analgesia.
     • Prilocaine bIt is an amide type of LA. It has intermediate onset and duration of action. It has poor vasodilatory effect, hence can be used without a vasoconstrictor. It is mainly used for infiltration and i.v. regional anaesthesia.
     • Articaine It is an amide local anaesthetic used in dentistry for infiltration and nerve block anaesthesia. It acts rapidly and has a duration of action of 1 h. It is expensive. It is also available with adrenaline. The adverse effects are methaemoglobinaemia, paraesthesia and neuropathies.
     • Eutectic mixture (EMLAs – a eutectic mixture of local anaesthetics: Lignocaine (2.5%) and prilocaine [2.5%]) The melting point of the mixture is less than that of either compound alone. It can anaesthetize intact skin. EMLA has to be applied 1 h before the procedure and is used for dermal anaesthesia during venesection and skin graft procedures. It should not be used on mucous membranes or abraded skin. It is contraindicated in patients with methaemoglobinaemia and infants.
     • Dibucaine It is a very potent, highly toxic and longest-acting LA. It is rarely used for spinal anaesthesia; is also available for topical application on mucous membrane and skin.
     • Benoxinate It is a surface anaesthetic; useful for corneal anaesthesia.
     • Benzocaine and butyl aminobenzoate Surface anaesthetics; cause minimal systemic toxicity; available as ointment and lozenges; used for haemorrhoids, anal fissure and sore throat.
     • Oxethazaine It is a topical anaesthetic and is used to anaesthetize gastric mucosa. It produces symptomatic relief in gastritis. It is available in combination with antacids.
     • Dyclonine It is used topically to relieve pain of radiation/chemotherapy-induced oral mucositis.

Techniques Of Local Anaesthesia

1. Surface anaesthesia (topical anaesthesia) LA is applied on the abraded skin and mucous membrane of oral cavity, nose, eyes, throat, upper respiratory tract, oesophagus, urethra, ulcers, burns, etc. Motor function is intact. Tetracaine 2%, lignocaine 2%–10%, benzocaine 1%–2%, etc. are used for topical application. Surface anaesthetics are available as solution, ointment, gel, jelly, patch, cream, spray, lozenges, etc.
   • Methods of Administration and Uses of Local AnaestheticsAddition of adrenaline does not prolong the duration of surface anaesthesia because of poor penetration. Topical anaesthetics are useful before injecting a local anaesthetic, subgingival and periodontal scaling.
2. Infiltration anaesthesia Local anaesthetic is injected directly into tissues to be operated; it blocks sensory nerve endings. The most frequently used LAs for infiltration are lignocaine (0.5%–1%), articaine, procaine (0.5%–1%) and bupivacaine (0.125%–0.25%). Addition of adrenaline to LA (1:50,000–250,000) prolongs the duration of anaesthesia. Infiltration anaesthesia is suitable only for small areas. The main disadvantage of infiltration anaesthesia is the requirement of large amounts of the drug to anaesthetize relatively small area. It can be used for drainage of an abscess, gingivectomy, excision of small swelling, suturing of cut wounds, before root canal treatment (interproximal papillary infiltration), etc. Infiltration anaesthesia is contraindicated, if there is local infection and clotting disorders.
3. Conduction block
   • Field block anaesthesia It is achieved by injecting the local anaesthetic near the apex of the tooth – blocks larger terminal nerve endings at the apex. For example, LA is injected into the maxillary region above the apex of tooth to be treated to produce field block. This technique is also used in case of minor procedures of scalp, anterior abdominal wall, upper and lower extremities in which a smaller dose produces larger area of anaesthesia.
   • Nerve block anaesthesia LA is injected very close to or around the peripheral nerve or nerve plexuses. It produces larger areas of anaesthesia than field block.
     • Maxillary nerve block: For palatal, buccal and pulpal procedures in one quadrant.
     • Anterior superior alveolar nerve block: Management of anterior teeth in one quadrant.
     • Middle superior alveolar nerve block: For procedures involving premolars in one quadrant.
     • Inferior alveolar nerve block: Management of multiple mandibular teeth in one quadrant.
     • Buccal nerve block: To anaesthetize buccal soft tissue in the mandibular molar region.
     • In nerve block anaesthesia, the requirement of LA is less than that of field block and infiltration anaesthesia.
   • Complications of local anaesthesia In addition to drug-related adverse effects mentioned above, other complications are:
   • Paraesthesia – resulting in trauma to soft tissues due to biting of lips and cheek.
   • Pain due to nerve injury and haematoma.
   • Facial nerve paralysis may occur following nerve block. Patient should be reassured that it is temporary.
4. Spinal anaesthesia It is one of the most popular forms of anaesthesia. Local anaesthetic is injected into the subarachnoid space to anaesthetize spinal roots.
   • Site of injection The anaesthetic is injected into the space between L_2-3and L3-4 below the lower end of the spinal cord. The level of anaesthesia is influenced by site of injection, amount of fluid injected, force of injection, specific gravity of the drug solution (hyperbaric [in 10% glucose], hypobaric [in distilled water] or isobaric) and position of the patient – lying prone/lateral or tilted with head-down position.
   • LAs used for spinal anaesthesia They are lignocaine, tetracaine, bupivacaine, etc. Addition of adrenaline to spinal anaesthetic increases the duration or intensity of block.
     • Uses Spinal anaesthesia can be used for surgical procedures below the level of umbilicus, i.e. lower limb surgery, caesarean section, obstetric procedures, surgery on perineum, appendectomy, etc.
   • Complications
     • Headache is due to leakage of CSF and can be reduced by using very fine needle.
     • Hypotension is due to blockade of sympathetic vasoconstrictor fibres to blood vessels. Venous return to the heart is reduced due to paralysis of skeletal muscles in the legs. Hypotension is treated by raising the foot-end and with sympathomimetics such as ephedrine, mephentermine and phenylephrine.
     • Respiratory paralysis: It is due to paralysis of intercostal muscles. Respiratory failure may occur due to respiratory centre ischaemia as a result of hypotension.
     • Septic meningitis and nerve injury are extremely rare at present because of good anaesthetic practice.
     • Postoperative urinary retention may occur.
   • Contraindications Spinal anaesthesia should not be used in children, vertebral abnormalities, sepsis in the region of lumbar puncture site, hypotension and shock.
5. Epidural anaesthesia LA is injected into epidural space, where it acts on spinal nerve roots. Lignocaine and bupivacaine are commonly used. It is safer, but the technique is more difficult than spinal anaesthesia. Epidural anaesthesia is slower in onset than spinal anaesthesia. It requires a much larger amount of the drug. It is useful in obstetric analgesia.

Drug Interactions

1. Lignocaine × propranolol: Propranolol by reducing hepatic blood flow, impairs the clearance of lignocaine, which may result in toxicity.
2. Procaine × sulfonamides: Procaine is hydrolysed to PABA – reduces the effect of sulfonamides.
3. Lignocaine with adrenaline × tricyclic antidepressants: Can precipitate hypertensive crisis.
4. Lignocaine with adrenaline × propranolol: Dangerous rise in BP due to unopposed alpha action of adrenaline.

Alcohols (Ethanol And Methanol)

The actions of alcohol are depicted.

• Ethyl alcohol follows zero-order kinetics of elimination.
• In chronic alcoholics, increased amount of toxic metabolite of paracetamol is formed as a result of induction of its metabolizing enzyme, CYP2E1.
• As alcohol is present in exhaled air, it can be detected by a breath analyser.

1. Therapeutic uses of alcohol
   • Antiseptic: 70% alcohol is used as an antiseptic on skin before giving injections and surgical procedures. Its antiseptic efficacy decreases above 90%. It should not be used on open wounds, mucosa and ulcers, as it is highly irritant. Not useful for disinfecting instruments as it promotes rusting.
   • Trigeminal and other neuralgias: Injection of alcohol directly into nerve trunk relieves pain by destroying them.
   • Prevent bedsores: Alcohol is used locally to prevent bedsores in bedridden patients.
   • Methanol poisoning: Ethanol competes with methanol for metabolic enzymes and saturates them. Hence, it prevents the formation of toxic metabolites of methanol (formaldehyde and formic acid).
   • Fever: Alcoholic sponges are useful to reduce body temperature.

Acute Ethanol Overdosage (Acute Alcohol Intoxication)

The signs and symptoms of acute alcohol intoxication are drowsiness, nausea, vomiting, ataxia, hypotension, respiratory depression, hypoglycaemia, etc.

• Treatment It is a medical emergency. The main aim of therapy is to prevent severe respiratory depression and aspiration of vomitus.
  • Maintain Airway, Breathing, Circulation, Fluid and Electrolyte balance; Gastric lavage if necessary.
  • Intravenous Glucose to correct hypoglycaemia.
  • Thiamine is administered as i.v. infusion in glucose solution.
  • HaemoDialysis helps to hasten the recovery.

Withdrawal Syndrome

Sudden reduction/stoppage of alcohol in chronic alcoholics results in alcohol withdrawal syndrome. It manifests as restlessness, tremors, insomnia, nausea, vomiting, hallucinations, delirium, convulsions and collapse.

• Treatment of alcohol withdrawal syndrome

1. BZDs (diazepam, chlordiazepoxide, etc.) are used to control anxiety, tremor, palpitation, sleep disturbances, confusion and convulsions associated with alcohol withdrawal.
2. Psychological support.

Chronic Alcoholism

Treatment of chronic alcoholism.

1. Psychotherapy, occupational therapy and rehabilitation.
2. Drug treatment of chronic alcoholism

Disulfiram (alcohol aversion therapy): It causes aversion to alcohol. Disulfiram inhibits aldehyde dehydrogenase and causes accumulation of acetaldehyde in blood and tissues (acetaldehyde syndrome).

• The signs and symptoms include nausea, vomiting, flushing, headache, sweating, tachycardia, palpitation, breathlessness, chest pain, hypotension, hypoglycaemia, confusion, shock and even death.
• This reaction is unpleasant; hence, the person on disulfiram develops aversion to alcohol. Drugs like metronidazole, griseofulvin and cefoperazone also have disulfiram-like action and produce similar reaction with alcohol.

Doctors should warn the patient not to take alcohol when they are on the above-mentioned drugs.

• • Naltrexone (opioid antagonist): It reduces alcohol craving and helps to maintain abstinence.
  • Acamprosate: It activates GABA receptors and reduces relapse.
  • Ondansetron (5-HT₃ antagonist): It reduces alcohol consumption.
  • Topiramate: It decreases craving for alcohol.

Methanol Poisoning (Methyl Alcohol Poisoning)

This occurs when methylated spirit is consumed or when liquor is adulterated with methyl alcohol. Methanol is a mild CNS depressant. It is metabolized to formaldehyde and formic acid which, in turn, cause metabolic acidosis and injury to the retina. The signs and symptoms of methanol poisoning are nausea, vomiting, abdominal pain, headache, vertigo, confusion, hypotension, convulsions and coma. Metabolic acidosis is due to formic acid, which also causes dimness of vision, retinal damage and blindness.

• Treatment

1. Patient is kept in a dark room to protect the eyes from light.
2. Maintain airway, breathing and circulation.
3. Gastric lavage is done after endotracheal intubation.
4. Intravenous sodium bicarbonate is given to correct acidosis and to prevent retinal damage.
5. Ethanol (10%) is administered via nasogastric tube. Ethanol competes with methanol for metabolic enzymes and saturates them, thus preventing formation of toxic metabolites – formaldehyde and formic acid. Methanol is excreted unchanged in urine and breath.
6. Fomepizole, an alcohol dehydrogenase inhibitor, is the preferred agent for the treatment of methanol poisoning. CNS depression is rare with fomepizole as compared to ethanol.
7. Calcium leucovorin is administered intravenously(folate adjuvant therapy) to enhance metabolism of formate, thereby decreasing its levels.
8. Haemodialysis is done to promote the excretion of methanol and its toxic metabolites.

Antiepileptic Drugs

Epilepsy is a Greek word that means convulsions. Epilepsy is a disorder of brain function characterized by paroxysmal cerebral dysrhythmia. Major types of epilepsies are shown below.

1. Generalized seizures
   • Generalized tonic–clonic seizures (GTCS; grand mal epilepsy): It is characterized by the following sequence of symptoms: Aura–epileptic cry–loss of consciousness–fall to the ground–tonic phase–clonic phase–period of relaxation– postepileptic automatism with confusional states.
   • Absence seizures (petit mal epilepsy): It is characterized by sudden onset of staring, unresponsiveness with momentary loss of consciousness.
   • Myoclonic seizures: It consists of single or multiple sudden, brief, shock-like contractions.
2. Partial seizures
   • Simple partial seizures (SPS): The manifestations depend on the region of cortex involved. There may be convulsions (focal motor symptoms) or paraesthesia (sensory symptoms) without loss of consciousness.
   • Complex partial seizures(CPS; temporal lobe epilepsy, psychomotor epilepsy): It is characterized by aura–amnesia–abnormal behaviour and automatism with impaired consciousness.
3. Chemical classification of antiepileptic drugs
   • Hydantoins: Phenytoin, fosphenytoin.
   • Barbiturate: Phenobarbitone.
   • Iminostilbenes: Carbamazepine, oxcarbazepine.
   • Carboxylic acid derivatives: Sodium valproate, divalproex.
   • Succinimide: Ethosuximide.
   • BZDs: Diazepam, lorazepam, clonazepam, clobazam.
   • Others: Lamotrigine, topiramate, gabapentin, pregabalin, vigabatrin, zonisamide, levetiracetam.
   • Clinical classification of antiepileptic drugs The classification of antiepileptic drugs is presented in Table.
   • Antiepileptic Drugs: Clinical Classification
4. Mechanism of action of antiepileptic drugs has been depicte

Phenytoin (Diphenylhydantoin)

Phenytoin is one of the most commonly used antiepileptic drugs. It has a selective antiepileptic effect and does not produce significant drowsiness.

1. Mechanism of action Phenytoin acts by stabilizing neuronal membrane and prevents spread of seizure discharges. The sodium channels exist in three forms: resting, activated and inactivated states. Phenytoin delays recovery of Na⁺ channels from inactivated state, thereby reduces neuronal excitability and inhibits high-frequency firing. At high concentrations, phenytoin inhibits Ca²⁺ influx into the neuron, reduces glutamate levels and increases responses to GABA.

1. Pharmacokinetics Phenytoin is absorbed slowly through the GI tract, widely distributed and highly (about 90%) bound to plasma proteins. It is almost completely metabolized in the liver by hydroxylation and glucuronide conjugation.
2. Repeated administration of phenytoin causes enzyme induction and increases the rate of metabolism of coadministered drugs.
3. Phenytoin exhibits dose-dependent elimination, i.e. at low concentration (<10 mcg/mL), elimination occurs by first-order kinetics and plasma half-life is 10–24 h; as the rate of administration increases, the metabolizing enzymes get saturated, kinetics changes to zero order and plasma half-life increases to 60 h; the plasma concentration increases markedly with slight increase in dose resulting in toxicity. Hence, therapeutic monitoring of phenytoin is essential for adjustment of dosage.
   • Uses Phenytoin is used for the treatment of
     • GTCS (grand mal epilepsy).
     • Partial seizures.
     • Trigeminal and other neuralgias.
     • Status epilepticus: Phenytoin is administered intravenously in normal saline (it precipitates in glucose).
   • Adverse effects Phenytoin has dose-dependent toxicity. The adverse effects are:
     • Hypertrophy and Hyperplasia of gums (due to defect in collagen catabolism) – seen on chronic therapy and can be minimized by proper oral hygiene.
     • Hypersensitivity reactions include skin rashes, neutropaenia and rarely Hepatic necrosis.
     • Hirsutism – due to increased androgen secretion.
     • Hyperglycaemia – due to decreased insulin release.
     • Megaloblastic anaemia – due to folate deficiency.
     • Osteomalacia – due to increased metabolism of vitamin D.
     • Hypocalcaemia – due to decreased absorption of Ca2+ from the gut.
     • Fetal Hydantoin syndrome – cleft lip, cleft palate, digital Hypoplasia, etc. due to the use of phenytoin during pregnancy.

At high concentrations, phenytoin may cause the following side effects:

1. CNS: Vestibulocerebellar syndrome – vertigo, ataxia, tremor, headache, nystagmus, psychological disturbances, etc. occur on chronic therapy.
2. CVS: Hypotension and cardiac arrhythmias may occur on i.v. administration.
3. GIT: Nausea, vomiting and dyspepsia can be minimized by giving phenytoin after food.

Fosphenytoin

It is a prodrug of phenytoin, which is converted to phenytoin by phosphatases. Dose of fosphenytoin is expressed as phenytoin equivalents (PE). It is available for i.m. and i.v. administration. Fosphenytoin can be administered in normal saline or glucose. It has significantly less irritant effect on the veins than phenytoin.

It is preferred to phenytoin in status epilepticus because of the above-mentioned advantages. The rate of i.v. infusion should not exceed 150 mg PE/minute. Hypotension and cardiac arrhythmias may occur with rapid administration.

Carbamazepine (Iminostilbene)

Carbamazepine is chemically related to tricyclic antidepressants (TCAs).

1. Mechanism of action Like phenytoin, carbamazepine slows the rate of recovery of Na+ channels from inactivation, thereby reducing the neuronal excitability.
2. Pharmacokinetics Carbamazepine is absorbed slowly and erratically from GIT, binds to plasma proteins, is well distributed in the body including the cerebrospinal fluid (CSF) and metabolizes in liver. Repeated use causes enzyme induction and reduces the effectiveness of the drug itself (autoinduction) as well as that of valproate, phenytoin, lamotrigine, topiramate, oral contraceptive (OC) pills, etc.
3. Adverse effects The common adverse effects of carbamazepine include sedation, drowsiness, vertigo, ataxia, diplopia, blurred vision, nausea, vomiting and confusion. Hypersensitivity reactions are skin rashes, eosinophilia, lymphadenopathy and hepatitis. Rarely, it causes bone marrow depression with neutropenia, aplastic anaemia and agranulocytosis. On chronic therapy, it may cause water retention due to the release of antidiuretic hormone (ADH).
4. Uses
   • Carbamazepine is one of the most commonly used antiepileptic drug. It is the drug of choice in GTCS and partial (SPS and CPS) seizures.
   • Carbamazepine is the drug of choice in the treatment of trigeminal and other neuralgias. The other drugs useful are phenytoin, gabapentin, TCAs (amitriptyline), etc.
   • Other treatment options are surgical division, cryosurgery, injection of alcohol or phenol in close proximity to nerve or ganglia. It is not effective for diabetic neuropathy.
   • Carbamazepine is used in the treatment of acute mania and bipolar disorder.

Oxcarbazepine (Iminostilbene)

Oxcarbazepine is an analogue of carbamazepine. Mechanism of action and therapeutic uses are similar to carbamazepine. It is a prodrug and is converted to active form after administration. Its enzyme-inducing property is much less; hence drug interactions are very few. It is less potent and less toxic than carbamazepine.

Phenobarbitone (Barbiturate)

Phenobarbitone is a barbiturate and was widely used as an antiepileptic drug. Its use has declined because of availability of safer drugs. It acts by potentiating GABA activity. Phenobarbitone is absorbed slowly but completely after oral administration; about 50% is bound to plasma proteins. Repeated administration causes enzyme induction and reduces the effectiveness of coadministered drugs.

1. Adverse effects The most common side effect of phenobarbitone is sedation, but tolerance develops gradually with continued administration. The other side effects are nystagmus, ataxia, confusion, megaloblastic anaemia and skin rashes. On chronic therapy, it may cause behavioural disturbances with impairment of memory in children.
2. Uses Phenobarbitone is effective in GTCS and partial seizures. It is the cheapest antiepileptic drug. It is also useful in the prophylactic treatment of febrile convulsions. In status epilepticus, phenobarbitone is injected intravenously when convulsions are not controlled with diazepam and phenytoin.

Ethosuximide (Succinimide)

It is effective for the treatment of absence seizures. It acts by inhibiting T-type Ca2+ current in thalamic neurons. It is completely absorbed after oral administration. The common side effects are GI disturbances like nausea, vomiting and anorexia. The other side effects are headache, hiccough, eosinophilia, neutropenia, thrombocytopenia with bone marrow depression and rarely skin rashes.

Valproic Acid (Sodium Valproate): Carboxylic Acid Derivative

Sodium valproate is a broad-spectrum antiepileptic drug.

1. Mechanism of action
   • Like phenytoin and carbamazepine, valproate delays the recovery of Na+ channels from inactivation.
   • Like ethosuximide, it blocks T-type Ca²⁺ current in thalamic neurons.
   • Increases the activity of GABA in the brain by:
     • Increased synthesis of GABA by stimulating GAD (glutamic acid decarboxylase) enzyme.
     • Decreased degradation of GABA by inhibiting GABA-transaminase (GABA-T) enzyme.
2. Pharmacokinetics Valproate is rapidly and almost completely absorbed from the GIT, highly (about 90%) bound to plasma proteins, metabolized in liver and excreted in urine.
3. Adverse effects
   • The common side effects related to GIT are nausea, Vomiting, Anorexia and abdominal discomfort.
   • CNS side effects include sedation, ataxia and Tremor.
   • A rare but serious complication is fulminant hepatitis (Liver); hence, it is avoided in children below 3 years of age. Monitoring of hepatic function is essential during valproate therapy. An elevation in liver enzymes may occur.
   • Teratogenicity: Orofacial and digital abnormalities; neural tube defects with increased incidence of spina bifida, so it should not be given during pregnancy.
   • The other adverse effects include skin Rashes, Alopecia and curling of hair; acute Pancreatitis may occur rarely.
4. Uses Sodium valproate is highly effective in absence, of myoclonic, partial (SPS and CPS) and GTCSs. Other uses of valproate include mania, bipolar disorder and migraine prophylaxis.

Diazepam, Lorazepam, Clonazepam (BZDs)

Diazepam and lorazepam are effective in controlling status epilepticus. Clonazepam, a long-acting BZD, is used in absence and myoclonic seizures. Intravenous diazepam is used in the emergency treatment of status epilepticus, tetanus, eclamptic convulsions, febrile convulsions, drug-induced convulsions, etc. Diazepam has a rapid onset but short duration of action, hence repeated doses are required. Diazepam can be administered rectally in children during emergency. Lorazepam is preferred in status epilepticus because:

1. It has a rapid onset and long duration of action.
2. It has less damaging effect on injected vein.
3. Adverse effects Intravenous diazepam and lorazepam may cause hypotension and respiratory depression. The main side effects of clonazepam are sedation and lethargy, but tolerance develops on chronic therapy. Other side effects are hypotonia, dysarthria, dizziness and behavioural disturbances like irritability, hyperactivity, lack of concentration, etc.

Newer Antiepileptics

These are lamotrigine, topiramate, zonisamide, gabapentin, pregabalin and vigabatrin.

They are administered orally. Important features are given in Table.

• Newer Antiepileptics

Status Epilepticus

It is a medical emergency and should be treated immediately. It is characterized by recurrent attacks of tonic–clonic seizures without the recovery of consciousness in between or a single episode lasts longer than 30 min.

1. Treatment
   • Hospitalize the patient.
   • Maintain airway and establish a proper i.v. line.
   • Administer oxygen.
   • Collect blood for estimation of glucose, calcium, electrolytes and urea.
   • Maintain fluid and electrolyte balance.

Dose and interactions of antiepileptic drugs are summarized in Table.

Doses and Drug Interactions of Antiepileptics

Analgesics

Analgesics are drugs that relieve pain without significantly altering consciousness. They relieve pain without affecting its cause.

Opioid Analgesics

Morphine is the most important alkaloid of opium – the dried juice obtained from the capsules of Papaver somniferum. Opium contains many other alkaloids, example codeine, thebaine, papaverine. The term ‘opiates’ refers to drugs derived from opium poppy, whereas ‘opioid analgesic’ applies to any substance (endogenous peptides or drugs), which produces morphine-like analgesia.

1. Classification of opioids
   • Opioid agonists
   • Natural opium alkaloids: Morphine, codeine, thebaine, papaverine, noscapine.
   • Semisynthetic opiates: Heroin, pholcodine, hydromorphone, oxymorphone.
   • Synthetic opioids: Pethidine, tramadol, tapentadol, methadone, dextropropoxyphene, fentanyl, alfentanil, sufentanil, remifentanil.
2. Opioid agonist–antagonists: Pentazocine, butorphanol, nalorphine, nalbuphine.
3. Partial µ-receptor agonist and κ-receptor antagonist: Buprenorphine.

Opioid Receptors

The three main types of opioid receptors are µ (mu), κ(kappa) and δ(delta). These receptor-mediated effects are given below.

1. µ: Analgesia (spinal +supraspinal level), respiratory depression, dependence, sedation, euphoria, miosis, decrease in GI motility.
2. κ: Analgesia (spinal +supraspinal level), respiratory depression, dependence, dysphoria, psychotomimetic effect.
3. δ: Analgesia (spinal +supraspinal level), respiratory depression, proconvulsant action.

Opioid Agonists

1. Mechanism of action Morphine and other opioids produce their actions by interacting with various opioid receptors – µ, δ and κ. They are located at spinal, supraspinal (medulla, midbrain, limbic system and cortical areas) and peripheral nerves. Morphine is the prototype drug.
2. Pharmacological actions of morphine Morphine has mainly CNS-depressant effects but also has stimulant effects at certain sites in the CNS.

• • CNS
    • The depressant effects:
      1. Analgesic effect: Mediated mainly through µ-receptors at spinal and supraspinal sites (central action), it is the most important action of morphine. At the spinal level, it decreases release of excitatory neurotransmitters from primary pain afferents in substantia gelatinosa of dorsal horn. The excitability of neurons in dorsal horn is decreased. In the supraspinal level, it alters transmission of pain impulses. It is a very potent and efficacious analgesic. It causes sedation, drowsiness, euphoria, makes the person calm and raises the pain threshold. Perception of pain and reaction to it (fear, anxiety and apprehension) are altered by these drugs. Moderate doses of morphine relieve dull and continuous pain, whereas sharp, severe intermittent pain such as traumatic or visceral pain requires larger doses of morphine. Opioids also act peripherally to alter the sensitivity of small nerve endings in the skin to painful stimuli associated with tissue injury/inflammation. Therefore, morphine relieves ‘total pain’.

1. • • 1. Euphoria (feeling of well-being): It is an important component of analgesic effect. Anxiety, fear, apprehension associated with painful illness or injury are reduced by opioids.
       2. Sedation: Morphine, in therapeutic doses, causes drowsiness and decreases physical activity.
       3. Respiratory depression: It depresses respiration by a direct effect on the respiratory centre in the medulla; both rate and depth are reduced because it reduces sensitivity of respiratory centre to CO2. Respiratory depression is the commonest cause of death in acute opioid poisoning.
       4. Cough suppression: It has a direct action on cough centre in the medulla.
       5. Hypothermia: In high doses, morphine depresses temperatureregulating centre and produces hypothermia.
     • The stimulant effects:
       1. Miosis: Morphine produces constriction of pupils due to stimulation of 3 cranial nerve nucleus. Some tolerance develops to this action. Pinpoint pupils are an important feature in acute morphine poisoning. Miosis is not seen on topical application of morphine to the eye.
       2. Nausea and vomiting: It is due to direct stimulation of the CTZ in medulla. 5-HT₃ antagonists are the drugs of choice to control opioidinduced nausea and vomiting. H₁-blockers, such as cyclizine or prochlorperazine may also be used.
       3. Vagal centre: It stimulates vagal centre in the medulla and can cause bradycardia.
     • Other effects:
       1. Physical and psychological dependence: Repeated use of opioids causes physical and psychological dependence.
   • CVS: Morphine produces vasodilatation and fall of BP. It mainly causes vasodilatation of peripheral vessels, which results in shift of blood from pulmonary to systemic vessels leading to relief of pulmonary oedema associated with acute left ventricular failure.

1. • GIT: It causes constipation by direct action on GI tract and CNS – decreases GI motility and increases tone of the sphincters.
   • Urinary bladder: It may cause urinary retention by increasing tone of urethral sphincter.
   • Biliary tract: It increases intrabiliary pressure by increasing tone of sphincter of Oddi.
   • Histamine release: Morphine is a histamine liberator and causes itching, skin rashes, urticaria, vasodilatation, bronchoconstriction, etc.
2. Pharmacokinetics On oral administration, morphine is absorbed slowly and erratically. It also undergoes extensive first-pass metabolism; hence, oral bioavailability of morphine is poor. Morphine is commonly administered by i.v., i.m. or s.c. routes. It can also be administered by oral, epidural or intrathecal routes. It is widely distributed in the body, crosses placental barrier and is metabolized in liver by glucuronide conjugation. Morphine-6-glucuronide has more potent analgesic action than morphine and is excreted in urine.
3. Adverse effects
   • Nausea, vomiting and constipation.
   • Respiratory depression.
   • Hypotension due to vasodilatation.
   • Drowsiness, confusion and mental clouding.
   • Itching (due to histamine release) and skin rashes.
   • Difficulty in micturition.
   • Respiratory depression in newborn due to administration of morphine to the mother during labour.
   • Drug tolerance develops to most of the effects of morphine (some tolerance develops to miotic effect). There is cross-tolerance among the opioids.
   • Seizure threshold is lowered.
   • Drug dependence (physical and psychological dependence) is the main drawback of opioid therapy. Psychological dependence is associated with intense craving for the drug. Physical dependence is associated with the development of withdrawal symptoms (abstinence syndrome) when administration of an opioid is stopped abruptly. The symptoms and signs are irritability, body shakes, yawning, lacrimation, sweating, fever, diarrhoea, palpitation, insomnia, rise in BP, loss of weight, etc. (the symptoms are just opposite to morphine actions). Dependence is mediated through µ-receptors. Treatment of morphine dependence:
     • Hospitalization of the patient.
     • Gradual withdrawal of morphine.
     • Substitution therapy with methadone. Opioid agonist like methadone is preferred because:
       1. It is orally effective.
       2. It has longer duration of action.
       3. Withdrawal symptoms are mild. 1 mg of methadone will substitute 4 mg of morphine. Later, methadone is gradually reduced and completely stopped within 10 days. Buprenorphine can also be used for the treatment of opioid dependence.
     • Pure opioid antagonist like naltrexone is used after detoxification to produce opioid blockade to prevent relapse in patients who have a sincere desire to leave the habit. It is the preferred antagonist because it is orally effective and has a long duration of action.
     • Psychotherapy, occupational therapy, community treatment and rehabilitation.
   • Acute morphine poisoning: The characteristic triad of symptoms are respiratory depression, pinpoint pupils and coma. The other signs and symptoms are cyanosis, hypotension, shock and convulsions. Death is usually due to respiratory depression. Treatment ofacute morphine poisoning:
     • Hospitalization.
     • Maintain airway, breathing and circulation.
     • Ventilatory support (positive pressure respiration).
     • Gastric lavage with potassium permanganate.
     • Specific antidote: Naloxone 0.4–0.8 mg intravenously; dose is repeated till respiration becomes normal. Naloxone is a pure antagonist, competitively blocks opioid receptors and rapidly reverses the respiratory depression. The duration of action of naloxone is short; hence, repeated administration is needed.

1. Contraindications
   • Head injury: Morphine is contraindicated in cases with head injury because:
     • Vomiting, miosis and mental clouding produced by morphine interfere with the assessment of progress in head injury patients.
     • Morphine → Respiratory depression → CO₂ retention → Cerebral vasodilation → ↑↑ Intracranial tension.
   • Bronchial asthma: Morphine may cause severe bronchospasm due to histamine release.
   • COPD: It should be avoided in patients with low respiratory reserve – emphysema, chronic bronchitis, cor pulmonale, etc.
   • Hypotensive states: It should be used cautiously in shock or when there is reduced blood volume.
   • Hypothyroidism and hypopituitarism: There is a prolonged and exaggerated response to morphine.
   • Infants and elderly: They are more prone to the respiratory-depressant effect of morphine. In elderly male, there is an increased chance of urinary retention.
   • Undiagnosed acute abdominal pain: Morphine, if given before diagnosis interferes with diagnosis by masking the pain. Its spasmogenic effect may aggravate the pain (biliary colic).

1. Codeine: Natural opium alkaloid

1. Codeine has analgesic and cough-suppressant effects; it is administered orally.
2. Compared to morphine:
   • It is less potent and less efficacious as an analgesic.
   • It has less respiratory-depressant effect.
   • It is less constipating.
   • It has low addiction liability.
3. It has selective cough suppressant effect (antitussive), hence used to suppress dry cough.
4. It potentiates analgesic effect of aspirin and paracetamol.
5. Codeine is used for relief of moderate pain. The main side effects are constipation and sedation.

2. Pholcodine

3. Pethidine (meperidine)

Pethidine is a synthetic opioid; it has some anticholinergic actions. Dry mouth and tachycardia can occur.

Comparative Features of Morphine and Pethidine

It can be administered by oral, i.v., s.c. and i.m. routes. It is well absorbed from the GI tract, but bioavailability is about 50% because of the first-pass effect; widely distributed in the body, crosses placental barrier and is metabolized in liver. The metabolites are excreted in urine.

1. Adverse effects The adverse effects of pethidine are similar to those of morphine. It can cause tremors, hallucinations, muscle twitches and rarely convulsions due to its metabolite, norpethidine. Tolerance, physical and psychological dependence can also develop with pethidine.
2. Diphenoxylate It is a pethidine congener and is useful in the treatment of diarrhoea. It is available in combination with atropine. It is rarely used at present because of its side effect (paralytic ileus).
3. Loperamide is a pethidine congener. It reduces GI motility and secretions but increases the tone of anal sphincter. It is used in the symptomatic treatment of diarrhoea. Common side effects are constipation and abdominal cramps.

Therapeutic Uses Of Opioids

1. As analgesic: Morphine and other opioids are potent and efficacious analgesics, hence used for moderate to severe painful conditions, such as acute myocardial infarction (MI), burns, pulmonary embolism, fracture mandible and long bones, bullet wound, etc. Opioids are also used to control severe pain in terminal stages of cancer. In renal and biliary colic, atropine is used with morphine to counteract the spasmogenic effect of morphine. Opioids are the preferred analgesics in severe painful conditions (WHO analgesic ladder)
   • Patient-controlled analgesia: This allows the patient to control the delivery of s.c., epidural or i.v. analgesic in a safe and effective way through a pump. The patient should inform nurse when he or she takes a dose so that it can be replaced.

1. Preanaesthetic medication: Opioids like morphine and pethidine are used about half an hour before anaesthesia because of their sedative, analgesic and euphoric effects; the dose of anaesthetic required is reduced.
2. Acute pulmonary oedema (cardiac asthma): i.v. morphine relieves breathlessness associated with acute left ventricular failure due to pulmonary oedema by:
   • Reducing preload on heart by peripheral vasodilatation.
   • Shifting blood from pulmonary to systemic circulation.
   • Reducing anxiety, fear and apprehension associated with illness.
3. Postanaesthetic shivering – pethidine is effective.
4. Cough: Codeine and dextromethorphan are used for suppression of dry cough.
5. Diarrhoea: Synthetic opioids such as loperamide and diphenoxylate are used for symptomatic treatment of diarrhoea.

1. Other opioids

The route of administration, uses and important features are represented in Table

Important Points and Uses of Other Opioids

1. Tramadol. It is a synthetic codeine derivative with weak agonistic activity at µ- receptors. It also inhibits the reuptake of NA and 5-HT. It decreases seizure threshold.
2. Tapentadol. It is a µ-agonist. It also predominantly inhibits reuptake of NE than 5- HT into the neurons. It is useful in mild to moderate pain. Adverse effects are similar to tramadol but vomiting is less.
3. Fentanyl. It is a synthetic opioid with a potent µ-agonistic effect (100 times more potent than morphine as an analgesic). Pharmacological actions are similar to morphine. Alfentanil, sufentanil and remifentanil are short-acting fentanyl analogues. They are useful for short procedures where intense analgesia is required.
4. Methadone. It is a synthetic opioid with agonistic effect at µ-receptors and has a long duration of action. Pharmacological actions are similar to morphine.
5. Dextropropoxyphene. It is structurally similar to methadone. The side effects are nausea, constipation, sedation, abdominal pain, etc. It may cause cardiotoxicity and pulmonary oedema.

Opioid Agonist–Antagonists And Partial Agonists

1. Pentazocine Pentazocine is an opioid agonist–antagonist. It has agonistic action at κ-receptors and weak antagonistic action at µ-receptors. In low doses, its pharmacological actions are almost similar to that of morphine. In higher doses, it causes sympathetic stimulation.
2. Buprenorphine It is a partial µ-receptor agonist and κ-receptor antagonist; it is about 25 times more potent than morphine as analgesic. The pharmacological actions are qualitatively similar to morphine but it has a delayed onset and prolonged duration of action. It can be administered by parenteral and sublingual routes.

Opioid Antagonists: Naloxone, Naltrexone And Nalmefene

They are pure opioid antagonists. These drugs have no agonistic activity. Naloxone, naltrexone and nalmefene competitively reverse the effects of both natural and synthetic opioids, but do not completely reverse buprenorphine-induced respiratory depression. Naloxone also blocks analgesic effect of placebo and acupuncture, and effects of endogenous opioid peptides. It is orally not effective because of high first-pass metabolism. It is short acting. On i.v. administration, it immediately antagonizes all the actions, especially respiratory depression, of morphine and other opioids. i.v. naloxone precipitates withdrawal symptoms in morphine and heroin addicts.

1. Uses of naloxone
   • The main therapeutic use of naloxone is for the treatment of morphine and other opioid poisoning.
   • In the treatment of opioid overdosage, i.v. naloxone rapidly reverses respiratory depression induced by opioids (except buprenorphine where it causes partial reversal of respiratory depression).
   • To treat neonatal asphyxia due to use of opioids in the mother during labour.
2. Uses of naltrexone
   • Naltrexone is orally more potent and has longer duration of action than naloxone.
   • Naltrexone is used for opioid blockade therapy to prevent relapse in opioiddependent individuals.
   • It is also used for the treatment of alcoholism, as it reduces the urge to drink.
   • Methylnaltrexone, a derivative of naltrexone, has only peripheral actions. It can be used for treatment of constipation due to opioids.
3. Nalmefene
   • It is administered intravenously.
   • It is longer acting than naloxone.
   • It is useful in the treatment of opioid overdosage.

Endogenous Opioid Peptides

Endorphins, enkephalins and dynorphins are naturally occurring substances present in the brain and other body tissues. They are called endogenous opioid peptides because their effects are similar to opium alkaloids (for example morphine) in their actions. These peptides appear to be involved in placebo and acupuncture-induced analgesia.

Psychopharmacology

The major types of psychiatric illnesses are psychoses and neuroses.

Differences between Psychoses and Neuroses

Antipsychotic Drugs

Antipsychotic drugs are also known as neuroleptic drugs or antischizophrenic drugs. Neuroleptic drugs are mainly used in schizophrenia, acute mania and other acute psychotic states.

• Classification
  • Phenothiazines: Chlorpromazine, triflupromazine, trifluoperazine, thioridazine, fluphenazine
  • Thioxanthenes: Flupenthixol
  • Butyrophenones: Haloperidol
  • Atypical antipsychotics: Clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine, amisulpride
  • Others: Loxapine, pimozide
• Mechanism of action of antipsychotics
  • Conventional antipsychotics → Mainly block dopamine (D₂) receptors in the limbic system and mesocortical areas.
  • Atypical antipsychotics → Block 5-HT₂ receptors in mesolimbic system.

1. Chlorpromazine (phenothiazines) Chlorpromazine is the prototype drug.

1. Pharmacological actions of chlorpromazine

1. • • CNS: In patients with schizophrenia, chlorpromazine:
       • Reduces agitation and aggressiveness.
       • Reduces spontaneous movements.
       • Suppresses hallucinations and delusions.
       • Relieves anxiety.
       • Corrects disturbed thought and behaviour.
       • Does not affect intelligence but impairs vigilance.
     • Endocrine Prolactin secretion is under the control of prolactin-releasing factor (PRF) and prolactin-inhibitory factor (PIF). PIF itself is dopamine, hence the blockade of DA-receptors in pituitary may cause increased production of prolactin leading to galactorrhoea, amenorrhoea and infertility in females; gynaecomastia in males.
     • Other actions
     • Tolerance to sedative and hypotensive actions develop within a few weeks.
2. Pharmacokinetics Phenothiazines are effective orally and parenterally. Chlorpromazine is highly bound to plasma proteins – reaches high concentration in the brain. It is metabolized in liver and excreted in urine.
3. Adverse effects of antipsychotics Important side effects of these drugs are dose-dependent extrapyramidal symptoms (EPS).
   • Parkinsonism: They are tremor, rigidity, hypokinesia, etc. Centrally acting anticholinergics (benzhexol, benztropine and antihistamines like promethazine and diphenhydramine) are effective in controlling these symptoms.
   • Acute dystonias: Uncontrolled muscular movements involving the face, tongue, neck, etc. It responds to centrally-acting anticholinergics, example benzhexol.
   • Akathisia: Feeling of restlessness – the person cannot sit at a place and has a desire to move about.
   • Neuroleptic malignant syndrome: It is a rare but serious complication characterized by muscular rigidity, hyperpyrexia, mental confusion and coma. It is treated with i.v. dantrolene. The above effects are reversible on the stoppage of therapy.
   • Tardive dyskinesia (Tardive – late occurring): It is characterized by involuntary movements of the mouth, tongue and upper limbs. It develops in about 20% of patients after months or years of antipsychotic treatment. Treatment is usually unsuccessful.
   • Muscarinic, α₁-adrenergic and H₁-receptor-blocking side effects.
   • Weight gain is common with clozapine and olanzapine.
   • Endocrine side effects are due to increased prolactin level resulting in amenorrhoea, galactorrhoea and infertility in females; gynaecomastia in males.
   • Hyperglycaemia and precipitation of diabetes can occur with chlorpromazine. Hypersensitivity reactions can occur – skin rashes, itching, dermatitis, leucopaenia and rarely obstructive jaundice. Agranulocytosis is a serious adverse effect with clozapine.

2. Haloperidol

1. Widely used antipsychotic drug; pharmacological actions are similar to chlorpromazine.
2. Causes severe extrapyramidal symptoms.
3. Has less seizure potential.
4. Does not cause weight gain.
5. Preferred agent for acute schizophrenia.

3. Atypical antipsychotics

These drugs exert antipsychotic effect mainly by 5-HT₂ blockade. They have weak D₂– blocking effects – low risk of extrapyramidal symptoms. Pharmacological actions andadverse effects of atypical antipsychotics – clozapine, olanzapine, risperidone, aripiprazole, and ziprasidone are given in Table.

Comparative Features of Antipsychotic Drugs

1. Therapeutic uses
   • Schizophrenia: The neuroleptics are the only efficacious drugs available for the treatment of schizophrenia. The atypical antipsychotics are commonly prescribed owing to the lower risk of EPS. Risperidone and olanzapine are frequently used. Clozapine is reserved for resistant cases of schizophrenia. Of the older agents, high-potency drugs like haloperidol and fluphenazine are commonly used.
   • Mania: Acute mania can be treated with a neuroleptic (chlorpromazine or haloperidol); lithium is used for maintenance therapy. Atypical antipsychotics can be used for acute mania. Lithium is not preferred in acute mania because of its slow onset of action and narrow margin of safety.
   • As antiemetic: These drugs (phenothiazines, haloperidol, etc.) produce antiemetic effect by blocking D₂-receptors in CTZ. However, they are not routinely used as antiemetics because of their side effects. Phenothiazine, such as prochlorperazine, is useful for prevention and treatment of nausea and vomiting associated with migraine or emesis due to anticancer drugs.
   • Intractable hiccough has been treated with chlorpromazine.
   • As adjuvant with selective serotonin reuptake inhibitors (SSRIs) in anxiety

Antianxiety Agents

1. BZDs: BZDs are the preferred anxiolytic drugs. Chlordiazepoxide, diazepam, lorazepam, oxazepam, alprazolam, etc. are used as anxiolytic agents. They act on limbic system and facilitate the inhibitory effect of GABA. They are mainly useful for short-term treatment of anxiety. Adverse effects are sedation, impairment of memory, confusion and dependence. Tolerance may develop to anxiolytic effect on long-term use.
2. Buspirone: Buspirone is a partial agonist of 5-HT_1A-receptor and causes selective anxiolytic effect. It has no sedative, anticonvulsant or muscle-relaxant effects. It does not potentiate the central effects of alcohol or other CNS depressants. There is no tolerance or drug dependence. It does not affect GABA transmission. It is mainly used in the treatment of generalized anxiety states. But its effect is delayed and may take 2 weeks to fully develop. So, it is not effective for acute cases.
3. β-Blockers: Propranolol and other nonselective β-blockers are used mainly to reduce symptoms of anxiety, such as tachycardia, palpitation, tremor and sweating.
4. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitor (venlafaxine): They are the preferred agents for most of the anxiety disorders except acute anxiety. Response is delayed.
5. H₁-blocker: Hydroxyzine, is a highly sedative first-generation H₁-blocker and has selective antianxiety action. It also has antiallergic, antiemetic and anticholinergic actions

Antidepressants

Depression is a common clinical condition associated with feeling of sadness, loss of interest, self-neglect, anorexia, sleep disturbances, suicidal feelings in severe cases, etc. Various hypotheses have been proposed for the pathogenesis of depression.

• Decrease in levels or function of monoamines (5-HT, NE, DA) in cortical and limbic system.
• Abnormalities in HPA axis, thyroid function and sex steroid levels.

1. Classification
   • Tricyclic antidepressants (Mnemonic: ANTI-DEP)
   • Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are Fluoxetine, fluvoxamine, citalopram, escitalopram, sertraline, paroxetine.
   • Serotonin and noradrenaline reuptake inhibitors (SNRIs): Duloxetine, venlafaxine.
   • Atypical antidepressants Trazodone, bupropion, mianserin, mirtazapine
   • MAO-A inhibitors Moclobemide, clorgyline

Tricyclic Antidepressants

Mechanism of action and pharmacological actions are described.

1. Pharmacokinetics TCAs are well absorbed through the GIT and are highly bound to plasma proteins. They are widely distributed in tissues including CNS. They are metabolized in liver.Some of them (imipramine, amitriptyline, etc.) produce active metabolites, which are responsible for the long duration of action of these drugs. These drugs are excreted mainly in urine as inactive metabolites.
2. Adverse effects of tricyclic antidepressants
   • ‘Atropine-like’ side effects: Dryness of mouth, blurring of vision, constipation, urinary retention, etc.
   • α₁-Adrenergic blocking effects: Postural hypotension, tachycardia, cardiac arrhythmias, etc.
   • H₁-blocking effects: Sedation and confusion.
   • Other effects: Increased appetite, weight gain; convulsions may be precipitated (seizure threshold is lowered).

Tricyclic antidepressants are contraindicated in patients with glaucoma, epilepsy, ischaemic heart disease and enlarged prostate. Other antidepressants are shown in Table.

Comparative Features of Antidepressants

MAO Inhibitors

Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the metabolism of biogenic amines. There are two isoforms of MAO. MAO-A is responsible mainly for metabolism of NA, 5-HT and tyramine. MAO-B is more selective for dopamine metabolism.

1. Moclobemide A selective and reversible inhibitor of MAO-A (RIMA) is relatively free of food and drug interactions. Hence, cheese reaction is rare. It is also devoid of anticholinergic, α₁– adrenergic blocking and sedative effects.
2. Drug interactions
   • Involving TCAs

1. • Serotonin syndrome Concomitant administration of SSRIs with MAO inhibitors produces severe undesirable effects like tremor, restlessness, muscle rigidity, hyperthermia, sweating, shivering, seizures and coma due to increased serotonin levels at the synapses, which is termed as serotonin syndrome.
   • SSRIs inhibit metabolism of a number of drugs such as TCAs, antipsychotics, β- blockers, phenytoin and carbamazepine and increase their plasma levels.
2. Cheese reaction Normally, tyramine in food is metabolized by MAO in gut and liver. So, very little tyramine reaches systemic circulation. When a patient on MAO inhibitor consumes food stuff rich in tyramine, it may result in fatal hypertensive crisis and cerebrovascular accidents. The preferred agent to treat this reaction is i.v. phentolamine

Uses Of Antidepressants

1. Depression: Antidepressants are used in the treatment of endogenous depression (major depression) and during the phase of depression in bipolar illness. The patient starts taking interest in daily activities, mood is elevated, concentration improves and agitation decreases. The patient becomes more responsive. SSRIs are preferred over TCAs because of:
   • Better tolerability.
   • Less side effects (do not cause hypotension and sedation; do not have anticholinergic effects; no precipitation of convulsions; do not cause cardiac arrhythmias).
   • Longer duration of action.
2. Anxiety disorders: SSRIs are used for the treatment of generalized anxiety disorders.
3. Obsessive-compulsive disorders (OCD): Clomipramine (TCA) and fluvoxamine (SSRI) are highly effective.
4. Nocturnal enuresis: Imipramine is effective.
5. Prophylaxis of migraine: Amitriptyline is effective.
6. Chronic pain including neuralgias: TCAs are effective in trigeminal, herpetic, postherpetic neuralgias, etc.

Drugs For Bipolar Disorder

Bipolar disorder (manic-depressive illness) is a psychiatric disorder in which depression alternates with mania. Mania is an affective disorder that manifests as elation, agitation, hyperactivity, uncontrolled thought and speech.

Drugs used in bipolar disorder are lithium, carbamazepine, sodium valproate, olanzapine, risperidone, haloperidol, etc.

1. Lithium was the first drug used for the treatment of mania. Antiepileptic drugs such as carbamazepine, sodium valproate and gabapentin have been approved for the treatment of manic-depressive psychoses (MDP; bipolar disorder).
   • Actions and mechanism Lithium reduces motor activity, decreases euphoria, relieves insomnia and stabilizes the mood. In the neuronal membrane:
     
     • Lithium, by inhibiting the above steps, reduces the release of IP₃ and DAG, which are second messengers for both α-adrenergic and muscarinic transmission.
     • Lithium is a monovalent cation that can mimic the role of Na⁺.
     • Lithium also decreases the release of NA and DA in the brain.
   • Other actions
     • Lithium may produce nephrogenic diabetes insipidus by blocking the action of ADH on collecting duct.
     • It increases total WBC count (leukocytosis).
     • It inhibits the release of thyroid hormones (T₃ and T₄).
   • Pharmacokinetics Lithium carbonate is effective orally, does not bind to plasma proteins and is distributed throughout the total body water. It is not metabolized and gets excreted in urine, saliva, sweat, etc. Lithium is a monovalent cation. The kidney handles lithium in the same way as Na⁺. About 80% of the filtered lithium is reabsorbed in the proximal tubules. Sodium depletion reduces the rate of excretion of lithium and thus increases its toxicity. Lithium has low therapeutic index, hence therapeutic drug monitoring (TDM) is essential for optimal therapy (normal 0.5–1.5 mEq/L). Estimation of salivary concentration can be used for noninvasive monitoring of lithium.
   • Adverse effects
     • GIT: Nausea, vomiting and diarrhoea.
     • CNS: Tremor, ataxia, drowsiness, headache, muscular weakness and slurred speech.
     • Renal: Polyuria, polydipsia due to inhibition of ADH action.
     • Goitre with hypothyroidism may occur.
     • Acute lithium toxicity manifests as confusion, convulsions, cardiac arrhythmias, coma and death.
     • Lithium should be stopped immediately; patient is treated with intravenous normal saline to restore Na⁺ levels, which in turn promotes the excretion of lithium.
   • Uses of lithium It is used as a prophylactic agent for bipolar disorder. It decreases the frequency and severity of both manic and depressive attacks; hence, it is called as mood stabilizer. Lithium has a slow onset of action, hence not useful for acute mania. Lithium is also useful in the prophylaxis of unipolar depression.
   • Drug interactions
     • Lithium × thiazides/furosemide: Thiazides and furosemide cause hyponatraemia. As a result, there will be a compensatory increase in the reabsorption of Na⁺ in PCT. Along with Na⁺, the reabsorption of lithium is also increased leading to toxicity.
     • Neuromuscular blockade induced by both depolarizing (succinylcholine) and nondepolarizing (pancuronium) neuromuscular blockers is prolonged in patients on lithium.
     • Lithium × haloperidol: Long-term lithium therapy may cause rigidity and potentiates the extrapyramidal symptoms of haloperidol.

Other Drugs Used In Mania And Bipolar Disorder

1. Sodium valproate: It is used for treatment of mania because of its rapid action, wider therapeutic index and better tolerability than lithium. It is also used prophylactically for bipolar disorder.
2. Carbamazepine: Carbamazepine, an antiepileptic drug, has a mood-stabilizing effect and is used in the treatment of bipolar disorder. It may be used alone or in combination with lithium or valproate. It is used prophylactically in bipolar disorder.
3. Atypical antipsychotics: Olanzapine, risperidone, aripiprazole, quetiapine, etc. are preferred agents to control acute attack of mania.
4. BZDs like lorazepam or clonazepam are used as adjuncts if patient is agitated