Autacoids And Respiratory System Notes

Autacoids And Respiratory System

Autacoids are produced by cells and act locally. Hence, they are also called ‘local hormones’. Various autacoids are histamine, serotonin (5-HT), prostaglandins (PGs), leukotrienes, angiotensin, kinins, and platelet-activating factor (PAF).

Histamine And Antihistamines

Histamine

Histamine is a biogenic amine present in many animal and plant tissues. It is also present in venoms and stinging secretions. It is synthesized by decarboxylation of the amino acid, histidine. Histamine is mainly present in storage granules of mast cells in tissues like skin, lungs, liver, gastric mucosa, and placenta. It is one of the mediators involved in inflammatory and hypersensitivity reactions.

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1. Mechanism of action and effects of histamine Histamine exerts its effects by binding to histamine (H) receptors.

1. Histamine liberators Many agents release histamine from mast cells.

1. Uses Histamine has no valid clinical use.
2. Betahistine It is a histamine analog that is used orally to treat vertigo in Meniere’s disease. It probably acts by improving blood flow in the inner ear. The side effects are nausea, vomiting, headache and pruritus. It should be avoided in patients with asthma and peptic ulcers.

H₁-receptor antagonists (H₁-blockers, antihistamines)

• Classification

• Mechanism of action of H₁-blockers H₁-antihistamines antagonizes the effects of histamine by competitively blocking H₁– receptors (competitive antagonism).

1. First-generation H₁-blockers are conventional antihistamines.
   • Pharmacological actions
     • H₁ blockers cause central nervous system (CNS) depression – sedation and drowsiness. Certain antihistamines have antiemetic, local anesthetic, and antiparkinsonian effects.
     • They have antiallergic action, hence most of the manifestations of Type-1 reactions are suppressed.
     • They have anticholinergic actions – dryness of mouth, blurring of vision, constipation, urinary retention, etc.
   • Pharmacokinetics H₁-antihistamines are well absorbed after oral and parenteral administration. They are distributed widely throughout the body, metabolized extensively in the liver, and excreted in urine.
   • Adverse effects
     • The common adverse effects are sedation, drowsiness, lack of concentration, headache, fatigue, weakness, lassitude, incoordination, etc. Hence, H₁– antihistamines should be avoided while driving or operating machinery. These adverse effects are rare with second-generation antihistamines.
     • Gastrointestinal (GI) side effects are nausea, vomiting, loss of appetite, and epigastric discomfort.
     • Anticholinergic side effects such as dryness of mouth, blurring of vision, constipation, and urinary retention. These effects are not seen with second-generation antihistamines.
     • Teratogenic effects of some H₁-blockers have been observed in animals.
     • Allergic reactions may occur rarely with these agents, especially contact dermatitis on topical application.

Uses

• Allergic diseases: H₁-antihistamines are used to prevent and treat symptoms of allergic reactions. For example, pruritus, urticaria, dermatitis, rhinitis, conjunctivitis and angioedema (except laryngeal edema) respond to these drugs.
• Common cold: They produce symptomatic relief by sedative and anticholinergic actions.
• Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects.
• As antiemetics: Promethazine, diphenhydramine, dimenhydrinate, etc. are useful for prophylaxis of motion sickness because of their anticholinergic action. They act probably on the vestibular apparatus or cortex. The sedative effect also contributes to their beneficial effect.
• These drugs are useful in drug-induced and postoperative vomiting. Promethazine in combination with other antiemetics is used to control vomiting due to cancer chemotherapy and radiation therapy.

• Parkinsonism: The imbalance between dopamine and acetylcholine (DA and ACh) in the basal ganglia produces parkinsonism. Promethazine, diphenhydramine, orphenadrine are used to control tremor, rigidity, and sialorrhoea of parkinsonism due to their anticholinergic and sedative properties. Promethazine and diphenhydramine are also useful for the treatment of idiopathic and drug-induced parkinsonism.
• H₁-blockers are used to control mild blood transfusion and saline infusion reactions (chills and rigors) and as adjuncts in anaphylaxis.
• Cinnarizine, dimenhydrinate, and meclizine are effective for controlling vertigo in Meniere’s disease and other types of vertigo. Their antihistaminic and anticholinergic actions are useful in this condition.
• Sedative and hypnotic: H₁-antihistamines (for example promethazine and diphenhydramine) are used to induce sleep, especially in children during minor surgical procedures.

1. Second-generation H₁-blockers Cetirizine, levocetirizine, loratadine, desloratadine, azelastine, fexofenadine, etc. are highly selective for H₁-receptors and have the following properties. They:
   • Have no anticholinergic effects.
   • Lack antiemetic effect.
   • Do not cross blood-brain barrier (BBB), hence cause minimal/no drowsiness.
   • Do not impair psychomotor performance.
   • Are relatively expensive.
   • Second-Generation H₁-Blockers
     Cetirizine is one of the commonly used second-generation antihistamines. In addition to the H₁-blocking effect, it can also inhibit the release of histamine. It causes minimal/no drowsiness. It is not metabolized in the body. Incidence of cardiac arrhythmias is rare with this drug.
   • Second-generation H₁-blockers are used in various allergic disorders – rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug, and food allergies.

Prostaglandins And Leukotrienes (Eicosanoids)

Prostaglandins

PGs are products of long-chain fatty acids. Arachidonic acid is the precursor for the biosynthesis of all PGs. The enzyme involved in the formation of PGs from arachidonic acid is cyclooxygenase (COX). The main PGs are PGE₂, PGF₂α and PGI₂. Another class of substances obtained from arachidonic acid by the action of lipoxygenase is leukotrienes.

There are two forms of COX, COX-1 and COX-2. COX-1 is constitutive (it is always present) and is widely distributed. It participates in various physiological functions such as protection of gastric mucosa, homeostasis, and regulation of cell division. COX-2 is induced during inflammation by cytokines and endotoxins.

1. Pharmacological actions and uses

1. • GI tract: PGE₂ and PGI₂ reduce acid secretion and increase the secretion of mucus in the stomach (cytoprotective action). Misoprostol (PGE₁ analog) is used for the prevention of nonsteroidal anti-inflammatory drug (NSAID)- induced ulcers.
   • Cardiovascular system: PGD₂, PGE₂ and PGI₂ cause vasodilatation. PGF₂α constricts pulmonary veins and arteries. Thromboxane A₂ (TXA₂) is a vasoconstrictor.
   • PGE₁ (alprostadil) is used to maintain the patency of ductus arteriosus before surgery.
   • Prostacyclin (PGI₂) decreases peripheral, pulmonary, and coronary resistance.
   • Platelets: PGI₂ inhibits platelet aggregation. Hence, it is used during hemodialysis to prevent platelet aggregation.
   • Eye: PGF₂α has been found to decrease intraocular tension. Its analogs, for example, latanoprost, bimatoprost, etc. are used in glaucoma.
   • Uterus: PGE₂ (low concentration) and PGF₂α contract the pregnant uterus. PGs are mainly used in mid-trimester abortion and missed abortions. Other uses include induction of labor, cervical priming, and postpartum hemorrhage.
   • Male reproductive system: PGE₁ (alprostadil) is useful for the treatment of erectile dysfunction.
     • Preparations and Uses of Prostaglandin Analogues
2. Adverse effects They are nausea, vomiting, diarrhea, fever, flushing, hypotension, and backache (due to uterine contractions). Injections are painful due to sensitization of nerve endings.

Preparations and uses of prostaglandin analogs are given in the Table.

Leukotrienes

These are obtained from arachidonic acid by the action of lipoxygenase.

1. Leukotriene antagonists

Nonsteroidal Anti-Inflammatory Drugs

1. Classification
   • Nonselective COX (cyclooxygenase) inhibitors:
     • Salicylates: Aspirin, diflunisal.
     • Propionic acid derivatives: Ibuprofen, naproxen, ketoprofen, flurbiprofen.
     • Fenamic acid derivatives: Mefenamic acid, flufenamic acid.
     • Acetic acid derivatives: Ketorolac, indomethacin.
     • Enolic acid derivatives: Piroxicam, tenoxicam, lornoxicam.
     • Preferential COX-2 inhibitors: Diclofenac, aceclofenac, nimesulide, meloxicam.
     • Highly selective COX-2 inhibitors: Etoricoxib, parecoxib.
     • Analgesic and antipyretics with poor anti-inflammatory effect: Paracetamol, nefopam.
2. Mechanism of action
   • COX is the enzyme responsible for the biosynthesis of various PGs. There are two well-recognized isoforms of COX: COX-1 and COX-2. COX-1 is constitutive and found in most tissues such as blood vessels, the stomach, and the kidney. PGs have an important physiological role in many tissues. COX-2 is induced during inflammation by cytokines and endotoxins and is responsible for the production of prostanoid mediators of inflammation.
   • Aspirin and most of the NSAIDs inhibit both COX-1 and COX-2 isoforms; thereby decreasing PGs and thromboxane synthesis. The anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX-2. Aspirin causes irreversible inhibition of COX activity. The rest of the NSAIDs cause reversible inhibition of the enzyme.
3. Pharmacological actions of aspirin and other NSAIDs Aspirin (acetylsalicylic acid) is the prototype drug. The other nonselective NSAIDs vary mainly in their potency, analgesic, and anti-inflammatory effects, and duration of action.
   • Analgesic effect: NSAIDs are mainly used for relieving musculoskeletal pain, dysmenorrhoea, and pain associated with inflammation or tissue damage. The analgesic effect is mainly due to peripheral inhibition of PG production. They prevent sensitization of peripheral nerve endings by inflammatory mediators. They also increase pain thresholds by acting at the subcortical site. These drugs relieve pain without causing sedation, respiratory depression, tolerance, or dependence. They are less efficacious than opioids as analgesics. Aspirin produces analgesia at doses of 2–3 g/day.
   • Antipyretic effect: The thermoregulatory center is situated in the hypothalamus. Fever occurs when there is a disturbance in the hypothalamic thermostat. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They promote heat loss by causing cutaneous vasodilatation and sweating. They do not affect normal body temperature. The antipyretic effect is mainly due to inhibition of PGs in the hypothalamus. The dose of aspirin for antipyretic effect is 2–3 g/day.
   • Anti-inflammatory effect: Anti-inflammatory effect is seen at high doses (aspirin: 4–6 g/day in divided doses). These drugs produce only symptomatic relief. They suppress signs and symptoms of inflammation such as pain, tenderness, swelling, vasodilatation, and leukocyte infiltration, but they do not affect the progression of underlying disease. The anti-inflammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of injury. They also affect other mediators of inflammation (bradykinin, histamine, serotonin, etc.), thus inhibiting granulocyte adherence to the damaged vasculature. NSAIDs also cause modulation of T-cell function, stabilization of lysosomal membrane, and inhibition of chemotaxis.
   • Antiplatelet (antithrombotic) effect: Aspirin in low doses (50–325 mg/day) irreversibly inhibits platelet TXA₂ synthesis and produces an antiplatelet effect, which lasts for 8–10 days, i.e. the lifetime of the platelets. Aspirin in high doses (2–3 g/day) inhibits both PGI₂ and TXA₂ synthesis, hence antiplatelet effect is lost. Aspirin should be withdrawn 1 week prior to elective surgery because of the risk of bleeding.

• • Acid-base and electrolyte balance: In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by the excretion of bicarbonate (compensated respiratory alkalosis). In toxic doses, the respiratory center is depressed which can lead to respiratory acidosis. Later, there is uncompensated metabolic acidosis.
  • GIT: Aspirin irritates the gastric mucosa and produces nausea, vomiting, and dyspepsia. The salicylic acid formed from aspirin also contributes to these effects. Aspirin also stimulates CTZ and produces vomiting.

• • CVS: Prolonged use of aspirin and other NSAIDs causes sodium and water retention. They may precipitate CCF in patients with low cardiac reserve. They may also decrease the effect of antihypertensive drugs.
  • Urate excretion: Salicylates, in therapeutic doses, inhibit urate secretion into the renal tubules and increase plasma urate levels. In high doses, salicylates inhibit the reabsorption of uric acid in the renal tubules and produce a uricosuric effect.

1. Pharmacokinetics Salicylates are rapidly absorbed from the upper GI tract. They are highly bound to plasma proteins, but the binding is saturable. Salicylates are well distributed throughout the tissues and body fluids and metabolized in the liver by glycine and glucuronide conjugation. In low doses, elimination follows first-order kinetics and with high doses as the metabolizing enzymes get saturated, it switches over to zero-order kinetics. After this, an increase in salicylate dosage increases its plasma concentration markedly, and severe toxicity can occur. Alkalinization of urine increases the rate of excretion of salicylates.
2. Dosage regimen for aspirin
   • Analgesic dose: 2–3 g/day in divided doses.
   • Anti-inflammatory dose: 4–6 g/day in divided doses.
   • Antiplatelet dose: 50–325 mg/day (low-dose aspirin).
3. Adverse effects
   • GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding. The ulcerogenic effect is the major drawback of NSAIDs, which is prevented/minimized by taking:
     • NSAIDs after food.
     • buffered aspirin (preparation of aspirin with antacid).
     • proton pump inhibitors/H₂-blockers/misoprostol with NSAIDs.
     • selective COX-2 inhibitors.
   • Hypersensitivity: It is relatively more common with aspirin. The manifestations are skin rashes, urticaria, rhinitis, bronchospasm, angioneurotic edema, and rarely anaphylactoid reaction. Bronchospasm (aspirin-induced asthma) is due to increased production of leukotrienes. The incidence of hypersensitivity is high in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria. Therefore, aspirin should be avoided in such patients.
   • In people with G6PD deficiency, the administration of salicylates may cause hemolytic anemia.
   • Prolonged use of salicylates interferes with the action of vitamin K in the liver → decreased synthesis of clotting factors (hypoprothrombinaemia) → predisposes to bleeding (can be treated by administration of vitamin K).
   • Reye’s syndrome: Use of salicylates in children with viral infection may cause hepatic damage with fatty infiltration and encephalopathy – Reye’s syndrome. Hence, salicylates are contraindicated in children with viral infections.
   • Pregnancy: These drugs inhibit PG synthesis, thereby delaying the onset of labor and increasing the chances of postpartum hemorrhage. In the newborn, inhibition of PG synthesis results in premature closure of ductus arteriosus.
   • Analgesic nephropathy: Slowly progressive renal failure may occur on chronic use of high doses of NSAIDs. Renal failure is usually reversible on stoppage of therapy, but rarely NSAIDs may cause irreversible renal damage.

Salicylism

Salicylate intoxication may be mild or severe. The mild form is called salicylism. The symptoms include headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhea, sweating, hyperpnoea, and electrolyte imbalance. These symptoms are reversible on the stoppage of therapy.

Acute salicylate poisoning

It is common in children. Manifestations are vomiting, dehydration, acid-base and electrolyte imbalance, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse, pulmonary edema, hyperpyrexia, and death.

1. Treatment There is no specific antidote for salicylate poisoning. Treatment is symptomatic.
   • Hospitalization.
   • Gastric lavage followed by administration of activated charcoal (activated charcoal adsorbs the toxic material – physical antagonism).
   • Maintain fluid and electrolyte balance. Correct acid-base disturbances.
   • Intravenous sodium bicarbonate to treat metabolic acidosis. It also alkalinizes the urine and enhances renal excretion of salicylates (since salicylates exist in ionized form in alkaline pH).
   • External cooling.
   • Hemodialysis in severe cases.
   • Vitamin K₁ and blood transfusion if there is bleeding.
2. Drug interactions
   • NSAIDs × glucocorticoids: Potentiation of GI complications – nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration, and GI bleeding.
   • NSAIDs potentiate the effects of oral anticoagulants, oral hypoglycaemic agents (Sulfonylureas), and methotrexate by displacing them from plasma protein
     binding sites.
   • Some of the NSAIDs (for example piroxicam) can impair the clearance of lithium leading to its toxicity.
   • NSAIDs × thiazides/furosemide: NSAIDs, by inhibiting PG synthesis, promote Na+ and water retention on chronic use. Thus, they decrease the diuretic efficacy of thiazides/furosemide.
   • NSAIDs × antihypertensives: By inhibiting PG synthesis, NSAIDs promote Na+ and water retention on chronic use and decrease the efficacy of antihypertensives.
3. Clinical uses of NSAIDs (for basis and explanation, see under pharmacological actions)
   • As analgesic: In painful conditions like headache, toothache, backache, body ache, muscle pain, joint pain, bursitis, neuralgias, and dysmenorrhoea. Selection of NSAIDs should be based on intensity of pain, degree of inflammation, coexisting disease, age, efficacy, safety, route of administration, and cost.
     • Paracetamol/ibuprofen is preferred for mild pain of simple extraction, gingivectomy, etc. Ibuprofen/diclofenac is preferred for moderate post-extraction pain. example removal of impacted the third molar.
     • For moderate to severe pain, a combination of NSAIDs (for example ibuprofen plus paracetamol) or NSAID + opioid can be prescribed. In children, paracetamol, aspirin, ibuprofen, and naproxen are approved for use.
   • As antipyretic: To reduce elevated body temperature in fever, paracetamol is preferred because:
     • GI symptoms are rare.
     • It does not cause Reye’s syndrome.
4. Osteoarthritis: In mild cases, paracetamol is used. In severe cases of osteoarthritis, other NSAIDs are more effective than paracetamol. Topical agents like methyl salicylate, diclofenac gel, and capsaicin cream can also be used.
5. Rheumatoid arthritis: NSAIDs have anti-inflammatory effects and can produce only symptomatic relief, but they do not alter the progression of the disease.
6. Acute rheumatic fever: Aspirin is the preferred drug. It reduces fever, and relieves swelling and joint pain, but does not affect the normal course of the disease.
7. Thromboembolic disorders: The antiplatelet effect of low-dose aspirin is made use of in the prophylactic treatment of various thromboembolic disorders, such as
   • Transient ischaemic attacks.
   • Myocardial infarction (MI)
     1. to reduce the incidence of recurrent MI.
     2. to decrease mortality in post-MI patients.
8. Other uses:
   • Medical closure of patent ductus arteriosus (indomethacin is preferred).
   • Colon and rectal cancer: Regular use of aspirin is reported to reduce the risk of cancer.
   • Aspirin is reported to reduce the risk and retard the onset of Alzheimer’s disease.
   • To control radiation-induced diarrhea.
   • To control pruritus and flushing associated with the use of nicotinic acid.
   • A low dose of aspirin may be useful in pre-eclampsia.
     • Aspirin per se is rarely used at present because of the following disadvantages:
       1. It has a short duration of action, and requires large doses and frequent administration.
       2. Gastric irritation and ulcerogenic effects are the main drawbacks of NSAIDs. The incidence is high with aspirin.
       3. Salicylates should be avoided in children with viral infections.
       4. NSAIDs may precipitate bronchospasm in patients with bronchial asthma (aspirin-induced asthma).
9. Other NSAIDs have similar mechanisms of action, pharmacological actions, therapeutic uses, and adverse effects. They vary mainly in their potency, duration of action, and analgesic and anti-inflammatory effects.
   • Nimesulide
     • Preferential COX-2 inhibitor.
     • Has analgesic, antipyretic, and antiinflammatory effects.
     • Used in dysmenorrhoea, osteoarthritis, skin soft tissue and bone inflammatory conditions.
     • It has been withdrawn in many countries.
     • Adverse effects: GI irritation is less than aspirin and other NSAIDs; skin rashes, itching, and hepatotoxicity have been reported – hence is banned for pediatric use in India.
   • Meloxicam
     • Preferential COX-2 inhibitor.
     • Has analgesic, antipyretic, and anti-inflammatory effects.
     • Is long-acting.

• Nonsteroidal Anti-inflammatory Drugs and Their Important Features

Selective Cox-2 Inhibitors

Some of the COX-2 inhibitors are parecoxib, etoricoxib, etc.

Parecoxib is a prodrug of valdecoxib and is administered parenterally; celecoxib and etoricoxib are given by enteral route.

Differences between Nonselective COX and Selective COX-2 Inhibitors

Paracetamol (Acetaminophen)

Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely distributed all over the body, and metabolized in the liver by sulfate and glucuronide conjugation. The metabolites are excreted in the urine. Differences between aspirin and paracetamol are given in Table.

Differences between Aspirin and Paracetamolses

1. Uses
   • As antipyretic: to reduce body temperature during fever.
   • As analgesic: to relieve headache, toothache, myalgia, dysmenorrhoea, etc.
   • It is the preferred analgesic and antipyretic in patients with peptic ulcer, hemophilia, bronchial asthma, and children.
2. Adverse effects
   • Side effects are rare, and occasionally cause skin rashes and nausea.
   • Hepatotoxicity: with acute overdose or chronic use.
   • Nephrotoxicity is commonly seen in chronic use.
3. Acute paracetamol poisoning Acute overdosage mainly causes hepatotoxicity – the symptoms are nausea, vomiting, diarrhea, abdominal pain, hypoglycemia, hypotension, hypoprothrombinaemia, coma, etc. Death is usually due to hepatic necrosis.
4. Mechanism of toxicity and its treatment

1. • The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and gets eliminated.
   • High doses of paracetamol cause depletion of glutathione levels. In the absence of glutathione, toxic metabolite (NAPQI) binds covalently with proteins in the liver and kidney and causes necrosis.
   • Alcoholics and premature infants are more prone to hepatotoxicity.
   • N-acetylcysteine or oral methionine replenishes the glutathione stores of the liver and protects liver cells.
   • Activated charcoal is administered to decrease the absorption of paracetamol from the gut.
   • Hemodialysis may be required in cases with acute renal failure.
2. Topical NSAIDs Topical formulations of NSAIDs are available. Systemic toxicity is minimal. Diclofenac, ibuprofen, naproxen, etc. are useful topically for musculoskeletal pain. They are used in backache, osteoarthritis, sprain, etc. Flurbiprofen and diclofenac eye drops are used in ophthalmic practice.

Respiratory System

Drugs Used In Treatment Of Cough

Cough is a protective reflex, intended to remove irritants and accumulated secretions from the respiratory passages. Drugs used in the symptomatic treatment of cough are as follows:

• Antitussives
  • Codeine, pholcodine, noscapine, dextromethorphan, antihistamines, chlophedianol, and antihistamines
• Pharyngeal demulcents
  • Lozenges, linctuses, licorice
• Expectorants
  • Sodium and potassium citrate, potassium iodide, guaiphenesin, ammonium chloride
• Mucolytics
  • Bromhexine, acetylcysteine, carbocisteine, ambroxol
• Cough may be:
  • Productive cough: Helps to clear the airway. Suppression of productive cough is harmful, as it may lead to infections. Treatment includes antibiotics for infection, expectorants, and mucolytics for cough.
  • Nonproductive cough: It should be suppressed.

1. Antitussives They inhibit the cough reflex by suppressing the cough center in the medulla. They are used for the symptomatic treatment of dry unproductive cough. Antitussives should be avoided in children younger than 1 year.
   • Codeine:
     • Has cough center suppressant effect.
     • Causes mild CNS depression, hence drowsiness can occur.
     • Causes constipation by decreasing intestinal movements.
     • Should be avoided in children and asthmatics.
     • Codeine is administered orally, has a mild analgesic effect, and has less addiction liability than morphine.
   • Pholcodine: Antitussive action is similar to codeine. It has no analgesic or addiction liability. It is administered orally and has a long duration of action.
   • Noscapine: It is an opium alkaloid with a potent antitussive effect. It is useful in spasmodic cough. It has no analgesic effect and does not cause constipation, addiction, or CNS depression. The side effects are nausea and headache; bronchospasm can occur in asthmatics.
   • Dextromethorphan: It is a centrally acting antitussive agent. It has no analgesic property, and does not cause constipation and addiction; mucociliary function in respiratory passages is not affected. It may cause sedation and hallucination.
   • Antihistamines: Diphenhydramine, chlorpheniramine, promethazine, etc. are useful in cough due to their sedative, antiallergic, and anticholinergic actions. They produce symptomatic relief in colds and coughs associated with allergic conditions of the respiratory tract.
   • Chlophedianol: It has long-lasting antitussive action.
2. Pharyngeal demulcents Syrups, lozenges, linctuses, or licorice may be used when a cough arises due to irritation above the larynx. They increase salivation and produce a protective soothing effect on the inflamed mucosa.
   • The syrup is a concentrated solution of sugar containing the drug to mask the bitter taste of the drug.
   • Lozenge is a solid dosage form placed in the mouth and sucked; it dissolves slowly to liberate the active ingredient. It soothes the irritated mucosa of the throat, e.g. dyclonine (local anesthetic) lozenge for sore throat.
   • Linctus is a viscous liquid sipped slowly to allow it to trickle down the throat; used for relief of cough, for example, linctus codeine.
3. Expectorants (mucokinetics) They increase the volume of bronchial secretion and reduce the viscosity of sputum; hence, cough becomes less tiring and productive. They include iodides, chlorides, bicarbonates, acetates, and volatile oils.
4. Mucolytics These agents break the thick tenacious sputum and lower the viscosity of sputum so that sputum comes out easily with less effort.
   • Bromhexine is a semisynthetic agent used orally. It has potent mucolytic and microkinetic effects
     • Bromhexine Lysosomal enzymes → Digests the mucopolysaccharides → Decreases viscosity of sputum → Cough becomes less tiring and productive.
     • The side effects are rhinorrhoea and lacrimation.
   • Acetylcysteine and Carbocisteine Acetylcysteine is a mucolytic used as an aerosol in the treatment of cough.
     • Acetylcysteine and carbocisteine → open disulfide bonds in mucoproteins of sputum → sputum becomes thin and less viscid → cough becomes less tiring and productive.
     • The side effects are nausea, vomiting, and bronchospasm.
       • Carbocisteine is administered orally. It may cause gastric irritation and, hence should be avoided in patients with peptic ulcer.

Drugs Used In The Treatment Of Bronchial Asthma

In bronchial asthma, there is impairment of airflow due to contraction of bronchial smooth muscle (bronchospasm), swelling of bronchial mucosa (mucosal edema), and increased bronchial mucus secretion. There is inflammation and hyperresponsiveness of the airways.

Several factors may precipitate attacks of asthma in susceptible individuals. They include allergy, infection, and psychological factors. Airway obstruction in asthma is mainly due to the release of mediators from sensitized mast cells in the lungs. They are histamine, serotonin (5-HT), PGs, leukotrienes (LTC₄ and LTD₄), proteases, PAF, etc. Bronchial asthma may be either episodic or chronic.

1. Acute asthma: It is characterized by an episode of dyspnoea associated with expiratory wheezing.
2. Chronic asthma: There is continuous wheezing and breathlessness on exertion; cough and mucoid sputum with recurrent respiratory infections are common.
3. Status asthmaticus (acute severe asthma): When an attack of asthma is prolonged with severe intractable wheezing, it is known as acute severe asthma.

• Classification of antiasthmatic drugs

1. Bronchodilators
   • Sympathomimetics
     • Selective β₂-adrenergic agonists: Salbutamol, terbutaline (short-acting); bambuterol, salmeterol, formoterol (long-acting).
     • Methylxanthines: Theophylline, aminophylline, theophylline, doxophylline.
     • Anticholinergics: Ipratropium bromide, tiotropium bromide.
2. Leukotriene receptor antagonists Zafirlukast, montelukast.
3. Mast cell stabilizers Sodium cromoglycate, and ketotifen.
4. Glucocorticoids
   • Inhaled glucocorticoids: Beclomethasone, budesonide, fluticasone, ciclesonide.
   • Systemic glucocorticoids: Hydrocortisone, prednisolone, methylprednisolone.
5. Anti-IgE monoclonal antibody: Omalizumab.

1. Sympathomimetics

• Mechanism of action

Adrenaline (nonselective sympathomimetic) It produces prompt and powerful bronchodilatation by acting through β2-adrenergic receptors. It is useful in acute attacks of asthma – 0.2–0.5 mL of 1:1000 solution is given subcutaneously. Its use has declined because of its dangerous cardiac side effects.

• • Selective – β₂-adrenergic agonists are the first-line drugs for bronchial asthma. For the mechanism of action – see the flowchart given above.
  • Selective β₂-Agonists
    They are well tolerated when inhaled. They may cause tremors, tachycardia, palpitation, hypokalemia, and, rarely, cardiac arrhythmias.

2. Methylxanthines

The use of methylxanthines in asthma has markedly diminished because of their narrow margin of safety and the availability of better antiasthmatic drugs (selective β2-agonists, inhaled steroids, and leukotriene antagonists).

1. Mechanism of action Methylxanthines inhibit phosphodiesterases (PDEs), thereby preventing the degradation of cAMP and cGMP. This results in the accumulation of intracellular cAMP and some tissues cGMP. Methylxanthines are competitive antagonists at adenosine receptors, which also results in bronchodilatation.

1. Pharmacokinetics Methylxanthines are well absorbed after oral and parenteral administration; food delays the rate of absorption of theophylline. They are well distributed all over the body; and cross placental and blood-brain barriers. They get metabolized in the liver and are excreted in the urine.
   • Theophylline: It is poorly water-soluble, hence not suitable for injection. It is available for oral administration.
   • Aminophylline: It is water soluble but highly irritant. It can be administered orally or slowly intravenously.
   • Etophylline: It is water soluble and can be given by oral, intramuscular (i.m.), or intravenous routes.
   • Doxophylline: It is:
     • A methylxanthine derivative.
     • Orally administered –once or twice daily.
     • Less likely to cause GI and CNS side effects.
2. Adverse effects They have a narrow margin of safety. They can cause tachycardia, palpitation, hypotension (due to vasodilatation), and sometimes sudden death due to cardiac arrhythmias.

1. Drug interactions
   1. Sympathomimetics × methylxanthines

Methylxanthines potentiate the effects of sympathomimetics:

1. 1. • Bronchodilatation (beneficial effect).
      • Cardiac stimulation (harmful effect).
   2. Phenytoin/rifampicin/phenobarbitone × theophylline: They are enzyme inducers, hence they accelerate the metabolism of theophylline and decrease its effect.
   3. Cimetidine/ciprofloxacin/erythromycin × theophylline: They are enzyme inhibitors, hence they potentiate the effects of theophylline by interfering with its metabolism.
2. Uses of methylxanthines
   • Bronchial asthma and chronic obstructive pulmonary disease (COPD): Theophylline is used as an additional drug in moderate and severe persistent bronchial asthma.
   • Apnoea in premature infants: Aminophylline/caffeine is used intravenously to reduce the duration of apnoea episodes. Caffeine is safer than aminophylline.

Anticholinergics

Ipratropium bromide and tiotropium bromide are atropine substitutes. They selectively block the effects of acetylcholine in the bronchial smooth muscles and cause bronchodilatation. They do not affect mucociliary clearance. They have a slow onset of action and are less effective than sympathomimetic drugs in bronchial asthma.

These anticholinergics are the preferred bronchodilators in COPD and can also be used in bronchial asthma. They are administered by the inhalational route and act primarily on larger airways. Tiotropium is longer-acting and more efficacious than ipratropium.

Combined use of ipratropium with β₂-adrenergic agonists produces greater and more prolonged bronchodilatation, hence they are used in acute severe asthma.

Leukotriene Receptor Antagonists

These drugs competitively block the effects of cysteinyl leukotrienes (LTC₄ and LTD₄) on bronchial smooth muscle. Thus, they produce bronchodilatation, suppress bronchial inflammation, and decrease hyperreactivity.

They are well absorbed after oral administration, highly bound to plasma proteins, and metabolized extensively in the liver. They are effective for prophylactic treatment of mild and moderate persistent asthma (in combination with mother drugs). They are well tolerated and produce fewer adverse effects – headache, skin rashes, and rarely eosinophilia.

Mast Cell Stabilizers

Sodium cromoglycate (cromolyn sodium) and ketotifen are mast cell stabilizers. They are not bronchodilators. They inhibit the release of various mediators – histamine, LTs, PGs, PAF, etc. by stabilizing the mast cell membrane. They also reduce bronchial hyperreactivity to some extent, but antigen-antibody reaction (AG–AB reaction) is not affected. The onset of action is slow.

Sodium cromoglycate is not effective orally, as it is poorly absorbed from the gut. In bronchial asthma, sodium cromoglycate is given by inhalation.

1. Uses
   • In allergic asthma, it is used as a prophylactic agent to prevent bronchospasm induced by allergens and irritants.
   • It can also be used in allergic conjunctivitis, allergic rhinitis, allergic dermatitis, etc. by topical route as a prophylactic agent.
2. Adverse effects: Systemic side effects are rare; it may cause symptoms of local irritation cough, bronchospasm, headache, nasal congestion, etc.
   • Ketotifen: The mechanism of action is similar to sodium cromoglycate; it has an additional H₁-blocking effect. It is orally effective but has a slow onset of action.

Glucocorticoids

1. Systemic: Hydrocortisone, prednisolone, methylprednisolone, and others.
2. Inhalational: Beclomethasone, budesonide, fluticasone, etc.

Glucocorticoids induce the synthesis of ‘lipocortin’, which inhibits phospholipase A₂ and thereby prevents the formation of various mediators such as PGs, TXA_2, and SRS-A. Glucocorticoids have antiallergic, anti-inflammatory, and immunosuppressant effects. They:

1. Suppress inflammatory response to AG–AB reaction.
2. Decrease mucosal edema.
3. Reduce bronchial hyperreactivity.

Glucocorticoids do not have a direct bronchodilating effect, but they potentiate the effects of β₂-adrenergic agonists. They also prevent the development of tolerance to β2- adrenergic agonists.

Inhaled glucocorticoids such as beclomethasone, budesonide, and fluticasone are used as prophylactic agents in bronchial asthma. Inhaled corticosteroids are used in patients with persistent asthma who require inhaled β₂ agonists frequently. They are well tolerated. Systemic side effects are rare with these agents.

The common side effects are hoarseness of voice, dysphonia, and oropharyngeal candidiasis. These can be reduced by using a spacer and rinsing the mouth after each dose; oral thrush can be treated effectively by topical antifungal agents, nystatin, or hamycin.

A combination of a long-acting β-agonist (LABA) with a steroid is available, for example, fluticasone + salmeterol; and budesonide + formoterol. They have synergistic action; used in bronchial asthma and COPD. They are used in moderate and severe persistent asthma.

Systemic glucocorticoids are used in acute severe asthma and chronic severe asthma.

Long-term use of systemic steroids produces severe side effects such as gastric irritation, Na⁺ and water retention, hypertension, muscle weakness, osteoporosis, and hypothalamic–pituitary–adrenal axis (HPA axis) suppression.

Anti-IgE Monoclonal Antibody: Omalizumab

Omalizumab prevents the binding of immunoglobulin E (IgE) to mast cells and thus prevents mast cell degranulation. It has no effect on IgE already bound to mast cells. It is administered parenterally route.

It is used in moderate-to-severe asthma and allergic disorders such as nasal allergies and food allergies. It is approved for use in patients older than 12 years of age. It causes local side effects such as redness, stinging, itching, and induration.

Inhalational Devices

They are as follows:

1. Pressurized metered dose inhaler (pMDI): It is a handheld device that can be used alone or with a spacer. It has a pressurized container (canister) with a drug along with a propellant (hydrofluoroalkane [HFA]) and other substances as a solution or suspension. A specific amount of drug is delivered as a fine aerosol into the airways. The small particles reach the smaller airways whereas large ones are deposited in the oral cavity (minimized by using a spacer). Proper coordination is required between use of the device and breathing (difficult for children and the elderly). The patient has to be trained for the correct use of the device.
2. Dry powder inhalers: Spinhaler and Rotahaler. A capsule (rotacap) containing the fine powder form is placed in the Rotahaler.
3. Nebulizers: Useful in acute severe asthma, and COPD and for delivering drugs to young children and the elderly. The drug is delivered in the form of a mist that can easily reach the airways. They are expensive but, unlike pMDI, do not require coordination.

Antiasthmatic agents available as inhalants are β₂-adrenergic agonists (salbutamol, terbutaline, salmeterol and formoterol), anticholinergics (ipratropium bromide and tiotropium bromide), mast cell stabilizers (sodium cromoglycate) and glucocorticoids (fluticasone, beclomethasone, budesonide, etc.).

Treatment Of Acute Severe Asthma (Status Asthmaticus)

1. Humidified oxygen inhalation.
2. Nebulized β₂-adrenergic agonist (salbutamol 5 mg/terbutaline 10 mg) + anticholinergic agent (ipratropium bromide 0.5 mg).
3. Systemic glucocorticoids: Intravenous hydrocortisone 200 mg i.v. stat followed by i.v. hydrocortisone 100 mg q6h or oral prednisolone 30–60 mg/day, depending on the patient’s condition.
4. Intravenous fluids to correct dehydration.
5. Potassium supplements: To correct hypokalaemia produced by repeated doses of salbutamol/terbutaline.
6. Sodium bicarbonate to treat acidosis.
7. Antibiotics to treat the infection.