Antihistamine drugs

Antihistamine drugs are drugs which have opposite effect of Histamine. these also known as histamine antagonists or blockers.

Classification of antihistamine drugs

Classification H₁ antagonists based on chemical structure

• Antihistamine drugs are classified into different groups based on their chemical class and also based on the sedation produced as side effect.
  1. First generation
     • Ethanolamines– Diphenhydramine
     • Ethylenediamines- Triplenamine
     • Alkylamines- Chlorpheniramine
     • Piperazines- Cyclizine
     • Phenothiazines- Promethazine
  2. Second generation
     • Alkylamines- Acrivastin
     • Piperazines- Terfenadine, Cetirizine

Classification of H₁ antagonists based on sedation

1. First generation
   • High sedation- Diphenhydramine ,Dimenhydramine, Promethazine
   • Moderate sedation- Pheniramine, Antazoline, Trimeprazine, Cyproheptadine
   • Low sedation- Chlorpheniramine, Mepyramine
2. Second generation
   • No sedation- Terfenadine, Astemizole, Loratadine, Cetirizine
   • Anti vertigo- Cinnarizine

H₁ Antihistamines

H₁ Antihistamines are histamine antagonist or blocker which blocks or inhibit H₁ receptors.

Pharmacological actions of H₁ antihistamines

Antagonism of histamine

H1 antagonists drugs block the histamine induced, bronchoconstriction, contraction of the intestinal and other smooth muscles and the triple response. Fall of blood pressure by low doses of histamine can be blocked, but additional doses of H₂ antagonists are required to block the fall completely.

Release of adrenaline from the adrenal medulla can be abolished by pretreatment with antihistaminics. Constriction of larger blood vessels is also antagonized. Action of histamine on gastric secretion is singularly not affected by these drugs.

Antiallergic action

Many manifestations of immediate hypersensitivity are suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic fall in blood pressure is only partially prevented. The drug of choice for anaphylactic shock is only epinephrine.

On central nervous system

The older (first generation) antihistamincs produce variable degree of CNS depression. This is dependent on the compound’s ability to penetrate blood brain barrier and its affinity for the central H₁ receptors. Some individuals experience stimulant effects like restlessness and insomnia.

Excitement and convulsions are frequently seen at toxic doses. The second generation antihistaminics are practically non sedating. Based on their central nervous system depression, some antihistaminics are used for preventing motion sickness, to reduce tremors, rigidity and sialorrhoea of Parkinsonism. Some are also effective as antitussives.

Anticholinergic action

Antagonistic to muscarinic actions of acetylcholine. If used concurrently with atropine or its substitutes, phenothiazines, tricyclic antidepressants or disopyramide, the anticholinergic action adds up. Second generation antihistaminics are not anticholinergic.

Local anaesthetics

Some drugs like mepyramine and antazoline have strong while others have weak membrane stabilizing property. However, they are not used clinically as local anaesthetics because they cause irritation when injected.

On blood pressure

Most antihistaminics cause a fall in blood pressure on intra venous injection but not on oral administration.

Uptake of nor-adrenaline

Antihistamines inhibit the neuronal uptake of noradrenaline.

Pharmacokinetics of H₁ antihistamines

1. Adequately absorbed orally
2. Bioavailability is approximaely 60%
3. Not interferred by the presence of food in stomach
4. Crosses placenta,and reaches milk,but penetration in brain is poor
5. Excreted unchanged in urine and bile,rest as oxidized metabolites
6. Elimination half life is 2-3 hours

Side effects and toxicity of H₁ antihistamines

1. Side effects are mild but common.
2. Tolerance develops to repeated dose.
3. Sedation, diminished alertness and concentration are observed. Light headedness, motor in co-ordination, fatigue and tendency to fall asleep, loss of appetite, nausea, epigastric disturbance, psychomotor disturbance, dryness of mouth, alteration in bowel movements, urinary hesitancy and blurred vision are some side effects observed.
4. Local application may cause contact dermatitis. Some agents are teratogenic.
5. In acute overdosage excitation, tremors, convulsions, flushing, hypotension, fever and death due to respiratory and cardiovascular failure are noticed.
6. Terfenadine and Astimizole were found to cause cardiac arrhythmias (even banned in some countries)

Clinical uses of H₁ antihistamines

1. Allergic reaction like hay fever
2. Motion sickness, vertigo and sedation
3. Pruritus
4. Common cold
5. Parkinsonism

H₂ Antihistamines

H₂ Antihistamines are histamine antagonist or blocker which blocks or inhibit H₂ receptors. H₂ receptor antihistamines are: Cimetidine, Ranitidine, famotidine, Roxatidine, Nizatidine, Loxatidine. These are the most popular drugs for peptic ulcer (This will be discussed in detail in “Anti-Ulcer drugs” in Systemic Pharmacology subject)

Cimetidine(prototype example), ranitidine ,nizatidine and roxatidine are competitive in action Famotidine competitive and non competitive in action. Loxatidine is non competitive in action.

H₂ antagonists block histamine gastric secretion, cardiac stimulation (in guinea pigs), uterine relaxation (in rat), and bronchial relaxation.

Pharmacological actions of H₂ antihistamines

1. H₂ antagonists block histamine induced gastric secretion, cardiac stimulation (in guinea pigs), uterine relaxation in rat) and bronchial relaxation (H₂ blockers potentiate histamine induced bronchospasm)
2. Attenuate fall in BP due to histamine,specially at the late phase response with high doses
3. Selective in action
4. Have no effect on H₁ mediated responses or on other transmitter/autacoid.
5. Significant in vivo action of H₂ blockers is marked inhibition of gastric secretion.
6. Basal, psychic,neurogenic and gastric phases of secretion are suppressed dose dependantly.
7. Secretory responses to Ach, gastrin, insulin, alcohol,food are attenuated.
8. Reflects the permissive role of histamine in amplifying responses to other secretions.
9. Reduces acid output,volume of pepsin content and intrinsic fator secretion.
10. Normal vitamin B₁₂ absorption is not interfered
11. Have antiulcerogenic effect (60-70% inhibition of 24hour acid output).
12. Gastric ulceration due to NSAIDs, cholinergic and histaminergic agents is prevented
13. They do not possess any direct effect on gastric or oesophageal motility or sphincter tone.

Clinical uses of H2 antihistamines

1. Duodenal ulcer
2. Gastric ulcer
3. Stress ulcers and gastritis
4. Zollinger-Ellison Syndrome
5. Gastroesophageal reflux
6. Prophylaxis of aspiration pneumonia
7. Certain cases of urticaria with H₁ antagonists