Antihistamines: How They Work, Types, And Side Effects Question And Answers

Histamine And Antihistamines

Autacoids:

• Autacoids are substances formed in various tissues, have complex physiological and pathological actions and act locally at the site of synthesis.
• They have a brief action and are destroyed locally.
• Hence they are called ‘local hormones’. They differ from true hormones which are produced by specific cells and reach their target tissues through circulation. Greek: autos = self, akos = remedy.

Read And Learn More: Pharmacology Question And Answers

Autacoids include:

• Histamine
• 5-hydroxytryptamine
• Angiotensin
• Kinins
• Prostaglandins
• Leukotrienes
• Platelet-activating factor (PAF)

Histamine:

• Histamine (tissue amine, Histos = tissue) is a biogenic amine formed in many tissues mainly lungs, skin and intestines and is stored in the granules of the mast cells and basophils in an inactive form.
• Degranulation of the mast cells releases histamine. Histamine found in the brain serves as a neurotransmitter. Histamine acts on H₁, H₂, H₃ and H₄ receptors.
• In the stomach, histamine acts on H₁ receptors on the gastric parietal cells to stimulate acid secretion.

Histamine receptors and blockers:

• H₁:  Antihistamine, for example, Promethazine, Ioratadine
• H₂: Ranitidine used in dyspepsia
• H₃: Thioperamide application in obesity, sleep, and neuropsychiatric diseases
• H₄: Clobenpropit chronic inflammatory conditions.

Histamine substitutes:

• Betazole is an H₂ agonist and can be used in gastric function tests.
• Betahistine is an H₁ agonist that may be used to control vertigo in Meniere’s disease.

Histamine Antagonists/Antihistamines

Question 1. Name the antihistamines. Write their uses and adverse effects.
Or
Write short notes on promethazine/chlorpheniramine.
Answer:

Antihistamines competitively block H1 histamine receptors.

Antihistamines Classification:

Antihistamines Actions:

•  Blockade: Blockade of actions of histamine on smooth muscles of the gut, bronchi, blood vessels, and triple response.
• Sedation: First-generation antihistamines cause CNS depression with sedation, dizziness, inability to concentrate, and disturbances of coordination.
• Antimotion sickness and antiemetic effects: Some first-generation antihistamines like promethazine, and diphenhydramine prevent motion sickness and vomiting due to other labyrinthine disturbances. Some of them also control vomiting of pregnancy and doxylamine was used for this with pyridoxine.
• Anticholinergic actions: Many first-generation H₁ blockers have anticholinergic properties with antisecretory (used in rhinorrhea), antiemetic and antiparkinsonian effects.
• Other actions:
  • Local anesthetic effects in high doses.
  • Some of them block α₁-adrenergic and 5-HT receptors.
  • Few block the potassium channels resulting in cardiac arrhythmias.
  • Some like cetirizine inhibit the release of histamine from the mast cells which helps in the treatment of allergies.

Blockade Pharmacokinetics:

Antihistamines are well-absorbed on oral administration, widely distributed in the body, metabolized in the liver, and excreted in the urine.

Blockade Adverse reactions: Adverse reactions are mild and tolerance develops.

• Sedation, dizziness, motor incoordination, and inability to concentrate make driving dangerous while on antihistamines.
• Anticholinergic effects like dryness of mouth, blurred vision, constipation, and urinary retention may be troublesome.
• Epigastric distress, allergic reactions, and headache can also occur. Many of them are teratogenic.

Blockade Drug Interactions:

1. First-gen antihistamines + CNS depressants (barbiturates, alcohol) → sedation added up.
2. First-gen antihistamines + Drugs with anticholinergic effects → anticholinergic effect added up.

Antihistamines Uses:

Allergic conditions: For prevention and treatment of symptoms of allergies like allergic rhinitis, allergic conjunctivitis, hay fever, urticaria, pruritus, some allergic skin rashes and pollinosis. They relieve the pain, and itching in ivy stings and insect bites.

Common cold: First-generation antihistamines reduce rhinorrhea and provide symptomatic relief because of antimuscarinic properties. Sedation also helps.

1. Motion sickness: Given 30–60 minutes before the journey, prevent motion sickness promethazine, dimenhydrinate, flunarizine, meclizine, and cyclizine are useful.
2. Vertigo: Meniere’s disease, vestibular disturbances dimenhydrinate, meclizine, cinnarizine used.
3. Antiemetic: Promethazine to prevent drug-induced and postoperative vomiting. Doxylamine is used in ‘morning sickness’.
4. Preanesthetic medication: Promethazine for sedative, anticholinergic and antiemetic effects.
5. Hypnotic: Sedative antihistamines like diphenhydramine and promethazine are sometimes used to induce sleep.
6. Parkinsonism: Diphenhydramine, orphenadrine, and promethazine are used in drug-induced Parkinsonism due to their anticholinergic actions.
7. Cough: Due to postnasal drip-diphenhydramine helps. Antihistamines are used in many cough syrups; cough due to allergy may respond.
8. Dystonia: Promethazine may be used to relieve acute dystonia due to antipsychotic drugs

Second Generation/Nonsedative Antihistamines:

Question 2. Write a short note on second-generation antihistamines Or list the advantages of second-generation antihistamines over first-generation ones.
Answer:

Second-generation antihistamines like loratadine, desloratadine, cetirizine, and azelastine are commonly used in allergic conditions.

Advantages Over First Generation Antihistamines:

• Selective H₁ blockers.
• No sedation because they poorly cross the blood-brain barrier.
• No anticholinergic side effects pure H₁ blockers.
• Some of them are long-acting.

Disadvantages Over First Generation Antihistamines:

• Therapeutic uses are limited to allergic disorders
• Not effective in motion sickness, cough, rhinorrhea, vomiting and sedation.
• More expensive than first-generation antihistamines.

Over First Generation Antihistamines Adverse effects:

Second-generation agents are generally safe, but some of them can cause QTc prolongation.

Over First Generation Antihistamines Uses :

Allergic disorders like allergic rhinitis and urticaria.

• Azelastine: Azelastine is a newer second-generation antihistamine that also inhibits the release of histamine.
• Other mediators of allergy; given intranasally, it reduces hypersensitivity of the airways as it has good topical antiallergic activity.
• The onset of action is within 30 minutes.

Serotonin

5-hydroxytryptamine (serotonin) is found in various plant and animal tissues including banana, pineapple, wasp, and scorpion stings. Seven subtypes of 5-HT receptors ( 5-HT _1–7) are presently known. All are G protein-coupled receptors except 5-HT₃ which is a ligand-gated ion channel.

Serotonin Actions:

1. CVS: A characteristic triphasic response is seen in blood pressure following IV injection:

• The initial fall in BP is due to increased vagal activity.
• The rise in BP is due to the vasoconstriction of large vessels
• A fall in BP is due to arteriolar dilation.

2. Gastrointestinal tract:

• Increases GI motility and contraction → diarrhea. Activation of 5-HT₄ receptors in the gut promotes ACh release resulting in a prokinetic effect.

3. Other actions:

1. Behavior 5-HT is a neurotransmitter in the CNS and is involved in the control of behavior, mood, and emotion. SSRIs are used in the treatment of depression.
2. Emesis: 5-HT₃ receptors present in the gut and in the vomiting center participate in vomiting.
3. Platelets: Serotonin promotes platelet aggregation (5-HT₂).
4. Respiratory system: 5-HT causes weak bronchoconstriction (5-HTA).
5. Stimulation of sensory nerve endings: Serotonin causes pain if injected into the skin.
6. Skeletal muscles: In ‘serotonin syndrome’ hyperreflexia, increased muscle contractions are noted.

Serotonin Agonists:

Question 3. Name the serotonin agonists and antagonists, and write their therapeutic indications.
Or
Explain why sumatriptan is used in migraine
Answer:

• Sumatriptan a 5 HT _1D/1B-agonist is effective in acute migraine and cluster headaches.
• Stimulates 5-HT HT _1D/1B receptors on presynaptic trigeminal nerve endings and blocks the release of vasodilator peptides.
• The triptans also constrict the cerebral blood vessels.
• Given orally/SC at the onset of an attack, sumatriptan relieves headache (first-line drug in acute migraine) and also suppresses nausea and vomiting of migraine but is short-acting (t½ 2 hours).

Serotonin agonist’s Adverse effects:

• Dizziness, altered sensations, weakness, chest discomfort, and neck pain. It is contraindicated in coronary artery disease.
• Zolmitriptan, almotriptan, frovatriptan, rizatriptan, naratriptan, and eletriptan are other triptans with better bioavailability, longer action, ability to cross BBB, and lower cardiac side effects.

Serotonin agonists Other drugs:

• Buspirone is a 5-HT_1A agonist-antagonist used as an antianxiety agent.
• Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine inhibit the reuptake of serotonin in the synapse and prolong its activity. They are used in depression.
• Withdrawn drugs: Cisapride (5-HT₄ agonist) a prokinetic agent, tegaserod (5-HT₄ agonist) used in irritable bowel syndrome, and dexfenfluramine an appetite suppressant are now withdrawn.

Serotonin Antagonists:

Question 4. Write a short note on serotonin antagonists.
Answer:

Cyproheptadine:

• Blocks 5-HT₂, H₁ histamine, and cholinergic receptors.
• It increases appetite and is used to promote weight gain, especially in children but the weight gained is also lost after withdrawing the drug.
• It is also used in carcinoid tumors, serotonin syndrome, and postgastrectomy dumping syndrome.
• Cyproheptadine is often prescribed for pruritus and seasonal allergy where it could help due to its H₁ receptor-blocking effects.
• Cyproheptadine can cause some drowsiness, dryness of mouth, dizziness, and ataxia.

Ondansetron: It is a 5-HT₃ antagonist used as an antiemetic.
Clozapine: The atypical antipsychotic clozapine is an antagonist at 5HT _2A/2C– receptors.

• Retanserin: Another 5-HT₂ blocker without alpha-blocking actions.
• Lorcaserin: An agonist at 5-HT_2C receptors—approved for use in obesity as it decreases appetite.

Ergot Alkaloids

• Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects rye, millet, and other grains.
• Consumption of such grains results in ‘ergotism’ manifested as gangrene of the hands and feet, hallucinations, and other CNS effects.
• Natural ergot alkaloids include ergometrine, ergotamine, and ergotoxine. The semisynthetic derivatives are also available.

Ergot Alkaloids Actions:

• Ergot alkaloids have agonist, partial agonist, and antagonistic actions at 5-HT and alpha-adrenergic receptors and agonistic actions at CNS dopamine receptors.
• Thus their actions are complex.
• Some of them are powerful hallucinogens, for example, Lysergic acid diethylamide (LSD).
• They cause stimulation of smooth muscles—vascular and uterine smooth muscles. The vasoconstrictor effect is responsible for gangrene.

Ergot Alkaloids Adverse effects:

Nausea, vomiting, and diarrhea are common. Prolonged use results in gangrene due to persistent vasospasm.

Ergot Alkaloids Uses:

• Migraine ergotamine is used for acute attacks.
• Postpartum hemorrhage ergometrine can be used for the prevention and treatment of PPH but not preferred now.

Drugs influencing serotonin activity: