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Here are comprehensive, exam-oriented notes from the Shanbhag Pharmacology source on Autacoids and Respiratory System (Histamine, Antihistamines, 5-HT, Migraine, Prostaglandins & Leukotrienes):

📚 AUTACOIDS & RESPIRATORY SYSTEM — EXAM NOTES

(Shanbhag Pharmacology)

PART 1: HISTAMINE & ANTIHISTAMINES

⭐ AUTACOIDS — Quick Definition

Produced by cells, act locally → also called "local hormones"
Examples: Histamine, Serotonin (5-HT), Prostaglandins, Leukotrienes, Angiotensin, Kinins, PAF

⭐ HISTAMINE — Key Points

Biogenic amine; synthesized by decarboxylation of histidine
Stored in mast cell granules (skin, lung, liver, gastric mucosa, placenta)
Mediator of inflammatory and hypersensitivity reactions

HISTAMINE RECEPTORS — HIGH YIELD TABLE

Receptor	2nd Messenger	Effect
H1	↑ Ca²⁺	Smooth muscle contraction, ↑ capillary permeability
H2	↑ cAMP	↑ Gastric acid secretion
H3 (presynaptic autoreceptor)	↓ cAMP	↓ Histamine in brain, lung, skin, gastric mucosa
H4	↓ cAMP	Chemotaxis, cytokine secretion

HISTAMINE LIBERATORS

AG:AB reaction, food (crab, fish), bile salts
Drugs: Morphine, d-TC, dextran, hydralazine
Effects: itching, urticaria, flushing, hypotension, tachycardia, bronchospasm, angioedema

BETAHISTINE (Histamine Analogue)

Used orally for vertigo in Meniere's disease
Mechanism: improves blood flow in inner ear
Side effects: nausea, vomiting, headache, pruritus
Avoid in: asthma, peptic ulcer

⭐ H1-RECEPTOR ANTAGONISTS (ANTIHISTAMINES)

CLASSIFICATION

First Generation (Conventional): Diphenhydramine, Dimenhydrinate, Promethazine, Cinnarizine, Cyclizine, Meclizine, Hydroxyzine, Pheniramine, Chlorpheniramine maleate, Cyproheptadine, Clemastine, Triprolidine

Second Generation (Non-sedating): Cetirizine, Levocetirizine, Azelastine, Mizolastine, Loratadine, Desloratadine, Fexofenadine, Ebastine, Rupatadine

MECHANISM OF ACTION

Competitive antagonism at H1 receptors
Histamine (agonist) → H1 Receptors ← Antihistamines (antagonists)

FIRST-GENERATION H1-BLOCKERS — Properties

Pharmacological Actions:

CNS depression - sedation, drowsiness (some have antiemetic, local anaesthetic, anti-parkinsonian effects)
Antiallergic - suppress Type I reactions
Anticholinergic - dry mouth, blurred vision, constipation, urinary retention

Pharmacokinetics:

Well absorbed orally and parenterally
Widely distributed, metabolized in liver, excreted in urine

Adverse Effects:

Sedation, drowsiness, psychomotor incoordination → avoid while driving/operating machinery
GI: nausea, vomiting, loss of appetite
Anticholinergic: dry mouth, blurred vision, constipation, urinary retention
Teratogenic (in animals)
Allergic reactions (contact dermatitis on topical use)

USES OF FIRST-GENERATION ANTIHISTAMINES

Use	Drug(s)
Allergic diseases (urticaria, rhinitis, conjunctivitis)	All H1-blockers
Common cold (symptomatic relief)	Sedating antihistamines
Preanesthetic medication	Promethazine
Antiemetic	Promethazine, Diphenhydramine, Dimenhydrinate
Parkinsonism	Promethazine, Diphenhydramine, Orphenadrine
Vertigo (Meniere's)	Cinnarizine, Dimenhydrinate, Meclizine
Sedation/Hypnotic (children, minor surgery)	Promethazine, Diphenhydramine
Blood transfusion reactions (chills, rigors)	H1-blockers
Anaphylaxis (adjunct)	H1-blockers

Antiemetic Mechanism: Motion → Vestibular apparatus (M, H1) → Cerebellum → Vomiting centre (M, H1)

Parkinsonism: Due to imbalance between DA (↓) and ACh (↑) in basal ganglia

SECOND-GENERATION H1-BLOCKERS — Properties

No anticholinergic effects
Lack antiemetic effect
Do not cross BBB → minimal/no drowsiness
Do not impair psychomotor performance
Relatively expensive

SECOND-GEN DRUGS — INDIVIDUAL FEATURES (HIGH YIELD)

Drug	Route/Duration	Key Features
Cetirizine	p.o., 12-24 hr	Also inhibits histamine release; good skin concentration; poorly crosses BBB; may cause drowsiness
Levocetirizine	p.o., 12-24 hr	More potent, fewer adverse effects than cetirizine
Loratadine/Desloratadine	p.o., 24 hr	Long-acting, nonsedating; no cardiac arrhythmias
Fexofenadine	p.o., 12-24 hr	Active metabolite of terfenadine; nonsedating; avoid in prolonged QT interval
Azelastine	Topical (nasal spray, eye drops)	Also inhibits histamine release; rapid onset, long duration; taste alteration, burning sensation
Rupatadine	p.o.	H1-blocker + blocks platelet-activating factor

Uses of 2nd-gen: Rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug/food allergies

For allergic rhinitis: fexofenadine, cetirizine, mizolastine, rupatadine (oral); azelastine (nasal spray)
Eye drops for allergic conjunctivitis: azelastine, levocabastine

⭐ ANTIVERTIGO DRUGS — Summary

Cinnarizine (1st-gen H1, decreases Ca²⁺ entry into vestibular cells)
Promethazine, Diphenhydramine (H1-blockers)
Hyoscine (anticholinergic)
Prochlorperazine (phenothiazine)
Betahistine (H1-analogue)
Acetazolamide, thiazides, furosemide (diuretics)
Diazepam
Amitriptyline (TCA)
Glucocorticoids

PART 2: SEROTONIN (5-HT) — AGONISTS & ANTAGONISTS

⭐ KEY FACTS ABOUT 5-HT

Synthesized from tryptophan (amino acid)
High concentration in: intestine, platelets, brain
7 subtypes of receptors (5-HT1–7); all G-protein coupled except 5-HT3 (ligand-gated ion channel)

5-HT RECEPTOR TABLE (HIGH YIELD)

Receptor	Location	Actions	Drugs
5-HT1	CNS, cranial blood vessels	↓ 5-HT release (autoreceptors); constriction of cranial blood vessels	Buspirone (partial agonist); Triptans (selective 5-HT1B/1D agonists); Ergotamine
5-HT2	Platelets, smooth muscles, cerebral cortex, fundus, choroid	Platelet aggregation, smooth muscle contraction, neuron activation, CSF production	Ketanserin (antagonist); Cyproheptadine (antagonist); Methysergide; Atypical antipsychotics
5-HT3	CTZ, NTS, parasympathetic nerve terminals (GIT)	Vomiting, peristalsis	Ondansetron, Granisetron (antagonists)
5-HT4	GIT, CNS	Peristalsis	Metoclopramide, Prucalopride (agonists)

5-HT ANTAGONISTS — SUMMARY

Drug	Action	Use/Notes
Cyproheptadine	H1 + 5-HT2A blocker; anticholinergic	Carcinoid syndrome, postgastrectomy dumping; increases appetite; side effects: dry mouth, drowsiness, weight gain
Ketanserin	5-HT2A antagonist + α1-blocker	Antihypertensive effect
Ondansetron/Granisetron	5-HT3 antagonists	Antiemetics
Clozapine, Olanzapine, Quetiapine, Risperidone	5-HT2 blockers	Schizophrenia (atypical antipsychotics)
Methysergide	5-HT2A/2C antagonist	Prophylaxis of migraine (long-term use → abdominal and pulmonary fibrosis)

ERGOT ALKALOIDS

Drug	Receptor Action	Effects	Use	ADR
Ergotamine (natural)	Partial agonist/antagonist at α, 5-HT1, 5-HT2	Smooth muscle contraction (blood vessels, uterus, gut)	Acute migraine (oral, sublingual, suppository, rectal)	Vomiting, diarrhoea; overdose → severe vasospasm → gangrene
Dihydroergotamine (DHE)	Predominant α-blockade; weak 5-HT and α-agonist	Less vasoconstriction than ergotamine	Acute migraine (oral, i.m., s.c.)	Nausea, vomiting
Ergometrine (natural)	Partial agonist at 5-HT2; weak action at α-receptors	Major action: uterine contraction; minimal vasoconstriction	Postpartum haemorrhage (i.m., i.v.)	Nausea, vomiting, rise in BP
Bromocriptine (semi-synthetic)	D2-agonist	Decreases prolactin release	Parkinsonism, galactorrhoea (oral)	Vomiting, hypotension

Contraindications of Ergot Alkaloids: Ischaemic heart disease, hypertension, peripheral vascular disease, renal disease

PART 3: DRUG THERAPY OF MIGRAINE ⭐

Migraine Attack: aura (visual disturbance) → severe throbbing headache with photophobia, nausea, vomiting

DRUGS FOR ACUTE ATTACK

1. NSAIDs (mild-moderate migraine): Paracetamol, aspirin, ibuprofen, naproxen, diclofenac, mefenamic acid

2. Antiemetics (oral/parenteral): Metoclopramide, Domperidone, Prochlorperazine, Promethazine, Diphenhydramine

3. Ergot Preparations:

Ergotamine: partial agonist at 5-HT1B/1D → constricts dilated cranial blood vessels + decreases inflammation
Combined with caffeine (increases absorption + vasoconstriction)
DHE (Dihydroergotamine): safer for parenteral use (i.m., i.v., s.c.)

4. Triptans (DRUGS OF CHOICE for moderate-severe migraine):

Examples: Sumatriptan, Rizatriptan, Eletriptan, Almotriptan, Zolmitriptan, Naratriptan, Frovatriptan

Mechanism: Selective 5-HT1B/1D agonists

Abnormal dilatation of cranial blood vessels → Cerebral ischaemia → Migraine attack
Triptans → constrict dilated cranial blood vessels + AV shunts → Restore cerebral blood flow
Also: decrease 5-HT and vasoactive peptide release from presynaptic nerve endings
Inhibit extravasation of plasma proteins in perivascular space

Route: All oral; Sumatriptan also s.c. and nasal; Zolmitriptan also nasal Half-life: Sumatriptan = 2 hours; Frovatriptan and Naratriptan = longer half-life

Adverse Effects of Triptans: Paraesthesia, tightness/flushing/dizziness in chest, nausea, rise in BP, coronary vasospasm

Contraindications of Triptans:

Pregnancy
Ischaemic heart disease
Peripheral vascular disease
Hypertension
Risk factors for coronary artery disease
Triptan + Ergot = NOT together (neither within 24 hours of ergot derivative)

PROPHYLAXIS OF MIGRAINE (Note ABCD — HIGH YIELD)

Letter	Drug Class	Examples
A	Antidepressants (TCAs)	Amitriptyline
B	Beta-blockers	Propranolol, Timolol, Atenolol, Metoprolol (Propranolol most effective)
C	Calcium channel blockers	Verapamil, Flunarizine (selective for cerebral; also Na⁺ channel blocking)
D	Anticonvulsants ("D"rugs for epilepsy)	Gabapentin, Sodium valproate, Topiramate
Others		Methysergide, Cyproheptadine (rarely used)

Note: CCBs should NOT be co-administered with β-blockers. Flunarizine is selective for cerebral Ca²⁺ channels.

PART 4: PROSTAGLANDINS (PGs) & LEUKOTRIENES ⭐

KEY FACTS

Products of long-chain fatty acids
Precursor: Arachidonic acid
Enzyme: Cyclooxygenase (COX) forms PGs from arachidonic acid
COX-1: Constitutive (always present); widely distributed
COX-2: Inducible during inflammation (by cytokines and endotoxins); also constitutively found in brain and kidney
Leukotrienes: obtained from arachidonic acid by lipoxygenase (LOX)

PHARMACOLOGICAL ACTIONS & USES (HIGH YIELD)

1. GI Tract:

PGE2 and PGI2: ↓ acid secretion, ↑ mucus secretion (cytoprotective)
Misoprostol (PGE1 analogue): used for prevention of NSAID-induced ulcers

2. Cardiovascular:

PGD2, PGE2, PGI2: vasodilation
PGF2α: constricts pulmonary veins and arteries
TXA2: vasoconstrictor
PGE1 (Alprostadil): maintains patency of ductus arteriosus before surgery

3. Pulmonary hypertension:

Prostacyclin (PGI2) → decreases peripheral, pulmonary, coronary resistance
PGI2 (Epoprostenol): treats pulmonary hypertension; analogues: Treprostinil, Iloprost

4. Platelets:

PGI2: inhibits platelet aggregation (useful in haemodialysis)
TXA2: promotes aggregation

5. Eye:

PGF2α analogues (Latanoprost, Bimatoprost, Travoprost, Unoprostone): used in glaucoma (topical eye drops, ↓ IOP)

6. Uterus:

PGE2 (low conc.) and PGF2α: contract pregnant uterus
Used in mid-trimester abortion, missed abortion, hydatidiform mole
PGE2 and PGF2α: induce labour at term; promote cervical ripening

7. Male reproductive system:

PGE1 (Alprostadil): used in erectile dysfunction

PROSTAGLANDIN ANALOGUES — TABLE (HIGH YIELD)

Drug	Type	Route	Use
Dinoprostone (PGE2)	PGE2	Vaginal tab/gel	Induction of labour, mid-term abortion, termination of pregnancy
Dinoprost (PGF2α)	PGF2α	Intra-amniotic injection	Mid-term abortion
Carboprost (15-methyl PGF2α)	PGF2α analogue	i.m.	Mid-term abortion, control of PPH
Gemeprost (PGE1)	PGE1	Vaginal pessary	Cervical priming in early pregnancy
Alprostadil (PGE1)	PGE1	i.v. infusion, intracavernosal	Maintain ductus arteriosus; erectile dysfunction
Misoprostol (PGE2)	PGE2 analogue	Oral, vaginal pessary	Peptic ulcer, abortion, PPH
Epoprostenol/Treprostinil/Iloprost (PGI2)	PGI2	i.v. infusion	Pulmonary hypertension
Latanoprost/Bimatoprost/Unoprostone/Travoprost (PGF2α)	PGF2α	Topical (eye drops)	Glaucoma

THERAPEUTIC USES IN OBSTETRICS

Abortion: Dinoprostone, Misoprostol (+mifepristone/methotrexate), Carboprost (2nd trimester), Gemeprost and Dinoprost
Induction of labour: PGE2 (softens cervix)
PPH: Carboprost (i.m.) and Misoprostol (oral)

Adverse Effects of PGs: Nausea, vomiting, diarrhoea, fever, flushing, hypotension, backache (due to uterine contractions); injections painful due to nerve sensitization

LEUKOTRIENES

Obtained from arachidonic acid by lipoxygenase
Leukotriene antagonists: see p. 259 (Montelukast, Zafirlukast — used in asthma)

⭐ QUICK-FIRE HIGH YIELD FACTS (EXAM SHORTCUTS)

Fact	Answer
Histamine is synthesized from	Histidine
Histamine stored in	Mast cell granules
H1 receptor 2nd messenger	Ca²⁺
H2 receptor 2nd messenger	cAMP (↑)
H3 receptor	Presynaptic autoreceptor; ↓ cAMP
Betahistine used for	Vertigo in Meniere's disease
1st-gen antihistamine for antiemetic	Promethazine, Dimenhydrinate
1st-gen antihistamine for vertigo	Cinnarizine, Dimenhydrinate, Meclizine
2nd-gen antihistamine causing drowsiness	Cetirizine (mildly)
Only 5-HT receptor that is NOT G-protein coupled	5-HT3 (ligand-gated)
5-HT3 antagonists (antiemetics)	Ondansetron, Granisetron
Drug of choice — acute severe migraine	Triptans (5-HT1B/1D agonists)
Triptan with shortest half-life	Sumatriptan (2 hours)
Triptan + ergot contraindication	Never within 24 hours of each other
Best beta-blocker for migraine prophylaxis	Propranolol
COX-1 vs COX-2	COX-1 = constitutive; COX-2 = inducible by inflammation
Precursor for PGs and leukotrienes	Arachidonic acid
Enzyme for PGs	COX (Cyclooxygenase)
Enzyme for Leukotrienes	Lipoxygenase
Misoprostol used for	NSAID-induced ulcers, abortion, PPH
Alprostadil (PGE1) used for	Ductus arteriosus patency, erectile dysfunction
PGI2 analogue for pulmonary hypertension	Epoprostenol, Treprostinil, Iloprost
PGF2α eye drops for glaucoma	Latanoprost, Bimatoprost, Travoprost
Carboprost used for	Mid-term abortion + PPH control
Methysergide long-term side effect	Abdominal and pulmonary fibrosis
Rupatadine unique feature	H1-blocker + blocks platelet-activating factor
Fexofenadine is active metabolite of	Terfenadine

Exam Tip: Remember migraine prophylaxis as "ABCD" — Antidepressants, Beta-blockers, Calcium channel blockers, Drugs (anticonvulsants). Triptans are preferred for acute moderate-severe attacks. Never combine Triptans with Ergot preparations.

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