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Cholinergic Drugs (Cholinomimetics)

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1. Cholinoceptor Types

• Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 170

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2. Direct-Acting Cholinomimetics

A. Choline Esters

The muscarinic receptor is strongly stereoselective: (S)-bethanechol is almost 1000 times more potent than (R)-bethanechol.

B. Alkaloids

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3. Organ System Effects of Direct-Acting Muscarinic Agonists

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4. Indirect-Acting Cholinomimetics (Anticholinesterases)

A. Reversible Inhibitors

Neostigmine also has modest direct nicotinic agonist activity at the NMJ in addition to AChE inhibition. - Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 322

B. Irreversible Inhibitors (Organophosphates)

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5. Pharmacological Effects of Anticholinesterases

CNS

• Low doses: EEG activation, alerting response
• High (toxic) doses: generalized convulsions -> coma -> respiratory arrest

Cardiovascular

• Moderate doses: Modest bradycardia, decreased cardiac output, increased vascular resistance (net modest BP rise)
• High (toxic) doses: Marked bradycardia, severely decreased cardiac output, hypotension
• In Alzheimer's patients on AChE inhibitors, BP monitoring is important as hypertension may require dose adjustment of antihypertensives

Neuromuscular Junction

• Therapeutic doses: Potentiate ACh -> increased muscle strength (used in myasthenia gravis, reversal of NMJ blockade)
• Toxic doses: Depolarizing blockade -> fasciculations -> paralysis (including respiratory muscles)

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6. Toxidrome: Cholinergic Crisis / SLUDGE / DUMBELS

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7. Treatment of Cholinergic Toxicity (Organophosphate Poisoning)

1. Atropine (muscarinic antagonist) - high doses to block muscarinic effects; repeat every 5-15 min until secretions dry
2. Pralidoxime (2-PAM) - reactivates phosphorylated AChE if given before aging occurs (within hours); effective against nicotinic effects (muscle paralysis) that atropine does not reverse
3. Benzodiazepines - for seizure control
4. Supportive care: airway management, supplemental O2

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8. Clinical Applications Summary

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Key Memory Aid: Direct vs. Indirect

DIRECT → Bind cholinoceptors (muscarinic/nicotinic)
  Choline esters:  ACh, Methacholine, Carbachol, Bethanechol
  Alkaloids:       Pilocarpine, Muscarine, Nicotine

INDIRECT → Inhibit AChE → ↑endogenous ACh
  Reversible:  Edrophonium, Neostigmine, Pyridostigmine, Physostigmine
               Donepezil, Rivastigmine, Galantamine (CNS - Alzheimer's)
  Irreversible: Organophosphates (insecticides, nerve agents)

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Histamine Pharmacology

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1. Histamine: Chemistry & Synthesis

• Mast cells (tissue) and basophils (blood) - in granules complexed with heparin
• Enterochromaffin-like (ECL) cells of the gastric mucosa
• CNS neurons (hypothalamus, tuberomammillary nucleus)

• Immunologic: IgE-mediated (Type I hypersensitivity) - antigen crosslinks IgE on mast cells
• Non-immunologic: drugs (morphine, tubocurarine, vancomycin), bee/wasp venom, physical stimuli (cold, trauma), complement (C3a, C5a)

1. N-methyltransferase -> N-methylhistamine -> methylimidazoleacetic acid
2. Diamine oxidase (histaminase) -> imidazoleacetic acid

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2. Histamine Receptors

H1 and H2 both mediate vasodilation (H1 via endothelial NO release; H2 via direct smooth muscle effect). Together they produce the full hypotensive response seen in anaphylaxis. - Katzung, p. 437

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3. Organ System Effects of Histamine

The Triple Response of Lewis (intradermal histamine injection)

1. Red spot - local vasodilation (direct H1)
2. Flare - surrounding redness from axon reflex
3. Wheal - local edema from increased capillary permeability

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4. H1-Receptor Antagonists (Antihistamines)

First-Generation H1 Blockers (Sedating)

Second-Generation H1 Blockers (Non-sedating)

Sedation occurs in ~50% of patients taking first-generation antihistamines but only ~7% with second-generation agents. - Katzung, p. 443

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5. Pharmacological Actions of H1 Blockers

CNS

• First-gen: sedation, drowsiness, impaired psychomotor performance, antiemetic (H1 + muscarinic)
• At high doses: CNS stimulation (especially in children) -> tremors, insomnia, convulsions
• Second-gen: no significant CNS effects

Anticholinergic Effects (First-gen only)

• Dry mouth, urinary retention, constipation, blurred vision, tachycardia
• Useful therapeutically as antiemetics and for motion sickness

Local Anesthetic Effect

• First-gen agents (diphenhydramine) block Na+ channels; used as topical anesthetics when conventional agents are unavailable

Alpha-adrenergic Blockade

• Promethazine and some phenothiazine antihistamines can cause postural hypotension

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6. Clinical Uses of H1 Antagonists

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7. H2-Receptor Antagonists

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8. H3 & H4 Receptor Pharmacology

• H3 agonists: Decrease histamine and neurotransmitter (ACh, dopamine, NE, 5-HT) release in CNS
• H3 antagonists/inverse agonists: Pitolisant (also called tirosant) - approved for narcolepsy (promotes wakefulness by increasing histaminergic tone)
• H4 receptor: Expressed on immune cells (mast cells, eosinophils, T cells); involved in chemotaxis and inflammation - currently under investigation as targets for allergic and inflammatory diseases

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9. Adverse Effects & Toxicity of H1 Antihistamines

Important: Terfenadine and astemizole (early second-gen agents) were withdrawn due to fatal cardiac arrhythmias (torsades de pointes) when combined with CYP3A4 inhibitors (ketoconazole, erythromycin). Fexofenadine (active metabolite of terfenadine) is safe.

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10. Summary: Quick Classification Table

HISTAMINE AGONISM (Endogenous histamine effects)
  H1 → bronchoconstriction, vasodilation, permeability, pruritus, CNS arousal
  H2 → gastric acid, + chronotropy, vasodilation
  H3 → CNS autoreceptor (inhibits own release + other NTs)
  H4 → immune cell chemotaxis

H1 ANTAGONISTS
  1st Generation (sedating):
    Diphenhydramine, Chlorpheniramine, Promethazine, Hydroxyzine, Meclizine
  2nd Generation (non-sedating):
    Loratadine, Cetirizine, Fexofenadine, Levocetirizine, Desloratadine

H2 ANTAGONISTS (anti-ulcer):
    Famotidine, Cimetidine

H3 INVERSE AGONIST (narcolepsy):
    Pitolisant

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