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Overview

Overview. Definition and classification Alkaloids Quaternary and non-quaternary synthetics Mechanism of action (MOA) Prototypes: atropine; scopolamine Therapeutic uses Toxicity Contraindications. Definition: Drugs that block the actions of ACh at:

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Overview

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  1. Overview • Definition and classification • Alkaloids • Quaternary and non-quaternary synthetics • Mechanism of action (MOA) • Prototypes: atropine; scopolamine • Therapeutic uses • Toxicity • Contraindications

  2. Definition: Drugs that block the actions of ACh at: • central and peripheral muscarinic receptors • nicotinic receptors at neuromuscular junction {NMJ} • nicotinic receptors in ganglia Often referred to as anticholinergics or antimuscarinics

  3. Classification Anticholinergic drugs Antimuscarinic Antinicotinic M 1—selectiveNonselective Ganglion blockers Neuromuscular blockers

  4. Antimuscarinics Naturally occurring compounds (Belladonna alkaloids) Atropine scopolamine Quaternary compounds: Ipratropium Propantheline Non-quaternary compounds Dicyclomine Homatropine

  5. Mechanism of action • -reversible blockade of ACh at muscarinic receptors by competitive binding-reversal by increasing ACh or agonist ----> decreased blockade • Nonselective blockers compete for both M1 and M2 receptors (eg. atropine) • Selective blockers compete for M1 (eg. pirenzepine)

  6. CLASSIFICATION OF ANTIMUSCARINIC DRUGS Tertiary amines Quaternary ammonium compounds -Atropine -Scopolamine -Homatropine -Cyclopentolate -Tropicamide -Dicyclomine -Pirenzepine -Benztropine -Trihexyphenidyl -Propantheline -Methantheline -Glycopyrrolate -Mepenzolate -Methscopolamine -Ipratropium

  7. Atropine • -prototype antimuscarinic drug-derived from Atropa belladonna (deadly nightshade) and Datura stramonium (thorn apple) History: • during the Italian renaissance dilated pupils were considered desirable • plant extracts were used as cosmetic eye drops • hence the name belladonna or "beautiful lady" in Italian

  8. SENSITIVITY OF DIFFERENT ORGANS TO ATROPINE Dose (mg) Affectedorgans 0.25-0.5 Heart (M1 autoreceptor on postganglionic parasympathetic terminals); lacrimal, salivary and sweat glands. 0.5-1 heart (M2 receptors); lacrimal, salivary and sweat glands: sphincter muscle of iris. 1-2 Above organs affected; ciliary muscle. 2-5 Above organs more affected; intestinal, bronchial and bladder smooth muscle; gastric glands; CNS.

  9. Atropine Pharmacokinetics Atropine is relatively lipid soluble and readily crosses membranebarriers. The drug is well distributed into the CNS and other organsand is eliminated partially by metabolism in the liver and partiallyby renal excretion. The elimination half-life is approximately 2 hours, and the duration of action of normal doses is 4-8 hoursexcept in the eye, where effects last for 72 hours or longer.

  10. Actions 1.Cardiovascular system effects • Heart: • low dose bradycardia(M1) • high dose tachycardia(M2) • Vascular • no (direct) effect • except, dilate cutaneous vessels (red as a beet) • block hypotensive effect of muscarinic agonists

  11. Actions 2.Extravascular smooth muscle • Eye: • mydriasis (dilation of iris sphincter) • cycloplegia (relaxation of ciliary muscle) • Increase in IOP • Bronchial: relaxation- Decreased tracheobronchial secretions- Decreased mucociliary clearance (not with ipratropium) • GIT: decreased tone, motility (antispasmodic effect) • Urinary: relaxation of detrusor, ureter; constriction of sphincter • Glands decrease in all secretions

  12. Mydriatic antimuscarinics

  13. OPHTHALMIC ACTIONS OF ATROPINE Atropine limits focusing to distant objects Accomodation is blocked by atropine

  14. Eye Fluid Production and Pressure Cornea Anteriorchamberangle Iris Trabecularmeshwork Schlemm’scanal (out) Pupil Posteriorchamber Ciliarybody (in) Lens Vitreous Zonule Cassel, Billig, Randall Fig 8-2

  15. Glaucoma Closed-Angle Glaucoma Open-AngleGlaucoma Blocked drainage of aqueous Blocked drainage of aqueous Anterior chamber open Anterior Chamber angle closure Blockage at trabecular meshwork Cassel, Billig, Randall Fig 8-4 Cassel, Billig, Randall Fig 8-3

  16. Actions 3.Central nervous system • Action at respiratory center • therapeutic dose: faster deeper breathing • larger doses: depression of respiration • Cerebral centers: • low doses: sedation • high doses: restlessness, amnesia, delirium • higher doses: stupor; coma • Note: with therapeutic doses, atropine generally has less CNS sedative effects

  17. Therapeutic uses Eye • - Iritis, iridocyclitis, choroiditis (to prevent adhesion formation) • - For funduscopic examination (mydriasis) • - For measurements of refractive errors (cycloplegia) Gastrointestinal system • Irritable bowel syndrome. Reduce motility for reduction of pain, constipation, or diarrhea • - Abdominal colic, biliary colic. • - Diarrhea (from mild dysentery, diverticulitis, or drug induced).

  18. Therapeutic uses • Urologic disorders Detrusor hyperreflexia, enuresis Increase bladder capacity Decrease bladder pressure • Cardiovascular system - Cardiopulmonary resuscitation (when vagal hyperactivity is the cause of cardiac arrest). - Sinus or nodal bradycardia (due to myocardial infarction, hyperactive carotid sinus reflex, etc.) - A-V block (due to increased vagal tone). • Preoperative use (to block cardiovagal reflexes)

  19. Therapeutic uses • Anesthesiology (partly historical) • Prevention of bronchial and salivary secretions • Prevent bronchospasm • Reversal of reflex bradycardia or hypotension during surgery • Organophosphate overdose

  20. Side effects They are consequences of their pharmacological actions and largely depend on the therapeutic uses of the drug. Thus, when atropine is used to treat diarrhea, the appearance of tachycardia is considered a side effect, but when the same drug is used to counteract sinus bradycardia, the appearance of stypsis is regarded as a side effect.

  21. Side effects constipationUrinary retention hyperthermiaMydriasis headacheBlurred vision DizzinessFlushing, dry skin ExcitementHeart palpitation Mental confusion, memory loss, hallucinations

  22. Belladonna Poisoning: • Nonprescription drugs • Plants of the Solanaceae family • Antiparkinsonian drugs

  23. Classic symptoms of belladonna poisoning: • Hot as a hare • Dry as a bone • Red as a beet • Blind as a bat • Mad as a hatter • Bloated as a toad

  24. Contraindications - Glaucoma - Prostatic hypertrophy - Urinary tract obstruction - Gastrointestinal tract obstruction - Gastric ulcer - Infectious diarrhea - Reflux esophagitis - Tachyarrhythmias - Angina - Hyperthyroidism - Old age - Pregnancy

  25. SCOPOLAMINE • Source • Chemical nature of the molecule • Nature of blockade • Changes in the dose response curve of muscarinic agonists in the presence of scopolamine • Lower doses of scopolamine (0.1 - 0.2 mg) produce greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia • Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine

  26. SCOPOLAMINE • Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria • In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine • Therapeutic use - prophylaxis of motion sickness;

  27. Bronchial smooth muscle relaxation- Decreased tracheobronchial secretions- Decreased mucociliary clearance (not with ipratropium)

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