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ANTICHOLINERGICS drugs which are used as emergency and pre medication drugs in Anesthesia
- 2. INTRODUCTION • One group of cholinergic antagonists has already been discussed: the nondepolarizing neuromuscular blocking agents. • These drugs act primarily at the nicotinic receptors in skeletal muscle. • This Topic presents the pharmacology of drugs that block muscarinic receptors. • Although the classification anticholinergic usually refers to this latter group, a more precise term would be antimuscarinic. • In this presentation, the mechanism of action and clinical pharmacology are introduced for three common anticholinergics: atropine, scopolamine, and glycopyrrolate. • The clinical uses of these drugs in anesthesia relate to their effect on the cardiovascular, respiratory, cerebral, gastrointestinal, and other organ systems
- 3. MOA • Anticholinergics are esters of an aromatic acid combined with an organic base. • The ester linkage is essential for effective binding of the anticholinergics to the acetylcholine receptors. • This competitively blocks binding by acetylcholine and prevents receptor activation. • The cellular effects of acetylcholine, mediated through second messengers, are inhibited. • Muscarinic receptors are not homogeneous, and receptor subgroups have been identified, including central nervous system (M1,4,5 ), autonomic ganglia and gastric parietal cells (M1 ), cardiac (M2 ), and smooth muscle (M3 ) receptors. • These receptors vary in their affinity for receptor antagonists
- 4. Cont…
- 5. CLINICAL PHARMACOLOGY General Pharmacological Characteristics • In normal clinical doses, only muscarinic receptors are blocked by the anticholinergic drugs discussed in this presentation. The clinical response to an anticholinergic drug depends on the degree of baseline vagal tone.
- 6. 1. Cardiovascular • Blockade of muscarinic receptors in the sinoatrial node produces tachycardia. • This effect is especially useful in reversing bradycardia due to vagal reflexes (eg, baroreceptor reflex, peritoneal traction, oculocardiac reflex). • A transient slowing of heart rate in response to smaller intravenous doses of atropine (<0.4 mg) has been • reported. The mechanism of this paradoxical response is unclear. These agents promote • conduction through the atrioventricular node, shortening the P–R interval on the electrocardiogram and antagonizing heart block caused by vagal activity. • Atrial arrhythmias and nodal (junctional) rhythms occasionally occur.
- 7. Cont…. • Anticholinergics generally have little effect on ventricular function or peripheral vasculature because of the paucity of direct cholinergic innervation of these areas despite the presence of cholinergic receptors. • Presynaptic muscarinic receptors on adrenergic nerve terminals are known to inhibit norepinephrine release, so muscarinic antagonists may modestly enhance sympathetic activity. • Large doses of anticholinergic agents can produce dilation of cutaneous blood vessels (atropine flush).
- 8. 2. Respiratory • Anticholinergics inhibit respiratory tract secretions, from the nose to the bronchi, a valuable property during endoscopic or surgical procedures on the airway. • Relaxation of the bronchial smooth musculature reduces airway resistance and increases anatomic dead space. • These effects are more pronounced in patients with chronic obstructive pulmonary disease or asthma. 3. Cerebral • Anticholinergic medications can cause a spectrum of central nervous system effects ranging from stimulation to depression, depending on drug choice and dosage. • Cerebral stimulation may present as excitation, restlessness, or hallucinations. Cerebral depression, including sedation and amnesia, reliably occurs with scopolamine. • Physostigmine, a cholinesterase inhibitor that crosses the blood–brain barrier, promptly reverses anticholinergic actions on the brain.
- 9. Gastrointestinal • Salivation is markedly reduced by anticholinergic drugs. Gastric secretions are also decreased with larger doses. • Decreased intestinal motility and peristalsis prolong gastric emptying time. Lower esophageal sphincter pressure is reduced. • Anticholinergic drugs do not prevent aspiration pneumonia. Ophthalmic • Anticholinergics (particularly when dosed topically) cause mydriasis (pupillary dilation) and cycloplegia (an inability to accommodate to near vision). • Acute angle closure glaucoma is unlikely but possible following systemic administration of anticholinergic drugs. Genitourinary • Anticholinergics may decrease ureter and bladder tone as a result of smooth muscle relaxation and lead to urinary retention, particularly in men with prostatic hypertrophy Thermoregulation • Inhibition of sweat glands may lead to a rise in body temperature (atropine fever).
- 10. ATROPINE Physical Structure • Atropine is a tertiary amine. • The levorotatory form is active, but the commercial product is a racemic mixture. Dosage & Packaging • As a premedication, atropine is administered intravenously or intramuscularly in a range of 0.01 to 0.02 mg/kg, up to the usual adult dose of 0.4 to 0.6 mg. • Larger intravenous doses of up to 2 mg may be required to completely block the cardiac vagal nerves in treating severe bradycardia. • Atropine sulfate is available in a multitude of concentrations.
- 11. Clinical Consideration • Atropine is a potent anticholinergic drug used for bradyarrhythmia. • It affects the heart and bronchial smooth muscle. • Patients with coronary artery disease may not tolerate its effects. • Ipratropium bromide, a derivative, is used for bronchospasm with limited systemic absorption. • Ipratropium solution is effective for acute bronchospasm, especially in COPD, often combined with a β-agonist like albuterol. • Atropine has minimal central nervous system effects at usual doses. • It can cause mild postoperative memory deficits and excitatory reactions at toxic doses. • A dose of 0.01 to 0.02 mg/kg provides an antisialagogue effect. • Caution is needed in narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.
- 12. Cont… • Intravenous atropine treats organophosphate pesticide and nerve gas poisoning. • Organophosphates inhibit acetylcholinesterase, leading to bronchorrhea, respiratory collapse, and bradycardia. • Atropine reverses muscarinic stimulation effects but not nicotinic receptor-induced muscle weakness. • Pralidoxime (2-PAM) can reactivate acetylcholinesterase and is used in poisoning cases.
- 13. SCOPOLAMINE Clinical Considerations • Scopolamine is a more potent antisialagogue than atropine and causes greater central nervous system effects. • Clinical dosages usually result in drowsiness and amnesia, though restlessness, dizziness, and delirium are possible. • The sedative effects may be desirable for premedication but can interfere with awakening following short procedures. • Scopolamine has the added virtue of preventing motion sickness. • The lipid solubility allows transdermal absorption and transdermal scopolamine (1 mg patch) has been used to prevent postoperative nausea and vomiting. • Because of its pronounced mydriatic effects, scopolamine is best avoided in patients with closed-angle glaucoma.
- 14. Physical Structure • Scopolamine, a tertiary amine, differs from atropine by the addition of an epoxide to the heterocyclic ring.
- 15. GLYCOPYRROLATE Dosage & Packaging • The usual dose of glycopyrrolate is one-half that of atropine. • For instance, the premedication dose is 0.005 to 0.01 mg/kg up to 0.2 to 0.3 mg in adults. Glycopyrrolate for injection is packaged as a solution of 0.2 mg/mL
- 16. Clinical Considerations • Because of its quaternary structure, glycopyrrolate cannot cross the blood–brain barrier and is almost devoid of central nervous system and ophthalmic activity. • Potent inhibition of salivary gland and respiratory tract secretions is the primary rationale for using glycopyrrolate as a premedication. • Heart rate usually increases after intravenous but not intramuscular administration. • Glycopyrrolate has a longer duration of action than atropine (2–4 h versus 30 min after intravenous administration).