Anti-Cholinergics Asmah Nasser, M.D.
Anti-Cholinergics • Cholinergic blockers( Anti-cholinergics or parasympatholytics) - class of drugs that block the actions of acetylcholine in the PSNS • Cholinergic blockers allow the SNS to dominate and, therefore, have many of the same effects as the adrenergics. • Muscarinic receptor blockers • Nicotinic receptor blockers
WHAT ARE THE DRUG TARGETS? • Block/Antagonize Muscuranic Receptors • Prevent the release of acetylcholine • Prevent formation of acetylcholine • Deplete acetyl choline storage
Muscarinic receptor blockers 1.Natural alkaloids: Atropine, Scopolamine 2.Semi synthetic drugs : • Homoatropine, tropicamide, (short acting) • Benztropine, ipratropiumglycopyrrolate, Dicyclomaine
Atropine • Muscarinic receptor blocker • Not hydrolyzed by cholinesterase, long duration of action • Actions of Atropine: • Decreased salivary, bronchial and sweat secretion • Mydriasis and cyloplegia (loss of accommodation reflex) • Tachycardia • Constipation • Urinary retention • Excitation /hallucinations
Uses of Atropine • Muscuranic Blocker • To produce mydriasis in refraction error testing (short acting preparations of atropine are preferred) • To treat Heart block, Bradycardia • To treat Cholinesterase inhibitors / Oragnaophosphate (OP)pesticides poisoning • Anti-Diarrheal agent
Atropine • Contrindications of Atropine: • Glaucoma (closed angle) • Urinary retention • Benign prostatic hypertrophy • Paralytic Ileus • Myasthenia Gravis
Other Muscarinic Blockers • Tropicamide: which acts for 4 hours is preferred to produce mydriasis and cycloplegia in refraction error testing and fundoscopy • Benztropine (drug of choice) for treatment of drug-induced Parkinsonism • Ipratropium bromide:Bronchial asthama • Scopolamine: to prevent Motion sickness
Scopolamine • Competitive Muscuranic receptor antagonist • M1 > M2 and M3 • Reduces Nausea • Uses: Prevent sea sickness, used in motion sickness, nausea, etc • Used in a transdermal patch because of CNS side effects
Ipratropium bromide • Muscuranic Anatagnist • Blocks M3 (for smooth muscle contraction) • If used inhaled, will prevent bronchospams bronchodilation • Decreases the secretions made in the respiratory mucosa • Uses: Asthma
Nicotinic Receptor blockers • There are 2 subtypes of Niotinic Receptors: • Nn and Nm • Nn is found in nerves, at the ganglion • Nm is found on muscles.
Nicotinic receptor blockers Ganglionic blocking drugs: Trimethaphen Neuromuscular blockers : • Nondepolarizing: D-tubocurarine , Atracurium • Depolarizing: Succinylcholine
Ganglionic Blocking Drugs • Blocks the Sympathetic and Parasympathetic ANS. • Effects are dependant on the organ sympathetic or parasympathetic activity in that organ is reduced • Side effects are combined with both Symapathetic and Parasynmpathetic Symptoms (depends on what tone that the organ is predominantly supplied by) • Hexamethonium : Not used • Trimethaphen: Used to treat severe hypertensive crises
Ganglionic blockers • Trimethaphen • Nn receptor antagonist. Blocks sympathetic and parasympathetic nervous system • Uses: Hypertensive Crsis • Side effects: Mixed loss of Sympathetic (hypotension) and Parasympathetic Nervous System (tachycardia, constipation, urinary rentention, dry mouth, etc…)
Hemicholinium • Indirect Cholinergic Antagonist • Blocks reuptake/recycle of Choline from the synapse to the pre-synaptic neuron • Not in clinical use
Skeletal Muscle Relaxants Asmah Nasser, M.D.
Neuromuscular blockers • Nm blockers blocks acetylcholine at the Nm receptor. Used in Surgery for skeletal muscle relaxation • Non-depolarizing • Long acting: Tubocurarine, Pancuronium, Doxacuraium • Intermediate acting: Atracurium • Short acting: Miyacurium • Depolarizing: Succinylcholine (shorting acting)
Non-depolarizing Nm Blocker • Example: Turbocurarine (long acting) • MOA: After blocking NM receptors, they prevent depolarization of muscle membrane and muscle contraction • Halothene and Aminoglycosides increase the actions of Nm blockers • Affinity for Nm not much higher than Nn • Side effects: • Ganglionic blocker hypotension • Releases histamine Hypotension, bronchospasm
Other Non-depolarizing Antagonists • Atracurium • Metabolism: By plasma Cholinesterase • Safe in patients with Renal Failure • Intermediate Duration of Action (15 minutes) • Miyacurium • Short acting (minutes) • Used in short procedures (intubations)
Depolarizing Nm Blockers: Succinylcholine • It stimulates the Nm receptor, similar to Ach • Persists at receptor at high concentration, because it is not destroyed by AChE at the Nm junction • “Desensitizes” the end plate by occupying the receptors and causing a “persistent depolarization” leads to flaccid paralysis of muscle • Rapid onset and short duration of action (4-5 minutes) than other Nm blockers • Used mostly in very short procedures (intubation)
Side effects of Succinylcholine • Is metabolized rapidly by plasma pseudocholinestrase. • Side effect: • Therefore pts who have a congenital deficiency is pseudocholinesterase can’t metabolize Succinylcholine toxicity “Succinylcholine Apnea” • Malignant hyperthermia • Hyperkalemia Arrythmias
Antidote? • Neostigmine is used to reserve the effects of Non-depolarizing agents. • It inhibits the cholinesterase enzyme, increasing the amount of acetylcholine in the synapse, displacing Nm antagonists from the post-synaptic receptor.
Malignant hyperthermia • Is an autosomal dominant genetic disorder of skeletal muscle • It is associated with mutations in the gene for the skeletal muscle ryanodine receptor (RYRl), the calcium release channel of the sarcoplasmic reticulum • The specific biochemical abnormality is an increase in free calcium concentration in skeletal muscle cells
Malignant hyperthermia • Rapid onset of hypertension and tachycardia, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance with acidosis, following exposure to a triggering agent. • Is a rare but important cause of anesthetic morbidity and mortality. • Occurs in susceptible individuals who undergoes general anesthesia with inhaled agents (halothene) and skeletal muscle relaxants( eg, succinylcholine).
Treatment of Malignant Hyperthermia Dantrolene : • MOA: Prevents calcium release from the sarcoplasmic reticulum
What to know! • Know the different Cholinergic receptors! • Uses of Atropine, Benztropine, Ipatropium • Know about Ganglionic blockers, their side effects (and why they get those side effects). Know about the use of Trimethaphan • Know the difference between Depolaring and Non-Depolaring Neuromuscular blockers • Know about Malignant Hyperthermia
Pretest question • Of the many types of adrenergic receptors found throughout the body, which is most likely responsible for the cardiac stimulation that is observed following an intravenous injection of epinephrine? • a. α1-adrenergic receptors • b. α2-adrenergic receptors • c. β1-adrenergic receptors • d. β2-adrenergic receptors • e. β3-adrenergic receptors
Pretest Question • Applied to the skin in a transdermal patch (transdermal therapeutic delivery system), this drug is used to prevent or reduce the occurrence of nausea and vomiting that are associated with motion sickness. • a. Diphenhydramine • b. Chlorpromazine • c. Ondansetron • d. Dimenhydrinate • e. Scopolamine
Pretest Question • Which of the following antimuscarinic drugs is used by inhalation in the treatment of bronchial asthma? • a. Dicyclomine hydrochloride • b. Cyclopentolate hydrochloride • c. Ipratropium bromide • d. Methscopolamine bromide • e. Trihexyphenidyl hydrochloride
Pretest Question • A male patient is brought to the emergency department (ED) following ingestion of an unknown substance. He is found to have an elevated temperature, hot and flushed skin, dilated pupils, and tachycardia. Of the following, which would most likely cause these findings? • a. Propranolol • b. Methylphenidate • c. Prazosin • d. Guanethidine • e. Atropine
Preest Question • Of the following, which will not be blocked by atropine and scopolamine? • a. Bradycardia • b. Salivary secretion • c. Bronchoconstriction • d. Skeletal muscle contraction • e. Miosis
Practice Question Competitive Antagonists at the Nm junction include which of the following? A. Dantrolene B. Atracurium C. Mecamylamine D. Isoflurophate E. Succinylcholine
Practice Question Hereditary deficiency in what enzyme can lead to prolonged side effects of Succinylcholine? G6PD Plasma Cholinesterase Pseudocholinesterase Cytochrome Oxidase Liver transaminase
Practice Question Dantrolene is the drug of treament for Malignant hypertherma because: Dantrolene blocks Ca2+ release from the SR Dantrolene induces contraction of skeletal muscle Dantrene increases the rate of succinylcholine metabolism Succinylcholine binding to the Nicotinic receptor is blocked by dantrolene Dantrolene acts centrally to reduce fever
Practice Questions Which of the following agents, when applied topically to the eye, would induce both mydriasis and cycloplegia? Phenylephrine Carbachol Prazosin Atropine
Practice Question Neostigmine would be expected to reverse which one of the following conditions? Paralysis of skeletal muscle by a competitive (non-depolarizing) muscle relaxant Paralysis of skeletal muscle by depolarizing muscle relaxant Cardiac slowing induced by stimulation of the vagus nerve Pupillary miosis induced by bright light