Cholinergic Flashcards
Bella Donna Alkaloids
Antimuscarinic. Naturally occurring. Very potent. Includes atropine, hyoscyamine, scopalamine.
Atropine
Antimuscarinic. Used to treat tachycardia in critical care situations with pronounced vagal activity. Also used to dilate pupils, and as a pre-anesthetic topical prep (reduces respiratory secretions and facilitates intubation).
Hyoscyamine
Antimuscarinic. Used to treat overactive GI tracts (IBS, chronic gastric cramping).
Scopalamine
Antimuscarinic. Anti-nausea, anti-seasickness.
Synthetic antimuscarinics
Benztropine, Ipratropium
Benztropine
Antimuscarinic. Used to manage sx of movement disorders (e.g. extrapyramidal syndrome caused by antipsychotics and others)
Ipratropium
Antimuscarinic. Inhaled anticholinergic used to treat pts with COPD to keep secretions under control. Avoids taking a systemic anticholinergic.
Therapeutic effects M-receptor antagonists: ulcers
Selective blockage of the M1 receptors of parietal cells; inhibits acid secretion
Therapeutic effects M-receptor antagonists: asthma
Blockade of m-receptors on bronchioles SM inhibits the constricting effects of parasympathetic innervation. (Ipratropium)
Therapeutic effects M-receptor antagonists: 1st degree AV block
Blockade of m-receptors on the AV node prevents in an antagonistic fashion the slowing of conduction caused by the PSNS. This improves conduction in minor blocks (atropine).
Therapeutic effects M-receptor antagonists: pre-surgery
Inhibits secretions in the upper airways. Inhibits reflex-induced bradycardia and/or cardiac arrest during surgery. (atropine, glycopyrrolate)
Therapeutic effects M-receptor antagonists: IBS
Inhibits propulsive contractions and hypersecretion caused by PSNS. Use of quaternary ammonium derivatives retards absorption and limits systemic effects. (methscoplomine)
Quaternary derivatives
Antimuscarinic drugs that are polar, and therefore do not readily cross the blood brain barrier to enter the CNS.
Therapeutic effects M-receptor antagonists: hyperhidrosis
Inhibits sweating
Therapeutic effects M-receptor antagonists: ocular exams
Causes pupil dilation. (homatropine)
Therapeutic effects M-receptor antagonists: mushroom poisoning
Some mushrooms contain potent m-receptor agonists, which can cause hypersalivation, bradycardia, bronchospasm, hallucinations). Treated with atropine as antidote.
Therapeutic effects M-receptor antagonists: anticholinesterase poisoning
Anticholinesterases include insecticides and nerve gas. Atropine is used to treat ODs from these drugs.
Therapeutic effects M-receptor antagonists: motion sickness
Prophylactic effectiveness against motion sickness (scopolamine–lipid soluble, CNS effects).
Adverse effects M-receptor antagonists: tachycardia
Blockade of m-receptors in the SA node inhibits vagal effects on the heart. Tachycardia can result.
Adverse effects M-receptor antagonists: Xerostomia (dryness of the mouth)
Blockade of m-receptors in salivary glands inhibits salivation of vagal innervation.
Adverse effects M-receptor antagonists: blurred vision
Can inhibit actions of the ciliary muscles (control lens shape), and therefore cause blurry vision. (Cycloplegia: paralysis of accommodation). Also causes dilation of pupils.
Adverse effects M-receptor antagonists: Sedation
Anticholinergic agents that are lipid soluble can cross into the brain and have sedative effects.
Adverse effects M-receptor antagonists: Anhydrosis
Blockade of m-receptors on the sweat glands inhibit sweat production.
Adverse effects M-receptor antagonists:
Tachycardia, Xerostomia (dry mouth), blurred vision, sedation, anhydrosis (decrease in sweating).
Primary receptor at ganglia:
Nicotinic (Nn)
Ganglionic blockers reduce transmission at which ganglia?
Sympathetic and parasympathetic
Nicotine
Depolarizing ganglionic blocker. Agonist. Initial stimulation followed by a polarization blockade.
At moderate doses can produce arousal (agonistic effect). At high doses can cause depression and coma (antagonistic effect).
Mecamylamine
Non-depolarizing blocker. Antagonist. No initial response. Used in the past to treat HTN, but there are better drugs now.
Effects of ganglionic blockage on: systemic arterioles
Predominant innervation: SNS
Vasodilation and reduction of blood pressure
Effects of ganglionic blockage on: cardiac ventricles
Predominant innervation: SNS
Depressed contractility
Effects of ganglionic blockage on: cardiac SA node
Predominant innervation: PSNS
Tachycardia
Effects of ganglionic blockage on: salivary glands
Predominant innervation: PSNS
Xerostomia
Effects of ganglionic blockage on: sweat glands
Predominant innervation: SNS cholinergic
Anhydrosis
Effects of ganglionic blockage on: somatic cells
Very high doses of mecamylamine can block NMJ receptors and cause paralysis
Bethanechol
Muscarinic receptor agonist
Muscarine
Muscarinic receptor agonist - no therapeutic use
Pilocarpine
Muscarinic receptor agonist
Arecoline
Muscarinic receptor agonist - psychoactive
Therapeutic uses of muscarinic receptor agonists:
Gastric Atony: stimulates tonic movement of gastric muscles (bethanechol)
Urinary retention: stimulates SM of GU tract, leading to contractile activity and urinary excretion (bethanechol)
Xerostomia: stimulates secretion of saliva by salivary glands (pilocarpine eye drops)
Glaucoma: stimulates meiosis and ciliary body constriction, which allows for better fluid drainage through the canal of Schlemm, and relieving some intraocular pressure.
Adverse effects of muscarinic receptor agonists
Marked meiosis
Respiratory distress: overstimulation of bronchial SM leads to bronchospasm and hypersecretion
Hypersalvation
Sweating
Intestinal hyperactivity: overstimulation of intestinal SM and glands leads to abdominal cramps and diarrhea.
Hypotension: overstimulation of vascular endothelial cells leads to NO-dependent vasodilation
Bradycardia: overstimulation of the SA node and other cardiac cells can lead to severe bradycardia and other arrhythmias.
Nicotine cardiac effects:
Tachycardia (primary due to Epi released from the adrenal medulla)
Nicotine blood vessel effects:
Vasoconstriction (due to increased sympathetic stimulation from ganglia, as well as Epi released by the adrenal medulla, resulting in increased blood pressure)
With continued use of nicotine, what can happen?
Tolerance to nicotine can develop
Nicotine somatic effect:
At toxic doses, leads to muscle twitching and eventually a polarizing blockade of ganglia and in the NMJ.
Nicotine CNS effects:
Low concentration: increased attention, performance, ability to concentrate
Positive reinforcement due primarily to stimulation of dopamine release
Decreased appetite and increased metabolic activity.
Withdrawal from nicotine can cause HA, restlessness, irritability, insomnia, and increased appetite.
Varenicline
Partial nicotinic agonist. (Chantix). Antagonist action blocks reinforcing properties, agonist action helps to relieve withdrawal symptoms.
Acetylcholinesterase inhibitors
Prevent the breakdown of acetylcholine, producing a pro-cholinergic effect. Not M or N receptor specific, increase ACh levels at all synapses.
Activation of M receptors
Parasympathetic stimulation
Activation of N receptors
Initial stimulation followed by depolarization blockade
Cholinesterase inhibitors are broken into four categories:
Short acting competitive inhibitor at active site of enzyme (Edrophonium)
Noncompetitive inhibitors block entry to active sites of AChE noncompetitively, lasting hours. Used to treat Alzheimer’s dz (Donepezil, Tacrine, Galantamine, Rivastigmine)
Carbamates produce a slow hydrolysis of a carbamate enzyme (Physostigmine, neostigmine, pyridostigmine, carbaryl [insecticide])
Organophosphates produce very slow hydrolysis of phosphorylated enzyme (days to weeks, adding a phosphate bond that cannot be removed). Two categories: Insecticides (malathion, parathion: prodrugs). Nerve gases (Sarin, VX: extremely toxic, very lipid soluble and volatile, high degree of dermal and pulmonary absorption).
Edrophonium
AChE inhibitor. Very short acting (minutes) competitive inhibitor. Used primarily for diagnosis and dose adjustment in Myasthenia Gravis
Donepezil
Noncompetitive AChE inhibitor. Lipophilic reversible inhibitor which produces effective inhibition of AChE in the CNS. Used to treat Alzheimer’s dz, duration of action 6-8 hours
Physostigmine
AChE inhibitor. Used for treatment of glaucoma. Lipid soluble, safe.
Rivastigmine
AChE inhibitor. Used for treatment of Alzheimer’s dz. Route via patch and pill.
Neostigmine, Pyridostigmine
AChE inhibitor. Quaternary derivative of physostigmine: does not cross BBB. Used for treatment of myasthenia gravis, and to reverse paralysis from non-depolarizing muscle blockers (tubocurarine, pancuronium, atracurium)
Carbaryl
Carbamate AChE inhibitor. Home and garden insecticide
Malathion, Parathion
Organophosphate AChE inhibitor. Prodrug (metabolized quickly to inactive compound by mammals and birds, but not insects or fish). Used in aerial crop dusting, mosquito control spraying, home and garden, and lice treatment.
Sarin, VX
Organophosphate AChE inhibitor. Nerve gases. Irreversible AChE inhibitor. Extremely toxic, lipid soluble, high potency, volatile. Used in warfare, large stockpiles in US and Russia.
Therapeutic uses of AChE inhibitors
Belladonna poisoning: AChE inhibitors increase ACh levels, competitively overriding the receptor blockade in atropine poisoning.
Nerve gas poisoning: it’s thought that prophylactic treatment with reversible AChE inhibitors protects against subsequent phosphorylation of the enzyme by organophosphates.
Alzeheimer’s dz: CNS acting anticholinesterases increase brain levels of ACh, thought to overcome some deficits from Alzheimer’s (tacrine, donepezil)
Myasthenia gravis: muscle weakness associated with deficits in Nm receptors at the NMJ. AChE inhibitors increase the ACh levels at the junction, activating a greater percent of the remaining Nm receptors.
Side effects of AChE inhibitors (acronym)
DUMBELS Diarrhea, Diaphoresis Urination Miosis Bradycardia, Bronchospasm, Bronchorrhea Emesis Lacrimation Salivation, Sweating
SLUDGE Salivation, Sweating Lacrimation Urination Diarrhea, Diaphoresis Gastrointestinal upset Emesis
AChE inhibitor toxicity: respiratory paralysis/asphyxia mechanism:
Paralysis of diaphragm and intercostal muscles.
Respiratory congestion and bronchoconstriction
CNS respiratory depression
Treatment for AChE inhibitor toxicity
Respiratory support, atropine (sx relief) and pralidoxime (2-PAM). 2-PAM restores AChE by having a higher affinity for the organophosphate than AChE. Before aging occurs, 2-PAM is able to rip away the organophosphate.
Treatment for myasthenia gravis:
Immunosuppressants and AChE inhibitors. Immunosuppressants decrease the destruction of remaining Nm receptors. AChE inhibitors increase the amount of ACh in the NMJ. (Neostigmine, Pyrodostigmine, Ambenonium). Dx with edrophonium (nml pt would have decreased muscle strength due to depolarization blockade. Pt with MG would have increased muscle strength).
