Cholinergic Pharmacology
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41 terms
Terms | Definitions |
|---|---|
 M1 Receptor:location, signaling mechanism, and response? | Mainly CNS, autonomic ganglia Gq-> PLC->increase IP3->increase Ca increase in cognitive functions |
| M2 Receptor: Location, signaling mechanism, and response? | mainly heart Gi->inhibit AC->decrease cAMP->increase K channel opening decreased ionotropic (force of contraction) and chronotropic (HR) effect. |
| M3 Receptor: Location, signaling mechanism, and response? | mainly smooth muscle and glands Gq--increase intracellular Ca smooth muscle contraction and grandular secretions |
| Effects of ACh on Nicotinic receptors (PSNS stimulation): NMJ, Autonomic Ganglia, adrenal medulla | Neuromuscular Junction (NMJ): Triggers skeletal muscle contraction. Autonomic Ganglia: Increases ganglionic transmission. Overall effect depends on relative predominance of sympathetic and parasymptathetic tone at the end organs Adrenal medulla: Increase secretion of NE. |
| CNS effects of ACh (PSNS stimulation) | Modulation of sleep, wakefulness, learning and memory. Neural plasticity Pain suppression |
| Effects of ACh on Muscarinic receptors in Peripheral tissues (PSNS stimulation) | GI TRACT: Increased GI motility and secretions; relaxation of GI sphincters HEART: Decreased heart rate, conduction and contractility VASCULATURE: Dilation of most vasculature (M3 receptors) BRONCHI: Constriction of the bronchi, with increased bronchial secretions URINARY BLADDER: Constriction of smooth muscle and relaxation of urinary bladder sphincters EYE: Pupillary constriction (miosis) and accommodation to near vision SALIVARY,LACRIMAL, SWEAT GLANDS: Increased secretions |
| Direct-acting muscarinic agonists | Occupy receptor sites for ACh on the membranes of the effector cells of the postganglionic cholinergic nerves Cause increased stimulation of the cholinergic receptor |
| Indirect-acting cholinergic agonists | -React with the enzyme acetylcholinesterase (AChE) and prevent it from breaking down the ACh that was released from the nerve -Cause increased stimulation of the ACh receptor sites |
| Bethanechol | direct acting muscarinic agonist Actions: Acts directly on cholinergic receptors to mimic the effects of acetylcholine; increases tone of detrusor muscles and causes emptying of the bladder. |
| Indirect-Acting Cholinergic Agonists | -DO NOT REACT DIRECTLY WITH ACh RECEPTORS -React chemically with acetylcholinesterase in the synaptic cleft to prevent it from breaking down Ach. -ACh released from the presynaptic nerve accumulates, stimulating the ACh receptors. -Clinically useful agents bind reversibly to acetylcholinesterase, so effects are short lived. |
| Myasthenia Gravis | Definition Chronic muscular disease caused by a defect in neuromuscular transmission Autoimmune disease; patients make antibodies to ACh receptors, causing gradual destruction of them Symptoms Progressive weakness and lack of muscle control with periodic acute episodes |
| Reversible AChE Inhibitors in Myasthenia Gravis | Neostigmine (Prostigmine): Has a strong influence at the neuromuscular junction Pyridostigmine (Regonol, Mestinon): Has a longer duration of action than neostigmine Ambenonium (Mytelase): Available only in oral form; cannot be used if patient is unable to swallow tablets Edrophonium (Tensilon, Enlon): Diagnostic agent for myasthenia gravis. |
| M4 receptors: location, signaling mechanism, and response? | mainly CNS: forebrain Gi->increase K channel opening autoreceptor (will be in presynaptic terminal: most NT have autorec) |
| M5 receptors: location, signaling mechanism, and response? | mainly CNS: substantial nigra, VTA Gq->increase Ca drug seeking behavior/reward pathways: makes people addicted to smoking. |
| Pyridostigmine | Actions: Reversible cholinesterase inhibitor that increases the levels of acetylcholine, facilitating transmission at the neuromuscular junction |
| Alzheimer's Disease | A progressive disorder involving neural degeneration in the cortex Leads to a marked loss of memory and of the ability to carry on activities of daily living Cause of the disease is not yet known There is a progressive loss of ACh-producing neurons and their target neurons |
| Reversible AChE Inhibitors in Alzheimer's Disease | Tacrine (Cognex) First drug to treat Alzheimer's dementia Galantamine (Reminyl) Used to stop progression of Alzheimer's dementia Rivastigmine (Exelon) Available in solution for swallowing ease Donepezil (Aricept) Has once-a-day dosing |
| Donepezil | Indications: Treatment of mild to moderate Alzheimer's disease Actions: Reversible cholinesterase inhibitor that causes elevated acetylcholine levels in the cortex, which slows the neuronal degradation of Alzheimer's disease |
| Reversible AChE Inhibitors: Adverse Effects | Bradycardia Hypotension Increased GI secretions and activity Increased bladder tone Relaxation of GI and genitourinary sphincters Bronchoconstriction Pupil constriction |
| Nerve Gas action | Irreversible AChE inhibitor Action -Leads to toxic accumulations of ACh at cholinergic receptor sites -Can cause parasympathetic crisis and muscle paralysis |
| Nerve Gas effects | Neuromuscular effects: Twitching Weakness Paralysis Respiratory failure ANS effects: Reduced Vision Small pupil size Drooling Sweating Diarrhea Nausea Abdominal pain Vomiting CNS effects Headache Convulsions Coma Respiratory arrest Confusion Slurred speech Depression Respiratory depression |
| Reversing agent of Nerve Gas | Pralidoxime -Protopam -Antidote for irreversible acetylcholinesterase inhibitors -reactivates the blocked enzyme -most useful in treating peripheral drug effects |
| Muscarinic Antagonists: Anticholinergic Drugs | Action -Used to block the effects of acetylcholine on muscarinic receptors. -Lyse, or block effects of the PSNS; also called parasympatholytic agents Uses -Decrease GI activity and secretions (treat ulcers) -Decrease parasympathetic activities to allow the sympathetic system to become more dominant |
| Major effects of must antagonists | Increase heart rate: bc supress musc effect in your heart Decrease GI activity Decrease urinary bladder tone and function Pupil dilation Cycloplegia: Loss of accommodation to near vision |
| Atropine | Prototype of muscarinic antagonists -Derived from the plant Belladonna -Block ONLY the muscarinic effectors in the PSNS and cholinergic receptors in the SNS -Acts by competing with ACh for the muscarinic ACh receptors -Does not block the nicotinic receptors Have little or no effect at the neuromuscular junction |
| Effects of Atropine | Depresses salivation and bronchial secretions Dilates the bronchi Inhibits vagal responses in the heart Relaxes the GI and genitourinary tracts Inhibits GI secretions Causes mydriasis (dilation of the pupil) Causes cycloplegia |
| adverse effects of atropine | Blurred vision Mydriasis Cycloplegia Photophobia Palpitations, bradycardia (loop effect) Dry mouth, altered taste perception Urinary hesitancy and retention Decreased sweating; predisposition to heat prostration |
| clinically relevant anticholinergics | -atropine: blocks PSNS effects in many situations -dicyclomine: relaxes GI tract; treats hyperactive or irritable bowel -glycopyrrolate: adjunct in the treatment of ulcers -propantheline: adjunct in the treatment of ulcers -ipratropium bromide-treatment of asthma and COPD |
| Ipratropium bromide | By blocking muscarinic (M3) receptors ipratropium produces bronchodilation and decreased respiratory secretions A potent antimuscarinic agent that is poorly absorbed after aerosol administration to the airways and is therefore not associated with systemic atropine effects. A quaternary ammonium derivative of atropine, ipratropium bromide is an effective bronchodilator. No CNS effects The failure of higher doses of the muscarinic antagonist to further inhibit the response in these individuals indicates that mechanisms other than parasympathetic reflex pathways must be involved. valuable for patients intolerant of inhaled beta-agonist agents. |
| Agonists on autonomic ganglia | Nicotine, Lobeline: Alkaloids from tobacco plants. Stimulate nicotinic receptors in autonomic ganglia. Both SNS and PSNS systems are activated. End result depends on relative predominance of either systems at the end organs. |
| Effects of Nicotine | -CVS: effects are mainly sympathomimetic -Dramatic hypertension and tachycardia -GI and Urinary tracts: effects are mainly parasympathomimetic (Nausea, vomiting, diarrhea, increased urination) -Increased secretions (bronchial, salivary, sweat) -NMJ: initial muscle contraction followed by muscle fasciculations and ultimately flaccid muscle paralysis (depolarization blockade). |
| nicotinic receptor agonists on NMJ | Succinylcholine: choline ester not metabolized by AChE and highly selective to NM receptors Depolarize the cell membrane continuously resulting in depolarization blockade End result is "Flaccid Muscle Paralysis" USE: Muscle relaxants during anesthesia |
| ganglion blockers | Hexamethonium Trimethaphan |
| NMJ blockers | Tubocurarine, Pancuronium, Atracurium -quaternary ammonium compounds; do not cross BBB -competitive antagonists to Nm ACh receptors in the end plate of NMJ -Confers non-depolarizing block of NMJ resulting in muscle paralysis -Sequence of blockade: (recover in pop way) eye muscles, muscles of face, limbs and pharynx, and respiratory muscles |
| NMJ blockers onset/duration | succinylcholine: (antagonist but acts like agonist)--fast onset and short duration atracurium:intermediate onset/duration Pancuronium: intermediate onset and long duration Tubocurarine: slow onset and long duration |
| at blood vessels, the predominate tone is what? and what are the effects of ganglionic blockade? | SNS; vasodilation and hypotension |
| at the heart, the predominate tone is what? and what are the effects of ganglionic blockade? | PSNS; tachycardia |
| at the GI Tract, the predominate tone is what? and what are the effects of ganglionic blockade? | PSNS constipation; decreased secretions |
| at the urinary bladder, the predominate tone is what? and what are the effects of ganglionic blockade? | PSNS Urinary retention |
| at the salivary glands, the predominate tone is what? and what are the effects of ganglionic blockade? | PSNS dry mouth |
| at sweat glands, the predominate tone is what? and what are the effects of ganglionic blockade? | SNS absence of sweating |
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