Cholinergic Agonists Flashcards by Trevor Berlo

Cycle of ACh

1) made from acetyl-CoA+choline
2) ACh stored in neruons (quanta)
3) Release of ACh when neruons stimulated by an action potential
4) bind to ACh receptors
5) AChE breaks down ACh
6) acetyl-CoA and choline are recycled

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Two types of receptors that bind ACh

Muscarinic receptors

nicotinic receptors

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Muscarinic Receptors

are at the effector organ level of parasympathetic nervous system
no muscarinic receptors on the sympathetic side

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Nicotinic Receptor

at the ganglionic level of the parasympathetic side and sympathetic side of autonomic NS

bind ACh released from pre-ganglionic and pass to post ganglionic neurons

no inhibitory capabilities-only relay efferent messages sent from CNS

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2 Roles of ACh at Muscarinic Receptors in Parasymathetic NS

1) ACh is released that ACTIVATES muscarinic receptors on target organs (alters organ function by creating a positive stimulus ex contraction of muscle)
2) ACh is released and binds to receptors on nerve terminals to inhibit release of other NT’s (alters organ function by creating negative stimulus (ex relaxation of muscle)

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Role of ACh at Nicotinic Receptors in the Somatic NS

nicotinic receptors present at neruomuscular jxn of skeletal muscles

ACh (or agonist) binding=depolarization of nerve cell=positive stimulus (muscle contraction)

Prolonged binding to receptor causes postganglionic neuron to stop firing=skeletal muscle relxes and prevents further depolarization=muscle paralysis (negative stimulus)

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Cholinomimetic Agnet

Nonacetylcholine compound that mimics actions of ACh

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Cholinomimetic Agents as stimulants (direct agonists)

directly bind to ACh receptors (mimic ACh and bind to receptors)

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Cholinomimetic Agents as AChE inhibitors (indirect agonists)

indirect cholinergic action by inhibiting break down of ACh, ACh will stay in synapse longer and will continue to produce cholinergic action….same action as if you gave more ACh

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Types of Muscarinic Receptors

M1, M2, M3, M4, M5

M1, M3, M5–>cellular excitation (+ response)
M2, M4–>inhibit cellular excitability (-response, relaxation)

compounds will bind as either agonists or antagonists (agonsits will get effect you want plus side fx)

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Where are Muscarinic receptors founds

Mainly on autonomic effector organs

heart, smooth muscle, brain, exocrine glands

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Types of Nicotinic Receptors

Nm–neuromuscular junction

Nn–nicotinic receptors in any other location (CNS, adrenal medulla, autonomic ganglia)

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Direct Acting Cholinomimetics

Esters of Choline
Ex: acetylcholine

Alkaloids (compounds often taken from plants)
ex:muscarin and nicotine

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Choline Esters-Quarternary Ammoniums

makes insoluble lipid (quarternary nitrogen notrogen, wont get to the brain, cant cross BBB–dont usually have CNS problems)

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Characteristics of Quarternary Ammoniums

Hydrophilic (stay in soln and go where blood goes)

Hydrolyzed by AChE–affects their 1/2 life

Variations of structure alter binding affinity to receptors and susceptibility to hydrolysis by AChE

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Cholinomimetic Alkaloids

Tertiary Amines–CAN cross the BBB and cause CNS effects because it’s neutral charged

4 examples of cholinomimetic alkaloids:
Tertiary:
pilocarpine, nicotine, lobeline
Quarternary:
Muscarin (so it cant cross BBB cuz its + charge)

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Characteristicts of Cholinomimetic Alkaloids

well absorbed orally
lipid soluble–> allows for larger volumes of distribution
Not susceptible to AChE

Indirect Acting Cholinomimetic

act by inhibiting AChE

Types of AChE inhibitors

simple alcohols– quarternary ammonium (edrophonium) able to inhibit AChE.

Carbamate esters– of alcohols with quarternary or tertiary ammonium (neostigmine, physostigmine, pyridostigmine)

Organophosphates (pestisides) (echothiophate, isofluorophate)

Binding DIfferences Between AChE Inhibitors

Simple alcohols–> bind weakly and reversibly to AChE=shorter half-life of less than 10 mins

Carbamate Esters-bind reversibly but tighter to AChE=Prolonged half-life 30 minutes to 6 hours

Organophosphates–>covalent binding,extremely stable (nearly irreversible)= very long half-life of hundreds of hours

Cholinomimetic Effects on Eye

contraction of iris sphincter smooth muscle=miosis (pupillary constriction)

contraction of ciliary muscle=responsile for focusing/accomidation

facilitate flow of aqueous humor out of anterior chamber so that you dont have buildup of aqueous fluid in posterior chamber–tx glaucoma

Cholinomimetic Effect on Respiratory System

contraction of smoother muscle in bronchial tree, stimulates secretions from tracheobronchial mucosa

Cholinomimetic Effects on the GI Tract

Increase secretory and motor activity- stimulates salivary and gastric gland secretions

increase peristalsis, relaxes GI sphincters allowsing GI contents to pass along tract

used to tx–>post op ileus congenital megacolan

Cholinomimetic Effects on GU tract

stimulates detrusor muscle (contracts), and relaxation of trigone and sphincter muscles of bladder–> triggers voiding

tx urine retention (use bethanecol, neostigmine)

Direct Cholinomimetics effects on Cardiovascular System (muscarinic agonists)

REDUCE PERIPHERAL VASCULAR RESISTANCE--> vasodilation reduces BP which causes an indirect reflex to increase HR (body's compensatory mechanism) also can decrease HR and reduces C/O difficult to predict what it will do so ACh agonists aren't used often in CV system

Indirect Cholinomimetics effects on Cardiovascular System

AChE inhibitors=increase cholinergic activity in synapse see same effects you see in muscarinic agonist Negative chonotropic-bradycardia Negative Inotropic-drop in C/O modest drop in Bp

Cholinomimetic Effect on Secretory glands

exaggerated muscarinic activity--> sweaty, tearing, increased mucous production/discharge from nose

Direct Cholinomimetics on CNS: Nicotinic Receptors

induce tremor, stimulate emesis (vomiting), stimulate respiratory center

Direct Cholinomimetics on CNS: Muscarinic Receptors

muscarin can't cross the BBB, but there are muscarin receptors in the brain and muscarinic LIKE compounds can get to brain and trigger them induce tremor, hypothermia, interfere w/nociception (ability of body to recognize toxin)

Indirect Cholinomimetics effects on CNS

low concentration causes little effect high concentration causes convulsions, coma, respiratory arrest ex: exposure to organophosphates

Use of Cholinomimetics for Alzheimers

AD=not enough receptors, soo tx with AChE inhibitors AChE inhibitors-->ACh will hang around longer in the synapse and bind to more receptors not curing but will slow progression Ex: tacrine, donepezil, galantamine, rivastigmine

Use of Cholinomimetics with Smoking Cessation

Varenicline (chantix)--> direct nicotinic agonist, it will bind to nicotinic receptors in brain, decreases cravings and pleasurable effects of cigs

Indirect Cholinomimetic Effects on Peripheral Nervous System

will cause discharge of sympathetic and parasympathetic nervous systems Sympathetic--tachycardia or vagal induced bradycardia Parasympathetic- GI, nausea, vomiting, diarrhea, urinary voiding

ACh at Neuromuscular Junction

ACh is released and binds to NICOTINIC receptors on muscle fibers=depolarization=contraction of muscle

Indirect Cholinomimetic effect on Neuromuscular Junction

AChE inhibitors Low Dose-prolong effect of ACh=increased strenght Medium Dose- muscle fibrillation=less effcitve use of muscle High Dose= blocks muscle depolarization=paralysis

Use of Cholinomimetics to Tx Mysthenia Gravis

increase muscle fxn Mysthenia Gravis- antibodies bind to receptors and block ACh binding...give AChE inhibitor that allows ACh to have more time in synapse and find receptors to bind to that aren't being blocked by antibody doesnt cure but improves muscle fxn

Use of Cholinomimetics Reverse Neuromuscular Paralysis

neostimine

Use of Cholinomimetics to Tx Anticholinergic Intoxification

excessive anticholinergics-->dont eleict response they just sit on the receptor and block it-->cause arrhythmias give AChE inhibitors like physostigmine to increase tje amnt of ACh at receptor sites

Toxicity of Direct Muscarinic Agonists

N/V/D, urinary urgency. salivatiom, sweating, cutaneous vasodilation, bronchial constriction tx with atropine and anticholinergics

Toxicity of Direct Nicotinic Agonists

ex acute nicotine toxicity-->CNS stimulation, convulsions, coma, respiratory arrest, skeletal muscle depolarization, leading to blockade, respiratory paralysis. Htn and cardiac arrhythmias.

Toxicity of Cholinesterase Inhibtors

Organophosphates and carna,ate cholinesterase inhibitors symptoms--muscarinic excess (miosis, salivation, sweating, bronchial eonstriction, diaphragm paralysis, vomiting, diarrhea, convulsions) Tx-antidote-parenteral atropine pr pralidoxime