Cholinergic Agonists Flashcards
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
Two types of receptors that bind ACh
Muscarinic receptors
nicotinic receptors
Muscarinic Receptors
are at the effector organ level of parasympathetic nervous system
no muscarinic receptors on the sympathetic side
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
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)
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)
Cholinomimetic Agnet
Nonacetylcholine compound that mimics actions of ACh
Cholinomimetic Agents as stimulants (direct agonists)
directly bind to ACh receptors (mimic ACh and bind to receptors)
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
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)
Where are Muscarinic receptors founds
Mainly on autonomic effector organs
heart, smooth muscle, brain, exocrine glands
Types of Nicotinic Receptors
Nm–neuromuscular junction
Nn–nicotinic receptors in any other location (CNS, adrenal medulla, autonomic ganglia)
Direct Acting Cholinomimetics
Esters of Choline
Ex: acetylcholine
Alkaloids (compounds often taken from plants)
ex:muscarin and nicotine
Choline Esters-Quarternary Ammoniums
makes insoluble lipid (quarternary nitrogen notrogen, wont get to the brain, cant cross BBB–dont usually have CNS problems)
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
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)
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
