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Autonomics
Key points in Syllabus
| Question | Answer |
|---|---|
| What does Botulism A block? Proteins? | exocytosis of Acetylcholine causing flacid paralysis. Toxins proteases cleave: VAMP, SNAP-25, syntaxin which are neccessary for exocytosis of ACh. |
| What does alpha-latrotoxin (mechanism) | Black widow spider venom; Ca dependent stimulation of neurotransmitter vesicle fusion with plasma membrane;release of cytoplasmic transmitter into nerve jxns through pores induced in plasma membrane; |
| Where is Butyrocholinesterase found? Other names for it? | Pseudocholinesterase, in plasma and liver. |
| Receptors Epi hits, norepi? | Epi hits everything. Norepi everything but B2. |
| Curare (function) | South american arrow poison, blocks nicotinic effects of acetyl choline |
| Atropine (function) | alkaloid from deadly nightshade plant selectively blocked the muscarinic effects. |
| Nicotinic Cholinergic Receptors | ligand gated ion (Na, Ca); Pentamers; 2 ACh must bind to alpha; Found at NMJ, all autonomic ganglia, chromaffin cells of adrenal medulla. |
| M1,3,5 | Gq->PLC->PIP2->IP3+DAG->contraction of smooth muscle + secretion |
| M2,4 | Gi/o->activate K channels-|Adenylate Cyclase-|volt gated Ca channels-> decreas. inotropy/chronotropy. |
| Which M receptor predominates in the heart? | M2 |
| Rate limiting step for Norepi syn? | first step: tyrosine->dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. |
| Epi syn (pathway and enzymes) | Tyrosine->DOPA->dopaminep->(into vesicle)->norepi->epi;Enzymes:tyrosine hydroxylase; DOPA decarboxylase; Dopamine B hydroxylase (DBH); phenylethanolamine N-methyltransferase (PNMT); |
| Vesicular contents (4) | transmitter, ATP, chromagrins, dopamine-B-hydroxylase (DBH); |
| Norepi inactivation | Reuptake:transport into presynaptic neuron by transporter; Different from the one responsible for reuptake of dopamine in the vesicles; diffusion also plays a small role. |
| Which enzymes inactivate catecholamines (2)what is their role? | Monoamine Oxidase(MAO): mitochond. enzyme, metabolizes trans. in the nerve term; Catechol-O-methyltransferase (COMT): wide distrib, metabolism of circulating catecholamines-> normetanephrine (NMN); Little/no role in syn. cleft=inhib. doesn't incr. act. |
| Vanillylmandelic acid (VMA; 3-methoxy-4-hydroxymandelic acid) Fxn. Clinical relevance? | Fxn-> metabolite by action of MAO and COMT on catecholamines;Clin. relevance-> measure metab in urine for pheochromocytoma. |
| Alpha-1 adrenergic; Most important location? | Gq->PLC->Ca; Located on structures innervated by sympathetic neurons; Ca mediated smooth muscle contraction and glandular secretion; |
| Alpha-2 Adrenergic; notable location? | Gi/Go-|inhib. Adenylate cylase->activate K channels-|inhib. volt. gated Ca channels->hyperpolarization;presynaptic on adrenergic nerve terminals-> mediate feedback inhib. of norepi release; |
| Beta1&2 | Gs->Adenylyl cyclase->cAMP->contraction;B1->heart;B2->smooth muscle; B3->adipose tissue, stimulate lipolysis; |
| What is not innervated by the parasympathetic nervous system? | Vascular system. |
| Name two important fxnal. prop of ACh | Quaternary Amine: + charge-> low penetration into CNS;Ester bond for degradation |
| Locations of ACh release (5)Name receptors in those areas | Autonomic Ganglia: Nicotinic (Ng)Parasymp. post. gang. neuroeffector jxns (NEJ): exocrine glands, smooth muscle, viscera->muscarinic;CNS-> nicotinic and muscarinicNon innerv. tissues: endothelial cells-> muscarinic; |
| hemicholinium | blocks choline transport into nerve terminal;transport mediated by Na symporter-> rate limiting step. |
| Nicotinic/Muscarinic: classic agonist/antagonist | Nicotinic: nicotine/d-tubocurarine;Muscarinic: muscarine/atropine |
| ACh binding: Excitatory/Inhibitory effects | Excitatory: depolarization of post synp. membranes, increase in cytosolic Ca;Inhibitory: hyperpolarization of postsynaptic membranes; |
| alpha-latrotoxin (symptoms) | severe pain, muscle spasms from site of bite, heavy sweating, stomach cramps, naus/vomit, tightness in chest/dif. breathing, increas BP; |
| Botulinum A toxin (Botox) therapeutic applications (5) | strabismus, blepharospasm, focal dystonia, hyperhydrosis, cosmetic procedures; Local inject effects last for weeks. |
| Tetanus Toxin | Enters inhibitory interneurons in spinal cord, blocks release of inhib substances similar to MOA of Botulinum toxin on stimulatory neurons. leads to tetanus. |
| Butyrylcholinesterase (BChE) 3 properties | Prefers butyrylcholine as substrate; General distribution; Interst for metabolism of some drugs. |
| Categories of cholinesterase inhibitors (2)Give one example of each | Reversible: physostigmine;Irreversible: organic phosphates (DFP) |
| Poisonous snakes (mech) | krait/cobra-> alpha toxins, peptides that interact with cholinergic receptors with high affinity and specificity--> irreversible antagonism. |
| Dual response of nicotinic receptor | stimulation followed by desensitization: Cont. or massive stimulation of nicotine receptors-> failure to repolarize postsyn. jxn. or desensitization of the receptors. |
| Two unique nicotinic receptor subtypes and drugs that pref. block: | Ganglionic (Ng): block pref by hexamethonium (n=6) located at synapses in autonomic ganglia and adreanl medulla;Neuromuscular (Nm): blocked pref by decamethonium (n=10) at neuromuscular synp. on somatic system |
| Muscarinic receptors: effects of stimulation, what drug blocks all types | GPCR; Effects of stim: slower graded response, used to reg intrinsic activity of organs; All blocked by atropine; |
| Tertiary v. Quaternary amines | Tertiary uncharged and can penetrate BBB (CNS);Quaternary amines charged can't get in. but have additional nicotinic blocking activity. Ex. methonium compounds tertiary amines so no effect on nicotinics in the CNS; |
| nicotinic activation; action by atropine | larger doses are required to stimulate nicotinic receptors (as opposed to muscarinic); atropine has no effect at nicotinics??? |
| Nicotinic muscarinic distribution (4) and Cholinergic induced activity | muscarinics in neuro effector jxns (NEJ); muscarinic recp. in non innervated cells and periph. vasculature; ganglionic muscarinic receptors, depends on penetration; nicotinic ganglionic and neuromuscular receptors- at higher concentrations; |
| Choline esters (3) | 1) acetylcholine: rapid degradation;2)Methacholine: resist. hydrolysis, BChE>AChE; muscarinic and nicotinic effects (Optho).3) Bethanechol: totally resistant to BChE/AChE; muscarinic agonist pronounced in GI and urinary tract smooth muscles; |
| Belladonna Alkaloids (2) Fxn. | Antimuscarinics/Cholinergic Antagonists;Atropine/Scopolamine; Competitive inhibition; tertiary amines->CNS; Atropine>scolp; T1/2=2-4 hrs. |
| Synthetic muscarinic antagonists; (2 Bold) Advantages | Shorter half life = tropicamide;Quat. by local admin= ipratropium/tiotropium;Select. for receptors: pirenzipine (M1), oxybutin (M3); |
| Hierarchy of atropine efficacy | Secretions (salivation/bronchial/sweat) > eye fxn. > UT and GI motility > Gastric Acid secretion; |
| Reason for differential efficacy of atropine | Extent of regulation by parasympathetic tone and involvement of intraneurons/reflexes rather than intrinsic differences in muscarinic receptors; |
| Antimuscarinic intoxication (causes/symptoms/treatment) | Conjuctival application, berries or seeds with alkaloids; fatalities uncommon.Symptoms: antiparasympathetic/abnormal mental state;Treatment: AChE inhibitor physiostigmine, diazapam for psychotic effects; |
| Cholinesterase inhibitors Therapeutic uses (5) | therapeutic: treat myastenia gravis, alzheimers, ophtho, atony of GI and urological tract, term of competitive blocking drugs; |
| Cholinesterase inhibitors (toxilogical properties/low v. high dose) | tox: insecticides and chemical warfare;low dose: enhance endogenous stimulationhigh dose: stimulation through natural leakage of ACh; |
| Reversible AChE inhibition Competitive (2 bold drugs) | Competive: Edrophonium short acting quaternary amine; use for fxnal tests (myasthenia gravis);Donepezil - long acting tertiary amine- CNS effects; |
| Reversible AChE inhibition Carbamoylating (2 bold drugs) | Carbamoylating agents (covalently carbamoylate the active site of esterases- reversed by slow hydrolysis, t1/2 2-6 hrs.)Physostigmine - tertiary amine;Neostigmine - quarternary amine; |
| Irreversible AChE inhibition (1 bold drug) | Organophosphate: phosphorylate the active site; reversal is very slow;Ex. DFP/ malathion, sarin; |
| Sites of AChE Inhibition (4) | At all cholinergic jxns.Post ganglionic parasympathetic muscarinic jxns., ganglionic nicotinic jxns., neuromuscular nicotinic jxns., CNS jxns. |
| General structure of Organic phosphates | Phosphothiolate structure - not active until sulfur exchanged for an oxygen by mixed fxn oxidase (humans do well insects don't);Thioester sub- hydrolysis of group detoxifys. |
| Treatment for Cholinesterase inhibitors (3) | Atropine - reduce muscarinic effects;supportive measures as required;Cholinesterase Reactivators (Oximes-Pralidoxime) only effective against phosphorylating agents. USE EARLY. |
| nicotine receptor (name/location) | alpha-4-beta-2 nicotinic receptors in the nucleus accumbens and prefrontal cortex through stimulated release of dopamine and reward perception. |
| Varenicline | selective partial agonist for A4B2 nicotinic receptors. Modestly stimulate reward and avoid withdrawal symptoms and will block further stimulation by nicotine from smoking. |
| Bupropion | Atypical antidepressant enhances noradrenergic and dopaminergic activity, but inhibiting reuptake of the respective neurotransmitters. Antagonist to nicotinic receptors. |
| Agents that inhibit Ganglionic Nicotinic receptors- all competitive antagonists (3) | hexamethonium - prototype for ganglionic receptors.mercamylamine - secondary amine CNS effectsTrimethaphan- quaternary sulfonium. |
| Ganglionic Nicotinic receptor blockers Clinical utility | hypertensive crisis during acute dissecting aortic aneurysm, controlled hypotension in surgery (alt. to sodium nitroprusside), Control autonomic hyperreflexia associated with injuries to uppper spinal cord. |
| Depolarizing Agents | Agonists for NMJ nicotinic receptor through prolonged stimulation of the receptor and desensitization (Phase II block) Slow recovery.Phase I Block excess ACh more prolonged sig. loss of K from muscle. |
| Neuromuscular blocking agents (clinical uses) | Surgical anesthesia, orthopedic procedures, intubation, electroshock therapy. |
| Malignant hyperthermia | Genetic mutation in the ryanodine receptor; combination of halothane and succinylcholine causes widespread muscular rigidity and rapid rise in temperature. |
Created by:
blue_duck