1DENTAL PHARMACOLOGY EXAM 2 REVIEWFeb. 25, 2011This document has been edited with Infix PDF Editor - free for non-commercial use.To remove this notice, visit: www.iceni.com/unlock.htm-2- Overview of Autonomic PharmacologyPharmacological (not anatomical) Division of PNS: Cholinergic vs. AdrenergicCholinergic: All preganglionic and parasympathetic postganglionic Acetylcholine is theneurotransmitter at ganglia, nmj, and muscarinic tissue synapsesAdrenergic: Postganglionic sympathetic neurons (most). Norepinephrine is thetransmitterExceptions: Cholinergic transmission in sympathetic system - all ganglia, adrenal medulla, sweatglands (muscarinic) Dopaminergic innervation in sympathetic system - renal blood vesselsImportant steps of Neurotransmission: Synthesis, storage, release, recognition, andmetabolism. Know where drugs can intervene, and what are the differences between cholinergic andadrenergic systems in terms of these 5 steps.Cholinergic Neurons: Rate limiting step is choline transport into neurons. Mostimportant mechansim of degradation is AchEAdrenergic Neurons: Kow the enzymes involved in synthesis and degradation. Use of VMA in 24-hr urine for diagnosis of pheochromocytoma (how does itwork). Uptake is one of the many mechanisms for removal of released NE. Negative feedback by an autoreceptor (what is this).Receptor FunctionsAgonistic vs antagonisticDirect-acting vs. indirect-acting (e.g. inhibition of AchE has same effect as Achoverdose)Know for major organ systems which type of innervation predominates and what itseffect is. If both types are present, know their opposite effects. 1) Eye 2) Heart 3)Vascular smooth muscle 4) Bronchial smooth muscle 5) GI tract 6) Genitourinary tract7) Glands (sweat, salivary) [remember: “Flight or Fight” vs. “Rest and Digest”]If you know the predominant innervation of the systems above, you will be able topredict the physiological consequences resulting from pharmacological activation orblockade of adrenergic or cholinergic receptors.“Functional types” of cholinergic synapse/receptors: Muscarinic receptors at end organ(G-protein linked receptors) Nicotinic receptors at nmj, ganglia (ion-channel linked receptors)-3-Activation of Muscarinic receptors causes DUMBELS syndrome: Defecation, Urination,Miosis, Bronchoconstriction, Emesis, Lacrimation, SalivationActivation of adrenergic receptors causes different effects: Relative potency of Epi, NE,and Isoproterenol. Know the major difference between "1 and "2 receptors. Knowhow different tissue distribution results in different effects: $1 (heart), $2 (blood vessels),and $3 (adipose tissue).CHOLINERGIC NEURONSAcetylcholine is the transmitter; know its synthesis and breakdown Activity terminated by hydrolysis of transmitter by AchEKnow the 2 “functional types” of cholinergic synapse/receptors Muscarinic receptors at end organ (G-protein linked receptors) Nicotinic receptors at nmj, ganglia (ion-channel linked receptors)Both types activated by acetylcholine and its stable ester analogs (bethanachol, carbachol) (Why is Ach not an effective drug?)Know the physiological consequences of activation of Muscarinic receptors Drop in blood pressure due to activation of non-innervated muscarinic receptorscausing NOS release and relaxation in vascular smooth muscle often accompanied by reflex tachycardiaUseful muscarinic agonists - pilocarpine (glaucoma), bethanechol (bladder or gi atony)Inhibition of AchE has the same effect as Ach “overdose” (prolongs its action at thesynapse) types of Ach inhibitors - reversible (eg Neostigmine, Physostigmine) irreversible (organophosphate pesticides and nerve gasses)Effects - primarily muscarinic (dumbels syndrome); nicotinic effects (ganglionic and nmj)only at high doses-4-Death can be caused by respiratory insufficiency (bronchoconstriction, secretion, centraldepression, depolarizing ganglionic blockade)Antidotes - Atropine -blocks muscarinic end-organ effects Pralidoxime - reactivates AchEClinical uses of AchE inhibitors (reversible): glaucoma, myasthenia gravis, atropinepoisoning, Alzheimers disease (semi-experimental)Muscarinic Antagonists: Atropine, scopalomine autonomic effects: tachycardia, pupil dilation, cycloplegia, loss of secretion,bronchodilation (once used as antiasthmatic) vasodilation, decreased gut motilitycentral effects: hallucination, delerium, treat motion sickness (scopolamine) Antidote to atropine poisoning: Physostigmine (penetrates CNS)Atropine useful in treating poisoning due to AchE inhibitionGanglionic Blockers (Antinicotinic) Competitive inhibitors - Mecamylamine and Trimethaphan These do not affect muscarinic or NMJ nicotinic receptors Originally used vs hypertension (vasodilation due to interruption of sympathetic vasculartone), Trimethaphan used in extreme emergency (dissecting Aortic aneurism), but nototherwise useful due to mulltiple, often unpredictable side effects (global ganglionicblockade)Nicotine will initially stimulate postsynaptic ganglionic nicotinic receptors (agonism),producing sympathetic effects in the cardiovascular system and parasympathetic effectsin the gut; however, it is not hydrolyzed by AchE and a depolarizing ganglionic blockade(antagonism) results with complex effects Neuromuscular Blockers (Antinicotinic) act at NMJ Competitive (non-depolarizing) blockers: Tubocurarine, pancuronium,vecuroniumUseful for producing skeletal muscular paralysis during surgery Have some antiganglionic and antivagal (muscarinic) side effectsDepolarizing blocker: succinylcholine activates nicotinic receptor (initial fasciculations), then repolarization is inhibitedand blockade results Also useful in surgery due to rapid onset; beware of genetic defect in serumesterase (greatly prolonged paralysis)-5-ADRENERGIC NEURONSNorepinephrine is the main transmitter; epinephrine is a “long distance” transmitteralso dopamineKnow important steps in adrenergic transmitter (catecholamine) metabolism: Synthesis, vesicular uptake and storage, triggering of release, release, activation ofpostsynaptic receptors, activation of presynaptic receptors, uptake, catabolism Know examples of drugs that can affect each of these steps Subtypes of postsynaptic (and presynaptic) receptors: alpha 1 and 2, beta 1 and 2 (and3), dopaminergic;Important sites of alpha 1 receptors - vascular smooth muscle, iris radial muscle,piloerector musclealpha 2 - presynaptic terminals (feedback) Plateletsbeta 1 - heartbeta 2 - bronchial smooth