1DENTAL PHARMACOLOGY EXAM 2 REVIEWMarch 5, 2009DRUG-RECEPTOR INTERACTIONSKnow general characteristics of signal-transducing receptorsBind to a ligand (drug or endogenous molecule)Participate in a signaling cascadeDistinguish from non-receptor-mediated drug actionGraded or Dose-Response effects (vs. all-or-none)Understand “occupational theory” of drug actionMolecular basis (ligand-receptor interaction)Mathematical descriptionOccupational theory: Response = Max Response * [D]/(Kd +[D])Shapes of dose-response curves Significance of Kd ligand dissociation constant half-max binding when [D] = Kd Understand the difference between Potency and EfficacyKnow the general mechanism of drug-receptor interaction, and recognize dose-response curvesfor:AgonistsAntagonistsCompetitiveNon-competitivePartial AgonistsInverse AgonistsBiochemical Classification of Receptors: Know the general characteristics and mechanism ofaction for:Membrane-bound receptorsG protein-coupledLigand-regulated ion channelsTyrosine Kinase-linkedGuanyl cyclase-linked(Know some specific examples of each type)Cytosolic/nuclear “soluble” receptorsUnderstand basic mechanisms of receptor regulationDesensitization, homologous or heterologousSpare receptors-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 the transmitterExceptions: Cholinergic transmission in sympathetic system - all ganglia, adrenal medulla, sweat glands(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 ofVMA in 24-hr urine for diagnosis of pheochromocytoma (how does it work). Uptake isone of the many mechanisms for removal of released NE. Negative feedback by anautoreceptor (what is this).Receptor FunctionsAgonistic vs antagonisticDirect-acting vs. indirect-acting (e.g. inhibition of AchE has same effect as Ach overdose)Know for major organ systems which type of innervation predominates and what its effect is. Ifboth types are present, know their opposite effects. 1) Eye 2) Heart 3) Vascular smooth muscle 4) Bronchial smooth muscle 5) GI tract 6) Genitourinary tract 7) 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 to predict thephysiological consequences resulting from pharmacological activation or blockade of adrenergicor 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, andIsoproterenol. Know the major difference between "1 and "2 receptors. Know how differenttissue distribution results in different effects: $1 (heart), $2 (blood vessels), and $3 (adiposetissue).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 receptors causing NOSrelease 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 the synapse) 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 athigh 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, atropine poisoning,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 vascular tone),Trimethaphan used in extreme emergency (dissecting Aortic aneurism), but not otherwise usefuldue to mulltiple, often unpredictable side effects (global ganglionic blockade)Nicotine will initially stimulate postsynaptic ganglionic nicotinic receptors (agonism), producingsympathetic effects in the cardiovascular system and parasympathetic effects in the gut; however,it is not hydrolyzed by AchE and a depolarizing ganglionic blockade (antagonism) results withcomplex effects Neuromuscular Blockers (Antinicotinic) act at NMJ Competitive (non-depolarizing) blockers: Tubocurarine, pancuronium, vecuroniumUseful for producing skeletal muscular paralysis