Know general characteristics of signal-transducing receptors: Bind to a ligand (drug or endogenous molecule) Participate in a signaling cascade Distinguish from non-receptor-mediated drug action Graded or Dose-Response effects (vs. all-or-none) Understand “occupational theory” of drug action Molecular basis (ligand-receptor interaction) Mathematical description Occupational 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 Efficacy.
Know the general mechanism of drug-receptor interaction, and recognize dose-response curves for: Agonists Antagonists Competitive Non-competitive Partial Agonists Inverse Agonists Biochemical Classification of Receptors: Know the general characteristics and mechanism of action for: Membrane-bound receptors G protein-coupled Ligand-regulated ion channels Tyrosine Kinase-linked Guanyl cyclase-linked (Know some specific examples of each type) Cytosolic/nuclear “soluble” receptors Understand basic mechanisms of receptor regulation Desensitization, homologous or heterologous Spare receptors -1- OVERVIEW OF AUTONOMIC PHARMACOLOGY.
PHARMACOLOGICAL (NOT ANATOMICAL) DIVISION OF PNS: Cholinergic vs. Adrenergic Cholinergic: All preganglionic and parasympathetic postganglionic Acetylcholine is the neurotransmitter at ganglia, nmj, and muscarinic tissue synapses Adrenergic: Postganglionic sympathetic neurons (most). Norepinephrine is the transmitter Exceptions: Cholinergic transmission in sympathetic system – all ganglia, adrenal medulla, sweat glands (muscarinic) Dopaminergic innervation in sympathetic system – renal blood vessels Important steps of Neurotransmission: Synthesis, storage, release, recognition, and metabolism.
Know where drugs can intervene, and what are the differences between cholinergic and adrenergic systems in terms of these 5 steps. Cholinergic Neurons: Rate limiting step is choline transport into neurons. Most important mechansim of degradation is AchE Adrenergic Neurons: Know the enzymes involved in synthesis and degradation. Uptake is one of the many mechanisms for removal of released NE. Negative feedback by an autoreceptor (what is this).
Receptor Functions Agonistic vs antagonistic Direct-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. 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 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 the physiological consequences resulting from pharmacological activation or blockade of adrenergic or cholinergic receptors.
“Functional types” of cholinergic synapse/receptors: Muscarinic receptors at end organ (Gprotein linked receptors) Nicotinic receptors at nmj, ganglia (ion-channel linked receptors) Activation of Muscarinic receptors causes DUMBELS syndrome: Defecation, Urination, Miosis, Bronchoconstriction, Emesis, Lacrimation, Salivation Activation of different adrenergic receptors causes different (and tissue-specific) effects: Relative potency of Epi, NE, and Isoproterenol. Know the major difference between alpha1 and alpha2, beta1 and beta2 receptors.
Know how different tissue distribution results in different effects: beta 1 (heart), beta2 (blood vessels), and beta3 (adipose tissue). -2- CHOLINERGIC NEURONS Acetylcholine is the transmitter; know its synthesis and breakdown Activity terminated by hydrolysis of transmitter by AchE Know 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 NOS release and relaxation in vascular smooth muscle often accompanied by reflex tachycardia Muscarinic agonists Direct agonism: Useful muscarinic agonists – pilocarpine (glaucoma), bethanechol (bladder or gi atony) Indirect agonism: 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 at high doses Death can be caused by respiratory insufficiency (bronchoconstriction, secretion, central depression, depolarizing ganglionic blockade) Antidotes to Ach toxicity Atropine -blocks muscarinic end-organ effects Pralidoxime – reactivates AchE Clinical 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 motility central effects: hallucination, delerium, treat motion sickness (scopolamine) Antidote to atropine poisoning: Physostigmine (penetrates CNS) -3- Atropine useful in treating poisoning due to AchE inhibition Ganglionic 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 useful due to mulltiple, often unpredictable side effects (global ganglionic blockade) Nicotine will initially stimulate postsynaptic ganglionic nicotinic receptors (agonism), producing sympathetic 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 with complex effects.
Neuromuscular Blockers (Antinicotinic) act at NMJ Competitive (non-depolarizing) blockers: Tubocurarine, pancuronium, vecuronium Useful for producing skeletal muscular paralysis during surgery Have some antiganglionic and antivagal (muscarinic) side effects Depolarizing blocker: succinylcholine activates nicotinic receptor (initial fasciculations), then repolarization is inhibited and blockade results Also useful in surgery due to rapid onset; beware of genetic defect in serum esterase (greatly prolonged paralysis) ADRENERGIC NEURONS.
Norepinephrine is the main transmitter; epinephrine is a “long distance” transmitter also dopamine, which can interact with dopaminergic and adrenergic receptors Know important steps in adrenergic transmitter (catecholamine) metabolism: Synthesis, vesicular uptake and storage, triggering of release, release, activation of postsynaptic 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 (and 3), dopaminergic;
Important sites of alpha 1 receptors – vascular smooth muscle, iris radial muscle, piloerector muscle alpha 2 – presynaptic neuronal membrane (negative feedback) Platelets beta 1 – heart beta 2 – bronchial smooth muscle, uterus, liver (glycogenolysis) dopaminergic receptors – renal vascular smooth muscle -4- Know relative selectivity of drugs (adrenergic agonists and antagonists) for alpha and beta receptors For beta agonists and antagonists, know relative selectivity for beta 1 and beta 2 Know effects of alpha and beta activation and blockade on following systems:
Vascular smooth muscle, peripheral resistance Heart, cardiac output (also reflex- know this pathway) Bronchial smooth muscle Eye (aDrenergic, raDial muscle, Dilation, myDriasis) Uterus Indirect Acting Drugs (major importance is illustration of mechanism): Acting on Metabolism: Metyrosine, Tyramine, Phenelzine, alpha methyl dopa Acting on release: Amphetamine, guanethidine, bretylium Acting on vesicular transport and storage: reserpine Acting on uptake: Cocaine, imipramine alpha 2 agonists: clonidine -5-