Pharmacology I - PM 716 C9 NE Agonists Slides PDF

PM 716 Pharmacology I Chapter 9 NE Agonists Sympathomimetics RMRocco, PhD PM716 C9 Adrenoceptor Activators 1  Case Study A 68 year old male, light headed when he stands, worse after meals, decreased sweating, urinary retention, On alpha 1 antagonist fo...

PM 716 Pharmacology I Chapter 9 NE Agonists Sympathomimetics RMRocco, PhD PM716 C9 Adrenoceptor Activators 1  Case Study A 68 year old male, light headed when he stands, worse after meals, decreased sweating, urinary retention, On alpha 1 antagonist for urinary retention (tamsulosin) but it worsened his orthostatice hypotension. Supine bp 167/84 mm Hg and standing 106/55 mm Hg. Heart rate did not compensate. Diagnosis pure autonomic failure not caused by other diseases or drugs. PM716 C9 Adrenoceptor Activators 2  Case Study Patient has lost sympathetic tone. Tamsulosin, an alpha blocker, made condition worse. Midodrine, an alpha agonist may help. Patient must avoid over the counter sympathomimetics and sympatholytics. PM716 C9 Adrenoceptor Activators 3 The Catecholamines PM716 C9 Adrenoceptor Activators 4 Adrenergic Neurotransmitters J. Axelrod (1912- 2004) Nobel Prize, 1970 Discovers uptake and release of the catecholamine neurotransmitters. PM716 C9 Adrenoceptor Activators 5  Sympathomimetics Adrenergic agonists Adrenal (L. add + renal) Sympathetic (from sympathy) Adrenergic neurons release norepinephrine (NE) Locations: CNS and link between ganglia and effector organs in PNS. PM716 C9 Adrenoceptor Activators 6  Sympathetic Drugs/Terms Norepinephrine (NE) Epinephrine (EP) (Adrenalin®) Dopamine (DA) Catecholamines (biological amines derived from amino acid tyrosine) double hydroxy Adrenergics (Gr. work) NE, EP, DA. PM716 C9 Adrenoceptor Activators 7  Receptor Organization Sympathetic Pathway CNS Ach NE Adrenergic Receptors a1a2 b1b2 Parasympathetic Pathway CNS Ach Ach Muscarinic Receptors Somatic Pathway CNS Ach Nicot Recp PM716 C9 Adrenoceptor Activators Skel Muscle 8  NE at Adrenergic Neurons (1) Synthesis from tyrosine (2) Storage in vesicles (3) Release of NE into synapse (4) Receptor binding (5) Re-uptake into neuron (6) Removal by MAO PM716 C9 Adrenoceptor Activators 9  Adrenergic Receptors Alpha1 Alpha 2 vasoconstriction inhibits NE release increase peripheral inhibits insulin release resistance increase BP mydriasis increase closure bladder sphincter PM716 C9 Adrenoceptor Activators 10  Adrenergic Receptors Beta 1 Beta 2 tachycardia vasodilation increased lipolysis dec peripheral resis. increased myocardial bronchodilation contractility relax uterine sm increased renin release PM716 C9 Adrenoceptor Activators 11 Chapter 9 Adrenoceptor Agonists & Sympathomimetic Drugs PM716 C9 Adrenoceptor Activators 12 © The McGraw-Hill Companies, Inc,  Adrenergic Drugs Direct-Acting Indirect-Acting epinephrine (cause release of NE) norepinephrine tyramine isoproterenol amphetamine phenylephrine PM716 C9 Adrenoceptor Activators 13  Adrenergic Drugs Mixed Action Drugs ephedrine metaraminol direct acting drugs that also cause release of NE. PM716 C9 Adrenoceptor Activators 14  Cardiac Innervation Sympathetic Parasympathetic NE Ach - Relaxation - + Constriction + Ach blocks stimulation Blood Vessels Heart of heart by NE. PM716 C9 Adrenoceptor Activators 15 Sympathomimetics PM716 C9 Adrenoceptor Activators 16 Chapter 9 Adrenoceptor Agonists & Sympathomimetic Drugs PM716 C9 Adrenoceptor Activators 17 © The McGraw-Hill Companies, Inc, Chapter 9 Adrenoceptor Agonists & Sympathomimetic Drugs PM716 C9 Adrenoceptor Activators 18 © The McGraw-Hill Companies, Inc,  Alpha 1 Receptors Contractssmooth Vascular (increase muscle bp) Pupillary dilator Contracts (mydriasis) muscle Pilomotor smooth muscle Contracts (erect hair) PM716 C9 Adrenoceptor Activators 19  Alpha 2 Receptors Inhibits transmitter Adrenergic and cholinergic release nerve terminals Platelets Some vascular Stimulates aggregation smooth muscle Pancreatic beta cells Contractions Fat cells Inhibit insulin release Inhibits lipolysis PM716 C9 Adrenoceptor Activators 20  Beta 1 Receptors Heart Increase rate and force Stimulate Juxtaglomerular renin release. cells (kidney) PM716 C9 Adrenoceptor Activators 21 Chapter 9 Adrenoceptor Agonists & Sympathomimetic Drugs PM716 C9 Adrenoceptor Activators 22 © The McGraw-Hill Companies, Inc,  Beta 2 Receptors Smooth Relaxes Muscle respiratory uterine vascular Liver Glycogenolysis Pancreatic Beta Cells Insulin release Somatic motor nerve terminals (voluntary Causes muscles)tremor PM716 C9 Adrenoceptor Activators 23  Dopamine Receptors Dopamine Renal and other 1 splanchnic blood vessels……dilation and decreased resistance (lowered BP) Nerve terminals…..Inhibits adenylyl cyclase. Dopamine 2 PM716 C9 Adrenoceptor Activators 24  Sympathomimetic Drugs Mimic the actions of NE produced by nerve terminals in the ANS and epinephrine (EP) produced by adrenals (the catecholamines). Direct Acting by binding to receptors (NE and EP) Indirect Acting by releasing NE from vesicles (amphetamines) or block NE reuptake (TCAs, cocaine). PM716 C9 Adrenoceptor Activators 25 Chapter 9 Adrenoceptor Agonists & Sympathomimetic Drugs PM716 C9 Adrenoceptor Activators 26 © The McGraw-Hill Companies, Inc,  Indirect Agonists Drugs release NE stored in neuron vesicles. Actions are widespread (CNS, PNS) and non-specific. Amphetamine (Adderall®) Ephedrine (po and nasal spray) Phenylpropanolamine PM716 C9 Adrenoceptor Activators 27  Sympathomimetics Amphetamine Cocaine Dextroamphetamine (Dexedrine®) Dopamine (Intropin®) Ephedrine Epinephrine (Adrenalin®) Isoproterenol Methamphetamine (Desoxyn®) Methylphenidate (Ritalin®) PM716 C9 Adrenoceptor Activators 28  Sympathomimetics Oxymetazoline (Neo-Synephrine 12-hour®) Pemoline Phendimetrazine Phenylephrine (Neo-Synephrine®) Pseudoephedrine (Sudafed®) Tricyclic Antidepressants (TCAs) PM716 C9 Adrenoceptor Activators 29  Sympathomimetics Modafinil Norepinephrine Methoxamine Terbutaline Albuterol Metaproterenol Epinephrine Dexmedetomidine Midodrine PM716 C9 Adrenoceptor Activators 30  Sympathomimetics Phenylpropanolamine Ritodine Clonidine Dobutamine PM716 C9 Adrenoceptor Activators 31  Indirect Acting Agonists Releases NT Amphetamine Uptake Inhibitor Cocaine MAO Inhibitor Pargyline Entacapone PM716 C9 Adrenoceptor Activators 32  Sympathomimetic Receptors Raymond Ahlquist in 1948 proposed two different receptors for the binding of catecholamines. Alpha receptors bind EP ≥ NE ≥ isoproterenol Beta receptors bind isoproterenol ≥ EP ≥ NE PM716 C9 Adrenoceptor Activators 33  Agonist Drug Binding Agonist drug binds to adrenergic receptor G-protein activated G-protein activates adenylate cyclase (AC) ATP cAMP Inactive kinase Active kinase Phosphorylation Muscle contracts. PM716 C9 Adrenoceptor Activators 34  Sympathomimetics Beta Receptors: Subtypes B1 B2 B3 Beta 1 equal affinity for NE and EP Beta 2 higher affinity for EP than NE Beta 3 mixed All binding results in increased cAMP PM716 C9 Adrenoceptor Activators 35  Sympathomimetics Alpha Receptors: Subtypes A1 and A2 A1 binds prazosin (blocker, next section) A2 binds yohimbine (not in clinical use) Dopamine Receptors Five subtypes identified and cloned. PM716 C9 Adrenoceptor Activators 36  Sympathomimetics Drug Selectivity for these receptors Alpha Agonists Mixed Alpha and Beta Beta Agonists Dopamine Agonists PM716 C9 Adrenoceptor Activators 37  Sympathomimetics All receptors are G-Protein coupled Variations in the G-Protein alpha protein subunits Gs stimulates adenyl cyclase Gi inhibits adenyl cyclase Gq couples alpha receptors to phospholipase C. PM716 C9 Adrenoceptor Activators 38  Alpha1 Receptors Stimulate polyphosphoinositide hydrolysis which forms inositol triphosphate (IP3) and diacyglycerol (DAG). Ca++ activates protein kinases and cell stimulation. PM716 C9 Adrenoceptor Activators 39  Beta and Alpha2 Receptors A2 receptors inhibit adenylyl cyclase and lower cAMP levels. B1, B2, and B3 activation increases cAMP levels. PM716 C9 Adrenoceptor Activators 40  Dopmaine Receptor Activation stimulates adenylyl cyclase and increases cAMP second messenger. PM716 C9 Adrenoceptor Activators 41  Receptor Desensitization Repeated exposure to catecholamines (endogenous) or drug agonists receptors become less responsive to the drugs or catecholamine. (same as tolerance, refractoriness and tachyphylaxis). Homologous Desensitization: loss of response in the receptors exposed. (receptor becomes phosphorylated by activated kinases) Heterologous Desensitization: loss of response in receptors not exposed to the drug. (activated kinase phosphorylates receptors downstream) PM716 C9 Adrenoceptor Activators 42  Points to Remember Alpha 1 Receptors Located on most vascular smooth muscles. Agonists cause contraction. Beta 1 Receptors Located in heart. Agonists increase rate. Beta 2 Receptors Respiratory and uterine smooth muscle. Agonists relax. PM716 C9 Adrenoceptor Activators 43  Direct Acting Sympatholytics Only NE and EP activate both A and B phenylephrine clonidine alpha 1 alpha 2 = NE EP dobutamine isoproterenol terbutaline beta 1 beta 2 = PM716 C9 Adrenoceptor Activators 44  More Points To Remember Only Ep and NE activate (agonists) at BOTH alpha and beta receptors. All other direct acting drug agonists act at EITHER alpha or beta receptors. Alpha 1 stimulation (with agonist) causes mostly vasoconstriction (phenylephrine) PM716 C9 Adrenoceptor Activators 45 Pharmacokinetics Isoproterenol pure Isoproterenol Pure alpha alpha Absorption and distribution varies with substitutions on the basic phenylethylamine ring Methoxamine, pure beta. PM716 C9 Adrenoceptor Activators 46  Beta Agonists DRUG RECEPTOR CLINICAL EFFECT Dobutamine Beta 1 Increase cardiac rate Dobutrex® and output Isoproterenol Beta 1 = Beta 2 Isuprel® Albuterol Beta 2 Relieve Proventil® bronchoconstriction Terbutaline Brethine® PM716 C9 Adrenoceptor Activators 47  Alpha Receptor Agonists DRUG RECEPTOR CLINICAL EFFECT Phenylephrine Alpha 1 Nasal decongestant Neo-Synephrine® Midodrine Alpha 1 Increase BP ProAmatine® Clonidine Alpha 2 Lower BP through Catapres® CNS actions. PM716 C9 Adrenoceptor Activators 48 Anaphylaxis Epinephrine is drug of choice for immediate treatment of anaphylactic shock. PM716 C9 Adrenoceptor Activators 49  Bronchi Beta agonists (mostly Beta 2) are drugs of choice in treatment of acute asthmatic bronchoconstriction. Short acting such as terbutaline, albuterol, metaproterenol. PM716 C9 Adrenoceptor Activators 50 Cardiovascular NE increases Blood flow in acute heart failure, and some types of shock, beta 1 agonists. PM716 C9 Adrenoceptor Activators 51  CNS Amphetamines mostly for weight loss, attention deficit disorder, narcolepsy, and abused for mood altering effects. PM716 C9 Adrenoceptor Activators 52  Eye Alpha agonists used topically to reduce conjunctival itching caused by allergy (phenylephrine). Eye drops. Treatment of glaucoma (epinephrine) PM716 C9 Adrenoceptor Activators 53  Genitourinary Tract Beta 2 agonists (ritodrine, terbutaline) suppress premature labor. Ephedrine to improve urinary continence. (acts on Alpha receptors in the trigone Ephedrine Sulfate of the bladder). PM716 C9 Adrenoceptor Activators 54  Sympathomimetics Cardiovascular: (a) Blood Vessels: alpha increase arterial smooth muscle resistance, beta2 promote smooth muscle relaxation (lower BP). (b) Heart: mostly beta1, activation increases Ca++ flux, with electrical and mechanical changes. (c) Blood Pressure: Alpha activation elevates BP, beta activation decreases BP through decreased peripheral resistance. PM716 C9 Adrenoceptor Activators 55  Sympathomimetics EYE: alpha agonists increase outflow of aqueous humor, beta decrease the production of this fluid. RESPIRATORY: B2 bronchial smooth muscle cause relaxation. GI: Beta receptors relax smooth muscles, A2 decrease muscle activity presynaptically by reducing release of Ach PM716 C9 Adrenoceptor Activators 56  Sympathomimetics GENITOURINARY TRACT: uterus, beta receptors induce relaxation, alpha in bladder promotes contraction. EXOCRINE GLANDS: salivary glands, control water and amylase secretion. METABOLIC: Beta receptors on fat cells increase lipolysis. PM716 C9 Adrenoceptor Activators 57  Cardiovascular Effects of NE NE: increase total peripheral resistance increase arterial pressure stimulates alpha receptors with constriction of all vascular beds BP rises Increase in BP causes parasympathetic output to heart (reflex activity) to increase. Heart rate slows down despite NE activation of Beta 1 receptors. PM716 C9 Adrenoceptor Activators 58  Sympathomimetics Phenylephrine: pure alpha agonist, raise BP. Methoxamine: alpha agonist used to raise BP Midodrine: prodrug converted into desglymidodrine an alpha1 agonist, used to raise BP Ephedrine: (Ma-huang), crosses BB and is a mild stimulant, raise BP, activates beta in lung, used in asthma (smooth muscle relaxation). Primatene® PM716 C9 Adrenoceptor Activators 59  Selective Sympathomimetics Dexmedetomidine: centrally acting alpha2 selective, used for sedation during intubation procedures. Tyramine: found in high conc in fermented foods (cheese, beers). Acts like NE because it is a precursor to the catecholamines. Contraindicated in patients taking MAO inhibitors. PM716 C9 Adrenoceptor Activators 60 Clonidine (Catapres®) Activates (agonist) at Alpha 2 receptors in the CNS and PNS. (1) CNS: Causes decrease in sympathetic outflow and blocks stimulation of the heart. (2) PNS: Activates presynaptic Alpha 2 receptors on nerve endings and inhibits release of NE (blocks vasoconstriction). PM716 C9 Adrenoceptor Activators 61  Dopamine (Intropin®) Dopamine (DA) receptors (five subtypes) located throughout the body (CNS and PNS). At high doses DA acts like EP. At low doses DA causes renal and coronary vasodilation. DA also activates Beta 1 receptors in the heart. Used to treat shock (decreased tissue perfusion). PM716 C9 Adrenoceptor Activators 62  Importance of Receptor Type in Clinical Practice. Patient with long history of reactive airway disease. Presents with mild heart attack. Problem: relax bronchials without stimulating the heart (increase cardiac workload) Beta 2 receptor agonists specific to lung (albuterol, terbutaline, metaproternol). PM716 C9 Adrenoceptor Activators 63 Epinephrine (adrenalin) Potent vasoconstrictor and cardiac stimulant which causes rise in BP. PM716 C9 Adrenoceptor Activators 64 Norepinephrine Similar effects to epinephrine. PM716 C9 Adrenoceptor Activators 65 Isoproterenol Potent beta agonist, with little effect on alpha receptors. Potent vasodilator. PM716 C9 Adrenoceptor Activators 66  Sympathomimetic Drugs Raise BP: drug reactions, decreased blood volume, infections etc Direct acting NE, phenylephrine or methoxamine are used. Shock: complex cardiovascular syndrome with reduced tissue perfusion, efficacy not clear. Reduce Blood Flow in Tissues: surgery, reduce diffusion of local anesthetics. Cocaine in nose surgery, NE with lidocaine for local anesthesia. PM716 C9 Adrenoceptor Activators 67  Sympathomimetics Anaphylaxis: shock from immediate IgE mediated reactions. EP reverses the fall in BP, bronchospasm, mucous membrane congestion. CNS: modafinil (amphetamine analog) used for narcolepsy. In attention-deficit hyperactivity disorder (ADHD) in children, methylphenidate or clonidine. PM716 C9 Adrenoceptor Activators 68  Sympathomimetics General cardiovascular adverse effects; hypertension, precipitation cardiac ischemia, and cardiac failure. CNS only cocaine and amphetamine readily cross BBB and cause ADRs. PM716 C9 Adrenoceptor Activators 69  Summary I (1) Catecholamines (NE, EP, DA) (2) Receptor organization (3) NE neurons (6 steps) (4) Alpha 1 and 2 activation (5) Beta 1 and 2 activation (6) Direct vs Indirect activating drugs (7) Mixed Action agonists PM716 C9 Adrenoceptor Activators 70  Summary 2 (8) DA receptors (9) Sympathomimetic Drugs (Slides 21-24) (10) EP, NE, isoproterenol binding to alpha and beta receptors. (11) G protein subunits and adrenergics (12) Receptor desensitization (13) Clonidine and presynaptic receptor agonists. PM716 C9 Adrenoceptor Activators 71