Download Pharmacology Ch 10 132-142 Adrenergic Pharmacology

Pharmacology Ch 10 132-142
Adrenergic Pharmacology
-Studies agents that act on pathways mediated by endogenous catecholamines norepinephrine,
epinephrine, and opamine
-sympathetic nervous system is a major source of catecholamine production and release
-effects include: increasing rate and force of cardiac contraction, modifying peripheral resistance
of arterial system, inhibiting release of insulin, stimulating hepatic release of glucose,, increasing
adipocyte release of free fatty acids
-Catecholamines are major effectors of sympathetic signaling
Catecholamine Synthesis, Storage, and Release – synthesized by modification of TYROSINE
primarily at sympathetic nerve endings and at chromaffin cells
-epinephrine predominantly synthesized in chromaddin cells of adrenal medulla
-sympathetic neurons produce norepinephrine as primary neurotransmitter
-tyrosine is transported into neurons via an aromatic AA transporter that used Na gradient to
cross the neuronal membrane
-FIRST STEP IN SYNTHESIS – oxidation of tyrosine  dihydroxyphenylalanine (DOPA) mediated
by tyrosine hydroxylase (TH) and is the RATE-LIMITING STEP in catecholamine synthesis
-DOPA  Dopamine through a nonspecific aromatic AA decarboxylase
-Dopamine  norepinephrine by dopamine-B-hydroxylase
-norepinephrine  epinephrine by phenylethanolamine N-methyltransferase (PNMT)
in the adrenal medulla
-conversion of tyrosine  dopamine occurs in cytoplasm; dopamine is transported into synaptic
vesicles by an antiporter called vesicular monoamine transporter (VMAT1)
-only inside vesicles is dopamine converted to norepinephrine
-3 distinct vesicle transporters: VMAT1 is peripheral (adrenal, sympathetic ganglia). VMAT2 is in
CNS, VAChT is in cholinergic neurons and motor nerves
-these antiporters use proton gradient generated by H+/ATPase in vesicular membrane to
concentrate dopamine on the inside
-norepinephrine condenses with ATP in vesicle and is secreted with ATP
-in adrenal medullary cells, norepinephrine is transported back into cytoplasm were PNMT
converts it to epinephrine; after which it goes BACK into vesicles for storage
-activation of sympathetic nervous system and catecholamine release is initiated by signals in
areas of CNS like limbic system; after which axons synapse with preganglionic neurons in
intermediolateral columns of spinal cord and project to sympathetic ganglia
-preganglionic neurons use ACETYLCHOLINE as neurotransmitter to activate nicotinic
ACh receptors to depolarize membrane and generate postsynaptic potentials in
postganglionic neurons
-Hexamethonium and mecamylamine block ganglionic nicotinic ACh receptor
-arrival of action potential opens voltage gated Ca channels and Ca influx triggers
exocytosis of catecholamine-containing vesicles
-ziconotide is a drug that treats severe pain
-norepinephrine rapidly diffuses away and regulates target tissue responses (smooth
muscle tone) by activating adrenergic receptors
Reuptake and Metabolism of Catecholamines – effect is terminated by either reuptake of
catecholamine into presynaptic neuron, inactivation, or diffusion way from synapse
-Reuptake of catecholamine is mediated by a selective catecholamine transporter
norepinephrine transporter (NET) or Uptake 1
-90% of norepinephrine is taken up by this process
-Uptake 1 is a symporter that uses inward Na gradient to concentrate catecholamines in
the cytoplasm of sympathetic nerve endings and limiting postsynaptic response
-inside cytoplasm, catecholamines are concentrated again by VMAT
-Metabolism of catecholamines requires two enzymes: MAO and catechol-O-methyltransferase
(COMT)
-MAO is mitochondrial and exists as MAO-A and MAO-B
-MAO-A degrades serotonin, norepinephrine, and dopamine
-MAO-B degrades dopamine
-MAO inhibitors can treat depression
Catecholamine Receptors – adrenergic receptors (adrenoceptors) are selective for
norepinephrine and epinephrine; and are divided into α1, α2, and β classes and are all G
protein-coupled receptors
-all classes are subdivided into three subtypes: α1A, α1B, α1D; α2A, α2B, α2C; β1, β2, β3
α1 and α2 Adrenergic Receptors – involves Gq pathway that activates phospholipase C, which
cleaves phosphatidylinositol-4,5-bisphosphate to generate IP3 and diacylglycerol (DAG)
-downstream targets include L-type Ca channels, K channels, and MAP kinase pathways
α1 receptors expressed in vascular smooth muscle, GU smooth muscle, GI smooth muscle,
prostate, heart, liver, and other cell types
-in vasculature, α1 receptors increase endogenous Ca stores and influx of Ca, leading to
activation of calmodulin and muscle contraction  increase vascular resistance and
increase blood pressure
-also causes contraction of GU smooth muscle and can treat benign prostatic hyperplasia
α2 receptors activate Gi (inhibitory) which inhibits adenylyl cyclase to decrease cAMP levels,
activation of G protein coupled K channels (causing hyperpolarization), and inhibition of
membrane Ca channels in neurons
-all of these decrease neurotransmitter release from target neurons
-α2 receptors are on both presynaptic and postsynaptic neurons
-presynaptic α2 function as autoreceptors to inhibit sympathetic transmission
-α2 receptors are also on platelets and pancreatic β cells, where they mediate platelet
aggregation and inhibit insulin release, respectively
-MOST IMPORANT approach to α2 function is to treat hypertension. α2 receptor agonists act at
CNS to decrease sympathetic flow to periphery to result in decreased norepinephrine release at
sympathetic nerve terminals and decrease vascular smooth muscle contraction
β-Adrenergic Receptors – divided into β1, β2, β3 and all activate a stimulatory G protein Gs. Gs
activates adenylyl cyclase to increase intracellular cAMP  activates protein kinases (PKA) to
phosphorylate proteins like ion channels
-β1-Adrenergic Receptors are localized in HEART and KIDNEY; in kidney they are on renal
juxtaglomerular cells, where receptor activation causes RENIN release
-stimulation of cardiac β1 receptors causes increase in force of contraction and heart rate
-force of contraction is mediated by increased phosphorylation of Ca channels
-heart rate is mediated by rate of phase 4 depolarization of SA node
-β2-Adrenergic Receptors – expressed on skeletal and smooth muscle and liver. In smooth
muscle, activation stimulates Gs, adenylyl cyclase, cAMP, and PKA  phosphorylates myosin
light chain kinase to reduce affinity for Ca/Calmodulin leading to relaxation of contractile
apparatus
-can also relax bronchial smooth muscle by activation of K channels (hyperpolarization)
-in hepatocytes, activation of Gs system initiates phosphorylation cascade to activate glycogen
phosphorylase and catabolism of glycogen  increase plasma glucose
-in skeletal muscle, activation of pathways stimulates glycogenolysis and promotes K uptake
-β3 Receptors are expressed on ADIPOSE TISSUE and lead to increased lipolysis
Regulation of Receptor Response – when agonist binds adrenoceptor, dissociation of G proteins
leads to downstream signaling as well as negative feedback mechanism that limits tissue
responses. Accumulation of βγ subunits in membrane recruits a G protein receptor kinase to
phosphorylate receptor and inactivates it
-phosphorylated receptor can bind to β-arrestin that sterically inhibits receptor/G protein
interaction to silence receptor; can also down regulate receptor on membrane
Epinephrine – agonist at both α and β adrenoceptors;
-at LOW concentrations, epinephrine has β1 and β2 effects, and at HIGH concentrations it
affects α1 receptors as well
-at β1 receptors, epinephrine increases cardiac contractile force and cardiac output  increase
oxygen consumption and systolic BP
-at β2 receptors, epinephrine causes vasodilation to decrease peripheral resistance and
decrease diastolic blood pressure; also increases blood flow to skeletal muscle, relaxes bronchial
smooth muscle, and increases concentrations of glucose/fatty acids in blood
-epinephrine treats ANAPHYLAXIS
-epinephrine prolongs effect of local anesthetics
Norepinephrine – agonist at α1 and β1 receptors but NO effect at β2 receptors
-administration of norepinephrine increases both systolic (β1 effect) and diastolic pressure and
total peripheral resistance
-treats hypotension in patients with distributive shock due to sepsis
Dopamine – cannot cross BBB; dopamine activates many CNS and peripheral receptors
-can activate D1 dopaminergic receptors in renal, mesenteric and coronary vascular beds
-activate adenylyl cyclase in vascular smooth muscle  increase cAMP  vasodilation
-at high concentrations, dopamine can activate β1 receptors and α1 receptors (vasoconstriction)
-used in treatment of shock caused by low cardiac output and accompanied by compromised
renal function
Inhibitors of Catecholamine Synthesis – limited clinical utility because they inhibit formation of
all catecholamines.
-α-Methyltyrosine inhibits tyrosine hydroxylase in nerve terminals to stop catecholamine
synthesis and used to treat hypertension associated with pheochromocytoma (tumor of
enterochromaffin cells that produce norepinephrine and epinephrine)
-can cause significant hypotension and sedation
Inhibitors of Catecholamine Storage – catecholamines originate from de novo synthesis and
recycled transmitter; in short term, an agent to inhibit storage in vesicles can increase net
release of catecholamine from synaptic terminal and mimic sympathetic stimulation
-over LONG period, agent depletes pool of available catecholamine and inhibits
sympathetic activity
-Resperine binds to vesicular antiporter VMAT to irreversible inhibit it  vesicles lose ability to
concentrate and store norepinephrine and dopamine
-at low doses, resperine causes neurotransmitter to leak into cytoplasm where it is
destroyed by MAO
-at high concentrations, leak is high enough to overwhelm MAO in presynaptic neuron
and the high concentration of transmitter exits from cytoplasm to synaptic space
through NET acting in reverse; efflux has a transient sympathetic effect
-because it is irreversible, over time the stores are depleted and could take weeks for
new vesicles to form, to reverse the effect of sympathetics
-Tyramine is a dietary amine metabolized by MAO in GI and liver; patients taking inihbitors of
MAO have tyramine absorbed by gut and taken into sympathetics, where it is transported to
synaptic vesicles by VMAT to displace norepinephrine and massive nonvesicular release of
norepinephrine from nerve terminal via reversal of NET and can cause hypertension
-Octopamine, a metabolite of tyramine can be stored in vesicles long time to replace
norepinephrine, can cause hypotension
-Guanethidine is activately transported by NET into neurons where it concentrates in
transmitter in vesicles and displaces norepinephrine leading to its depletion
-inhibits cardiac sympathetic nerves leading to reduced cardiac output and blocks
sympathetically mediated vasoconstriction  reduced cardiac preload
-inhibition of sympathetic responses by guanethidine can lead to symptomatic
hypotension following exercise or standing up
-Guanadrel – also a false neurotransmitter and treats hypertension, but not a first-line agent
-Amphetamine – displaces endogenous catecholamines from storage vesicles, weak inhibitor of
MAO, and blocks catecholamine reuptake mediated by NET and DAT
-increased alertness, decreased fatigue, depressed appetite, insomnia; treats depression
and narcolepsy
-Ephedrine, Pseudoephedrine, and phenylpropanolamine –activate adrenergic responses
-Methylphenidate – treats ADHD and increases attention
Inhibitors of Catecholamine Reuptake – can exert powerful sympathomimetic effect by
prolonging time that catecholamine remains in synaptic cleft
-cocaine is a potent inhibitor of NET to completely eliminate transport (unlike other uptake
inhibitors (imipramine and fluoxetine)
-cocaine promotes vasoconstriction due to capacity to inhibit norepinephrine uptake
-Tricyclic Antidepressants (TCAs) inhibit NET-mediated reuptake of norepinephrine into
presynaptic terminals and allow accumulation of it in synapse to treat depression
Inhibitors of Catecholamine Metabolism – Monoamine oxidase inhibitors (MAOIs) prevent
secondary deamination of catecholamines transported into presynaptic terminals or taken up
into tissues such as liver
-in absence of metabolism, more catecholamines accumulate in presynaptic vesicles for release
-Most MAOIs are oxidized by MAO to reactive intermediates which irreversibly inhibit MAO
-since there are two forms of MAO, MAO-A and MAO-B; there are selective and nonselective
agents
-pehelzine, iproniazid and tranylcypromine are nonselective MAOIs
-clorgyline – selective for MAO-A
-Selegiline selective for MAO-B (treats parkinsons)
-Brofarmine, Befloxatone, and moclobemide are new reversible inhibitors of MAO-A
-MAOIs are used to treat depression
-use of MAOIs is contraindicated with SSRIs because it may cause serotonin syndrome
characterized by restlessness, tremors, seizures, and coma
Receptor Agonists – therapies for hypertension, asthma, ischemic heart disease, heart failure
α1-Adrenergic Agonists – increase peripheral vascular resistance and elevate blood pressure
-may also cause sinus bradycardia by activating reflex vagal responses by baroreceptors
-methoxamine treats shock (α1 agonist)
-phenylephrine, oxymetazole, tetrahydrozoline constrict vascular smooth muscle for nasal
congestion and ophthalmic hyperemia
-oxymetazole is also an agonist for α2 receptors
-phenylephrine also treats shock
-Clonidine – α2 receptor agonist that lowers blood pressure by acting in brainstem vasomotor
centers to suppress sympathetic outflow to periphery; can cause bradycardia due to decreased
sympathetic activity
Guanabenz and Guanfacine – α2 agonists
Dexmedetomidine – α2 receptor agonist that can cause sedation in surgical patients
-suppression of sympathetics helps avoid swings in BP in surgical patients and also has
analgesic properties
α-Methyldopa – precursor to the α2 agonist α-methylnorepinephrine, which is released by
adrenergic nerve terminal to act presynaptically as an α2 agonist resulting in decreased
sympathetic flow and lowers blood pressure (used in pregnant women)
β-Adrenergic Agonistis – stimulation of β1 receptors causes increase in heart rate and force of
cardiac muscle contraction
-stimulation of β2 receptors causes relaxation of vascular, bronchial, and GI smooth muscle
-Isoproterenol is a nonselective β-agonist which lowers peripheral vascular resistance and
diastolic blood pressure, while systolic BP remains unchanged or slightly increased
-can increase cardiac contractility and heart rate, cardiac output is increased
-can also relieve bronchoconstriction in asthma (β2 effect)
-Dobutamine – has 2 stereoisomers in racemic mixture. The (-) isomer acts as both α1 agonist
and β1 agonist, whereas the (+) isomer is an α1 antagonist and a POTENT β1 agonist
-the α1 agonist/antagonist balance out, and so this is a selective β1 agonist with more
prominent inotropic effect (cardiac contractility) than chronotropic (heart rate)
-can treat severe heart failure
-β2 selective agonists treat asthma and are better than epinephrine in that their effects are
limited to select tissues; important to limit β1 stimulation so as not to affect the heart
-these agents relax bronchial smooth muscle and decrease airway resistance
Metapoterenol – β2 selective agonist treats obstructive airway disease + acute bronchospasm
Terbutaline and Albuterol are two other agents in this class
Salmeterol is a long acting β2 agonist
Receptor Antagonists
α-Adrenergic Antagonists – block endogenous catecholamines from binding α1 and α2
receptors to cause vasodilation, decreased BP, and decreased peripheral resistance
-baroreceptor reflex usually attempts to compensate by increases in HR and cardiac output
-Phenoxybenzamine – rarely used in the clinic blocks both α1 and 2 receptors irreversibly
-Phentolamine – reversible, nonselective α-adrenoceptor antagonist used in preoperative
management of pheochromocytoma
-Prazosin – 1000x affinity for α1 receptors than for α2. Results in decreased peripheral vascular
resistance and dilation of venous vessels (decreases venous return to heart)
-antihypertensive drug, may cause postural hypotension and syncope w/ first dose
-Terazosin and doxazosin – longer half-life than prazosin
-α1 not often used to treat hypertension because diuretics are more effective
-α1 antagonists can treat benign prostatic hyperplasia
-α1A receptor is in GU smooth muscle, and Tamsulosin is an antagonist of this receptor
Yohimbine – blocks α2-autoreceptors leading to increased release of norepinephrine with
subsequent stimulation of cardiac β1 receptors and peripheral vasculature α1 receptors
-α2 selective antagonists also cause increased insulin release through blockade of α2 receptors
in pancreatic islets (which suppress insulin secretion)
-Yohimbine treats erectile dysfunction too
β adrenergic Antagonists – block the positive chronotropic and inotropic actions of endogenous
catecholamines at β1 receptors to decrease heart rate and myocardial contractility
-drugs decrease BP in hypertensive patients but do NOT lower BP in normotensive patients
-long term use causes fall in peripheral vascular resistance
-nonselective β blockers also block β2 receptors in bronchial smooth muscle and can cause lifethreatening bronchoconstriction in asthma patients
-Propanolol, nadolol, and timolol are nonselective β blockers that do NOT block α receptors
-treat hypertension and angina, and tolerated in COPD patients
-Nadolol is also efficacious in prevention of bleeding from esophageal varices in cirrhosis
patients
-long half life and renal excretion without hepatic metabolism
-penbutolol is another drug in this class
-Levobunolol and carteolol are nonselective β blockers indicated in eyedrops for
glaucoma treatment
-Labetalol and carvedilol block α1, β1, and β2 receptors;
-for Labetalol α1 blockade lowers peripheral resistance and β blockade contributes to
decrease in blood pressure
-Pindolol is a partial β1 and β2 agonist; blocks action of endogenous norepinephrine at β1
receptors and treats hypertension, but also partially stimulates β1 receptors leading to overall
decreases in resting heart rate and BP
-Acebutolol is a partial agonist at β1 adrenoceptors with no effect at β2 recpetors; treats
hypertension
-Esmolol, metoprolol, atenolol, and betaxolol are all β1 selective blockers, distinguished by
elimination half-lives
-esmolol has short half life (3-4 minutes), metoprolol and atenolol have intermediate
half lives at (4-9 hours)
-Nebivolol – novel β1 selective adrenergic blocker that has property of promoting vasodilation
by nitric oxide release from endothelial cells