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32 Cards in this Set
- Front
- Back
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Six broad classes of action of sympathomimetic amines
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1) peripheral excitatory effects on smooth muscle (vasoconstriction and mydriasis) by alpha receptors
2) peripheral inhibitory effects like - decreasing GI motility (alpha and beta), dilating bronchial musculature and vasodilation on some blood vessels (beta receptors) 3) cardiac excitatory effects - beta 4) metabolic effects - increase in rate of liver and skeletal muscle glycogenolysis and liberation of free fatty acids from adipose tissue - beta 5) CNS stimulatory action - increased wakefulness and decreased appetite, not classified according to receptor type 6) endocrine actions - secretion of insulin (beta increase, alpha decrease) and secretion of renin (beta increase) |
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Epinephrine
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non-selective adrenergic agonist; least specific - acts at all adrenergic receptors
Actions: 1) Decrease in blood flow (alpha receptors - cutaneous, mucosal, renal) 2) Increase in blood flow (beta at skeletal muscle, cerebral, coronary) 3) increased cardiac stimulation (beta 1 - increased inotropy, chronotropy, automaticity) 4) bronchodilation - beta 2 5) inhibition of intestinal muscle tone - alpha and beta 2 6) inhibition of uterine muscle tone late in pregnancy - beta 2 Route of administration: -ineffective orally - broken down by MAO and COMT; usually given IM or SC or nebulized Side effects: -fear, palpitation, discomfort; hypertensive and hyperthyroid patients are sensitive to effects; cerebral hemorrhage and cardiac arrhythmias are possible if given IV Therapeutic uses: -acute hypersensitivity reactions; local vasoconstriction to keep local anesthetics to area of injection |
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Norepinephrine
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a non-selective adrenergic agonist; but more specific than E (potently stimulates all alpha and cardiac beta-1, not beta-2 so won't get opposing actions on the vasculature)
-more marked incerase in diastolic pressure than with E, greater reflex compensation if pressures are higher -limited use in treatment of shock |
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Phenylephrine
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alpha-1 agonist, epinephrine without one ring hydroxyl
Therapeutic uses: -pressor agent in hypotensive states -mydriasis -nasal decongestion |
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Clonidine
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alpha-2 agonist; used as anti-hypertensive
-alpha-2 receptors on presynaptic adrenergic nerve terminals, NE binding for feedback inhibition -also alpha-2 receptors in brain -both of these are anti-sympathetic |
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Isoproterenol
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non-selective beta agonist; better interaction with beta receptors than E or NE --> strong CV effects
-IV injection gives increased rate and force of contraction and transient increase in systolic pressure, but beta receptor stimulation in vasculature causes decreased blood pressure -relaxes broncial and GI smooth muscles -administered like E -metabolized primarily by COMT (the large isopropyl moiety on the amino group makes it a poor substrate for MAO) -toxicity like E |
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Terbutaline
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beta 2 agonist (avoids direct effects on beta 1 in the heart); used for the treatment of asthma; administered as inhalation aerosol (also reduces cardiac effect)
-less susceptible than isoproterenol to metabolic breakdown (not a substrate for COMT) |
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Ritodrine
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beta 2 agonist; used for the treatment of asthma; inhalation aerosol; not a substrate for COMT; IV and oral used to inhibit uterine contractions when labor begins prematurely (but with questionable efficacy)
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Albuterol
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beta 2 agonist, used for treatment of asthma; inhalation aerosol; not a substrate for COMT
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Metabolism of Adrenergic Agonists
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-catecholamines are not effective orally, they are destroyed in the GI tract and metabolized by MAO and COMT in the liver
-noncatecholamines are not metabolized by COMT -if these compounds are alpha-methylated on the side chain, they are no longer susceptible to degredation by MAO -noncatechol, alpha-methylated compounds are orally effective and have a long duration of action |
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Mechanism of action of sympathomimetic amines with indirect actions
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works either by getting transported into the terminal by NET and then causing NE to flow out of the vesicle and out of the terminal (tyramine and amphetamine) or simply by inhibiting NET (cocaine)
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Tachyphylaxis
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repeated doses of a drug given at short intervals produce successively smaller responses
example - amines with primarily indirect actions --> repeated IV injections of tyramine or omphetamine will produce a smaller rise in BP with each succeeding injection; whereas, repeated injections of E or NE will produce constant repsonses -evidence that indirectly acting amines release NE from a "readily mobilized pool" which can be exhausted and not replenished rapidly |
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Tyramine
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-sympathomimetic amine with indirect action
-dopamine without 3-OH on ring -cause release of monoamines -Hypertensive crisis (in persons taking MAO inhibitor, consumption of food or drink containing much tyramine, which is not metabolized due to MAO blockade, results in huge release of NE) False Transmitter (tyramine is taken up efficiently both into synaptic terminal and into storage granule where it is converted by DBH into octopamine (which tends to stay in the granule because of beta-OH like NE), acts as a false transmitter because it is released but is unable to cause physiological effects |
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Structure of sympathomimetic amines
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most are congeners of phenylethylamine
-optimal length of side chain - two carbons for sympathomimetic activity (more or fewer carbons = less activity) -beta hydroxlation (at first carbon next to ring) increases alpha and beta activity and decreases lipid solubility (CNS penetration) -larger alkyl on amino = greater beta stimulatory effect (example, E has more B2 than NE because of methyl group, and isoproterenol has max beta effects) -substitution of large moieties on amino group = insensitive to MAO -selective beta-2 activity associated with large amino substituent (esp. with 3 and 5 position hydroxyls on ring) -OH at 3 and 4 carbons on ring = max alpha and beta -OH at 3 and 5 on ring = enhance beta-2 selectivity -loss of both OH groups increase lipid solubility (CNS activity) |
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Amphetamine
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sympathomimetic amine with indirect action
-peripheral effects like tyramine -no OH groups on ring and side chain has alpha-methyl (not susceptible to MAO), so effective orally and have long duration of action -CNS stimulant, euphoric effect on mood, anorexia -Toxicity - CNS (restlessness, talkativeness, irritability, insomnia and with large doses psychosis like schizophrenia) -Therapeutic uses - narcolepsy, ADHD in children, appetite suppression (rare) |
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Ephedrine
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sympathomimetic amine with direct and indirect action
alpha and beta agonist, also releases NE |
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Dopamine
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-not very effective peripherally
-metabolized by both COMT and MAO (only administered IV); does not readily cross the blood brain barrier -CV effects (at low doses - increases renal blood flow; higher doses - will stimulate cardiac B1 receptors to increase cardiac output; still higher doses - will stimulate vascular alpha receptors to cause generalized vasoconstriction -Therapeutic use - treatment of severe congestive heart failure with compromised renal function -side effects like E |
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Therapeutic Uses of Sympathomimetic Drugs
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1) Vasoconstriction (alpha 1)
-hypotensive state (phenylephrine, ephedrine, metaraminol, epinephrine) -nasal decongestion (phenylephrine) -reduce spread of local anesthetics and loss of blood during surgery (epiephrine and metaraminol) 2) pupillary dilation (alpha 1) -opthalmic procedures (epinephrine, phenylephrine, ephedrine) 3) Vasodilation (alpha 2) -hypertension (clonidine) 4) Smooth muscle relaxation (beta 2) -COPD (salmeterol, long acting) -asthma (terbutaline, metaproterenol, albuterol) -premature labor (ritodine) 5) CNS effects - arousal -narcolepsy (ampthetamine) -ADHD (ampthetamine, methylphenidate) |
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Phenoxybenzamine
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Non-selective alpha-receptor antagonist
-irreversible inhibition occurs as phenoxybenzamine loses a Cl atom, cyclizes, and alkylates the receptor (maximum response reduced no matter how high the concentration of agonist) -Pharm effects: -alpha 1 receptors on blood vessels blocked --> vasodilation --> increased baroreceptor reflex (increased sympathetic input to heart) --> alpha 2 receptors on nerve endings in heart when inhibited lead to increased NE --> cardiac stimulation! -orthostatic hypotension - no vasoconstriction in response to increased sympathetic firing when a person stands Epinephrine reversal (administration of E after phenoxybenzamine produces only depressor responses since alpha receptors are blocked, ie - E binds only beta receptors on blood vessels --> vasodilation) |
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Phentolamine
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reversible alpha-receptor antagonist
competitive blocker Pharm effects: -cardiac effects like phenoxybenzaine (stimulatory) -parasympathomimetic GI tract stimulation -release of histamine |
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Prazosin
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alpha 1 selective antagonist (think blood vessels!)
-lowers blood pressure -tends not to increase heart rate (as do other vasodilators) -95% bound to plasma protein -postural hypotension, syncopeY |
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Yohimbine
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alpha 2 selective antagonist
-competitive -structurally related to another Rauwolfia alkaloid, reserpine -increases sympathetic outflow from CNS to increase blood pressure and heart rate (probably by blocking post-syn alpha-2 receptors) -could also have sympathomimetic effect mediated peripherally by blockage of inhibitory pre-syn alpha-2 receptors -opposite effect of clonidine |
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Types of beta receptor antagonists
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Nonselective (propranolol, timolol, pindolol), lipid soluble, somewhat shorter acting
B1 selective (atenolol, acebutalol, metoprolol) Third generation (carvedilol, celiprolol, nebivolol); block beta and have some other action that causes vasodilation |
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Structure and effect of beta blockers
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b blockers structurally resemble beta agonists
-effects: -reduce heart rate and oontractility (esp. evident during excercise) -decrease blood pressure (perhaps because of reduced cardiac output) -bronchoconstriction in asthmatics (disadvantage of propranolol as antihypertensive compared to beta1 specific drugs |
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Pharmacokinetics of beta blockers
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some beta blockers (propranolol, and other first generation) are lipid-soluble, well absorbed from gut, largely metabolized by the liver and with short plasma half-lives (plasma half-lives do not always correlate with duration of pharm effect)
-other beta blockers (like atenolol) are more water soluble and some are absorbed incompletely from the gut, longer plasma half-lives and eliminated unchanged by the kidney |
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Timolol
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non-selective (first generation) beta blocker
short acting lipid soluble, well absorbed from gut, largely metabolized by liver |
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Propranolol
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non-selective, first generation beta blocker
-first pure beta antagonist -lipid-soluble, well absorbed from gut, largely metabolized by liver, short plasma half-life |
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Atenolol
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beta1 selective (second generation) beta blocker
-long acting -more water soluble, absorbed incompletely from gut, longer plasma half life, eliminated unchanged by kidney |
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Carvedilol
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third generation beta blocker, produces vasodilation in addition to cardiac effect (via alpha 1 block)
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Methyldopa
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competes with dopa for Dopa decarboxylase enzyme (so get synthesis of methylnorepinephrine rather than NE --> methylnorepinephrine is a false transmitter and has a greater affinity for alpha 2 than alpha 1
-binding to post-syn alpha 2 receptors in CNS is probably responsible for antihypertensive effects -like clonidine |
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Reserpine
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inhibits Mg++/ATP-dependent uptake of NE into vesicles without inhibiting uptake across axonal membrane
-binds VMAT2 irreversibly -NE is thus deaminated and inactivated by MAO and the nerve terminal becomes depleted of NE -depletes stores of catecholamines (and serotonin) in CNS and PNS; a single dose can cause complete NE depletion within 24 hours lasting for a number of days, stores repleted after 7-14 days |
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Clinical Uses of Sympatholytic Drugs
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1) Hypertension
-prazosin (peripheral alpha block) -methyldopa (reduction of sympathetic outflow from CNS) -beta blocker 2) Extertional angina -beta blockers 3) Congestive Heart Failure (reduce ability of heart to pump enough blood) -alpha antagonists -beta blockers 4) Arrhythmia -beta blocker 5) Pheochromocytoma (tumor blocking chrommafin cells of adrenal medulla and get lots of NE pouring out leading to CV problems) -Phenoxybenzamine (peripheral alpha 1 block) -Metyrosine (inhibition of catecholaminie synthesis, blocks tyrosine hydroxylase) 6) Glaucoma -timolol (reduces production of aqueous humor?) |
