Flashcards in Adrenergic Pharmacology Deck (68):
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Synthesis and Storage of Dopamine (DA), norepinephrine (NE, and epinephrine
Tyrosine transported from plasma into nerve cell via Na+ dependent carrier. Oxidation to DOPA by tyrosine hydroxylase (rate limiting step). DOPA decarboxylated to form DA. DA transported into synaptic vesicles for protection via amine transporter system. DA hydroxylated to norepinephrine by dopamine B-hydroxylase within vesicle. NE is transported back to cytoplasm and methylated to epinephrine in adrenal medulla and stored in chromaffin cells.
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Release of NE
Action potential triggers calcium influx, causing release of vesicles through exocytosis
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Binding to Receptor
Postsynaptic (alpha and beta that work w/ g protein secondary messenger system) receptor activated by binding of NE --> intracellular response via 2nd messenger
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Drugs that affect synthesis/uptake/release
Alpha methyltyrosine, reserpine, tyramine. guanethidine, amphetimine, cocaine, imipramine, fluoxetine, tricyclic antidepressents, phenelzine, selegiline
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Alpha-methyltyrosine
Inhibits tyrosine hydroxylase
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Reserpine
Blocks VMAT, transport of bioamines from cytoplasm into vesicles.
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Tyramine
Dietary amines usually metabolized by MAO in GI and liver. In pt with MAO inhibitors tyramine is absorbed, large amounts cause displacement of vesicular NE and non vesicular release resulting in HTN crisis.
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Guanethidine
Displaces NE in storage vesicles, leading to gradual depletion of NE
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Amphetamine
Displaces endogenous NE, blocks reuptake by NET and DAT
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Cocaine
Potent inhibitor of NET, eliminated catecholamine transport
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Imipramine, fluoxetine
Inhibitors of NET
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Tricyclic antidepressents
Blocks Na+/K+ ATPase, blocks NET, prevents uptake of epinephrine and NE and increases DOA
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Phenelzine
Inhibits MAO-A, increasing NE and 5-HT serotonin content. Inhibits metabolism of NE and seratonin
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Selegiline
Inhibits MAO, increasing DA.
Low doses for tx of Parkinson Disease
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Adrenergic Receptors
Alpha and beta based on affinity to adrenergic agonists
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Alpha affinity
Epinephrine binds the best, then NE, and lastly isoproteranol
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Beta affinity
Isoproteranol > epinephrine > norepinephrine
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Activity of Agonists- Alpha 1
Vasoconstriction
Increases PVR, BP, mydriasis, and increased closure of the sphincter of bladder
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Activity of Agonists- Alpha 2
Central feedback receptor
Inhibit NE release (auto receptors) resulting in lowered BP, inhibit insulin release
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Activity of Agonists- Beta 1
Primary receptor located in the heart
Tachycardia, increased myocardial contractility, resulting in increased cardiac output, increased release of renin (controls BP), and increased lipolysis
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Activity of Agonists- Beta 2
Primarily located in the vasculature and lungs
Vasodilation, decreased PVR, decreased DBP, bronchodilation, increased muscle and liver glycogenolysis, increased glucagon release, relax uterine smooth muscle.
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Desensitization of receptors
Make receptors unavailable for interaction through sequestion. Down regulate receptors, and unable to couple G-proteins.
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Symapthyomimetic
Adrenergic drug which acts directl on adrenergic receptors activating them. Aka adrenergic agonists.
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Endogenous catecholamines
Epinephrine, NE, and DA
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Characteristics of adrenergic agonists- catecholamines
OH group in the 3,4 position of the benzene ring
Rapid inactivation because of enzymes scattered through various tissues
OH groups prevent penetration to the CNS
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Characteristics of adrenergic agonists- non-catecholamines
Lack catechol OH group, have linger half lives and have higher lipid affinity- CH3
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Characteristics of adrenergic agonists- substitution on amine nitrogen
Increase affinity for Beta-receptors
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Adrenergic agonist- direct effect
Epinephrine, NE, albuterol, pirbuterol, terbutaline, dobutamine, dopamine, isoproteranol, phenylephrine, clonidine, salmeterol, and formoterol
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Adrenergic agonist- indirect
Amphetimine and tyramine
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Adrenergic agonist- mixed
ephedrine
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Epinephrine
Interacts with both alpha and beta
Low dose- mainly beta effects (vasodilation); high dose- alpha effects (vasoconstriction
CV: + inotropic, + chronotropic- increased CO
Alpha effects- vasoconstricts arterioles
B2- vasodilates vessels to liver and skeletal muscle
Net result- increased SBP w/ slight decrease in DBP
Respiratory- bronchodilation of smooth muscle (B2)
Hyperglycemia-decreased insulin release (alpha2) increased glycogenesis, increased release of glucagon (B2)
Lypolysis B1
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Epinephrine therapeutic uses
Emergent tx of asthma, glaucoma, anaphylaxis, w/local anesthetics to prolong DOA through vasoconstriction
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Epinephrine Pharmacokinetics
Rapid onset w/ IV, given sub-Q, inhalation, endotrancheal, and topically
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Epinephrine ADRs
CNS- anxiety, fear, tension, HA, tremor, hemorrahage, increased BP, cerebral hemorrhage
CV-arrhythmias
Pulmonary edema
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Epinephrine Interaction
Hyperthyroidism- exaggerated CV effects due to increased production of receptors
Cocaine- exaggerated CV effects due prevention of re-uptake.
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Norepinephrine
At therapeutic doses alpha 1 and beta 1 receptors are afected
CV- vasoconstriction in periphery (including kidney) reulting in elevated BP, baroreceptor reflex: increase BP -> increased vagal activity stimulation baroreceptors causing bradycardia.
Tx use shock through vascular resistance, increase BP
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Dopamine
Low doses act predominately on D1 receptors in renal, mesenteric, and coronary vascular beds (vasodilation).
Higher doses a positive inotrope (action at beta1)
High doses- vasoconstriction via alpha 1 receptors
DOC for shock, at appropriate doses is useful in management of low CO associated with compromised renal function such as in severe CHF.
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alpha1 selective agonists
Methoxamine, phenyleprhine, oxymetazoline,
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Methoxamine
Alpha 1 selective agonist
Not used often but used to tx shock
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Phenylephrine
Alpha 1 selective agonist
Used like psuedofedrin, Topical constrict vascular smooth muscle in relief or nasal congestion
Not catechol derivative so substrate for COMT
Induces reflex bradycardia when given parenterally, raises BP due to vasoconstriction.
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Oxymetazoline
Alpha 1 selective agonist
Topical, constrict vascular smooth muscle in relief of opthamic hyperemia.
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Adreneric agonist- Alpha 2 selective agonists
Feedback, decrease E and increase NE
Clonidine, a-methyldopa, and guanfacine
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Chlonidine
Alpha 2 selective agonist
Lowers BP by suppressing sympathetic outflow
ADR dry mouth and sedation
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a-methyldopa
alpha 2 selective agonist
Metabolized to a-methylnorepinephrine which is an a agonist in CNS to decrease sympathetic outflow
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Gaunfacine
a-2 agonist in CNS to decrease sympathetic outflow
ADR dry mouth and sedation
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Adrenergic agonist- B nonselective agonists
Isoproterenol and dobutamine
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Isoproterenol
Nonspecific B agonist (acts at B1 and B2)
CV: + inotropic and chronotropic effects (B1); vasodilation of arterioles of skeletal muscle (B2)
Pulmonary- bronchodilation (B2)
Uses- stimulates heart in emergencies
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Dobutamine
B1 selective
Increases cardiac rate and output, usted to increased CO in CHF, racemic mixture cancers out alpha
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Adrenergic Agonist- B2 selective agents
Albuterol. pirbuterol, terbutaline, salmeterol, and formoterol
Predominately in the lung and vasculature
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Albuterol, pirbuterol, terbutaline
Adrenergic Agonist- B2 selective
Short acting bronchodilators (less cardiac stimulation)
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Salmeterol and formoterol
B2 selective agents
B2 long acting bronchodilator
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Indirect Adrenergic Agosist
Cause body to release more neurotransmitters. Cause NE and Serotonin release from presynaptic terminals
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Amphetamine
Indirect adrenergic agonist
CNS stimulant, increases BP by alpha effect of vasculature, beta effect on heart
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Mixed action adrenergic agonists
Cause NE release and stimulates receptros
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Ephedrine
Mixed action
Alpha, beta, and CNS stimulant
Use- nasal sprays due to local vasoconstrictor activity; urinary incontinence
Long DOA
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Therapeutic uses of agonists
Shock, hypotension, cardiac arrest, and local vasoconstriction, narcolepsy, weight reduction, ADHD
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Adrenergic Antagonists- alpha blockers
Reverse vasoconstrictive action of epinephrine, side effects commonly observed with nonselective alpha blockers- orthostatic hypotension, reflex tachycardia, vertigo, and sexual dysfunction
Ex- phenoxybenzamine, phetolamine, prazosin, doxazosin, and , tamulosin
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Phenoxybenzamine
Adrenergic antagonist Alpha blocker
Irreversible, nonselective and noncompetitive block, tx of pheochromocytoma to preclude HTN crisis that can result from manipulating tissue.
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Phentolamine
Adrenergic antagonist Alpha blocker
Competitive, nonselective block (alpha 1 and 2 response is more E being created and alpha 1 decreased vasoconstriction)
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Prazosin, doxazosin, terazosin
Adrenergic antagonist Alpha blocker
Selective alpha1 blocker- used for vasodilation
Tx- hypertension, BPH, CHF by relaxing the arterial and venous smooth muscle and decreased PVR.
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Tamsulosin
Adrenergic antagonist Alpha blocker
Tx of BPH (benign prostate hyperplasia)
Inhibitor of Alpha 1 receptor on smooth muscle of prostate (decreases tone of bladder neck and prostate and improves urine flow.)
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Adrenergic antagonists- beta blockers
Work by blocking beta
Ex- prpranolol (prototype), timolol, nadolol, acebutolol, atenolol, metoprolol, and esmolol
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Propranolol (prototype)
Adrenergic antagonist beta blocker
Nonselective
Uses- lowers BP, used to tx angina, cardiac arrhythmias, MI, glaucoma, prophylaxis for migraines
Effects- lowers cardiac output (rate and force), prevents vasodilation, bronchoconstriction, increased Na retention, decreased glycogenolysis, and glucagon secretion
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Timolol and nadolol
Adrenergic antagonist beta blocker
Nonspecific beta blocker
Uses- glaucoma and HTN
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Acebutolol, atenolol, metoprolol, esmolol
Adrenergic antagonist beta blocker
Preferentially blocks beta 1 receptors- cardioselective
Eliminates unwanted bronchoconstriction, little effect of CHO- metabolims, or PVR
Useful in hypertensive DM pt on insulin or oral hypoglycemics
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Adverse effects of beta-receptor antagonists
Cause of exacerbate HF, life threatening bradycardia in pt w/ AV conduction defects, withdrawl syndrome, life threatening increase in airway resistance in patients w/ COPD and asthma, and blunts recognition of hypoglycemia in patients w/ type 1 DM.
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Adrenergic Antagonists w/ partial activity
Pindolol and acebutal
Weakly stimulate B1 and B2. Used for HTN
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