Flashcards in Adrenergic Pharmacology Deck (42):
Synthesis of catecholamines
Tyrosine is taken up into the nerve terminal when it is hydroxylated to dihydrocyphenylalanine (DOPA) by tyrosine hydroxylase [note: this is the rate limiting step]. DOPA is decarboxylated to dopamine (DA) by aromatic L-amino acid decarboxylase.
Storage of catecholamines
DA actively transported into vesicle by vesicular monoamine transporter 2 (VMAT2) [promiscuous for all monoamines, susceptible to reserpine]. In the vesicle DA is hydroxylated to NE by dopamine beta-hydroxylase.
In the adrenal medulla NE is further N-methylated to epinephrine by phenylethanolamine-N-methyltransferase (PNMT)
Release of catecholamines
Influx of calcium causes vesicles to fuse with membranes. Guanethidine blocks
Presynaptic regulation of NE release
NE along with cotransmitters, neuropeptide Y and ATP, feedback on prejunctional receptors [alpha2, y2 and p1 respectively] to inhibit transmitter release. NE binding to beta2 results in enhanced neurotransmitter release
Termination of actions of catecholamines
Metabolism of catecholamines does not occur in synaptic cleft. Reuptake and dilution are responsible. [Note: reuptake via NET or DAT is blocked by cocaine, SSRIs, SNRIs and TCAs (imipramine)]
Catecholamine metabolism in nerve terminal
MAO is associated with the mitochondrial surface. Two subgroups: MOA-A preferentially metabolizes NE and 5-HT (serotonin). MAO-B like DA and phenylethylamine best. Both are found in the brain. A is also present in GI, liver, placenta and skin. B is in platelets and lymphocytes. Vanyllylmandelic acid is the major end product, renally excreted, ultra high levels present in pheochromocytoma.
blocks the synthesis of NE by inhibiting TH
inhibits AAADC and forms "false neurotransmitter," alpha-methylnorepinephrine.
Bretylium and guanethidine
prevent release of NE
Tyramine, ephedrine and amphetamine
rapid, brief NE liberation both by displacing NE in extracellular fluid, and by facilitated exchange diffusion for the outward transport of NE. They also mobilize NE in vesicles by competing for vesicular uptake processes.
Alpha adrenergic receptors
epinephrine > norepinephrine >> isoproterenol.
alpha1 has a higher affinity for phenylephrine. Postsynaptic, constricts smooth muscle by Gq activation (PIP3 -> DAG and IP3 -> activation of protein kinase C and release of Ca++ resepectively.)
alpha2 selectively binds clonidine. Presynaptic, feedback inhibition, mediated by Gi and decreased cAMP levels. [Note: tamsulosin selectively treats BPH because it binds only alpha2A which is present in the urinary tract and not alpha2B in the blood vessels]
Beta adrenergic receptors
isoproterenol > epinephrine > norepinephrine.
Beta1 equal affinity for NE and E.
Beta2 higher affinity for E than NE (make it particularly responsive to circulating E)
Beta3 involved in lipolysis, detrussor muscle
All beta receptors are mediated by Gs to increase intracellular cAMP
Blood pressure control mechanisms
Cardiac output - dependent on venous return and heart rate (thus CO is under the control of RAAS and SANS)
Blood volume - dependent on renin-angiotensin-aldosterone system
Peripheral vascular resistance - dependent on RAAS and SANS
A drop in blood pressure (as measured by the aortic arch and the carotid sinus) results in SANS firing which causes: increased heart rate, increase ventricular contractility, increase total peripheral resistance, and vascular tone.
An increase in blood pressure results in PANS firing causing a decrease in heart rate.
Reflex can be blocked by ganglion blocking drugs - hexamethonium. Reflex tachycardia can be blocked with beta1 antagonist. Reflex bradycardia can be blocked with muscarinic antagonist
Can trigger ANS and endocrine feedback loops, resulting in tachycardia and salt and water retention. Beta blockers and diuretics are often part of anti-hypertensive regimens.
sympathomimetic drugs - direct acting agonist
Responses are not reduced by prior treatment with reserpine or guanethidine. Actions of direct-acting amines may actually increase after transmitter depletion because the loss of the endogenous neurotransmitter induces compensatory changes that up-regulate receptors
Sympathomimetic drugs - indirect-acting agonist
Act by releasing or displacing NE from vesicles, blocking reuptake of NE, blocking MAO or COMT. The response is abolished if there is prior treatment with reserpine or guanethidine
Sympathomimetic drugs - mixed-action agonist
Effects are blunted, but not abolished by prior treatment with reserpine or guanethidine
Interacts with alpha and beta receptors (B>A). Effects are dose-dependent: low dose = beta effects (vasodilation). high dose = alpha effects (vasoconstriction).
Cardiovascular effects: Increase contractility and rate of contraction (positive ionotrope: beta1). Constricts arterioles in the skin, mucous membranes and viscera (alpha). Dilates liver and skeletal muscle vessels (beta2). Renal blood flow decreases. Increased systolic blood pressure with slightly decreased diastolic
Respiratory: powerful bronchodilator (beta2) and inhibits histamine release.
Hyperglycemia: glucose liberation (Beta2) and decreased insulin release (alpha2)
Lipolysis: beta2 on adipose tissue
Used to treat anaphylaxis, acute asthma, cardiac arrest, adjunct to local anesthetics.
Rapidly metabolized by MAO and COMT, metanephrine and vanillylmandelic acid excreted in urine.
Adverse effects include restlessness, tremor, tension, headache, and palpitation. Can induce cerebral hemorrhage and cardiac arrhythmia, diabetic patients may need to increase insulin doses
Direct acting catecholamine. Stimulates alpha1 > alpha2 > beta1
Cardiovascular effects include rise in peripheral resistance from vasoconstriction in most beds including kidney. Increase in systolic and diastolic BP. Does not induce compensatory vasodilation in skeletal muscle, weak B2 activity.
Baroreceptor reflex: NE increases BP, inducing rise in vagal activity causing reflex bradycardia. Preadministration of atropine blocks vagal transmission and NE stimulation of the heart can be seen as tachycardia.
Therapeutic use in treating shock.
Given IV, duration 1-2 minutes, MAO and COMT metabolism, excretion in urine.
Adverse Effects are similar to epinephrine with additional blanching, sloughing off of skin and necrosis associated with injection site due to extreme vasoconstriction. Impaired circulation can be treated with phentolamine
Direct-acting synthetic catecholamine, stimulates beta1 and 2, rarely used therapeutically,
Cardiovascular actions - intense stimulation of the heart, dilate skeletal muscle arterioles, greatly reduces mean arterial and diastolic blood pressure.
Potent bronchodilator, may still be useful intreating AV block.
Adverse effects similar to epinepthrine
direct-acting natural catecholamine, stimulates D1, beta1 and alpha1. Effects are dose dependent. low dose = just D1, high dose = D1, beta1, and alpha1.
Cardiavascular effects - positive inotropic and chronotropic effects, at very high dose stimulates alpha1 causing vasocontriction.
Renal and visceral effects - dilates renal and splanchnic arterioles
Therapeutic drug of choice for cardiogenic and septic shock, especially in the context of oliguria. Also used to treat hypotension and severe heart failure in patients with low or normal peripheral vascular resistance or oliguria.
Adverse effects - same as sympathetic stimulation, rapidly metabolized by MAO and COMT so effects are short lived.
Agonist of periperal dopamine D1 receptors. Used as a rapid active vasodilator to treat sever hypertension in hospitalized patients, acts of coronary arteries, kidney arterioles and mesenteric arteries
Adverse effects - headache, flushing, dizziness, nause, vomiting and tachycardia
Synthetic direct-acting catecholamine, beta1 receptor agonist. Increases cardiac rate and output with few vascular effects. Used to increase CO in acute heart failure and MI, inotropic effect after cardiac surgery because it does not significantly increase O2 demands on myocardium.
Adverse effects - used with caution in atrial fibrillation, because it increases AV conductance, others similar to epinephrine. Tolerance may develop with prolonged use.
Direct-acting synthetic adrenergic agonist that stimulates both alpha1 and alpha2 receptors.
Actions at the vessels supplying the nasal mucosa and conjunctiva causing vasoconstriction and decreasing congestion.
Found in many over the counter short term nasal spray decongestants and in ophthalmic drops for eye redness relief.
Adverse effects from systemic circulation (inevitable) include nervousness, headaches, and trouble sleeping. Local effects include irritation, sneezing, rebound congestion and dependence with long term use.
direct-acting, synthetic adrenergic, binds to alpha1 receptor.
vasoconstrictor - raise both systolic and diastolic pressure, no effect on heart itself, induces reflex bradycardia
Used to treat hypotension in hospitalized or surgical patients, especially those with rapid heart. Acts as a nasal decongestant when applied topically or taken orally. Ophthalmic solution for myadriasis.
Can cause hypertensive headache and cardiac irregularities
alpha2 agonist, acts presynaptically to decrease sympathetic outflow to the periphery.
Used for the treatment of hypertension, minimize withdrawal from opiates, tobacco and benzodiazepines.
Adverse effects commonly include lethargy, sedation, constipation, and xerostomia, abrupt discontinuance can cause rebound hypertension
Albuterol and terbutaline
short-acting beta2 agonist.
Used as bronchodilators and administered by a metered-dose inhaler, management of acute asthma symptoms. Terbutaline is also used off label as a uterine relaxant to suppress premature labor.
Adverse effects include tremor, restlessness, apprehension, and anxiety. If administered orally, may cause tachycardia or arrhythmia especially in underlying cardiac disease. MAOI increase risk of cardiovascular effects and concomitant use should be avoided
Salmeterol and formoterol
Long-acting beta2 agonists, single metered-dose inhalation device. Prolonged bronchodilation of 12 hours, has delayed onset, not for monotherapy but highly effective with a corticosteroid.
Used to treat nocturnal asthma in symptomatic patients taking other asthma medications.
Increase the risk of asthma related death.
NET substrate, reuptake inhibitors, reverse transport of NE, NE mobilizer. Also acts as an alpha1 agonist in vasculature and beta1 simulatory effect in the heart.
Uses are as a CNS stimulant in the treatment of children with ADHD, narcolepsy, and for appetitie control.
Adverse effects include aggressiveness, paranoid hallucinations, panic states, hypertension and arrhythmias, major potential for abuse, drug interation with MOA-A inhibitors causing hypertensive crisis.
found in fermented foods, normally oxidized by MOA-A in gut and liver, but if patient in on MOAI, tyramine can precipitate a hypertensive crisis.
unique among local anesthetic, block sodium-chloride-dependent norepinephrine transport to uptake NE, NE acculumates in the synaptic space. Potentiation of E and NE actions
Mixed-action adrenergic agents. Release stored NE and directly stimulate alpha and beta receptors, actions are similar to epinephrine, but less potent.
Not catecholamines, poor MAO and COMT substrates so long duration of action. Raise S and D blood pressures by vasoconstriction and cardiac stimulation. Used to treat asthma and hypotention, but has been replaced by more effective drugs. Ephedrine produces a mild stimulation of the CNS - increases alertness, decreases fatigue, and prevents sleep. Pseudoephedrine is used orally to treat nasal and sinus congestion.
Excellent oral absorption and BBB penetration, Ephedrine is eliminated largely unchanged in urine, while pseudoephedriun is incompletely metabolized by the liver before being excreted into the urine.
Nonselective, covalently linking antagonizt of alpha1 and alpha2 receptors. Irreversible and non-competitive. Duration 24 hours after few hour delay
Cardiovascular effects: prevents vasocontriction, decreased TPR causes reflex tachycardia. alpha2 blocking can contribute to increased cardiac output.
Treatment uses include pheochromocytoma and Reynaud disease and frostbite.
Adverse effects: postural hypotension, nasal congestion, nausea and vomiting, inhibit ejaculation, reflex tachycardia so caution should be used in patients with cerbrovascular or cardiovascular disease.
competitive alpha1 and 2 block that last approximately 4 hours. Causes epinephrine reversal. Causes reflex cardiac stimulation and tachycardia.
Therapeutic uses are for short term management of pheochromocytoma, prevent dermal necrosis after norepinephrine extravasation, and to treat hyoertensive crisis due to clonidine withdrawal or MOAI patients who ate tyramine.
Prozosin, terazosin, doxazosin, tamsulosin, and alfuzosin
selective competitive alpha1 blockers useful in hypertension treatment or the treatment of benign prostatic hyperplasia. All are excreted in urine except doxazosin which is excreted fecally.
Cardiovascular effects: decrease TPR, lower BP, minimal changes in cardiac output, renal blood flow or GFR. Tamsulosin is most selective for SM at bladder neck and prostate.
When treating hypertension with these agents, beware first dose effect orthostatic hypotension. alpha1 antagonists are not used as monotherapy.
Adverse effects: dizziness, lack of energy, nasal congestions, headache, drowsiness, and orthostatic hypotension, inhibition of ejaculation and retrograde ejaculation and floppy iris syndrome during eye surgery
Competitive alpha2 blocker, has been sexual stimulant but doesn't work, contraindicated in cardiovascular disease, psychiatric and renal dysfunction because it may worsen these conditions
Prototype beta-adrenergic antagonist, blocks beta1 and 2 with equal affinity.
Cardiovascular effects, diminishes CO, HR, SV, and renin release. Attenuate the expected increase in heart rate. Non-selective blockade prevents B2 skeletal muscle vasodilation. Decreased blood pressure, in patients with hypertension, TPR returns to normal with long term use.
Can exacerbate bronchoconstriction in COPD or asthma.
Decreases glycogenolysis and glucogenesis and decreased glucagon secretion. Hypoglycermia may occur after insulin injection.
Blocks the action of isoproterenol.
Used to treat hypertension, angina pectoris, myocardial infarction (protective effect on myocardium and decreased incidence of sudden arrhythmic death), Migraine (BBB penetration due to lipophlic nature) and hyperthyroidism.
Pharmacokinetics - good oral absorption, but first-pass effect brings only 25% to circulation. Volume of distribution is large. Extensively metabolized in liver (CYP450 - rifampin can decrease effects), metabolites excreted in urine.
Adverse effects: Bronchoconstriction with asthma, arrhythmias if stopped abruptly, sexual impairment reported - mechanism unknown, metabolic disturbance (hypoglycemia and increased LDL with decreased HDL), CNS effects (depression, dizziness, lethargy, fatigue, weakness, visual disturbances, hallucinations, short-term memory loss, emotional lability and vivid dreams)
Nadolol and timolol
Same as propranolol but more potent, nadolol has longer duration of action. Timolol reduces aqueous humor production in the eyes. Does not affect near vision of change pupil size, onset in 30 minutes, effects last 12-24 hours
Atenolol, betaxolol, bisoprolol, esmolol, metoprolol and nebivolol
Selective beta1 antagonists, minimizes unwanted bronchoconstriction - but asthma patients should still be monitored
Lowers BP in hypertension and increases exercise tolerance in angina - first line therapy for stable angina.
Esmolol has short half-life and is used to control blood pressure or heart rhythm during surgery.
Bisoprolol is the extended release formulation of metoprolol and is used for congestive heart failure.
Acebutolol and pindolol
not pure antagonists, weakly stimulate B1 and 2 receptors, said to have intrinsic sympathomimetic activity. Diminished effect on cardiac rate and cardiac output compared to beta-blocker without ISA.
Therapeutic uses: particularly effective in hypertensive patients with moderate bradycardia (these agents do not further decrease heart rate)