Adrenergic Agonists and Antagonists Flashcards
Adrenergic receptors
coupled to G proteins that mediate receptor signaling by altering ion channel conductance, adenylyl cyclase activity, PLC activation, as well as gene expression.
Alpha 1 adrenergic receptors
Epi > NE >>> ISO
most vascular smooth muscle- contracts, increases vascular resistance
pupillary dilator muscle- contract (mydriasis)
pilomotor smoothe muscle- erects hair
Alpha 2 adrenergic receptors
Epi > NE >>> ISO
adrenergic and cholinergic nerve temrinals - inhibits transmitter release
platelets- stimulate agrregation
some vascular smooth muscle- contracts
Beta 1 adrenergic receptors
ISO> Epi=NE
Heart - stimulates rate and force
Juxtaglomerular cells- stimulates renin release
Beta 2 receptors
ISO > Epi >> NE
respiratory, uterine, vascular smoothe muscle- relaxes
Liver- stimulates glycogenolysis
Pancreatic Beta cells - stimulates insulin release
somatic motor nerve temrinals (voluntary muscle) - causes tremor
Beta 3 receptors
Fat cells. stimulate lipolysis.
Dopamine 1 receptor
renal and other splanchnic blood vessels - relaxes, reduces resistance
Dopamine 2 receptor
Nerve terminals - inhibits adenylyl cyclase
Alpha 1 adrenergic receptors mechanism of action in vascular smoothe muscle
Positively coupled to PLC via Gq alpha protein.
When NE or Epi binds- Gq activates PL, which frees IP3 and DAG. IP3 causes Ca release from SR. increased Ca concentration causes muscle contraction
Alpha 2 receptor mechanism of action
negatively couple to adenylyl cyclase via Galphai.
this inhibits cAMP formation which reduces PKA. Phosporylation of N-type Ca channels is reduces, whcih reduces Ca influx during membrane depolarization. This reduces the vesicular release of NT.
Beta 1 adrenergic receptors mechanism of action in heart and muscle
positively coupled to adenylyl cyclase via Galpha-s proteins. increases cAMP
Positive chronotropy- î cAMP, î PKA, î phos of Ca channels in SA node, Î inward Ca current, faster nodal cell depolarization to to the firing threshold
Positive inotropy- Î cAMP, Î PKA phos of L-type Ca channels, larger trigger signal for release of Ca from SR, stronger contraction
this trigger Ca also enters the SR and builds up so that next trigger has a larger release of Ca through ryanodine receptors
Beta 2 adrenergic receptors mechanism of action in vascular smooth muscle
positively coupled to adenylyl cyclase via Galpha-s protein. increases cAMP
Î cAMP, Î PKA, phosphrylates and inactivates MLCK, reduces MLCK affinity for CAM, phosphorylation of MLC is inhibited, no cros bridges formed, mucle relaxation.
Alpha 2 receptor mechanism of action
Galpha-i subunit. inhibits adenylyl cyclase, whcih inhibits cAMP and PKA. This leads to activation of MLCK.
MLCK can bind to CAM and phosphorylate MLC causing contraction. (vascular smoothe muscle constriciton)
Isoproterenol (ISO)
cathecholamine with a large substitution on its amine group. makes it selectvie for beta adrenergic receptors.
non-selective B-adrenergic agonist. Potent B receptor agonist with no A receptor affinity.
B2- peripheral vasodilation, decreased diasotlic BP.
B1- positive inotropy and chronotropy. increas systolic BP which is overcome by vasodilation. Small increase in MAP, which may contribute to further reflex HR increase. Bronchodiation.
Therapeutic use: crdiac stimulation during bradycardia or heart block when peripheral resistance is high.
Toxicity: tachy arrythmias
Contraindications: Angina, particularly with arrythmias.
Epinephrine
Stimulates A1,A2,B1,B2 ( beta activation presmoniates at low concentrations)
short half life, metabolized by COMT
B2- peripheral vasodialtion, decrease diastolic BP, decreased TPR. bronchodilation
B1- positive inotropic an chonotripic effects, increased CO and systolic BP
A1- peripheral vasoconstriction. decreased bronchosecretions.
Therapeutic use: Anaphylaxis, cardiac arrest, heart block, bronchospasm, shock
Toxicity: Arrythmias, cerebral hemorrhage, anxiety, cold extremities, pulmonary edema
contraindications: late term pregnancy. coould affect fetal blood flow.
Norepinephrine
A1, A2, B1, little affinity for B2
Short half life, metabolized by COMT and MAO
A1- vasoconstriction. Î TPR, Î vasoconstriction, Î diastolic BP
B1- inotropic and chronotropic effects, î systolic BP. increased MAP
increased BP leads to baroreceptor response and decreased HR.
Therapeutic use: limited to vasodilatory shock
contraindications- pre existing vasoconstriction and ischemia. late term pregnancy.
Dopamine
Stim D1 receptors at low conc. also has affinity of B1 and alpha receptor, which may be activated at higher concentrations.
half life 2min, metabolized by MAO and COMT
D1- at low infusion rate decreased TPR
B1- at medium infusion rate. Î contractility, Î heart rate,
A- at higher infusion rates. Î BP and TPR
Therapeutic uses- hypotension due to low CO and cardiogenic shock. (will dilate renal and mesentric vacular beds)
toxicity- at low infusionrate hypotension, ischemia at high infusion rates.
contraindications- uncorrected tachyarrythmias, or ventricular fibrilation.
Dobutamine
B1>B2>A
B1 selective agonist. Degraded by COMT. half life 2-3 min
Increased CO (B1). no effect on vasculature or lung. positive inotropic effect is greater than positive chronotropic effect due to lack of B2 mediated vasodialtion and reflex tachycardia.
At higher doses may activate B2 and cause hypotension with reflex tachycardia.
Therapeutic use: Short term treatment of cardiac insufficiency, CHF, cardiogenic shock, or excess B-bloackade.
cardiac stress testing
Toxicity: Arryhtmias (B1), Hypotension ( B2 vasodialtion), hypertension from inotropic and chronotropic effects.
Terbutaline, Albuterol
Selective B2 agonists (can cause some B1 response at high dose). longer half life
no cardiovascular effect die to lack of B1 activity. Bronchodilation. Relaxation of pregnant uterus.
Therapeutic Use: Bronchospasm, COPD
Toxicity: tachycardia (B1), tolerance (B2), skeletal muscle tremor, activation of B2 receptors on pre-synaptic nerve terminals on somatomotor neurons = muscle tremor (B2)
Phenylephrine
A1 receptor agonist
not a catecholamine so not degraded by COMT, longer duration of action (less than 1 hour)
degraded by MAO
Cardiovascular: peripheral vasoconstriction, increased TPR and MAP, increased BP activates baroreceptor reflex which causes decreased HR.
Opthalmic: Dilates pupil
Bronchioles: decreases bronchiol (upper airway) secretion.
Therapeutic use: Hypotension during anestesia or shock, paroxysmal SVT, mydriatic agent, nasal decongestant.
Toxicity: hypertension
contraindicaitons: pts with HTN
Clonidine
selective A2 adrenergic agonist
cardiovascular: mild peripheral vasoconstriction, î BP, crosses BBB and reduces sympathetic output to vacular smooth muscle which overides initial vasoconstriction and reduces vasoconstriction and lowers BP. (CNS effect)
Therapeutic use: HTN caused by excessive sympathetic drive.
Toxicity: Dry mouth, sedation, bradycardia, withdrawel after long term use can cause a hypertensive crisis due to sudden increase in sympathetic activity.
amphetamine, methamphetomine, methylphenidate, ephedrine, pseudoephedrine, tyramine
amphetamine, methamphetomine, methylphenidate (dopamine reuptake inhibitor), ephedrine, pseudoephedrine, tyramine
Indirect sympathomimetics
Cross BBB
resistant to degradation by COMT and MAO (except tyramine which is degraded by MAO)
amphetamine like drugs are taken up by re-uptake proteins and cause reversal of the re-uptake mechanism resulting in release of NT in a Ca independent manner. increase in synaptic NE
high abuse due to central dopamine release
Cardiovascular effects- due to NE release. peripheral vasoconstriction, î BP (A1 & A2). positive ionotropy and increased conduction velocity, increased systolic BP (B1). increased systolic BP can cause baroreceptor reflex and decreaae HR.
CNS- stimulant, anorexic agent.
Therapeutic: ADD, narcolepsy, nasal congestion, ephedrine is a pressor agent for anesthesia
Toxicity: anxiety, tachycardia (B1)
Contraindications: Hypertension, atherosclerosis, history of drug abuse, MAO inhibitors used in the last 2 weeks.
Propanolol, Nadolol, Timolol
Non-selective Beta-blockers
timolol reduces production of aqeous humor
Cardiovascular effects: reduced HR & contractility, reduced renin release, reduced angiotensin, therefore reduced vasoconstriction. Reduced sympathetic activation.
Bronchioles: constriction in pts with asthma or COPD
Therapeutic use: Propranalol- Hypertension, heart failure, arrhythmia, MI, angine due to atherosclerosis. Nadolol- longe term angina, hypertension (20-24hrs) thyorotoxicosis, anxiety. timolol-glaucoma
Toxicity: Bronchospasm, masks symptoms of hypoglycemia, insomnia, depression, bradycardia, some can raise triglycerides
Contraindications: Bronchial asthma, sinus bradycardia, 2nd & 3rd degree heart block, cardiogenic shock.
Metoprolol, Atenolol, Esmolol
Cardioselective B1 blockers
reduced respiratory side effects
Cardiovascular effects: Decreased Hr, Decreased contractility, decreased renin release, reduced sympathetic activation
reduced production of aqeous humour
Therapeutic use: Hypertension (metoprolol, atenolol) angina, arryhtmia (esmolol). Esmolol has short half life, given in HTN crisis, SVT; unstable angina.
Toxicity: Dizziness, depression, insomnia, hypotension, bradycardia.
Contraindications: sinus bradycardia, 2nd and 3rd degree heart block, cardiogenic shock, severe heart failure.
Pindolol
Patrial Beta agonist for B1 and B2
cardiovascular effects: Won’t cause the bradycardia that beta blockers cause. Decreased BP, Decreased contractility, decreased renin release, decreased SNS activation.
Therapeutic: used when HTN is due to high SNS output. Used for people who are less tolerant of bradycardia and reduced excercise capacity cause by full B blockade.
Toxicity: Dizziness, Depression, insomnia, hypotension
Contraindications: sinus bradycardia, 2nd and 3rd degreee heart block, cardiogenic shock, severe heart failure.
Phenoxybenzamine, Phentolamine
Non-selective A-receptor antagonist
Phenoxybenzamine (irreversible), Phentolamine (reversible)
Cardiovascular effects: inhibit vasoconstriction, decrease BP (A blockade + unmasks B effects), increased inotropy and chronotropy due to pre-synaptic blockade of A2. Î NE, reflex î in NE in response to hypotension. unmasks vasodilatory effects of EPI (A and B).
Therapeutic use: Hypertension associated with perioperative treatment of pheocromocytoma (adrenomedullary tumor that produces EPI/NE), test for pheochromocytoma, dermal necrosis, sloughing with vasoconstrictor extravasation.
Toxicity: prolonged hypotension (orthostatc), reflex tachycardia, nasal congestion.
Contraindications: coronary artery disease (increases work of heart)
*Phentolamine is given to people on MAO inhibitors who eat tyramine containing foods*
Prazosin, Doxazosin, Terazosin
Selective A1 receptor blockers.
Cardiovascular effects: Inhibit vasoconstriction → vasodilation and decreased BP, less cardiac stimulation than non-selective A blockers due to preservations of A2-adrenergic function.
Therapeutic use: Hypertension, benign prostatic hyperplasia (prostate has a lot of A1 receptors).
Toxicity: Syncope, Orthostatic hypertension
