Adrenergic Agonists and Antagonists

Question 1

Adrenergic receptors

Answer 1

coupled to G proteins that mediate receptor signaling by altering ion channel conductance, adenylyl cyclase activity, PLC activation, as well as gene expression.

Question 2

Alpha 1 adrenergic receptors

Answer 2

Epi > NE >>> ISO

most vascular smooth muscle- contracts, increases vascular resistance

pupillary dilator muscle- contract (mydriasis)

pilomotor smoothe muscle- erects hair

Question 3

Alpha 2 adrenergic receptors

Answer 3

Epi > NE >>> ISO

adrenergic and cholinergic nerve temrinals - inhibits transmitter release

platelets- stimulate agrregation

some vascular smooth muscle- contracts

Question 4

Beta 1 adrenergic receptors

Answer 4

ISO> Epi=NE

Heart - stimulates rate and force

Juxtaglomerular cells- stimulates renin release

Question 5

Beta 2 receptors

Answer 5

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

Question 6

Beta 3 receptors

Answer 6

Fat cells. stimulate lipolysis.

Question 7

Dopamine 1 receptor

Answer 7

renal and other splanchnic blood vessels - relaxes, reduces resistance

Question 8

Dopamine 2 receptor

Answer 8

Nerve terminals - inhibits adenylyl cyclase

Question 9

Alpha 1 adrenergic receptors mechanism of action in vascular smoothe muscle

Answer 9

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

Question 10

Alpha 2 receptor mechanism of action

Answer 10

negatively couple to adenylyl cyclase via G_alphai.

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.

Question 11

Beta 1 adrenergic receptors mechanism of action in heart and muscle

Answer 11

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

Question 12

Beta 2 adrenergic receptors mechanism of action in vascular smooth muscle

Answer 12

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.

Question 13

Alpha 2 receptor mechanism of action

Answer 13

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)

Question 14

Isoproterenol (ISO)

Answer 14

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.

Question 15

Epinephrine

Answer 15

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.

Question 16

Norepinephrine

Answer 16

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.

Question 17

Dopamine

Answer 17

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.

Question 18

Dobutamine

Answer 18

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.

Question 19

Terbutaline, Albuterol

Answer 19

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)

Question 20

Phenylephrine

Answer 20

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

Question 21

Clonidine

Answer 21

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.

Question 22

amphetamine, methamphetomine, methylphenidate, ephedrine, pseudoephedrine, tyramine

Answer 22

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.

Question 23

Propanolol, Nadolol, Timolol

Answer 23

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.

Question 24

Metoprolol, Atenolol, Esmolol

Answer 24

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.

Question 25

Pindolol

Answer 25

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.

Question 26

Phenoxybenzamine, Phentolamine

Answer 26

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*

Question 27

Prazosin, Doxazosin, Terazosin

Answer 27

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