Cardiac Pharmacology

Androgen Receptor Subtypes

a ₁stimulate vascular smooth muscle (vasoconstriction)

b ₁stimulate heart rate, AV conduction, and contractility

b ₂relax vascular smooth muscle (vasodilation)

Drug actions at adrenergic, muscarinic, histamine and angiotensin receptors

1) HR: heart rate

2) SBP: systolic blood pressure

3) DBP: diastolic blood pressure

4) PP: pulse pressure (PP = SBP – DBP)

5) MAP: mean arterial pressure (MAP = DBP + 1/3PP)

also note: MAP = CO x PVR; CO = SV x HR

agonists (identified in bold letters under the heading RECEPTORS) have a short half-life as whereas the antagonists have a long half-life

pressor/repressor reflex: when blood pressure in the aortic arch changes, receptors send signals to the CNS to either stimulate the Parasympathetic Nervous System (to ß HR Þ ß BP) or the Sympathetic Nervous System (to Ý HR and constrict arterioles[a ₁response] Þ Ý BP)

Adrenergic Agonists

Norepinephrine (L form is active)

Receptor: a₁, b₁

Observation: ÝSBP ÝDBP ÝPP ßHR (reflex bradycardia)

Effect: potent vasoconstrictor direct heart effects not apparent because of reflex vagal tone

Epinephrine (methylated norepinephrine) – Adrenal enzyme methylates norepinephrine

Receptor: a₁, b₁, and b₂ ([b >>a ]affinity)

Observation: EPI INVERSION

Low Dose: ÝHR ÝSBP ßDBP ÝÝPP

High Dose: ÝSBP ÝDBP ÝHR

Effect: positive inotropic and chronotropic effects. Because its b -agonist properties are non-selective, it causes dilation in vascular beds rich in b₂ receptors (e.g. skeletal muscle) and vasoconstriction in beds rich in a ₁ receptors (e.g. skin). Effects on mean arterial pressure are dose-dependent because of differential affinities of a and b receptors

Isoproterenol – synthetic trimethylated norepinephrine

Receptor: b₁ and b₂

Observation: ÝÝHR ßßDBP (without significant change in SBP)

Effect: potent inotropic and chronotropic agent with vasodilation of skeletal muscle beds. No vasoconstrictor activity.

Phenylephrine – synthetic

Receptor: a₁

Observation: ÝSBP ÝBP ßHR (reflex bradycardia)

Effect: vasoconstrictor with no direct effects on the heart, reflex bradycardia in response to blood pressure increase.

Adrenergic Antagonists

Propranolol – Opposes isoproteranol

Receptor: b₁ and b₂

Observation: When coadministered with other drugs:

makes norepinephrine (a₁,b₁) and epinephrine (a₁,b₁,b₂) look like phenylephrine (a₁)

neutralizes effect of isoproterinol (b₁b₂)

ablates reflex tachycardia of histamine

Effect: non-selective b -blocker. Small effects by itself, but completely blocks inotropic and chronotropic effects of catecholamines. Also blocks reflex tachycardia which results from b ₁ sympathetic stimulation

Phentolamine – Opposes phenylephrine

Receptor: a₁

Observation: When coadministered:

makes norepinephrine cause only ÝÝHR

makes epinephrine (a₁,b₁b₂) look like isoproterenol (b₁b₂)

Effect: small effect by itself, but blocks pressor effects of catecholamines

Cholinergic Agonists

Acetylcholine – Slows things down

Receptor: Muscarinic and nicotinic cholinergic agonist

Observation:

Direct cardiac effect Þ Þ ßßHR; ßSA and AV node action

vasodilation Þ Þ ß SBP ß DBP (which paradoxically leads to reflex tachycardia, Ý HR)

Effect: Causes bradycardia and decrease in blood pressure. Dilation response not understood. Vagal reflex (Ý HR) may preclude direct effect.

Cholinergic Antagonists

Atropine – Opposes acetylcholine, activates system

Receptor: muscarinic receptors
Observation: Blocks pressor reflex and dilates pupils
Effect: blocks negative chronotropic and vasodilator effects of acetylcholine and reflex vagal effects because parasympathetic neurotransmitter is Ach.

Effects of Other Receptor Agonists

Histamine – Locally active; when systemicÞ shock

Receptor: H₁and H₂ agonist (parietal cells in stomach, basophils, mast cells)

Observation: ßßSBP ßßßDBP ÝHR (reflex tachycardia)

Effect: Vaso-and veno-dilator (autacoid); decreased blood pressure with venous pooling and reflex tachycardia.

Angiotensin II – An octapeptide that is the most potent pressor substance known

Receptor: angiotensin receptors

Observation: ÝÝSBP ÝÝDBP Þ ßßHR (reflex bradycardia)

Effect: it causes intense vasoconstriction and reflex bradycardia.