Cardiovascular: Pharmacology - Adrenoceptors Flashcards
How were adrenoceptors initially categorised?
By their relative affinities for various agonists:
Alpha-receptors: epinephrine >/= norepinephrine»_space; isoprenaline
Beta-receptors: isoprenaline > epinephrine >/= norepinephrine
Dopamine receptors: dopamine
Adrenoceptors are what type of receptor? How are they classified?
GPCRs
Classified on the basis of their alpha subunit
Outline the subunit and mechanism of a1-receptors
Subunit: Gq (coupled to phospholipase C)
Mechanism: phospholipase C hydrolyses polyphosphoinositides to produce IP3 and DAG, which increase intracellular Ca2+ (via release from stores and influx across membrane) - this leads to activation of various Ca2+ dependent protein kinases and other downstream signaling pathways
Describe the distribution and various effects of a1-receptors
Vascular smooth muscle: contraction (increases BP and may cause decreased HR due to baroreceptor reflex)
Pupillary dilator muscle: contraction (dilates pupil)
Pilomotor smooth muscle: piloerection
Prostate: contraction
Heart: positive inotropy (modest effect)
Give two examples of selective a1-agonists and explain their uses
Phenylephrine: mydriatic, decongestant, can be used to increase BP
Midodrine: for treatment of orthostatic hypotension (diminished baroreceptor responses in these patients so a1 activity causes marked increase in BP without decrease in HR)
Outline the subunit and mechanism of a2-receptors
Subunit: Gi (inhibits adenylyl cyclase)
Mechanism: adenylyl cyclase inhibition results in decreased cAMP (likely other signaling pathways also utilised but mechanisms unclear)
Describe the distribution and various effects of a2-receptors
Postsynaptic CNS neurons: multiple actions
Platelets: aggregation
Adrenergic and cholinergic nerve terminals: inhibits transmitter release
Some vascular smooth muscle: contraction (when administered locally, via rapid IV or in high doses)
Fat cells: inhibits lipolysis
Explain why a2-agonists can be used to treat HTN despite a2 activity at some vascular smooth muscle beds causing contraction
When given systemically the central effects (which lead to inhibition of sympathetic tone) obscure the peripheral vascular effects
Give three examples of selective a2-agonists and explain their uses
Clonidine: HTN treatment (may also cause sedation due to central effects)
Moxonidine: also an imidazoline agonist, results in less sedating effects than clonidine when used as HTN treatment
Dexmedetomidine: sedative agent (acts centrally by inhibiting noradrenergic nerve terminal activity)
Brimonidine: glaucoma
Explain the subunit and mechanism of B-receptors
All three subtypes (B1, B2, B3) have Gs subunit, which stimulates adenylyl cyclase to increase cAMP
B2 receptors may also couple to Gq receptors under certain conditions
Describe the distribution and various effects of B1-receptors
Heart: increased Ca2+ influx in SA node produces positive chronotropy (increased HR) and in AV node causes positive dromotropy (increased conduction velocity), also act as positive inotrope by increasing intrinsic myocardial contractility
Juxtaglomerular cells: increased renin release
Describe the distribution and various effects of B2-receptors
Respiratory smooth muscle: relaxation (bronchodilation)
Uterine smooth muscle: relaxation (prevent premature labor)
Vascular smooth muscle: relaxation (particularly in skeletal muscle vascular beds)
Skeletal muscle: increased K+ uptake
Liver: increased glycogenolysis
Describe the distribution and various effects of B3-receptors
Bladder: detrusor relaxation
Fat cells: increased lipolysis
Give an example of a selective B1-agonist and explain its uses
Dobutamine previously considered to be B1-selective but likely more complex (racemic mixture with mixed alpha and beta activity)
Positive inotropic agent with less reflex tachycardia (due to less activation of vasodilatory B2 receptors)
Give examples of selective B2-agonists and explain their uses
Salbutamol, terbutaline: asthma (short-acting), tocolytic
Salmeterol: asthma (long-acting)
Explain the mechanism of D1 vs D2 receptors
D1: adenylyl cyclase stimulation increases cAMP
D2: adenylyl cyclase inhibition decreases cAMP; K+ channel opening; decreased Ca2+ influx
Describe the distribution and effects of D1-receptors
Smooth muscle: dilates renal, splanchnic, coronary and cerebral blood vessels
Describe the distribution and effects of D2-receptors
Nerve endings: modulates neurotransmitter release (suppresses norepinephrine release)
Give an example of a selective B3-agonist and explain its use
Mirabegron: used to treat symptoms of OAB (urinary frequency, urgency)
Outline the pharmacodynamics of epinephrine
Alpha and beta adrenoceptor agonist: binds equally to all subtypes of alpha and beta adrenoceptors, acts through G proteins (Gq, Gi and Gs) to activate downstream signaling pathways
Effects on various organ systems:
- CV: potent vasoconstrictor (except in hepatic and skeletal muscle where it produces vasodilation due to B2 activity: may therefore produce a small decrease in DBP) and cardiac stimulant (both positive inotropy and chronotropy)
- Respiratory: bronchodilation
Outline the pharmacodynamics of norepinephrine
Predominantly alpha adrenoceptor agonist although may also activate B1 adrenoceptors with similar potency to epinephrine
Effects on various organ systems:
- CV: vasoconstrictor (increased SBP and DBP due to increased TPR), positive inotropy (via a1), compensatory baroreflex response may cause bradycardia (cancels out chronotropic effects of B1 stimulation)
Outline the pharmacodynamics of dopamine
Precursor to norepinephrine
Acts on D1 and D2 receptors, also acts as cardiac B1 agonist and at high doses vascular alpha agonist
- CV: at low doses causes decreased TPR due to D1 activity, at higher doses alpha agonism causes vasoconstriction and increased BP (i.e. acts similarly to epinephrine at high doses)
What is isoprenaline? What are its CV effects?
B agonist (little alpha activity)
Potent vasodilator with positive chronotropy and inotropy (increases CO, increases SBP but decreases DBP and may slightly decrease MAP)