Cardiovascular: Pharmacology - Adrenoceptors Flashcards by Hannah Meiklejohn

How were adrenoceptors initially categorised?

By their relative affinities for various agonists:
Alpha-receptors: epinephrine >/= norepinephrine&raquo_space; isoprenaline
Beta-receptors: isoprenaline > epinephrine >/= norepinephrine
Dopamine receptors: dopamine

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Adrenoceptors are what type of receptor? How are they classified?

GPCRs
Classified on the basis of their alpha subunit

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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

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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)

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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)

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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)

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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

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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

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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

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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

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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

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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

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Describe the distribution and various effects of B3-receptors

Bladder: detrusor relaxation
Fat cells: increased lipolysis

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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)

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Give examples of selective B2-agonists and explain their uses

Salbutamol, terbutaline: asthma (short-acting), tocolytic
Salmeterol: asthma (long-acting)

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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

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Describe the distribution and effects of D1-receptors

Smooth muscle: dilates renal, splanchnic, coronary and cerebral blood vessels

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Describe the distribution and effects of D2-receptors

Nerve endings: modulates neurotransmitter release (suppresses norepinephrine release)

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Give an example of a selective B3-agonist and explain its use

Mirabegron: used to treat symptoms of OAB (urinary frequency, urgency)

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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

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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)

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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)

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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)

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Give an example of a selective D1-agonist and explain its use

Fenoldopam: used IV to treat severe HTN (causes peripheral vasodilation in some vascular beds)

How does levodopa work?

Converted to dopamine and acts centrally to treat Parkinson's disease and prolactinaemia

Outline the relative receptor affinities for phenylephrine, clonidine, norepinephrine, epinephrine, dobutamine, isoprenaline, terbutaline, dopamine and fenoldopam

Phenylephrine: a1 > a2 >>>>> B Clonidine: a2 > a1 >>>>> B Norepinephrine: a1 = a2, B1 >> B2 Epinephrine: a1 = a2, B1 = B2 Dobutamine: B1 > B2 >>>> a Isoprenaline: B1 = B2 >>>> a Terbutaline: B2 > B1 >>>> a Dopamine: D1 = D2 >> B >> a Fenoldopam: D1 >> D2

What is the mechanism of action of amphetamine?

Indirect-acting sympathomimetic Via release of NA and to lesser extent dopamine Readily enters CNS

What is the mechanism of action of tyramine?

Indirect-acting sympathomimetic Normal by-product of tyrosine metabolic; normally metabolised by MAO in liver Acts by increasing catecholamine release from noradrenergic neurons

Explain why patients on MAOIs are counselled to avoid tyramine-containing foods such as beer, aged cheese, cured meats, etc

Tyramine is normally metabolised by MAO in the liver Bioavailability is markedly increased with MAO inhibition This causes marked hypertension

Give two examples of catecholamine reuptake inhibitors

Duloxetine (SNRI) Cocaine (inhibits transmitter reuptake at noradrenergic neurons)

Describe the pharmacodynamics of alpha antagonists

CV: decreased TPR and therefore BP, reflex tachycardia (especially if non-selective or if acting on a2-presynaptic receptors in heart), orthostatic hypotension (due to venodilation and venous pooling secondary to a1 antagonism of vascular smooth muscle) Eye: miosis ENT: nasal stuffiness GU: a1 antagonism produces relaxation of bladder and prostate

Explain the concept of "epinephrine reversal" as it pertains to alpha antagonists

Unopposed B2 effects of epinephrine in the presence of alpha antagonist causes hypotension

What are alpha antagonists typically used to treat?

Hypertension caused by excess circulating alpha agonists (e.g. in phaeochromocytoma, overdose of sympathomimetic drugs, or clonidine withdrawal) Urinary retention secondary to prostatic hyperplasia

Give four examples of alpha antagonists

Phenoxybenzamine Phentolamine Prazosin Tamsulosin

Outline the pharmacodynamics of phenoxybenzamine

Irreversible antagonist (duration of drug action ~14-48hrs or more as dependent on new receptor synthesis) Relatively selective for a1

What are the adverse effects of phenoxybenzamine?

Orthostatic hypotension Tachycardia

Outline the pharmacodynamics of phentolamine

Competitive a1 and a2 antagonist Causes decreased TPR but increased HR

What is the half life of phentolamine?

45 mins when given IV

What is phentolamine used for?

Phaeochromocytoma treatment Reversal of local anaesthesia with vasoconstrictor

Outline the pharmacodynamics of prazosin

Highly selective for a1, so less likely to cause increased HR May cause orthostatic hypotension

What is the bioavailability and half-life of prazosin?

Bioavailability: 50% Half-life: 3hrs

Outline the pharmacodynamics of tamsulosin

Competitive a1 antagonist (especially a1A and a1D subtypes) More selective for prostate smooth muscle Less likely to Whcause orthostatic hypotension

What is bioavailability and half-life of tamsulosin?

Bioavailability: high Half-life: 9-15hrs

Outline the pharmacokinetics of B-blockers generally

Absorption: usually well-absorbed with peak concentrations 1-3hrs post ingestion, sustained release preparations available for propranolol and metoprolol Bioavailability: limited to varying degrees for most B blockers with the exception of sotalol and pindolol, propranolol undergoes extensive first-pass metabolism and has low bioavailability but this is increased with higher doses (suggesting hepatic metabolism pathways may become saturated) Distribution: rapidly distributed, large Vd, propranolol highly lipophilic and readily crosses BBB Clearance: half-life typically 3-10hrs with the exception of esmolol (half-life 10mins)

Outline the pharmacodynamics of B-blockers generally

CV: decreased BP (likely due to decreased renin release and CNS effects), negative chronotropy and inotropy, negative dromotropy (decreased risk of ventricular arrhythmias and ectopics, may cause first degree HB), increased TPR acutely (due to B2 blockade in vasculature and alpha response to decreased CO) Respiratory: increased airway resistance (especially if nonselective) Eye: decreased IOP (due to decreased aqueous humour production) Metabolic/endocrine: decreased lipolysis, decreased glycogenolysis (due to B2 blockade), increased VLDL and decreased HDL Other: local anaesthetic "membrane stabilising" effects (not significant with systemic administration), sotalol has class III antiarrhythmic effects (K+ channel blockade)

Outline the selectivity, lipid solubility, half-life, bioavailability, and presence or absence of partial agonist and local anaesthetic activity of propranolol

Selectivity: none Partial agonist: no Local anaesthetic action: yes Lipid solubility: high Half-life: 3.5-6hrs Bioavailability: 30% (dose-dependent)

Outline the selectivity, lipid solubility, half-life, bioavailability, and presence or absence of partial agonist and local anaesthetic activity of metoprolol

Selectivity: B1 Partial agonist: no Local anaesthetic action: yes Lipid solubility: moderate Half-life: 3-4hrs Bioavailability: 50%

Outline the selectivity, lipid solubility, half-life, bioavailability, and presence or absence of partial agonist and local anaesthetic activity of atenolol

Selectivity: B1 Partial agonist: no Local anaesthetic action: no Lipid solubility: low Half-life: 6-9hrs Bioavailability: 40%

Outline the selectivity, lipid solubility, half-life, bioavailability, and presence or absence of partial agonist and local anaesthetic activity of labetalol

Selectivity: none Partial agonist: yes Local anaesthetic action: yes Lipid solubility: low Half-life: 5hrs Bioavailability: 30%

Outline the selectivity, lipid solubility, half-life, bioavailability, and presence or absence of partial agonist and local anaesthetic activity of esmolol

Selectivity: B1 Partial agonist: no Local anaesthetic action: no Lipid solubility: low Half-life: 10mins Bioavailability: 0%

What are some of the potential benefits of B1 antagonist selectivity?

Less bronchoconstriction Less risk of hypoglycaemia in insulin-dependent diabetics Safer in PVD (less vasoconstriction in skeletal muscle vasculature)

List three cardioselective B-blockers

Bisoprolol Nebivolol Carvedilol

What is unique about nebivolol?

Also causes vasodilation via increased NO

What is unique about carvedilol?

Also an alpha antagonist

What is unique about atenolol?

Also an a1 antagonist

List three partial B agonists (intrinsic sympathomimetic activity). What is the potential benefit of a partial agonist?

Cartelol Labetalol Pindolol Less likely to cause bradycardia

List four B-blockers with local anaesthetic action via Na+ channel blockade

Labetalol Metoprolol Propranolol Pindolol

Describe some possible effects of B-blocker toxicity

Exacerbation of asthma Worsening of PVD Hypoglycaemia CNS effects: vivid dreams, mild sedation When taken with verapamil: severe hypotension, bradycardia, heart failure, arrhythmia Arrhythmia due to Na+ channel blockade Cardiac decompensation if dependent on sympathetic drive Cool peripheries

What two drugs can be used to manage B-blocker toxicity?

Glucagon: stimulates heart directly via glucagon receptors Isoprenaline