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