Pharmacology of hypertension 2 Flashcards
What is the use of phentolamine in the treatment of hypertension?
Class - non-selective alpha blocker
Chemistry - small molecule
Pharmacology - targets adrenergic alpha receptors, competitive antagonist
Physiology:
Alpha 1 norm: G alpha subunit, PLC, IP3 increase Ca2+ increase - results in smooth muscle contraction
Therefore blockage causes vasodilation
Alpha 2 norm: Inhbit adenylyl cyclase, decrease Ca2+ entry prevent release of NA,
Therefore blockage - increases release of NA - (potentially side effects through action at beta receptors)
Clincal: mainly used in topical combination with aviptadil to treat erectile dysfunction, previously used for essential hypertension (rare now), can be used for cocaine toxicity but is not firsline.
What do you need to be cautious of when prescribing phentolamine?
Clincal use 1:
Hypertension - as a vasodilatant (yay!) however autoregulatory mechanism can cause reflex tachycardia in order to maintain cardiac output
Nature of non-selective alpha adrenergic receptor blocker - block of Alpha 2 - increase release NA - act on beta cause tachycardia.
What is the use of atenolol in the management of hypertension?
Summary: Can prevent the ANS and RAAS system-induced hypertension
Class: selective beta-1 blocker
Chemistry: small molecule
Pharmacology: competitive antagonist at B1 receptors
Physiology: norm - Beta 1 receptors - heart inc HR and JG cells in kidney renin secretion - blocked (mechanism AC- inc cAMP, noradrenaline) causes decreased cardiac output, alters baroreceptor reflex, deceased renin and decreased sympathetic outflow
Clinical: Essential hypertension, angina and arrhythmias.
How does the use of alpha adrenergic receptor blockers influence the use of beta blockers?
Alpha receptors blockers:
Alpha 1 - vasoconstrictor - blockers cause vasodilation
Alpha 2 - prevent NA release - blcokers increase NA release
If then given a selective B1 blocker - to prevent tachycardia - NA would accumulate and act on B2 receptors causing bronchodilation - combined with alpha adrenergic receptor blockers can resulting in severe hypotension risk of falls and fainting.
However if given a non-selective beta blocker - prevents NA action on beta 2 receptors - it can worsen hypertension.
What are the different classifications of adrenoreceptors and their second messenger system?
Alpha 1 receptors - vasoconstriction of periphral BV - activate PLC - increase IP3 - increase Ca2+
Alpha 2 receptors - prevent NA release from pre-synaptic terminal - inhibits adenylyl cyclase, decrease cAMP, decrease Ca2+ prevents vesicle fusion.
Beta receptors - 1- heart and JG cells - activate adenylyl cyclase convert ATP to cAMP increase Ca2+ - inc HR and inc renin
B
2- lungs - bronchodilator.
What are the clinical uses of adrenaline?
CRP
Acute hypotension
Anaphylaxis
What are the clinical uses of isoprenaline?
Beta adrenergic agonist
Approved for use in asthma (Beta 2 receptors)
What are the clinical uses of propanolol?
Non-selective beta antagonist
Approved for angina and effective in hypertension
What are the clinical uses of atenolol?
Selective beta 1 antagonist
Approved for hypertension.
What are the use of beta blockers as ant-dysrhythmic drugs?
Treatment of abnormal cardiac rhythms
Useful when abnormal rhythm is caused by excess sympathetic tone such as tachycardia.
What are the two main mechanisms through which cocaine brings about its effects?
1 - local anaesthetic - blocks voltage-gated sodium Ion Channels
2 - prevents neuronal uptake of Noradrenaline through NET - increases sympathetic tone via effects of adrenaline.
Suggest why beta blockers can not be used alongside cocaine.
Cocaine inhibition of NET leads to increased release of adrenaline
Increase adrenaline concentration in the synapse.
Combined with beta-blockers - leads to unopposed alpha-receptor agonism as no alternative for noradrenaline to bind to except alpha-adrenergic receptors.
Activation of alpha 1 receptors - causes skeltal muscle vasculature vasoconstriction, can worsen rather than cure hypertension.
Not countereffects by Beta 2 - vasodilatory effects
Beta 1 antagonists are less of a problem than non-selecitve antagonists.
What is the evidence for and against the use of beta blockers as an anti-hypertensive drug?
+Beta-blockers only when indicated for antother reason e.g angina, post MI, heart failure or heart rate control
+ twofer - one drug for two morbidities in a patient.
- inferior stroke control , hence should not be used after MI.
- risk of alpha adrenoreceptor unopposed agonism cause worse hypertension.
- No effect on atrial fibrillation which further increases risk of stroke.
_ lots of adverse effects including fatigue, sexual dysfunction and depression.
What is the use of baxodrostat in treatment of hypertension?
Class - is an aldosterone synthase inhibitor (ASI)
Chemistry - is a small molecule
Pharmacology - inhibits aldosterone synthase. (CYP11B2)
Note does not inhibit 11-beta hydroxylase (CYP11B1)
Physiology: Decreased conversion of deoxy-corticosterone to aldosterone, but still allows corticosterone production.
Clinical: treatment-resistant hypertension.
Note still under clinical trials
What are some of the enzymes involved in the production of corticosterone and aldosterone?
CYP11B2 has 11beta hydroxylase and aldosterone synthase activity, this converts deoxy-corticosterone to corticosterone then aldosterone. (inhibition of this - prevents RAAS mediated hypertension)
CYP11B1 is only 11-beta hydroxylase function converts deoxy-corticosterone to cortisone still allowing function of cortisol
