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
What are the NICE recommendations for monitoring different BP under 140/90 in clinic ?
Under 140/90 mmHg - check BP every 5 years and more often if gets closer
What are the NICE recommendations to the monitoring BP 140/90 - 179/119 in clinic?
140/90 to 179/119 - Offer ambulatory BP monitor, investigate for organ damage and cardiovascular risk
What are the NICE recommendations for monitoring BP 180/120 or more in clinic?
Assess for target organ damage
Consider Ambualatory BP monitor
Repeat clinic BP in 7 days if no target organ damage
Refer for same day specialist review if:
- retinal haemorrhage or papilloedma
- life threatening symptoms
- suspected pheochromocytoma
What does NICE recommend for monitoring of ABPM for under 135/85?
Every 5 years monitoring
If evidence of organ dysfunction consider alternative cause
What does NICE recommend for monitoring of ABPM for 135/85 - 149/94?
Lifestyle advice
If over 80 or BP above top range in clinic offer drugs
Less than 80 with organ damage, CVD or Diabets risk offer drugs.
If aged under 40 consider specialist intervention.
Offer annual review, support for adherence to treatment and educate on risks.
What does NICE recommend for monitoring of people with an ABPM of 150/95 mmHg or more?
Other lifestyle advice and drug treatment
If younger than 40yrs consider specialised evaluation of secondary causes and long term benefits/risk of treatments
Discuss risks of CVD, patient treatment preference, support treatment compliance, offer annual review, support for adherence to treatment.
How should you determine the different first line treatment for hypertension?
If T2D - ACEi or ARB
Without T2D
- younger 55yrs and not African family origin give ACEi or ARB
- Age 55 or over - Calcium channel blocker
- Black African or Black Caribbean family origin - Calcium channel blocker.
How should the drugs used in hypertension progress?
- Monotherapy
- ACEi or ARB to ACEi/ARB plus CCB or thiazide like diuretic
- ACEi?ARB + CCB + thiazide like diuretic
- remains uncontrolled offer low dose spironolactone, alpha blocker or beta blocker, confirm with ABPM and seek expert advice.
What should be involved in therapeutic monitoring?
Measuring drug level activity
Low therapeutic index
Benefit v harm
Unpredictable pharmokinetics.
What is the main risk associated with over prescription of anthi-hypertensice drugs?
Falls in elderly
Dose remains too high from when younger
RIsk of fractures and serious injury
Blood pressure becomes too low - hypotensive causes falls.
