CVShypertension23-24.pptx

CV Pharmacology: Antihypertensives Robert Sims HA209 [email protected]  Learning Objectives Describe the mechanisms by which drugs can affect different body systems to reduce blood pressure Recall the drugs that treat hypertension, especially: Angiotensin co...

CV Pharmacology: Antihypertensives Robert Sims HA209 [email protected]  Learning Objectives Describe the mechanisms by which drugs can affect different body systems to reduce blood pressure Recall the drugs that treat hypertension, especially: Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Calcium channel blockers Beta blockers Alpha blockers (Diuretics) You do need to know the MoAs of the less used antihypertensives!  Hypertension High blood pressure is chronic arterial BP over 140/90 mmHg Prehypertension over 120/80 mmHg Hypertensive crisis over 180/120 mmHg Essential hypertension: high BP without identifiable cause (95% of cases) Secondary hypertension: high BP due to known condition (usually heart, kidneys, etc.)  Risks of Hypertension Heart attack Thromboembolism, especially stroke Aneurysm (“ballooning” of blood vessel) Kidney failure (weakened blood vessels) Others (e.g. retinal damage, cognitive impairment, metabolic syndromes)  Main pharmacological strategies VASOMOTOR CENTRE PNS SNS Autonomic Baroreceptors feedback loop Heart Contractile Venous PVR Rate Force Tone Arterial Cardiac Stroke Venous Blood Output Volume Return Volume Pressure Hormonal feedback loop Renal Renin Angiotensin blood flow  Main pharmacological strategies Blood pressure = cardiac output x peripheral vascular resistance BP = CO x PVR CO = HR x SV Cardiac output = heart rate x stroke volume Reduce PVR: Dilate blood vessels Reduce cardiac output: Decrease heart rate – negative chronotropes Decrease contractile force – negative inotropes Decrease blood volume  Vasodilation Angiotensin converting enzyme (ACE) inhibitors Angiotensin receptor blockers Calcium channel blockers Alpha blockers Directly acting vasodilators (niche use) Others (niche use)  Vasodilators – side effects Common side effects of CCBs, alpha blockers, directly acting vasodilators: Oedema Flushing Postural hypotension (dizziness) Fatigue Reflex tachycardia (baroreceptor response) Headache  Calcium channel blockers L-type calcium channel blockers Reduce Ca2+-dependent contraction in smooth muscle a) Dihydropyridines selective for vascular muscle (-”dipine”) nifedipine, amlodipine, felodipine, lercanidipine, Used to prevent vasospasm (e.g. following cerebral aneurysm) b) Non-DHPs: verapamil is heart selective, diltiazem intermediate; reduce cardiac output → ↓BP  Alpha-blockers Doxazosin, Prazosin a1 adrenoreceptor activation causes vasoconstriction (Gq) Therefore a1 blockers vasodilatory: ↓PVR Effective at reducing BP and very well tolerated; side effects oedema, postural hypotension, dry mouth Commonly used, but rarely as first line antihypertensives… why?  Alpha-blockers High blood pressure per se doesn’t kill anyone – it’s the secondary effects that do. ALLHAT trial (late 90s) Arm of study examining doxazosin ended early: Increased risk of combined CVD (especially congestive heart failure)  Intracellular nucleotides Drugs that increase concentrations of cGMP in vascular tissue and promote vasodilation. Rarely used in hypertension. Nitrates e.g. glyceryl trinitrate, nitroprusside; NO → ↑cGMP. Phosphodiesterase inhibitors (e.g. sildenafil); prevent cGMP breakdown Drugs that increase concentrations of cAMP in vascular tissue (e.g. adenosine, epoprostenol) may work, but are in practice not used.  Directly acting vasodilators (Nitrates / nitroprusside) Minoxidil: opens K+ATP channels and hyperpolarise vascular smooth muscle cells Hydralazine: MoA unclear; multiple mechanisms? prevents IP3 mediated calcium release? “Dimoxinil” opens K+ATP channels? Drugs of last resort – low safety profile Usually prescribed with negative chronotropes (β-blockers) & diuretics Minoxidil also hair regrowth…  Renin – Angiotensin system Lung & kidney ↑ Sympathetic activity epithelia Kidney tubules Liver + ↑ water retention ACE + Adrenal + gland + Angiotensinogen Angiotensin I Angiotensin II ↑ aldosterone secretion + + Angiotensin causes salt & water retention → ↑BP + ↑ arterial vasoconstriction Renin Feedback system of Pituitary renin suppression ↑ ADH secretion – Kidney Water & salt retention  Angiotensin converting enzyme inhibitors “ACEIs” - Inhibit Angiotensin Converting Enzyme (ACE) Prevent conversion of angiotensin I to angiotensin II Reduce arterial pressure & cardiac load Non-peptide, orally active drugs -pril: e.g. captopril (first in class), ramipril, lisinopril, many others Side effects: Relatively mild for antihypertensives: dry cough / bronchospasm, hyperkalaemia, angioedema. Teratogenic.  Angiotensin receptor blockers (ARBs) …sartan, e.g. losartan, candesartan, valsartan, etc. Antagonists at angiotensin II type 1 receptors (AT1) Similar clinical effects to ACEIs. Similar side effects to ACEIs, but no dry cough. Also teratogenic. Generally used when patients resistant to ACEIs. Do not use both!  Renin Inhibitors Aliskiren (2007) Inhibit catalytic activity of renin and prevent hydrolysis of angiotensinogen to angiotensin I Regarded as modest effectiveness, safety concerns, dietary restrictions (especially fatty foods) No others passed clinical trials (yet)  Diuretics For MoAs & side effects see diuretics lecture (Dr. Haylor): Good second-third line treatments for high BP Thiazide diuretics (intermediate; most popular diuretics for high BP) Loop diuretics (powerful; infrequent for high BP) Potassium-sparing diuretics e.g. spironolactone (weak, adjunct where hypokalaemia is a risk)  Angiotensin / aldosterone ARBs ↑ Sympathetic activity e.g. Losartan Diuretics + ACEIs ↑ water retention e.g. Captopril ACE + + + Angiotensinogen Angiotensin I Angiotensin II ↑ aldosterone secretion + + Renin inhibitors + ↑ arterial vasoconstriction Renin Aliskiren ↑ ADH secretion – Water & salt retention  Beta-blockers β1 & β2 antagonists Second line hypertension treatment in UK, although commonly used Contraindicated in hypertensive individuals with asthma / COPD, diabetes (suppression of insulin release), some arrhythmias “…lol” – atenolol, bisoprolol, labetalol, etc. Often different ones preferred compared to arrhythmia  β-blockers in hypertension b1 / b2 receptor antagonism: negative chrono- and inotropic in heart b2 receptor antagonism: vascular smooth muscle constriction ! b1 receptor antagonism also decreases renin release (↓ angiotensin) BP = CO x PVR Beta-blockers:decrease cardiac output Transient increase in PVR Long-term decrease in PVR  Centrally acting antihypertensives Mostly obsolete for hypertension; last resort drugs Inhibit sympathetic activity by reducing noradrenaline release α2 agonists: clonidine methyldopa (α2 hypothesised) moxonidine (also other action?) NICE guidelines A: ACEI or ARB (low cost preferred) C: Calcium channel blocker D: Diuretic (usually thiazide) Black people and over 55s have less responsiveness to renin; ACEIs / ARBs less effective Multi-drug therapy is common. Even beta-blockers and (less so) alpha blockers are commonly used for hypertension  Consider circumstances Lifestyle changes should be first route for treatment Comorbidities: arrhythmias (β-blockers, CCBs) decreased renal function (diuretics) diabetes (β-blockers) heart failure (complex) benign prostatic hyperplasia (α-blockers) etc. Pregnancy: ACEIs and ARBs must be avoided Beta-blockers (labetalol) favoured, then CCBs  Severe hypertension BP 180/120 mmHg or higher – refer to same day specialist Assess for organ damage If non-accelerated treat hypertension normally with frequent (weekly) monitoring If accelerated (“hypertensive crisis”), aim to reduce BP by 25% in under 1 hour with parenteral administration e.g. nitrates / nitroprusside, CCBs, hydralazine, beta-blockers  Summary First line pharmacological treatments are ACEIs, ARBs and CCBs Then diuretics (usually thiazide first, then aldosterone antag.), beta- blockers, alpha blockers Finally others depending on refractoriness or circumstances Combination therapy extremely common in hypertension; many patients on NICE steps 2-4 Pictorial Summary From Rang & Dale’s Pharmacology, 8th ed., Chapter 22.  MBBS Learning Outcomes M2.I.CAR.PHM7 Outline the mechanisms of action and therapeutic use of drugs that target the heart and vascular system  Further Reading Rang & Dale’s Pharmacology, 8th ed., Chapter 22. Medical Pharmacology at a Glance