CVS Hypertension Lecture Notes PDF

CV Pharmacology: Antihypertensiv es Robert Sims HA209 [email protected] Lecture objectives Overview of physiological regulation of blood pressure Autonomic and hormonal feedback loops Heart, vasculature, blood volume Pharmacology of antihypertensive drugs Main us...

CV Pharmacology: Antihypertensiv es Robert Sims HA209 [email protected] Lecture objectives Overview of physiological regulation of blood pressure Autonomic and hormonal feedback loops Heart, vasculature, blood volume Pharmacology of antihypertensive drugs Main use vasodilators Renin-angiotensin system drugs Diuretics (briefly) The long tail-end of less used drugs Overview of clinical use and considerations Hypertension Prehypertension chronic >120/80 mmHg High blood pressure chronic >140/90 mmHg Severe hypertension chronic >180/120 mmHg Essential hypertension: high BP without identifiable cause (95%) Secondary hypertension: high BP due to known condition (usually heart, kidneys, etc.) Risks of hypertension Hypertension is not fatal itself, but leads to increased risk of mortality through associated factors: Heart attack Thromboembolism, especially stroke Aneurysm (“ballooning” of blood vessel) Kidney failure (weakened blood vessels) Others (e.g. retinal damage, cognitive impairment, metabolic syndromes) Blood pressure regulation VASOMOTOR CENTRE PNS SNS Autonomic Baroreceptors feedback loop Heart Contractil Venous PVR Rate e Force Tone Arterial Cardiac Stroke Venous Blood Pressure Output Volume Return Volume Hormonal feedback Renal loop blood Renin Angiotensi flow n Main 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 Renin – angiotensin system & diuretics Renin – angiotensin system ↑ Sympathetic Lung & kidney activity epithelia Kidney tubules Liver ↑ water retentio ACE n Angiotensinoge Angiotensin Angiotensin ↑ n I II aldosterone Adrenal gland secretion Angiotensin causes salt ↑ arterial Renin & water retention → ↑BP vasoconstricti on Feedback system of Pituitary renin suppression ↑ ADH – secretion Kidney Water & salt retention Angiotensin II (AT1) receptors Ang II AT1 receptor Gq ↑ vasoconstriction (blood vessels) ↑ noradrenaline release (CNS & ↑ SNS) PVR ↑ sodium reabsorption (kidneys) ↑ fluid ↑ aldosterone release (adrenal volume Angiotensin converting enzyme inhibitors Angiotensin Converting Enzyme (ACE) Converts angiotensin I to angiotensin II Also breaks down pro-inflammatory bradykinin ACEIs: non-peptide, orally active drugs Reduce peripheral resistance and cardiac load -pril: e.g. captopril (first in class), ramipril, lisinopril, many others Adverse effects relatively mild: Dry cough (via bradykinin) Angioedema (via bradykinin) Hyperkalaemia (aldosterone inhibition) Teratogenic Angiotensin receptor blockers (ARBs) …sartan, e.g. losartan, candesartan, valsartan, etc. Antagonists at angiotensin II type 1 (AT1) receptors Similar clinical effects to ACEIs Similar adverse effects to ACEIs, but no dry cough Some think should be first line choice over ACEIs Generally used when patients resistant to ACEIs… do not use both! β-blockers in hypertension β1 (+ β2) receptor antagonism: negative chrono- and inotropic in heart ! β2 receptor antagonism: vascular smooth muscle β 1 receptor antagonism in kidney also decreases renin constriction release (↓ angiotensin) Beta-blockers in hypertension: decrease cardiac output transient increase in PVR (SNS; constriction) long-term decrease in PVR 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 Often different ones preferred compared to arrhythmia “…lol” – atenolol, bisoprolol, labetalol, etc. β1 selective increasingly favoured Labetalol recommended as safe during pregnancy Diuretics For more details see diuretics lecture (Dr. Haylor): Loop diuretics (powerful; infrequent for high BP) Thiazide diuretics (intermediate; most popular diuretics for high BP) Potassium-sparing diuretics e.g. (weak, adjunct where hypokalaemia is a risk) Thiazide diuretics Thiazides - Inhibit Na / Cl + - Na+ Na+ cotransporter (NCC) in nephron Cl- K+ e.g. bendroflumethiazide Na+ Ca2+ Reduce reabsorption of K+ Na+ ions and water from water Increased urination; Ca2+ Cl- reduction of body fluid volume URINE BLOOD Additional diuretic Aldosterone receptor Na+ antagonist Na+ + K+ e.g. spironolactone K+ AR Ald Reduce expression of sodium transport proteins - Spironolactone ADH Reduce sodium reabsorption, reduce H 2O potassium excretion URINE BLOOD Vasodilators & other antihypertensives Vasodilators – adverse effects Common with CCBs, alpha blockers, directly acting vasodilators (e.g. nitrates, minoxidil, hydralazine) Caused by general vasodilation and/or impairment of body’s ability to regulate blood pressure: Oedema (fluid build-up) Flushing (skin reddening) Postural hypotension (→ dizziness) Fatigue Reflex tachycardia (baroreceptor response) Headache Calcium channels in hypertension L-type voltage-gated calcium channels L=“long”: activated by large potential changes, high conductance Very common, many cell types Differences in contractile mechanisms, channel structure and regulation cause different tissue responses by drug: Dihydropyridines (DHP) Selective for vasculature Non-DHPs Non-selective or cardioselective Calcium channel blockers Dihydropyridines (DHP) preferred for hypertension amlodipine, nifedipine, felodipine, lercanidipine Other vasodilation uses, e.g. vasospasm following cerebral aneurysm, Reynaud’s syndrome Non-DHPs preferred for arrhythmia verapamil is heart selective (reduce cardiac output = ↓BP) diltiazem intermediate, both heart and vasculature for more detail see antiarrhythmic drugs lecture Vasodilator adverse effects; constipation (mostly non-DHPs) Alpha-blockers Doxazosin, Prazosin α1 adrenoreceptor activation causes vasoconstriction (Gq) Therefore α1 blockers vasodilatory: ↓PVR Effective at reducing BP and very well tolerated; side effects oedema, postural hypotension, dry mouth… …but modest all-mortality outcomes ALLHAT trial (late 90s) Increased risk of combined CVD (especially congestive heart failure) with doxazosin compared to diuretic Other drug options Rarely used drugs – often modest effectiveness / low safety profile. For specialist use or emergencies. Centrally acting antihypertensives – α2 adrenoceptor agonists clonidine, methyldopa, moxonidine Nitrates – see lecture on anti-anginals K+ATP channel facilitators – hyperpolarise vascular smooth muscle minoxidil (better known for hair regrowth) Renin inhibitors – aliskiren Clinical use 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 Rapid referral – same day specialist if accelerated 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 Pictoral summary From Rang & Dale’s Pharmacology, 8th ed., Chapter 22. MBBS learning outcomes & further reading M2.I.CAR.PHM7 Outline the mechanisms of action and therapeutic use of drugs that target the heart and vascular system Rang & Dale’s Pharmacology, 8th ed., Chapter 22 Medical Pharmacology at a Glance