Drug Therapies for Hypertension and Angina

• Hypertension - aetiology:

  • Essential hypertension 80% cases
  • Caused by complex interaction of genes and environment
  • Not simple Mendelian single genes but interaction of genes some involving RAS (renin angiotensin system)
  • Renal diseases
  • Endocrine diseases
  • Steroid excess - hyperaldosteronism (Conn's syndrome)
• Hypertension - aetiology:

  • Vascular disease causes:
  • Renal artery stenosis
  • Fibromuscular disease in younger women
  • Atheroma in middle age older smokers
  • Coarctation (narrowing of the aorta as it exits the heart - rare)
  • Drugs etc
  • Amphetamines, cocaine, oestrogens (eg oral contraceptive pills), cyclosporin, sympathomimetic amines, erythropoeitin
• Renin-Angiotensin System: aldosterone increases peripheral resistance activates sympathetic nervous system increases heart rate and blood pressure. Also stimulates kidneys to retain sodium, which also raises blood pressure.

  
• The kidney senses a reduction in blood flow due to the reduced amount of sodium in the distal tubule, or a reduction in the glomerular filtration. This can lead to in increase in the release of renin: an enzyme which converts angiotensinogen to angiotensin I in the lung. Angiotensin I then gets converted to angiotensin II by ACE (angiotensin converting enzyme). Angiotensin II then binds to the angiotensin receptor, which results in the production of aldosterone. It also results in peripheral vasoconstriction, which increases blood pressure and the workload of the heart.

  
• Aldosterone is the main hormone in charge of preserving sodium, so increased amounts of aldosterone in the body mean that the kidneys retain more water and salt. Also activates sympathetic nervous system, which will increase heart rate and the forcefulness of the heartbeat (the contractility), this increase blood pressure too. Angiotensin II production should inhibit renin release (negative feedback system), but sometimes the system can get overwhelmed and the production gets out of control.

  
• Management of hypertension:

  • Aim to prevent myocardial infarction and stroke
  • Treatment also reduces risk of heart failure and renal failure
  • BP > 140/90 mmHg and vascular disease or cardiovascular risk > 20% 10 years offer lifecycle advice then drug treatment
  • Most pts with moderate or severe hypertension require drug therapy with 2 or more drugs to achieve target BP < 140/90
• Stage 1 hypertension:

  • Clinical blood pressure (BP) is 140/90 mmHg or higher and
  • ABPM (ambulatory blood pressure monitoring) or HBPM (home blood pressure monitoring) average is 135/85 mmHg or higher
  • Ok to monitor lifestyle modification arrange 24 hour monitor
• Stage 2 hypertension:

  • Clinical BP is 160/100 mmHg or higher and
  • ABPM (ambulatory blood pressure monitoring) or HBPM (home blood pressure monitoring) daytime average is 150/95 mmHg or higher
  • Lifestyle modification fairly urgent 24 hour monitor. Treatment of BP remains high in clinic or on 24 hour BP.
• Severe hypertension:

  • Clinical BP is 180 mmHg or higher or
  • Clinical diastolic BP is 110 mmHg or higher
  • Treat immediately; may be an emergency
• Management of hypertension:

  • Manage other vascular risk factors to reduce risk of MI and stroke
  • Smoking
  • Cholesterol lowering
  • Diabetes
  • Weight
  • Exercise
• ABCD categorisation:

  • A
  • ACEI (ACE inhibitors) - Lisinopril
  • ARBs (angiotensin receptor blockers) - Losartan
  • B - beta blockers - Atenolol
  • C - calcium channel blockers - Amlodipine
  • D - diuretics (thiazide like) - Indapamide
  • Alpha blockers - Doxazosin
  • Anti-aldosterone - Spironolactone
• Thiazide-like diuretics:

  • eg Indapamide
  • Mechanisms of action:
  • Increase excretion of Na, Cl, K and water
  • Blocks Na-Cl co-transport mechanism in the distal nephron
  • More Na then reaches the distal tubule where some is exchanged by Na-K transport to increase K loss
  • BP lowering related to decreased peripheral resistance - unrelated to Na loss
  • Can cause hyponatraemia
  • Gout flare
• Beta-blockers (β-adrenoceptor antagonists):

  • eg Atenolol
  • Mechanisms of action:
  • Decrease heart rate - decrease rate of spontaneous depolarisation, slow conduction in atria and AV (atrioventricular) node
  • Decrease myocardial contractility
  • Inhibition renin-angiotensin system
  • Decrease peripheral resistance
• Beta blockers:

  • Propranolol - non-selective antagonizes β₁ + β₂ adrenoceptors
  • Not used much now for management of hypertension or heart failure
  • Can help with stress-related symptoms
  • Anxiety-related BP
  • Atenolol - cardioselective: relatively selective β₁-adrenoceptors (heart) less antagonism β₂-adrenoceptors in lungs (cause bronchial vasoconstriction and wheeze)
  • β-blockers also used to treat stable heart failure along with ACEIs and the aldosterone antagonist spironolactone - improve survival if tolerated
  • Beta blockers can precipitate or exacerbate heart failure in unstable patients
• Adverse effects of beta blockers:

  • Bronchospasm (action on bronchial β₂-receptors)
  • Heart failure (due to negative inotropic effects)
  • Bradyarrhythmias, cold extremities, fatigue, sleepiness, vivid dreams
  • Blunting of recognition of hypoglycaemia in diabetes
  • Beta-blocker withdrawal syndrome - increased sensitivity to catecholamines can occur 3-10 days after discontinuation, which may lead to worsening angina
  • Sleep disturbance
  • Lichenoid eruptions
  • Increased tooth demineralisation
• 3 classes of calcium-channel blockers:

  • Dihydropyridine
  • eg Nifedipine - increases heart rate
  • eg Amlodipine - increases heart rate
  • Benzothiapine
  • eg Diltiazem - decreases heart rate
  • Phenylalkylamine
  • eg Verapamil - decreases heart rate
• Mechanisms of action of calcium-channel blockers:

  • Calcium interacts with calmodulin to produce smooth muscle contraction
  • Calcium channel blockers act on L type voltage sensitive calcium channels
  • Block Ca entry into smooth muscle cells -> vasodilation
  • Inhibit the slow calcium current in sinus and AV node where there is a Ca dependent upstroke to the action potential (sinus and AV node)
  • High concentrations they inhibit the myocardial calcium entry into myocardium and produce a -ve inotropic effect
• Mechanisms of action of calcium-channel blockers:

  • Haemodynamic effects
  • Decrease peripheral resistance
  • Decrease heart rate (diltiazem, verapamil)
  • Decrease coronary vascular resistance
• Adverse effects of calcium channel blockers:

  • Flushing, headache - most marked with short-acting preparations
  • Oedema - due to increased capillary permeability
  • Bradycardia + heart block (particularly in combination with β-blocker)
  • Heart failure (verapamil)
  • Gingival hyperplasia (dihydropyridines)
• Mechanisms of action of ACE inhibitors:

  • Inhibits conversion of Ang I and Ang II
  • Inhibits degradation of bradykinin which produces vasodilation by release of vascular NO (nitrous oxide) and prostaglandins
  • Reduces aldosterone secretion
  • Renal vasodilation
  • Commonly used in heart failure - improve survival
• Renin-angiotensin system:

  • Aldosterone increases peripheral resistance activates sympathetic nervous system increases heart rate and BP. Also stimulates kidneys to retain Na which also raises blood pressure.

  
• ACE inhibitors - adverse effects:

  • Renal failure especially in renal artery stenosis
  • Cough (10-15%) - possibly related to increased tissue bradykinin levels
  • Hyperkalaemia (high levels of potassium)
  • Angioedema - tongue swelling, anaphylaxis
  • Urticaria, skin rashes
  • Altered taste change - captopril
  • Burning mouth syndrome
  • Foetal injury
• Mechanism of action of angiotensin recetor blockers (antagonists):

  • Inhibit action of endogenous Ang II at Angiotensin II subtype 1 receptor
  • Vasodilation, decreased SNS activity
  • Do not produce cough unlike ACE inhibitors
  • AT1 blockers do not block AT2 receptor, which is exposed to high concentration Angiotensin

  
• Aldosterone antagonists:

  • Spironolactone is more effective in treating blood pressure than alpha blockers but can cause breast tenderness in men
  • Can also improve prognosis in heart failure
  • Also causes high potassium
  • Dangerous precipitate cardiac arrhythmias
  • Eplerenone is another alternative aldosterone antagonist that doesn't have effects on breast tissue but does have similar metabolic problems with K
• Alpha blockers - α₁-adrenoceptor antagonists:

  • Doxazosin
  • Block vascular smooth muscle α₁-adrenoceptors
  • Produce vasodilation which leads to fall in blood pressure
  • Baroreceptor mediated increased heart rate occurs
  • 'first dose' phenomenon - large decrease in BP occurs after first but not subsequent doses
• Drug combinations:

  • AB drugs - inhibit renin-angiotensin system
  • CD drugs - reduce peripheral resistance
  • Start with:
  • CCB (C) in older patients
  • ACEI (A) in younger patients
  • Combine A or B with C or D
  • Diuretic + ACE inhibitor
  • Calcium channel blocker + beta blocker
  • Avoid combination B and D - increase risk of developing new-onset diabetes
• Management of angina:

  • Aim of treatment to reduce symptoms (chest pain on exertion or rest) and reduce risk of MI stroke
  • Coronary angiography usually performed to identify coronary artery stenosis which may be amenable to stenting or coronary artery bypass grafting
  • Vascular risk factors (smoking, cholesterol, diabetes) need to be managed as in hypertension to reduce risk of MI and stroke
  • Anti-platelet therapy (aspirin) to reduce risk of MI and stroke
• Drug therapies for angina:

  • Nitrates - GTN, isosorbide di/mononitrate
  • Beta blockers - atenolol
  • Calcium channel blockers - diltiazem, verapamil, nifedipine
  • Potassium channel openers - nicorandil
  • Ivadridine
• Nitrates - mechanism of action:

  • NO donor, releasing NO by reaction of nitrates with tissue - SH (thiol) groups. Increased cGMP leading to smooth muscle relaxation
  • Nitrates relax arterial and venous smooth muscle (V > A).
  • Venodilation results in decreased ventricular end diastolic pressures with a fall in cardiac output and BP
  • Nitrates also directly dilate coronary arteries which increases blood supply to the heart
  • Redistribution of coronary blood flow to ischaemic myocardium may also occur during nitrate therapy. These effects lead to decreased cardiac oxygen demand.
• Nitrate preparations:

  • Sublingual GTN
  • Spray GTN
  • Oral isosorbide
  • Transdermal patches
  • Intravenous GTN, nitroprusside (only really used in intensive care settings)
• Nitrate tolerance:

  • Nitrates have a decreased effect at a given concentration after repeated doses
  • Mechanism is unclear, but may be due to depletion of sulfhydryl groups necessary to produce active intermediate metabolite of nitrates
  • Nitrate gap (8 hours) needed. Usually ensure nitrate free overnight
• Sinus node cell (human pacemaker cell):

  • Within each sinus node cell there are various ion channels which cross the cell membrane
  • They include calcium channels (long-lasting or L-type), the potassium channel and the If channels

  
• Beta blockers:

  • Catecholamines (like adrenaline and noradrenaline) increase myocardial oxygen demand during exercise through effects on heart rate and contractility
  • Beta-blockers decrease myocardial oxygen demand by decreasing the effects of norepinephrine and circulating epinephrine
  • Angina and exercise tolerance improved
• Potassium channel activators:

  • Nicorandil
  • Potassium channel activator with nitrate component
  • Vasodilation of arterioles and large coronary arteries
  • Venous vasodilation through stimulation of guanylate cyclase
  • Adverse effects:
  • Headache, flushing
  • Oral ulceration, myalgia
  • Angioedema
• Ivabradine:

  • Selectively inhibits the If channels in cardiac pacemaker cells
  • Lowers heart rate without any other action on cardiac function
• Clinical efficacy of ivabradine:

  • Anti-anginal and anti-ischaemic efficacy shown in trials
  • Efficacy similar to atenolol and amlodipine
  • Trials show maintenance of clinical efficacy up to 12 months
  • Procoralan is an effective anti-ischaemic agent, supporting the concept of selective If inhibition as a beneficial therapeutic strategy for patients with stable angina
  • Procoralan is as effective as atenolol and amlodipine, with trends favouring Procoralan for all parameters measured
  • In addition, Procoralan maintains a constant anti-anginal efficacy in the long-term

  
• Clinical efficacy of ivabradine:

  • The most frequent adverse effects are mild, transient visual effects of enhanced brightness
  • They are due to a pharmacological action of Procoralan on a similar current to the If current that is expressed in retinal cells - the Ih current
  • Visual effects are described as mild transient light spots at the edge of the field of vision
  • They're generally triggered by sudden changes in light intensity (eg going from a dark room into daylight)
• Ranolazine:

  • Effective in treating chronic angina
  • Inhibitor of the late sodium current (late INa)
  • Pharmacodynamically distinct from other antianginals
  • Haemodynamically neutral at therapeutic doses
  • May also lower fasting glucose and HbA1c