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• Hypertension is defined as a sustained elevation of blood pressure
  • Systolic blood pressure ≥ 140 mm Hg
  • Diastolic blood pressure ≥ 90 mm Hg

Important Equations

• Blood pressure equals cardiac output times peripheral vascular resistance which can be written as BP = CO x PVR
• Cardiac output equals heart rate times stroke volume written as CO = HR x SV

Short Term Regulation of Blood Pressure

• Arterial baroreceptors sense changes in blood pressure
• The medullary cardiovascular center processes those signals
• Signals sent to the autonomic system affect heart rate and stroke volume
• Total peripheral resistance and cardiac output regulate blood presssure
• Exercise, feelings of danger, cerebral ischemia, increased intracranial pressure, and severe hypoxia and hypercapnea affect blood pressure

Long term regulation of BP

• The renin-angiotensin-aldosterone system is responsible for long term BP regulation
• Angiotensin-converting enzyme is present in the endothelium of the lung vessels
• Angiotensin II has a vasoconstrictor impacts total peripheral vascular resistance and BP, and stimulates aldosterone secretion for long term regulation
• Aldosterone causes salt and water retention, increasing blood volume and BP

Diagnosis of Hypertension

• According to the European Society of Hypertension (ESH), hypertension is diagnosed when systolic BP ≥140 mm Hg and/or diastolic BP > 90 mm Hg
• The American cut-off for hypertension has been lowered to ≥130/80 mm Hg
  • BP range 130-139/80-89 mm Hg is now classified as stage 1 hypertension
• Diagnosis is based on 3 separate office visits and the severity of the hypertension
• The white-coat effect can affect some patients
• Ambulatory blood pressure measurement may be needed
• Home-based blood pressure measurements can be useful

Types of hypertension

• Primary hypertension is also known as essential hypertension
• Secondary hypertension impacts 10-15% of patients
  • Causes include phaechromocytoma, renal artery stenosis, Cushing's syndrome, and narrowing of the aorta
• Isolated systolic hypertension (ISH)
• Isolated diastolic hypertension (IDH)
• Combined systolic and diastolic hypertension (Combined SDH)

Hypertensive emergency/malignant hypertension:

• An accelerated form of severe hypertension associated with rising BP and causes damage to vessels and end organs
• Often indicated by renal damage, encephalopathy, retinal hemorrhage, angina, stroke, or myocardial infarction
• Management includes powerful vasodilators, diuretics and beta-blockers to lower blood pressure promptly, followed by a slower reduction

Resistant hypertension (RH)

• This is sustained rise in BP despite using 3 antihypertensive drug classes including a long-acting CCB, ACEI or ARB, and a diuretic at maximally tolerated daily doses
• RH also includes patients whose BP achieves target values while using ≥4 antihypertensive medications
• The diagnosis of RH requires assurance of antihypertensive medication adherence

Consequences of uncontrolled systemic hypertension

• Increases the risk of coronary thrombosis, strokes, and atherosclerosis
• Can cause renal failure
  • Persistently raised arterial blood pressure leads to hypertrophy of the left ventricle and remodeling of resistance arteries, with narrowing of lumen thus predisposing to arteriosclerosis

Goal of Treatment for Hypertension

• Reduce the risk of end-organ damage to the blood vessels in kidneys, heart, retina and brain which can lead to renal failure, coronary disease, cardiac failure, and stroke
• Treatment options can be non-pharmacological or pharmacological

Non-pharmacological opportunities for blood pressure control

• Weight Reduction
  • Recommendation,Maintain ideal body mass index (20-25kg/M²)
  • Expected systolic BP reduction, 5-10 mmHg per 10kg weight loss
• Eating plan
  • Recommendation, Eat diet rich in fruit, vegetables, low-fat dairy products. Eat less saturated and total fat
  • Expected systolic BP reduction, 8-14 mmHg
• Dietary Sodium restriction
  • Recommendation, Reduce dietary sodium intake to <100mmol/day <2.4g sodium or <6 g salt (sodium chloride)
  • Expected systolic BP reduction, 2-8 mmHg
• Physical Activity
  • Recommendation, Regular aerobic physical activity, e.g. brisk walking for at least 30 min most days
  • Expected systolic BP reduction, 4-9 mmHg
• Alcohol moderation
  • Recommendation, Men ≤ 21 units per week Women ≤ 14 units per week
  • Expected systolic BP reduction, 2-4 mmHg

Drugs for Hypertension

• Diuretics
  • Thiazide and loop diuretics
  • Aldosterone antagonists
  • K-sparing
• Adrenergic inhibitors
  • Peripheral and central agents
  • Alpha-blockers and beta-blockers
  • Alpha+beta-blockers
• Direct Vasodilators
• Calcium channel blockers
  • Dihydropyridine and Non dihydropyridine
• ACE-inhibitors
• Angiotensin-II blockers
  • Usually not monotherapy

Drug effects

• Beta Receptor blockers and peripherally acting sympatholytics
  • Organ target heart reduces force and rate of cardiac contraction
  • Lowers Cardiac Output
• Diuretics, Angiotensin inhibitors, Beta Receptor blockers targets the kidney
  • Decrease in blood volume
  • Lowers Cardiac Output
• Peripherally acting sympatholytics, Ca++ channel blockers, Direct vasodilators, Angiotensin inhibitors, heart
  • Relax vascular smooth muscle
  • Lowers Total Peripheral Resistance
• Centrally acting sympatholytics target the brain
  • Leads to Decreased sympathetic outflow
  • Lowers Cardiac Output and Total Peripheral Resistance

Drug treatment reccomendations

• Start treatment with either an ACEI or an ARB in patients who are likely to have normal or raised plasma renin (younger people)
• You may start with a thiazide diuretic or Ca2+ channel blocker (CCB) in older or in people of African origin who are more likely to have low plasma renin
• If blood pressure control is achieved reinforce lifestyle and adherence
• If NOT ACHIEVED titrate medications to maximum doses or consider adding a 2nd drug (ACEI, ARB, CCB, or Thiazide)
• Do NOT increase the dose of any one drug excessively this can cause adverse effects and engage the homeostatic control mechanisms
• If BP goal is achieved reinforce lifestyle and adherence.
  • If not, add a 3rd or 4th drug from a class not already selected

More drug information

• Addition of a 3rd or 4th drug, eg to ARB/diuretic or ARB/calcium channel blocker combination may be often needed
• A long-acting a-adrenoceptor antagonist like doxazosin is an option
• Doxazosin is used o.d and has a desirable effect on plasma lipids reducing the ratio of LDL:HDL lipids
• Beta-blockers are less well tolerated than ACEIs or ARBS
• They are useful for hypertensive patients with ẞ-blockage such as angina and heart failure

Staged Treatment of Hypertension using drugs:

• First-line drugs for monotherapy include thiazide diuretics OR beta blockers
• Alternative first-line drugs include ACE inhibitors, calcium channel blockers, selective a₁-blockers (prazosin), α + ẞ blockers (labetalol)
• Not preferred for monotherapy since they have significant reflex-mediated cardiac stimulation and cause water retention: Hydralazine, and minoxidil
• Combined use of 2 drugs:
  • Diuretic + Beta-blocker
  • Diuretic + ACE inhibitor
  • ACE inhibitor + calcium channel blocker
  • ARB + diuretic
  • A thiazide diuretic + a K-sparing diuretic
• Combined use of 3 drugs:
  • Diuretic + sympathoplegic agent + direct vasodilator
  • Diuretic + ACE inhibitor + direct vasodilator
  • Minoxidil increases pulse rate and/or sodium and water retention

Choosing drugs based on concomitant diseases

• Angina pectoris -bBeta-blockers, calcium channel blockers (Alternative: diuretics, ACE inhibitors)
• Congestive heart failure - Diuretics and ACE inhibitors (no verapamil and no Beta-blockers)
• Previous myocardial infarction - Beta-blockers, ACE inhibitors (Alternative: diuretics, calcium channel blockers)
• Diabetes (IDDM) - ACE inhibitors, calcium channel blockers, a-blockers(no diuretics and no Beta-blockers)
• Hyperlipidemia - ACE inhibitors, calcium channel blockers (no diuretics and no Beta-blockers)
• Asthma, and chronic pulmonary disease - Diuretics, calcium channel blockers (no Beta-blockers)

Drug contraindications

• Pregnancy-- ACE inhibitors, ARB Congestive Heart failure - Verapamil

Treatment of hypertensive emergencies

• Vasodilators (sodium nitroprusside, diazoxide, felodopam, hydralazine)
• Calcium channel blockers; reserpine, methyldopa, labetalol

Diuretics

• They are relatively safe, effective and, suitable for older adults
• Can be given orally alone or together with other agents
• Lower BP by depleting body sodium stores in two stages:
  • Reduction of total blood volume and therefore cardiac output; initially causes increase of peripheral vascular resistance
  • Cardiac Output returns to normal in 6-8 weeks after which, PVR declines.

Thiazide diuretics

• Examples of thiazide diuretics are hydrochlorothiazide, chlorthalidone, and indapamide
• Act on distal convoluted tubule and inhibit Na+-Cl- symport.
• Can counteract the Na+ and H₂O retention effect of hydralazine (direct vasodilator)
• Suitable for combined use.
• Particularly useful for elderly patients, but not effective when kidney function is inadequate
• Reduce blood K+ and Mg2+ levels, and induce hypokalemia and hyperuricemia, impair glucose tolerance increase serum cholesterol -Thiazides retain Ca2+ and decrease urine Ca2+ content

Loop Diurectics

• More powerful than thiazides using examples like, furosemide and bumetanide
• Often used for treatment of severe hypertension when direct vasodilators are administered and Na+ and H₂O retention becomes a problem
• They can be used in patients with poor renal function and those not responding to thiazides
• Loop diuretics increase urine Ca2+ content

K-sparing diuretics

• Include triamterene, amiloride (both are Na+ channel inhibitors)
• Spironolactone and eplirenone are aldosterone antagonists
• Spironolactone and eplirenone are, Used for treating hypertension in patients given digitalis.
• Enhance the natriuretic effects of other diuretics -Counteracts the K+-depleting effect of these diuretics

Diurectic toxicity

• Depletion of K+ (expect K+-sparing diuretics), leads to hypokalemia
• Increase uric acid concentration and precipitates gout, and increases serum lipid
• Diuretics are not for treating hypertension in patients with hyperlipidemia or diabetes

Centrally Acting Adrenergic Drugs

• Clonidine is a, a₂-imidazoline derivative that lowers sympathetic activity and increases parasympathetic tone, lowering BP and causing bradycardia.
• Binds a₂-Adrenergic receptor(AR) with higher affinity than a₁-AR
• Can lower BP due to negative feedback at the presynaptic neurons
• When given i.v., clonidine induces a brief rise of BP, which is followed by prolonged hypotension
• Considered to bind imidazoline receptors (IR)
• Reduce CO due to decreased heart rate and relaxation of capacitance vessels.
• Used for treatment of mild to moderate hypertension, often together with diuretics.
• Decreases renal vascular resistance helping improve renal blood flow and glomerular filtration
• Lipid-soluble and enters brain readily. Half-life is 8-12 h.
• Adverse effects are Sedation, and dry mouth and also causes Na+ and H2O retention
• Abrupt withdrawal may induce hypertensive crisis

Methyldopa.

• A prodrug that when metabolized becomes a-methylnorepinephrine, and is stored in neurosecretory vesicles in place of NE.
• A potent a-adrenergic receptor agonist and a vasoconstrictor in the PNS
• Reduces adrenergic outflow from the CNS and an overall reduced total peripheral resistance
• Doesn't alter most of the cardiovascular reflexes, helps maintain Cardiac output and blood flow to vital organs
• Reduces renal vascular resistance, can be used in patients with renal insufficiency
• Effect reaches maximum in 4-6 h and continues to 24 h. Not used as first drug in monotherapy, but effective when used with diuretics
• Side effects include sedation, lassitude, nightmares, lactation (due to inhibition of dopaminergic neuron in hypothalamus)
• Long-term use may cause development of autoantibodies against Rh locus and give positive Coomb's test
• Used for hypertension in pregnancy

Beta-blockers

• Young patients are preferred over elderly patients due to high occurrence of chronic lung and heart diseases in the elderly
• Used in treating hypertension with pre-existing conditions such as previous myocardia infarction, angina pectoris, migraine headache, heart failure
• Propranolol blocks beta 1 and beta 2 adrenergic receptors
• It inhibits renin production due to Beta 1 adrenergic antagonistic activity which helps those with high renin level
• Causes no prominent postural hypotension in mild to moderate hypertension patients.
• Metoprolol is less Beta 2 antagonistic than propranolol, and helps with patients who also suffer from asthma, diabetes, or peripheral vascular diseases.
• Selective antagonists include Atenolol, Betaxolol, Bisoprolol, Esmolol, Acebutolol, Metoprolol, and Nebivolol
  • Slower metabolism and longer half-life; can be administered once daily
• Non -selective drugs include Propranolol, Nadolol, Pindolol, Labetalol, Penbutolol, Sotalol Carvedilol
• Labetalol has some beta 2-agonistic effects
• Labetalol is used in treating hypertensive emergencies injectio or if it's caused by pheochromocytoma
• Carvedilol can be used in patients with congestive heart failure
• Side effects include;
  • Withdrawal syndrome (nervousness, tachycardia, angina, BP increase). -Reduced myocardial reserve and peripheral vascular insufficiency; exacerbate asthma, diabetes.
• Increased plasma triglycerides and decreased HDL cholesterol (propranolol). -CNS effects: lassitude, mental depression, insomnia, nightmares. -GI effects: diarrhea, constipation, nausea, vomiting.

Alpha 1-blockers

• Examples are Prazosin, tetrazosin, doxazosin, phentolamine, and phenoxybenzamine which are antagonists for Alpha 1 adrenergic receptor
• Prazosin, tetrazosin and doxazosin are competitive for Alpha 1 adrenergic receptor
• Phentolamine blocks both aplha 1 and alpha 2 adrenergic receptors
• Phenoxybenzamine is an irreversible blocker for both alpha 1  -AR and Alpha2 -AR, relaxing arterial and venous smooth muscles reducing PVR
• Prazosin is useful for mild to moderate hypertension, combined beta-blockers or diuretics may produce additive effects.
• Phentolamine and phenoxybenzamine are used for treatment of pheochromocytoma.
• Adverse effects/ toxicity;
• For prazosin, tetrazosin, and doxazosin, reflex tachycardia, first dose syncope are common.
• Concomitant use of Beta blockers may be necessary
• For phentolamine, increased cardiac stimulation (by blocking Alpha2-AR negative feedback) can cause severe tachycardia, arrhythmias, and myocardial ischemia
• Used in patients with phenoxybenzamine, postural hypotension may occur

Vasodilators: Mechanism of Action

• Relax smooth muscle (SM) of arterioles (and sometimes veins)
• It helps reduce systemic vascular resistance
• Compensatory Tachycardia may occur due to sudden fall in BP

Hydrazine and Sodium nitroprusside

• Hydrazine MoA: directly dilates arteries and arterioles used as 4th line to treat lower dose HT in combination with diuretics or beta-blockers
• Hydraine shouldn't be mixed with monotherapy causing reflex tachycardia
• Hydrazine Contraindicated in pregnancy and aortic stenosis.
• Sodium nitroprusside should be used with other antihypertensives increasing it's hypotensive effect
• Side effects are headache, nausea, postural hypotension, and palpitations
• Sodium nitroprusside MoA dilates all arteries and veins used in hypertensive emergencies with IV infusion in immediate action which takes seconds to act.
• Sodium nitroprusside shouldn't be administered with another anti hypertensive if pt is with pregnancy or hepatic diseases

Vasodilator effects

• Sodium nitroprusside increases arterial and venous vessels and is a powerful vasodilator for treatment of hypertensive emergencies
• Increases intracellular cGMP
• helps patients with cardiac failure because cardiac output increases due to afterload reduction.
• Effects last only less than 10 minutes after discontinuation. -Diazoxide, stimulates opening of K+ channels and stabilizes membrane potential at resting level and is a long lasting hypertensive agent and the result is usually, effectives usually with in half-life time up to 24 hours

Calcium Channel Blockers

• Verapamil, diltiazem and the dihydropyridine are examples of calcium channel blockers as family medications and all usually dilates all peripheral arterial arterial cells to inhibit BP by inhibiting calcium influx into all arterial and somatic cells also reducing cardic effect reducing the effect of nifedipine vasodilation by causing cardio arrhythmias

ACE inhibitors:

• ACE inhibtors can be the result of captopril, elanapril and can only become activated with lisolpril and rampril
• The M.o.A will be competitive ACEI molecules reducing AT-II and increasing the level of bradykinin thus increasing vaso dilation

Angiotensin II-antagonist are Non-petide

• ATII- inhibitors are the Losartan, valsartan, candesartan, irbesartan, telmisartan, eposartan and zolasartan
• Saralasin molecules require contionious infusion and are less preferred since the ACE has more spesificity targeting AT and less production of meta bolisim molecules
• The use is more spesific to ACEI to AHT and bradykinin is similar by preventing angioema and cough and has fewer more effects in pregannt wommen.

Side effects of ACE inhibitors

-Dry Cough -5 – 20% of patients -Has developmental defects during the 2nd & 3rd trimester which also require cessation from the pyhsician. -Angioneurotic Edema may be life-threatening - ~0.1 - 0.5% of patients -Severe swelling of the mouth, tongue, lips, and airways

Newer Drugs for HT

• Renin inhibitor like ALISKIREN -Aprocitentan is a endothelin antagonist and helps HT in PT