Hypertension Diagnosis and Management

• Hypertension is defined as a sustained elevation of blood pressure.
• Systolic blood pressure is ≥ 140 mm Hg, and diastolic blood pressure is ≥ 90 mm Hg.

Important Equations

• Blood pressure = Cardiac output x Peripheral vascular resistance (BP = CO x PVR).
• Cardiac output = Heart rate x Stroke volume (CO = HR x SV).

Short Term Regulation of Blood Pressure

• Arterial baroreceptors, the medullary cardiovascular center, and the autonomic system regulate blood pressure in the short term.
• Heart rate and stroke volume affect cardiac output and blood pressure.
• Exercise, feelings of danger, cerebral ischemia, intracranial pressure increases, and severe hypoxia/hypercapnea can affect blood pressure regulation.

Long Term Regulation of Blood Pressure

• The renin-angiotensin-aldosterone system is involved in long-term blood pressure regulation.
• Angiotensin II causes vasoconstriction, increases TPVR and BP, and stimulates aldosterone secretion.
• Aldosterone causes salt and water retention, which increases blood volume and BP.

Diagnosis of Hypertension

• According to the European Society of Hypertension (ESH), hypertension is diagnosed when systolic BP is ≥140 mm Hg and/or diastolic BP > 90 mm Hg.
• The American cut-off is ≥130/80 mm Hg, with 130-139/80-89 mm Hg now classified as stage 1 hypertension.
• Diagnosis is based on three separate office visits and the severity of hypertension.
• Ambulatory blood pressure measurement or home-based measurements may be useful to negate the white-coat effect.

Types of Hypertension

• Primary hypertension is also known as essential hypertension.
• Secondary hypertension accounts for 10–15% of patients, and can be associated with phaechromocytoma, renal artery stenosis, Cushing's syndrome, or narrowing of the aorta.
• Other types include isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and combined systolic and diastolic hypertension (Combined SDH).

Hypertensive Emergency

• Hypertensive emergency/malignant hypertension is an accelerated form of severe hypertension associated with rising BP.
• It involves rapidly progressing damage to vessels and end organs.
• Signs of hypertensive emergency can include renal damage, encephalopathy, and retinal hemorrhage, as well angina, stroke, or myocardial infarction.
• Hypertensive emergency is managed with powerful vasodilators (nitroprusside, fenoldopam, or diazoxide), diuretics (frusemide), and Beta-blockers to lower blood pressure quickly, followed by a more gradual reduction.

Resistant Hypertension (RH)

• Defined as a sustained rise in BP despite concurrent use of three antihypertensive drug classes, that includes a long-acting CCB, ACEI or ARB, and a diuretic at maximally tolerated doses.
• Also includes patients who achieve target BP values on four or more antihypertensive medications.
• Diagnosing RH necessitates assurance of antihypertensive medication adherence.

Consequences of Uncontrolled Systemic Hypertension

• Increases the risk of coronary thrombosis and strokes.
• Can lead to renal failure and atherosclerosis.
• Leads to hypertrophy of the left ventricle and remodeling of resistance arteries, resulting in arteriosclerosis.

Goal of Hypertension Treatment

• Reduce the risk of end-organ damage to blood vessels in the kidneys, heart, retina, and brain, as well as increased incidence of renal failure, coronary disease, cardiac failure, and stroke.
• Non-pharmacological and pharmacological treatment options are available.

Non-Pharmacological Opportunities for Blood Pressure Control

• Weight reduction, aiming for a body mass index between 20-25kg/M², may reduce systolic BP by 5-10 mmHg per 10kg weight loss.
• A diet rich in fruits and vegetables and low in saturated and total fat can reduce systolic BP by 8-14 mmHg.
• Reducing dietary sodium intake to <100mmol/day (<2.4g sodium or <6 g salt) can reduce systolic BP by 2-8 mmHg.
• Regular physical activity (brisk walking for at least 30 minutes) can reduce systolic BP by 4-9 mmHg.
• Alcohol moderation (≤21 units/week for men, ≤14 units/week for women) can reduce systolic BP by 2-4 mmHg.

Drugs for Hypertension

• Diuretics, direct vasodilators, calcium channel blockers, ACE inhibitors, and Angiotensin-II blockers can be used to treat hypertension.
• Diuretics include thiazide, loop diuretics, aldosterone antagonists and K-sparing diuretics.
• Adrenergic inhibitors include peripheral agents, central (α-agonists), alpha-blockers, beta-blockers, and Alpha+beta-blockers.

How Drugs affect blood presssure

• Beta-receptor blockers and peripherally acting sympatholytics decrease the force and rate of cardiac contraction, thus decreasing CO
• Diuretics and angiotensin inhibitors decrease blood volume, leading to decreased CO
• Peripherally acting sympatholytics and Ca++ channel blockers cause the relaxation of vascular smooth muscle, which decreases TPR
• Centrally acting sympatholytics decresae sympathetic outflow thus decreasing CO and TPR

Recommendations for Drug Treatment of Hypertension

• Start treatment with an ACEI or ARB in younger white people who are likely to have normal or raised plasma renin.

• A thiazide diuretic or Ca2+ channel blocker may be used in older people or Black people, who were more likely to have low plasma renin.

• If blood pressure control is achieved, reinforce lifestyle and adherence.

• If it is not achieved, titrate medications to maximum doses or consider adding a second drug (ACEI, ARB, CCB, Thiazide).

• The dose of any single drug should not be increased excessively, and additional drugs from different classes can be added if needed.

• Examples of 3rd or 4th drug additions include beta-blockers, aldosterone antagonists, alpha-adrenoceptor antagonists, and others.

• Additional drugs to ARB/diuretic or ARB/calcium channel blocker combinations is often required.

• Beta-blockers are less well tolerated than ACEIs or ARBs but are useful in hypertensive patients with angina and heart failure.

Staged Treatment of Hypertension

• First-line drugs for monotherapy: Thiazide diuretics OR beta blockers.
• Alternative first-line drugs: ACE inhibitors, calcium channel blockers, selective a₁-blockers (prazosin), α + ẞ blockers (labetalol).
• Drugs not preferred for monotherapy: Hydralazine, minoxidil (significant reflex-mediated cardiac stimulation and water retention).
• Combined use of two drugs: Diuretic + ẞ-blocker; Diuretic + ACE inhibitor; ACE inhibitor + calcium channel blocker; ARB + diuretic; A thiazide diuretic + a K-sparing diuretic. Combined use of three drugs: Diuretic + sympathoplegic agent + direct vasodilator; Diuretic + ACE inhibitor + direct vasodilator.

Hypertension Treatment by Comorbidities

• Angina pectoris: Beta-blockers, calcium channel blockers (Alternative: diuretics, ACE inhibitors).
• Congestive heart failure: Diuretics, ACE inhibitors (No verapamil; 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, no beta-blockers).
• Hyperlipidemia: ACE inhibitors, calcium channel blockers (No diuretics, no beta-blockers).
• Asthma, chronic pulmonary disease: Diuretics, calcium channel blockers (No beta-blockers).

Contraindications and Hypertensive Emergencies

• Pregnancy: ACE inhibitors and ARBs are contraindicated.
• Congestive Heart failure: Verapamil is contraindicated.
• Treatment of hypertensive emergencies: Vasodilators and Calcium channel blockers

Diuretics

• First-line drugs due to their safety and effectiveness.
• Suitable for older adults.
• Given orally, either alone or with other antihypertensive drugs.
• Lower blood pressure by depleting body sodium stores.
• The reduction of total blood volume initially causes increased peripheral vascular resistance, but the PVR will decline as cardiac output returns to normal in 6-8 weeks.

Diuretics: Thiazides

• Act on the distal convoluted tubule to inhibit Na+-Cl- symport.
• Can conteract the Na+ and H₂O retention effect of hydralazine (direct vasodilator).
• Suitable for combined use and particularly useful in elderly, but ineffective when kidney function is inadequate.
• Reduce blood K+ and Mg2+ levels, can cause hypokalemia and hyperuricemia, impair glucose tolerance, and increase cholesterol.
• Use carefully and monitor serum K+ levels in patients with cardiac arrhythmias and when digitalis is in use.
• Retain Ca2+ and decrease urine Ca2+ content.

Diuretics: Loop Diuretics

• Furosemide and bumetanide are more powerful than thiazides.
• Often used for treatment of severe hypertension when direct vasodilators are administered and Na+ and H₂O retention becomes a problem.
• Can be used patients with poor renal function & those not responding to thiazides.
• Increase urine Ca2+ content.

Diuretics: K-Sparing

• These include triamterene and amiloride which are both Na+ channel inhibitors.
• Spironolactone and eplirenone are aldosterone antagonists used with digitalis.
• Enhance the natriuretic effects of other diuretics like thiazides.
• Counteract the K+-depleting effect of other diuretics.

Diuretics: Adverse Effects and Toxicity

• K+ depletion and hypokalemia.
• Increase uric acid concentration and precipitate gout.
• Increase serum lipid concentrations.
• Diuretics are not used for patients with hyperlipidemia or diabetes.

Sympathoplegic/Sympatholytic Agents

• Centrally-acting adrenergic drugs act in the brain.
• Clonidine is an a2-imidazoline derivative and reduces sympathetic and increases parasympathetic tone.
• Leads to BP lowering and bradycardia.
• Binds a2-Adrenergic receptor with higher affinity than a1-AR, to lower BP due to negative feedback presynaptically.
• When given IV, clonidine causes a rise of BP, then prolonged hypotension.
• Thought to also bind imidazoline receptors (IR) that have not been molecularly cloned

Sympathoplegic/Sympatholytic Agents: Clonidine

• Reduces CO due to decreased heart rate and relaxation of capacitance vessels.
• Used for mild to moderate hypertension, and often together with diuretics.
• Maintains renal blood flow and glomerular filtration.
• Lipid-soluble and enters brain readily. Half-life is 8-12h.
• Adverse effects: Sedation, dry mouth, and also causes Na+ and H2O retention.
• Abrupt withdrawal may induce hypertensive crisis, so avoid in patients at risk of mental depression or taking tricyclic antidepressants.

Centrally Acting Antihypertensives: Methyldopa

• A prodrug that is metabolized to a-methylnorepinephrine, and stored in neurosecretory vesicles in place of NE.
• a-methyl-NE is a potent alpha-adrenergic receptor agonist and in the PNS is a vasoconstrictor.
• CNS effect is mediated by a2-AR, resulting in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance.
• Does not alter most of the cardiovascular reflexes and maintains cardiac output and blood flow to vital organs .
• Reduces renal vascular resistance and indicated for patients with renal insufficiency. Given orally.
• Maximum effect achieved at 4-6 h and continues to 24 h and effective when used with diuretics, but not as a first line drug.
• Adverse effects: Sedation, lassitude, nightmares, lactation from 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 treatment of hypertension in pregnancy because ACEIs and ARBs are contraindicated.

Antihypertensive Agents on Peripheral Nervous System: Beta-Blockers

• Young patients are preferred over elderly patients due to high occurrence of chronic lung and heart diseases in the elderly).
• Beta-blockers are less well tolerated than ACEIs and ARBs.
• Useful in treating hypertension with pre-existing conditions such as previous myocardia infarction, angina pectoris, migraine headache, & heart failure.

Beta-Blockers: Propranolol

• Antagonizes beta₁ and beta₂ AR.
• It inhibits renin production due to beta₁-antagonistic activity.
• Used in patients with high renin levels.
• Has no prominent postural hypotension in mild to moderate hypertension.
• Beta-blockers: Metoprolol
• Metoprolol antagonizes beta₂ to a lesser extent than propranolol, and it can used in patients who also suffer from asthma, diabetes or peripheral vascular diseases.

Beta Adrenergic Blockers: Pharmacological Actions

• Sympathetic stimulation activates beta-1 receptors on the myocardium
• Beta Blockers: Myocardial contractility, heart rate, cardiac output, cardiac work, oxygen comsumption

Beta-Blockers: Selective vs Non-Selective

• Beta₁-selective antagonists: Atenolol, Betaxolol, Bisoprolol, Esmolol, Acebutolol, Metoprolol, and Nebivolol.
• They have slower metabolism and longer half lives, thus can be administered daily.
• Non-selective Beta-Blockers: Propranolol, Nadolol, Pindolol, Labetalol, Penbutolol, Sotalol, Carvedilol

Beta Blockers: Additional Info

• Non -selective beta blocker Labetalol has some beta₂-agonistic effects.
• Labetalol treats hypertensive emergencies or hypertension resulting from pheochromocytoma (injection).
• Carvedilol can be used in patients with congestive heart failure

Beta Blockers: Adverse Effects and Toxicity

• Withdrawal syndrome that includes nervousness, tachycardia, angina, BP increase.
• Reduced myocardial reserve and peripheral vascular insufficiency; exacerbates asthma, diabetes.
• Increased plasma triglycerides and decreased HDL cholesterol.
• CNS effects such as lassitude, mental depression, insomnia, nightmares.
• GI effects like diarrhea, constipation, nausea, vomiting

Antihypertensive Agents Beta₁-Blockers

• Alpha₁-blockers include prazosin, tetrazosin, doxazosin, phentolamine, phenoxybenzamine.

Alpha₁-Blockers: Mechanism of Action

• Prazosin, tetrazosin, and doxazosin are competitive antagonists for alpha₁-AR
• Phentolamine is antagonist for both alpha₁ and alpha₂-AR.
• Phenoxybenzamine is an irreversible blocker for alpha₁ -AR and alpha₂-AR
• Blocking alpha₁-AR leads to relaxation of both arterial and venous smooth muscles and reduces PVR.

Alpha₁-Blockers: Therapeutic Use and Adverse Effects

• Prazosin treats mild to moderate hypertension.
• Use with propranolol or diuretics may produce additive effects.
• Phentolamine and phenoxybenzamine are used for treatment of pheochromocytoma.
• Side effects can include: Reflex tachycardia, first dose syncope are common along with arrhythmias and ischemia.

Direct Vasodilators

• Mechanism of action: Relax smooth muscle (SM) of arterioles (and sometimes veins), thereby reduce systemic vascular resistance.
• Compensatory Tachycardia may occur due to sudden fall in BP

Direct Vasodilators: Hydralazine

• MoA: directly dilates arteries and arterioles.
• Used as the fourth line of treatment when combined with B-blockers.
• PKs: Hepatic metabolism/acetylation
• Contraindications include pregnancy and aortic stenosis
• Adverse effects: headache, nausea, postural hypotension, and palpitations

Sodium Nitroprusside: Direct Vasodilator

• Dilates both veins and arteries.
• Primarily used for hypertensive emergencies.
• PKs: IV infusion, very fast onset (1-10min)
• Avoid in pregnancy, hepatic disease
• DI's include other anti-hypertensives.

Direct Acting Vasodilators Contd

• Sodium nitroprusside: administered through IV.
• It is a powerful vasodilator for treatment of hypertensive emergencies.
• MOA: vasodilates both arterial and venous through stimulating intracellular cGMP and has immediate affects that last less than 10 mins.
• Diazoxide: Stimulates opening of K+ channels and stabilizes membrane potential at resting level.
• Long Lasting for 4-12 hours (Half life of 24h)
• Used to treat with hypertensive emergencies.

Vasodilators: Calcium Channel Blockers (CCB)

• Verapamil, diltiazem and the dihydropyridine (eg, nifedipine) family.
• CCB's dilate peripheral arterioles and reduce calcium influx into arterial smooth muscle cells, and reducing BP.
• Verapamil decreases CO has a cardiac effect whereas nifedipine effects vasodilation.
• CCB'S also treat angina and arrhythmia's

Calcium Channel Blockers

• Calcium influx in smooth muslces helps constriction
• Calcium channel blockers lead to vasodilation

ACE Inhibitors

• Captopril, enalapril, lisinopril (lysine-derivative), benazepril, fosinopril, moexipril, quinapril and ramipril
• Competitive ACE Inhibitors
• Captopril and Lisinopril are the only active molecules
• block the formation of Angiotensin II
• Increase bradykinin
• Reduce vasoconstriction, Na and Water Retention
• Increase Vasodilation (B-Kinins)

The Blood Pressure System

• Liver produces angiotensinogen which the kidneys acts on
• The ACE-Inhibitor acts directly on Liver produces angiotensinogen which renin turns into angiotensin I. ACE increases the levels of Angiotensin II
• Angiotensin II causes vasoconstriction & ARBS act directly on this inhibition

ACE Inhibitors

• Effective treatments for Hypertension & Heart Failure & they work by relaxing Blood vessels, Decreasing blood volume & Decreasing O2 Demand.
• They block the action of Angiotensin enzymes.
• When BP falls, renin released produces angiotensin
• ACE prevents the conversion of angiotensin I into II

ACE Inhibitors Continued

• Used when Diuretics or B-Blockers are effective.
• More Affective with Hight Renin Levels.
• Reduces workload with patients after Myocardial Infarction.
• Adverse effects: Causes harm to fertility.
• Angioedema is rate as well as coughing, rashes, change of taste.
• Should NOT be combined with Spirolactone.

Angiotensin-II Antagonists

• Non-peptide ATII-inhibitors: Losartan, valsartan, candesartan, irbesartan, telmisartan, eprosartan, and zolasartan
• Competitive More specific to action & has non to less products metabolism
• Clinical use is similar to ACE inhibitors

ACE Inhibitors: Clinical Use

• Effective Blood Pressure Reducers
• Works against Vascular Resistance & Stimulate the Sympathetic Nervous System
• Increases Sodium Excretion & Decreases Blood Volume. (This leads to less Stress)
• For Congestive heart failure, is important for less O2 consumption

NEWER DRUGS FOR HYPERTENSION

• Renin inhibitors like ALISKIREN
• Aprocitentan - the first Endothelin Receptor Antagonist - used for the treatment of hypertension in patients.

Side Effects of newer Drugs

• Common: Dry Cough
• In rare cases Angioedema with throat swelling can occur.

Explore resistant hypertension criteria, arteriosclerosis links, and sodium's effect on blood pressure. Learn about non-pharmacological interventions like diet and weight loss for hypertension management. Understand the relationship between blood pressure control and renal health.