Cardiovascular System & Hypertension

Cardiovascular Pharmacology Overview

• Cardiovascular system diseases are a major cause of death
• Major pathologies include hypertension, heart failure, angina, hyperlipidemia, and blood disorders.

Physiological Mechanisms of Cardiovascular Function

• Cardiac Cycle: Regulated by the sinoatrial (SA) and atrioventricular (AV) nodes, alternating systole (contraction) and diastole (relaxation)
• Blood Pressure Control: Managed by baroreceptors, the Renin-Angiotensin-Aldosterone System (RAAS), and the autonomic nervous system (ANS)
• Cardiac Output (CO): CO = Heart Rate (HR) × Stroke Volume (SV), influenced by preload, afterload, and contractility
• Vascular Function: Maintains blood flow via vasodilation (nitric oxide) & vasoconstriction (endothelin)
• ANS Regulation:
  • Sympathetic activation increases HR and BP
  • Parasympathetic activation decreases HR and BP

Pathological Mechanisms of Cardiovascular Function

• Hypertension & Atherosclerosis: Can lead to heart disease, stroke, and vessel damage
• Heart Failure (HF):
  • Systolic: weak contraction
  • Diastolic: impaired relaxation
• Ischemic Heart Disease (IHD): Coronary blockage leads to angina or myocardial infarction (MI)
• Arrhythmias: Electrical dysfunctions (e.g., atrial fibrillation) increase stroke risk
• Cardiomyopathies & Valvular Diseases: Affect heart muscle & valve function
• Shock: Circulatory failure due to heart dysfunction, blood loss, or infection

Antihypertensive Drugs

• Used in hypertension management with different mechanisms of action
• Actions include vasodilation and heart rate reduction
• Decrease sympathetic outflow from the central nervous system
• Reduce sodium and water retention such as diuretics
• Can inhibit the RAAS system
• Some are also used for other cardiovascular disorders

Classification of Hypertension

• Primary (Essential) Hypertension:
  • No specific cause (90-95% of cases)
  • Linked to genetics, age, obesity, salt intake, and lifestyle factors
• Secondary Hypertension (Identifiable Cause, 5-10%):
  • Renal: Chronic kidney disease, renal artery stenosis
  • Endocrine: Hyperaldosteronism, pheochromocytoma, Cushing's syndrome, thyroid disorders
  • Cardiovascular: Coarctation of the aorta, vasculitis
  • Neurological: Increased intracranial pressure, autonomic dysfunction
  • Drug-Induced: Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, contraceptives, stimulants
  • Pregnancy-Related: Gestational hypertension, preeclampsia/eclampsia

Hypertension Risk Factors

• Non-Modifiable Risk Factors:
  • Age: Risk increases with age
  • Genetics: Family history of hypertension
  • Race/Ethnicity: More common in African, South Asian, and Middle Eastern populations
• Modifiable Risk Factors:
  • Obesity: Increased body weight raises blood pressure
  • Diet: High salt, low potassium, processed food intake
  • Physical Inactivity: Sedentary lifestyle contributes to high BP
  • Smoking & Alcohol: Nicotine and excessive alcohol elevate BP
  • Stress: Chronic stress leads to sustained hypertension
• Medical Conditions:
  • Diabetes & Insulin Resistance: Strongly linked to hypertension
  • Kidney Disease: Impaired kidney function increases BP
  • Sleep Apnea: Causes repeated blood pressure spikes

Hypertensive Crisis Classifications

• Hypertensive Urgency:
  • Severe form of hypertension with a rapid rise of blood pressure to > 180/120 mmHg
  • NOT associated with target organ damage
• Hypertensive Emergency:
  • Severe form of hypertension with rapid rise of blood pressure to >180/120mmHg and target organ damage
  • This organ damage includes hypertensive encephalopathy, heart failure and renal failure
  • If it’s associated with papilledema it is called malignant hypertension

Antihypertensive Drugs

• Diuretics
• Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors:
  • Angiotensin Converting Enzyme Inhibitors (ACEIs)
  • Angiotensin Receptor Blockers (ARBs)
  • Renin inhibitors: Inhibit renin enzyme as Aliskiren
• Calcium Channel Blockers (CCBs)
• Sympatholytic Drugs
• Direct Vasodilators (DVD)

Classification of Antihypertensive Drugs

• First-Line: Recommended for drug mono-therapy or in combination
  • Angiotensin Converting Enzyme Inhibitors (ACEIs)
  • Angiotensin Receptor Blockers (ARBs)
  • Calcium Channel Blockers
  • Diuretics
• Alternative drugs for selected patients
  • Alpha blockers, Beta Blockers
  • Central a2 agonists
  • Vasodilators

Nonpharmacological treatment of Hypertension

• Weight reduction
• Diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat: 8-14 mmHg
• Dietary sodium restriction: reduce daily dietary sodium intake to less than or equal to 5 g sodium chloride): 2 - 8 mmHg
• Physical activity: regular aerobic physical activity (at least 30 minutes/day, most days of the week): 4-9 mmHg
• Stop alcohol consumption
• Stop smoking
• Avoid Stress
• Control diabetes mellitus and atherosclerosis.

ACE Inhibitors and Angiotensin Receptor Blockers (ARBs)

• Mechanism of action:
  • ACEIs decrease the vasoconstrictor Ang II, increase the vasodilator Bradykinin and decrease aldosterone.
  • ACEIs decrease blood pressure by decreasing PR, without affecting CO or HR
  • Angiotensin receptor blockers antagonize angiotensin receptors

ACE Inhibitors and Angiotensin Receptor Blockers (ARBs)

• Examples:
  • ACE-inhibitors: Enalapril, Ramipril and Captopril
  • AT1 receptor antagonists (ARBs): Losartan and Valsartan
• Adverse effects:
  • First dose hypotension (administer the first does is at night without diuretics for 2 days)
  • Dry cough (5-30%) and angioneuretic edema due to bradykinin increase
  • Functional renal failure (if bilateral renal artery stenosis is present)
  • Hyperkalemia (avoid using with potassium-sparing diuretics)
  • Teratogenic (not used in pregnancy)
  • Sulfhydryl reactions of captopril (rash, proteinuria, taste disturbance)

Diuretics: Mechanism of Action

• Thiazide diuretics block the Na/Cl- transporter in the renal distal convoluted tubule
• Loop diuretics block the Na/K/2Cl transporter in the renal loop of Henle
• Potassium-sparing diuretics
• Thiazide diuretics: Hydrochlorothiazide and Indapamide
• Loop diuretics: Bumetanide and Frusemide
• Potassium-sparing diuretics
  • Aldosterone Antagonists e.g. Spironolactone, eplerenone
  • Non-Aldosterone Antagonists e.g. Triamterene & Amiloride

Diuretics additional info

• Diuretic Action decreases blood volumedecardiac output that can decreases blood pressure.
• Thiazide diuretics in addition have a direct vasodilator action by:
  • Depleting of Na from the arterial wall
  • Opening K Channels to cause Hyperpolarization,
  • Releasing of vasodilator PGs
• Indapamide: A thiazide analogue when used in a small dose it has a vasodilator activity, behaving also as a CCB, with some diuretic effect

Diuretics: Adverse Effects

• Hypokalemia and hypomagnesemia (danger with digitalis or lithium, in chronic arrhythmias or MI).
  • Combination with potassium sparing diuretics can prevent this effect.
• Hyperkalemia in case of potassium sparing diuretics (avoid in renal insufficiency or with ACEIs/ ARBs)
• Hyponatremia and hypercalcemia (Thiazide) (not in hyperparathyroidism), while hypocalcemia with loop diuretics possible
• Hyperuricemia
• Hyperglycemia
• Increase LDL
• Reversible erectile dysfunction (spironolactone, but also with other anti-hypertensives)

Calcium Channel Blockers

• Mechanism of action: Blocks voltage-gated calcium channels
• In heart: Decreases heart rate and contractility and thus decrease CO
• In blood vessels: vasodilation to decrease PR
• Examples:
• Non-Dihydropyridine: Diltiazem and Verapamil (more selective to the heart)
• Dihydropyridine: Nifedipine (short acting), Amlodipine (long acting) and nicardipine

Clinical note about Calcium Channel Blockers

• Adverse effects:
  • Short-acting preparations (e.g. Nifedipine capsules) cause flushing and headache and tachycardia (can worsen angina) thus should be avoided even sublingually
  • Ankle swelling (oedema) is common
  • Negative inotropic effect of verapamil
• Constipation is common with verapamil
• Interactions: Intravenous verapamil can cause circulatory collapse in patients treated concomitantly with b-adrenoceptor antagonists
• Clinical Use: Amlodipine is used mainly as antihypertensive, while verapamil and diltiazem as antiarrhythmic and antianginal

Beta Blockers

• Mechanism of action:
  • ẞ1-blocking decreases heart rate and contractility to thus decrease CO
  • Centrally decreases sympathetic activity and inhibits renin secretion
• Examples:
  • Non-selective ẞ-blockers: Propranolol, Labetalol and Carvedilol (also vasodilation by blocking a1)
  • Selective ẞ1-blockers: Atenolol ,Bisoprolol and Nebivolol (also vasodilator by increasing NO), and celiprolol (vasodilator as ẞ2-agonist) -Oral (once daily). IV only in emergencies (Esmolol)

Beta Blockers additional points

• Adverse effects include bradycardia and heart block, also causing the potential to be contraindicated in decompensated heart failure
• Fatigue, cold extremities, erectile dysfunction; nightmares (especially the non-polar such as propranolol) possible
• Hypoglycemia and lipid disturbances (with thiazides) are possible
• Can cause bronchospasm in the presence of asthma or COPD
• If sudden discontinuation after prolonged use, could cause tachycardia, arrhythmias and even death via ẞ-receptors upregulation.
• Increased toxicity with other -ve inotropic drugs such as verapamil or lidocaine
• Clinical Use:
  • B-blockers are only used a second measure as a beta blocker
  • B-blockers are commonly replaced with inhibitors, AT1-antagonists or calcium antagonists

adrenergic blockers

• Prazosin
• Doxazosin
• Terazosin
• Competitive block of a1-adrenoceptors, specifically tamsulosin, an a1a- blocker with greater prostate muscle selectivity and is used to treat prostate hyperplasia
• alpha-Beta adrenergic blockers:
  • Labetalol and carvedilol block both a1- ,B1- and B2- receptors
  • Carvedilol, although an effective antihypertensive, can treat heart failure by showing to reduce mortality associated with heart failure

Centrally acting adrenergic drugs

• Clonidine causes the a2 diminishes central adrenergic outflow
• Alpha-Methyldopa is a a2 -agonist which diminishes the adrenergic outflow from the CNS
  • Leads to reduce total peripheral resistance and a decreased blood pressure
  • Valuable in treating pregnant hypertensive patients

Direct Vasodilators

• Arteriodilators:
  • Hydralazine
  • Minoxidil
  • Diazoxide
• Venodilators:
  • Nitroglycerine for intravenous infusion in managing hypertensive emergencies
• Arteriovenodilators:
  • Sodium Nitroprusside

Antihypertensive drugs list and examples

• Angiotensin Converting Enzymes (ACE) inhibitors: Captopril, Enalapril, Lisinopril, Ramipril

• Angiotensin receptor antagonist (ARB): Losartan, Candesartan

• Calcium channel blockers (CCB): Nifedipine, Felodipine, Amlodipine, Verapamil, Diltiazem

• Diuretics: Chlorothiazide, Frusemide, Spironolactone, Triamterene, Amiloride

• ẞ-adrenergic blocker: Propranolol, Metoprolol, Atenolol

• a-adrenergic blocker: Prazosin, Terazosin

• Central sympatholytic: Clonidine, Methyldopa

• Vasodilators: Arteriolar: Hydralazine, Minoxidil, Diazoxide Arteriolar & venular: Sodium nitroprusside, Pinacidil

  Congestive heart failure (CHF) Definition

• Congestive heart failure (CHF) is a condition that occurs when the heart is unable to pump enough blood to meet the needs of the body's tissues

• Causes:

  • Artery disease
  • High blood pressure (hypertension)
  • Heart defects present at birth (Congenital heart disease)
  • Past heart attacks (myocardial infarction)
  • Heart muscle disease

Heart Failure Symtoms

• Shortness of breath with activity, rest, or sleeping
• Persistent coughing/wheezing that produces white/blood mucus
• Edema: swelling in extremities
• Tiredness and fatigue
• Increased heart rate and a heart remodels for enlargement

Drugs used in heart failure

• Stage A: At high risk for HF such as none
• Stage B: Asymptomatic structural heart disease is treated with ACE inhibitor and Beta Blocker
• Stage C Structural heart disease with previous or present symptoms of HF; ACE inhibitor , Beta Blocker and Angiotensin-receptor blocker and a Diuretic and Digoxin
• Stage D: Refractory HF requiring specialized interventions.

First Line Therapy Drugs for Heart Failure

• ACE Inhibitors (ACEIs) / Angiotensin II Receptor Blockers (ARBS)
  • Examples: Enalapril, Lisinopril (ACEIs); Losartan, Valsartan (ARBs) Mechanism: Inhibits RAAS leading to Vasodilation ->↓ afterload & preload and reduce Aldosterone -> Less sodium/water retention
  • Uses: Chronic HF, post-MI, and side effects include Hypotension, hyperkalemia and cough -Angioedema if caused by ACEIs

Beta Blockers (Reduce Cardiac Workload)

• Examples: Carvedilol, Metoprolol, Bisoprolol
• Blocks B1 receptors resulting in less HR & contractility less myocardial oxygen demand, prevents sympathetic overstimulation that worsens HF
• Chronic HF(Stable patients only) treated.
• Side effects Bradycardia, hypotension and fatigue

Diuretics (Reduce Fluid Overload) for Chronic Heart Failure Treatment such as...

• Thiazide for mild. (Hydrochlorothiazide
• LoopDiuretic for acute Decompensation: Furosemide, Bumetanide
• ReduceAldosterone: Spironolactone, Eplerenone (for HF with reduced ejection fraction
• All causing Increased urine output leading to reduce pulmonary & peripheral edema
• Electrolyte imbalances, dehydration, hypotension

Second-Line & Adjunct Therapy

• Digoxin (Positive Inotrope)
  • Inhibits Na+/K+ ATPase, intracellular calcium, slowing AV node conduction used in HF with Atrial uses: Chronic HF and Atrial fibrillation.
  • Side Effects: Arrhythmias, nausea and toxicity risk
• Therapeutic Index is Extremely low leading to risk of toxicity
• CNS Effects Malaise confusion and vertigos
• Gastrointestinal Effects Anorexia and intestinal cramping
• Cardiac Effects: Bradycardia and arrhythmias
• Visual Disturbances Yellow-tinted vision (xanthopsia).
• Contraindications AV block and Hypokalemia

Treating Heart Failure VasoDilator Second lin Therapy

• Reduces after load from use of Hydralazine + Isosorbide Dinitrate which functions as Nitroglycerin
• Hydralazine causes ARterial vasodilation while isosorbide dinitrate effects Venous dilation
• This used with Heart Failure in African American patients, ACEI/ARB intolerance
• Side effects Hypotension headache

SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors) as a Newer HF Therapy:

• Using Dapagliflozin and Empagliflozin.
• Inhibit SGLT2 in the proximal renal tubules, reducing glucose reabsorption and promoting urinary glucose excretion.
• Causes diuresis, reduces cardiac workload with HFrEF even in non daibetics, the side effects are urinary tract infection and dry skin
• Side effects UTIs and dehydration

Inotropes

• Increase Heart Cardiac Contractility in Acute HF
• Examples: Dobutamine (B1 agonist), Milrinone (PDE-3 inhibitor)
• Dobutamine that Increases contractility & CO and Milrinone does the same.
• Milrinone Increases CAMP and Vasodilation
• Uses: Acute decompensated HF and cardiogenic shock
• Side Effects: Arrhythmias and hypotension

Treating Hyperlipidemia

• Clinically important lipoproteins include:
  • LDL - Low-Density Lipoprotein
  • VLDL - Very Low-Density Lipoprotein
  • HDL - High-Density Lipoprotein
• Causes:Lack of exercise and high consumption of fatty acids-or a single inherited gene defect/
• A combination of genetics and lifestyle is the most common cause for hyperlipidemia
• Elevated levels of LDL cholesterol and triglycerides or low HDL results in increased heart failure

Lipid Lowering Drugs info

• Generally MUST be indefinitely or lipid levels with return
• They lower the production of lipoproteins through statins or can increase degradation by fibrates and PCSK9 inhibitors,
• Also can decreasing Cholesterol Absorption with Agents like ezetimibe which reduce absorption in the intestines,

Lipid Lowering Drug Classification

• Statins: Lovastatin, Atorvastatin and Simvastatin
• Fibrates: Gemfibrozil and fenofibrate
• Niacin, that Inhibits lipolysis
• Bile acid sequestrants: Colestipol and Cholestyramine
• Absorption inhibitors: Ezetimibe
• PCSK9 Inhibitors :Alirocumab and Evolocumab

Class, Examples, Mechanism of Action and Effets of Dyslipidemia Agents

• Statins (HMG-CoA Reductase Inhibitors):
  • Atorvastatin and Simvastatin
• Inhibits HMG-CoA reductase, reducing cholesterol reducing LDL->HDL->lower TG-causing myopathy,
• Fibrates:
  • Gemfibrozil and lowering Tg can cause hyperlipidemia increasing lipase activity
  • Can cause myopathy from statins
• Bile Acid Sequestion with Cholestyramine Colestipol Sequestion decreases lipid level and preventing its causes GI upset
• Absorption Inhibitor Ezetimibe inhibits cholesterol and transporter in the intestine causing Diarrhea Niacin B 3 Inhibits lipolysis by Reducing hepatic VLDL synthesis leading to hyperuricemia
• Alirocumab and Evolocumab are pcsk9 inhibitors

Explore the effects of the sympathetic and parasympathetic nervous systems on cardiovascular function, the complications of hypertension and atherosclerosis, and the use of diuretics. Learn about potential drug interactions and electrolyte imbalances.