Pharmacology CV Drugs 1

What is the cornerstone of toxicology according to Paracelsus?

"All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison." Any exogenous substance has the capacity to harm a living organism and thus behave like a poison.

How must drug exposure be balanced?

Drug exposure is always a risk, but it has to be balanced against the risk of leaving a disease untreated.

What are the three types of drugs mentioned?

Small molecules, biologics, medical gases.

What is cardiovascular disease (CVD)?

A general term for a group of conditions affecting the heart or blood vessels.

What are examples of acute CVD?

Myocardial infarction (MI) or stroke.

What are examples of chronic CVD?

Hypertension, heart failure.

How are CVD conditions related to each other?

Conditions can exacerbate one another – linked pathology.

What is a myocardial infarction (MI)?

A heart attack – loss of viability of heart tissue due to reduced blood supply.

What is a stroke?

Blockage of a major cerebral artery → ↓ oxygen supply → ↓ energy production → metabolic failure of brain tissue → loss of normal function.

How do chronic and acute CVD conditions interact?

Chronic conditions can increase the risk of acute cardiovascular events. Having an acute event can increase the likelihood of developing chronic disease. Therefore, cardiovascular conditions can self-perpetuate and exacerbate each other.

What conditions are included in the spectrum of CVD?

Hypertension, coronary artery disease, stroke, heart failure, peripheral arterial disease.

What common risk factors and pathophysiology do many CVD conditions share?

Atherosclerosis, endothelial dysfunction, chronic inflammation, hypertension.

Give an example of disease progression in CVD.

Hypertension → vascular damage → atherosclerosis → myocardial infarction or stroke.

Why is hypertension important in CVD?

It is one of the major modifiable risk factors for stroke, myocardial infarction, heart failure, and kidney disease. Treating hypertension significantly reduces cardiovascular mortality.

What is the early pathological change from CVD risk factors?

Vascular dysfunction.

How does vascular dysfunction present in healthy vs. diseased states?

In healthy individuals, blood vessels constrict and dilate normally. With ageing or disease, the vasculature becomes less functional – stiffening of arteries – reduced ability to contract and relax.

What is the link between vascular dysfunction and hypertension?

Stiff blood vessels may remain in a narrow state. To push the same blood volume through, pressure must increase → hypertension. Hypertension then causes further vascular damage, creating a vicious cycle: vascular dysfunction ↔ hypertension.

How does vascular dysfunction contribute to atherosclerosis?

Vascular dysfunction contributes to development of atherosclerotic plaques. Atherosclerotic plaque narrows the vessel lumen and obstructs blood flow. Red blood cells accumulate upstream when flow is restricted. If complete occlusion occurs, tissues downstream receive no blood supply.

What are the consequences of reduced blood flow?

Reduced oxygen delivery to tissues → metabolic mismatch. Oxygen is required for mitochondrial oxidative phosphorylation → ATP production. Without ATP, cellular metabolic processes fail.

What happens in coronary artery narrowing?

Mismatch between oxygen supply and demand in the heart. Early symptom: angina (chest pain) – warning sign of myocardial ischaemia.

What can severe blockage or prolonged ischaemia cause?

Acute myocardial infarction (MI) – death of heart tissue.

What can happen when an atherosclerotic plaque ruptures?

The fragment (thrombus/embolus) can travel and cause: pulmonary embolism, stroke (cerebral artery blockage), kidney ischaemia, or peripheral limb ischaemia.

How does acute MI relate to chronic heart failure?

Acute MI frequently leads to chronic heart failure. Risk of heart failure correlates with size of infarct – larger infarcts lead to greater likelihood of heart failure.

What severe complications can acute or chronic CVD cause?

Arrhythmias and sudden cardiac death / cardiac arrest.

What is a central early event linking CVD conditions?

Endothelial dysfunction: reduced nitric oxide (NO), increased inflammation, increased vascular stiffness.

Describe the steps of atherosclerosis development.

Endothelial injury/dysfunction. 2. LDL cholesterol enters vessel wall. 3. Oxidised LDL triggers inflammation. 4. Macrophages form foam cells. 5. Fatty streak → fibrous plaque → lumen narrowing.

Why does hypertension accelerate CVD?

High pressure causes endothelial damage, increased arterial wall stress, and faster atherosclerotic plaque formation. This is why hypertension is a major modifiable risk factor for MI, stroke, heart failure, and chronic kidney disease.

Compare stable vs. unstable plaque.

Stable plaque: thick fibrous cap, causes chronic narrowing → angina. Unstable plaque: thin cap prone to rupture, causes thrombosis → acute MI or stroke.

Why do many cardiovascular drugs overlap in their targets?

Common targets include: blood pressure reduction, reducing clot formation, reducing cholesterol, improving cardiac workload. Examples: ACE inhibitors, beta-blockers, antiplatelets, statins.

What is systolic pressure and its normal value?

Pressure in blood vessels at the peak of ventricular contraction. Normal value = 120 mmHg.

What is diastolic pressure and its normal value?

Pressure in blood vessels at its lowest at the end of ventricular relaxation. Normal value = 80 mmHg.

How does the WHO define hypertension?

A condition in which the blood vessels have persistently raised pressure.

When does hypertension occur in terms of the cardiac cycle?

When the heart is fully relaxed and the ventricles are fully filled with blood before the next contraction.

Why does clinical diagnosis of hypertension generally require multiple measurements?

Because BP fluctuates. This prevents false diagnosis due to transient stress (white coat hypertension).

What are the typical diagnostic thresholds for hypertension?

Clinic BP ≥140/90 mmHg. Ambulatory or home BP ≥135/85 mmHg.

What is the key defining feature of hypertension?

Blood pressure is persistently raised, not just temporarily elevated (e.g., during stress, exams, lecturing).

Describe the arterial pressure waveform.

Blood pressure changes during the cardiac cycle. The waveform rises during ventricular contraction and falls during relaxation.

What is the dicrotic notch?

A small feature in the arterial pressure waveform that occurs when the aortic valve closes. Brief backflow of blood causes a small rise in pressure before the pressure continues to fall.

How does the sympathetic nervous system (SNS) control blood pressure?

Works mainly through release of catecholamines. Effects: ↑ arterial resistance, ↑ total peripheral resistance (TPR), ↑ blood pressure.

What is the renin-angiotensin system (RAS)?

A kidney-derived hormonal system. Also called RAAS (renin-angiotensin-aldosterone system). Names used interchangeably.

How do kidneys regulate blood pressure?

Kidneys regulate sodium (Na⁺) and water excretion, which determines blood volume. ↓ Na⁺ and water excretion → ↑ body fluid volume → ↑ blood volume → ↑ blood pressure.

How do SNS and RAAS interact?

They are strongly interconnected. For example, angiotensin II (from RAAS) directly affects vascular smooth muscle and causes vasoconstriction.

What is the overall blood pressure control pathway?

SNS → ↑ arterial resistance → ↑ total peripheral resistance → ↑ mean BP. Renal Na⁺/water handling → changes blood volume → affects mean BP.

What are the effects of noradrenaline on different receptors?

α₁ receptors: vasoconstriction → ↑ TPR. β₁ receptors (heart): ↑ heart rate, ↑ contractility, ↑ cardiac output. β₁ receptors (kidney): stimulate renin release → activates RAAS.

What is the formula for Mean Arterial Pressure (MAP)?

MAP = Cardiac Output (CO) × Total Peripheral Resistance (TPR). Where CO = heart rate × stroke volume, and TPR = resistance of arterioles.

What triggers RAAS activation?

A drop in blood pressure or blood volume. Sympathetic nervous system activation stimulates renin release from juxtaglomerular cells of the kidney.

What are the steps of RAAS activation?

Renin converts angiotensinogen (from liver) → angiotensin I. 2. ACE converts angiotensin I → angiotensin II.

What are the actions of angiotensin II via AT₁ receptors?

Vasoconstriction, sympathetic stimulation, cellular hypertrophy, renovascular effects, and stimulation of aldosterone release → kidneys reabsorb Na⁺ and water → ↑ blood volume.

What is the gold standard for BP measurement outside hospital?

Sphygmomanometer.

What are other methods of BP measurement?

Indwelling arterial catheter (direct measurement in hospital) and pulse wave–derived estimation.

What is considered healthy BP?

What is slightly raised BP (pre-hypertension) and its management?

130–139 / 85–89 → lifestyle modification.

What is the hypertension threshold for people under 80 years?

≥140/90 → drug treatment.

What is the hypertension threshold for people over 80 years?

≥150/90 (due to arterial stiffening with age).

Why is the home BP measurement threshold reduced by 5 mmHg?

To account for white coat syndrome. Threshold becomes 135/85.

What lifestyle changes are recommended for pre-hypertension?

Stop smoking, reduce alcohol, improve diet (fruit/veg), stress reduction.

What are the NICE hypertension stages?

Stage 1: ≥140/90. Stage 2: ≥160/100. Stage 3: ≥180/120.

What is primary (essential) hypertension?

No identifiable cause (majority of cases). Usually due to multiple interacting factors: polygenic predisposition, environmental and lifestyle influences (high salt diet, unhealthy diet, stress, smoking, alcohol), obesity, insulin resistance.

What are causes of secondary hypertension?

Renal causes (renal artery stenosis, chronic kidney disease). Endocrine causes (primary hyperaldosteronism, Cushing syndrome, phaeochromocytoma, thyroid disease). Drug-induced causes (oral contraceptives, NSAIDs, corticosteroids).

How does aldosterone increase blood pressure?

Aldosterone causes ↑ Na⁺ reabsorption in kidney, ↑ water retention, ↑ blood volume → increased blood pressure.

What are the symptoms of hypertension?

Usually none (asymptomatic). If severe: dizziness, headache, nosebleeds. First presentation may be with complication (e.g., stroke, MI). Erectile dysfunction in men (erection depends on vasodilation; young men with ED may have BP measured).

What are the risks/complications of hypertension?

Stroke, myocardial infarction, heart failure, renal failure, vascular dementia (caused by reduced cerebral blood flow, often due to multiple small strokes over time → progressive loss of brain tissue and cognitive decline).

Why does hypertension cause target organ damage?

Persistent high BP causes chronic vascular damage affecting target organs: brain (stroke, vascular dementia), heart (MI, LVH → heart failure), kidney (chronic kidney disease → renal failure).

What is the relationship between BP and CVD risk on graphs?

Graphs use a semi-log scale; each step represents approximately doubling of risk. Maintaining normal BP significantly reduces CVD risk.

Why can't BP be reduced indefinitely?

A minimum BP is required for adequate organ perfusion. Example: postural hypotension – standing up quickly causes temporary reduced brain perfusion → brief dizziness. BP must be maintained within a physiological range: high BP → pathology; too low BP → inadequate tissue perfusion.

What did the SPRINT trial demonstrate?

Patients with baseline systolic BP ≥140 mmHg. Randomised to standard vs. intensive treatment (more aggressive BP lowering). Intensive group received more medications. Primary outcome (composite of death, hospitalisation, MI, other CV events) hazard ratio = 0.75 → 25% reduction in risk. Lowering BP reduces CV risk and improves outcomes. Targeting lower systolic BP (<120 mmHg) vs. standard (<140 mmHg) reduced CV events and mortality.

What is the first step in hypertension management?

Lifestyle measures. If BP remains high, medication is started.

What lifestyle interventions reduce BP?

Reduce salt intake, reduce body weight (ideal body weight), diet improvement, aerobic exercise, reduce alcohol intake, increase fruit and vegetable consumption. Examples sometimes suggested: beetroot juice, garlic.

How does beetroot juice reduce BP?

Contains nitrates → converted to nitric oxide (NO) → vasodilator → reduces BP by about 5–10 mmHg (less than most drugs).

How does garlic reduce BP?

Contains polysulfides that promote vasodilation.

What are the mechanisms by which lifestyle measures reduce BP?

Reduced salt intake: ↓ sodium retention → ↓ blood volume. Weight loss: ↓ cardiac workload and peripheral resistance. Exercise: improves vascular function and endothelial NO. Reduced alcohol: alcohol increases sympathetic activity. High fruit/veg intake: ↑ potassium → helps reduce BP.

What is the typical BP reduction from lifestyle changes?

Salt reduction: ~4–6 mmHg. Weight loss: ~5–20 mmHg (depending on weight lost). Exercise: ~4–9 mmHg. Lifestyle changes can sometimes delay or avoid drug therapy.

What is the ABCD classification of antihypertensive drugs?

A = ACE inhibitors / ARBs. B = Beta blockers. C = Calcium channel blockers. D = Diuretics (thiazide-like).

How does the renin-angiotensin system (RAS) control BP?

Drop in BP or fluid volume → activates SNS → stimulates renin release from kidney. Renin acts on angiotensinogen (from liver) → angiotensin I. ACE (mainly in lungs) converts angiotensin I → angiotensin II. Angiotensin II causes vasoconstriction and stimulates aldosterone release → ↑ Na⁺/water reabsorption → ↑ blood volume → ↑ BP.

What is the mechanism of ACE inhibitors?

Block ACE enzyme, preventing conversion of angiotensin I → angiotensin II. Effects: ↓ vasoconstriction, ↓ aldosterone-mediated Na⁺ and water reabsorption, ↓ blood volume → overall decrease in BP.

Give examples of ACE inhibitors.

Ramipril, enalapril, lisinopril, captopril.

What are the key pharmacological effects of ACE inhibitors?

↓ total peripheral resistance, ↓ blood volume, ↓ cardiac workload.

What are the major clinical uses of ACE inhibitors?

Hypertension, heart failure, post-myocardial infarction, diabetic nephropathy.

What are the important adverse effects of ACE inhibitors?

Dry cough (↑ bradykinin), hyperkalaemia, first-dose hypotension, angioedema (rare).

What are the contraindications of ACE inhibitors?

Pregnancy, bilateral renal artery stenosis.

Why do ACE inhibitors increase nitric oxide?

ACE normally breaks down bradykinin. ACE inhibition → ↑ bradykinin levels. Bradykinin stimulates NO release from endothelium → vasodilation.

Why are ACE inhibitors helpful in diabetes?

They reduce glomerular pressure and slow progression of diabetic nephropathy.

What are the two main mechanisms by which ACE inhibitors lower BP?

↓ Angiotensin II → less vasoconstriction. 2. ↓ Aldosterone → less Na⁺/water retention → ↓ blood volume.

What causes the ACE inhibitor cough?

ACE normally breaks down bradykinin → inactive peptides. ACE inhibition → ↑ bradykinin accumulation. If bradykinin accumulates in the lungs → dry cough.

What is the mechanism of Angiotensin Receptor Blockers (ARBs)?

Block AT₁ receptors directly. Effects: prevent vasoconstriction, reduce aldosterone release, ↓ Na⁺/water reabsorption, ↓ blood volume and BP.

What is the key difference between ARBs and ACE inhibitors?

ARBs act downstream of ACE. They do not increase bradykinin as much → less cough and angioedema.

When are ARBs used clinically?

When ACE inhibitors are not tolerated or contraindicated (e.g., pregnancy, renal artery stenosis). ACE inhibitors are generally first-line.

List RAAS drug targets with examples.

ACE inhibitors: ACE enzyme (ramipril, enalapril). ARBs: AT₁ receptor (losartan, candesartan). Renin inhibitors: renin enzyme (aliskiren). β-blockers: renin release (propranolol, atenolol).

How does RAAS inhibition lower BP?

↓ vasoconstriction (TPR) and ↓ aldosterone → ↓ Na⁺/water retention → ↓ blood volume.

Give examples of ARBs.

Losartan, irbesartan, candesartan.

What are the advantages of ARBs?

Beneficial to cardiac function, particularly beneficial in diabetics, very effective in young people, placebo-like side-effect profile, no cough seen with ACE inhibitors.

What are the disadvantages of ARBs?

Can cause renal impairment, should not be used in pregnancy.

Why do ARBs not cause cough?

They do not inhibit ACE, so bradykinin is not increased.

What are the effects of adrenergic receptor subtypes?

α₁: vasoconstriction → ↑ peripheral resistance → ↑ BP. α₂: inhibits norepinephrine release, acetylcholine release, insulin release. β₁: ↑ heart rate, ↑ myocardial contractility, ↑ renin release. β₂: vasodilation → ↓ peripheral resistance, bronchodilation, ↑ glycogenolysis, ↑ glucagon release, relaxation of uterine smooth muscle.

What are the key β₁ receptor effects that lower BP?

↓ heart rate, ↓ myocardial contractility, ↓ renin release.

How do β-blockers lower BP?

Mainly by blocking β₁ receptors: ↓ heart rate, ↓ cardiac output, ↓ renin release → ↓ RAAS activation.

Give examples of common β-blockers.

Propranolol, atenolol, metoprolol, bisoprolol.

Give examples of newer vasodilating β-blockers.

Nebivolol, carvedilol (may also ↑ NO release and cause peripheral vasodilation).

Describe the cellular mechanism of β-blockers.

Receptor blockade. 2. cAMP not produced. 3. PKA not activated. 4. ↓ Ca²⁺ influx and ↓ Ca²⁺ release from stores. 5. Contractile apparatus inhibited. 6. Smooth muscle relaxation → vasodilation → ↓ BP.

What are the three generations of β-blockers?

1st generation: non-selective (propranolol, sotalol). 2nd generation: β₁-selective (metoprolol, bisoprolol, atenolol). 3rd generation: additional mechanisms (carvedilol, nebivolol).