Antihypertensive Drugs | Pharmacology | Dr Najeeb💊

Antihypertensive Drugs

The lecture explains how blood pressure is regulated, how major antihypertensive drug classes alter those mechanisms, and how treatment choices and combinations are considered.

1. Initial Management

• Look for and address a cause: The lecturer distinguishes essential hypertension, with no clearly identified underlying cause, from secondary hypertension, which results from another disease process. Treating the underlying cause may lower blood pressure.
• For mild hypertension, begin with lifestyle measures where appropriate. The lecture lists:
  • Regular physical activity—suggested as 20–30 minutes, three times weekly.
  • Restricting added table salt rather than eliminating salt entirely.
  • Weight loss for people with obesity.
  • Stopping smoking and moderating alcohol intake.
  • Stress management, relaxation techniques, and biofeedback.
  • Potassium-rich foods, such as fruits and bananas.
  • Attention to blood lipids, including limiting red meat.

2. Physiological Basis for Lowering Blood Pressure

The lecturer presents blood pressure as depending mainly on cardiac output (CO) and total peripheral resistance (TPR).

• TPR is emphasized as a major determinant of diastolic pressure. Narrower arterioles increase resistance and tend to raise diastolic pressure; arteriolar dilation lowers resistance and tends to reduce it.
• Cardiac output is emphasized as a major determinant of systolic pressure. It depends on heart rate and stroke volume.
• Stroke volume is influenced by:
  • Contractility: Stronger contraction can increase stroke volume.
  • Preload: The amount of blood in the ventricle before contraction. Greater venous return and filling can increase stroke volume.
  • Afterload: The resistance against which the heart pumps, related in the lecture to peripheral resistance.
• Venous tone and total blood volume affect venous return and preload. Heart rate also affects filling time: a faster rate shortens diastole.

This framework is used to explain how drugs that affect the heart, blood vessels, kidneys, or sympathetic nervous system can lower blood pressure.

3. Antihypertensive Drug Classes and Mechanisms

A. Centrally Acting Sympatholytic Drugs

• Clonidine stimulates presynaptic α₂-adrenergic receptors in brainstem vasomotor pathways. This suppresses norepinephrine release and reduces sympathetic outflow.
• Methyldopa is taken up by adrenergic neurons and converted to α-methylnorepinephrine, a substitute transmitter that stimulates central α₂ receptors and inhibits sympathetic activity.
• Reduced sympathetic activity can lower heart rate and contractility, relax veins and arterioles, and reduce renin release.
• The lecturer also names guanabenz and guanfacine as centrally acting drugs.

B. Ganglion Blockers

• Drugs such as hexamethonium block autonomic ganglia, reducing sympathetic effects on the heart and blood vessels.
• The lecture says they are generally no longer used for hypertension because they also block parasympathetic transmission and cause widespread unwanted effects.

C. Sympathetic Nerve-Ending Drugs

The lecture describes three ways of reducing norepinephrine function at sympathetic nerve endings:

• Guanadrel: Enters adrenergic nerve endings and storage vesicles, displaces norepinephrine, and can be released in its place.
• Reserpine: Interferes with vesicular monoamine storage, depleting norepinephrine and other monoamines. The lecture associates this with depression and increased suicide risk.
• Metyrosine: Inhibits tyrosine hydroxylase, reducing catecholamine synthesis.

The resulting reduction in sympathetic signaling can lower cardiac stimulation, venous tone, arteriolar tone, and renin release.

D. α-Adrenergic Receptor Blockers

• α₁ blockade relaxes veins and arterioles:
  • Venous dilation reduces venous return and preload, tending to lower cardiac output and systolic pressure.
  • Arteriolar dilation reduces TPR and tends to lower diastolic pressure.
• Nonselective α blockers—phenoxybenzamine and phentolamine—block both α₁ and α₂ receptors. The lecturer explains that α₂ blockade removes an inhibitory feedback mechanism, potentially increasing norepinephrine release and causing tachycardia and palpitations.
• Selective α₁ blockers—prazosin, terazosin, and doxazosin—are presented as preferable for hypertension in the lecture.
• A key adverse effect is postural (orthostatic) hypotension: on standing, blood can pool in dilated veins, reducing venous return and brain perfusion. The lecture also mentions nasal stuffiness and sexual dysfunction.

E. β-Adrenergic Receptor Blockers

• β₁ blockade at the heart lowers heart rate, AV-node conduction, and contractility. This can reduce cardiac output and systolic pressure.
• Blocking β₁ receptors at the juxtaglomerular apparatus reduces renin release and can suppress the renin–angiotensin–aldosterone system (RAAS).
• Examples given include:
  • Propranolol, described as nonselective.
  • Atenolol, described as more β₁-selective.
• Carvedilol and labetalol are described as having both α- and β-blocking actions.
• The lecture notes that blocking β₂ receptors in skeletal-muscle vessels can limit vasodilation and contribute to exercise intolerance or fatigue.
• It cautions against abruptly stopping long-term β-blocker treatment, describing a risk of rebound sympathetic effects.

F. Direct-Acting Vasodilators

These drugs relax vascular smooth muscle without relying primarily on blocking sympathetic signaling.

• Diazoxide and minoxidil open ATP-sensitive potassium channels. Potassium leaving smooth-muscle cells makes them more negative (hyperpolarized), reducing their tendency to contract. The lecture presents these mainly as arteriolar dilators, lowering TPR and diastolic pressure.
• Hydralazine is presented mainly as an arteriolar dilator.
• Nitroprusside dilates both arteries and veins. Nitric oxide increases cyclic GMP, which inhibits the contractile process in smooth muscle. Arterial dilation reduces TPR; venous dilation reduces venous return and cardiac filling.
• Strong vasodilators may trigger reflex tachycardia and fluid retention. The lecture therefore discusses combining them with a β blocker and a diuretic.
• Hydralazine’s notable adverse effect is a lupus-like syndrome, described as more likely with prolonged use, higher doses, and slow acetylation.
• Minoxidil can cause excessive hair growth.

G. Calcium-Channel Blockers

• These drugs block L-type calcium channels in vascular smooth muscle and, to varying degrees, in the heart.
• In arterioles, less calcium entry reduces contraction, lowers TPR, and tends to reduce diastolic pressure.
• In the myocardium, reduced calcium entry can reduce contractility and cardiac output, tending to lower systolic pressure.
• The lecture contrasts:
  • Verapamil, with greater cardiac effects.
  • Diltiazem, with effects on both heart and vessels.
  • Nifedipine, with stronger arteriolar effects and less cardiac effect.
• Because some calcium-channel blockers and β blockers both slow or weaken cardiac activity, the lecture cautions against combining them without a specific reason and careful consideration.

H. ACE Inhibitors and Angiotensin-Receptor Blockers

The lecture reviews RAAS:

1. The kidney releases renin.
2. Renin converts liver-produced angiotensinogen into angiotensin I.
3. Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II.
4. Angiotensin II constricts arteries and veins and stimulates aldosterone release, contributing to salt and water retention.

ACE inhibitors—examples include captopril and enalapril—reduce angiotensin II formation and reduce bradykinin breakdown. The lecturer explains that this can:

• Dilate arteries and veins.
• Reduce aldosterone and salt-and-water retention.
• Reduce sympathetic activity.
• Help limit harmful cardiac remodeling.
• Protect the kidneys in diabetic nephropathy by reducing angiotensin-II-related constriction of the efferent arteriole and lowering pressure within glomeruli.

The lecture identifies dry cough and angioedema as possible effects associated with increased bradykinin. It describes angiotensin-receptor blockers (ARBs), such as losartan and other “-sartan” drugs, as blocking angiotensin II at its receptors and says they may be used when ACE-inhibitor cough or angioedema is a concern. It warns that ACE inhibitors and ARBs should not be used during pregnancy.

I. Diuretics

• The lecture identifies thiazide diuretics as commonly used and also mentions loop diuretics such as furosemide.
• By increasing sodium and water loss, they initially reduce blood volume, venous return, preload, stroke volume, and cardiac output.
• The lecturer says their longer-term blood-pressure effect also involves vasodilation.
• Diuretics are discussed as useful in combinations, including with vasodilators that promote fluid retention.

4. Why Drugs Are Combined

A drug that lowers pressure through one mechanism may trigger compensatory responses that push pressure back up.

• Vasodilation may trigger baroreceptor-mediated sympathetic activation, increasing heart rate and contractility.
• Reduced renal perfusion may trigger renin release and RAAS activation, promoting vasoconstriction and salt-and-water retention.
• Combining drugs with complementary actions may counter these responses and may allow lower doses than using one drug alone.

The lecture gives examples such as pairing hydralazine with a β blocker to limit reflex tachycardia, and with a diuretic to counter fluid retention.

5. Treatment Selection Discussed in the Lecture

The lecturer discusses matching drug choices to a patient’s other conditions and characteristics. Examples presented include diuretics for older people and Black patients, and β blockers or ACE inhibitors for younger or White patients, as well as choosing drugs to address coexisting conditions such as angina or diabetes.

These are the lecturer’s teaching points, not individualized treatment advice. Medication choice depends on the patient’s clinical circumstances and current medical guidance.

6. Hypertensive Emergencies

The lecture describes emergencies as either very high blood pressure without complications, or markedly elevated pressure with target-organ injury. Examples of injury mentioned include encephalopathy, severe retinopathy, left ventricular failure, ischemic heart disease, and kidney damage.

• Blood pressure should be reduced promptly but in a controlled way.
• The lecturer warns that dropping pressure too quickly can reduce brain perfusion because cerebral vessels that have adapted to sustained high pressure may not dilate immediately.
• The lecture gives an approximate goal of lowering pressure by about 25% in the first hour, followed by slower reduction.
• Intravenous sodium nitroprusside is presented as useful because its onset and offset are rapid and its infusion can be adjusted while pressure is monitored. The lecturer notes that it can release cyanide during metabolism and that it is light-sensitive.
• Other agents mentioned include labetalol, fenoldopam, nicardipine, and diazoxide.
• For aortic dissection, the lecture describes using nitroprusside with a β blocker to lower pressure while limiting reflex cardiac stimulation.

Speakers and Sources Featured

• Dr. Najeeb — lecturer and primary speaker.
• No guest speakers are identifiable in the supplied subtitles. The lecture refers to physiology and pathology material discussed in other lectures, but no additional named source or speaker is featured.