1. Antihypertensive Drugs
Pharmacology–I PHL-313
Antihypertensive Drugs
Dr. Hassan A. Madkhali Assistant Professor Department of Pharmacology E mail: 1

2. Introduction

3. Hypertension overview
Can be define as a persistent diastolic blood pressure greater than 90 mm Hg and systolic pressure greater than 140 mm Hg.
Asymptomatic; silent killer.
A specific cause of hypertension can be established in only
10–15% of patients.
A) Essential or primary hypertension
B) Secondary hypertension.
The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death.
SBP: systolic blood pressure
DBP: diastolic blood pressure
When the left ventricle ejects blood into the aorta, the aortic pressure rises. The maximal aortic pressure following ejection is termed the systolic blood pressure (SBP)
As the left ventricle is relaxing and refilling, the pressure in the aorta falls. The lowest pressure in the aorta, which occurs just before the ventricle ejects blood into the aorta, is termed the diastolic blood pressure (DBP)
A specific cause of hypertension can be established in only
10–15% of patients. Patients in whom no specific cause of hypertension
can be found are said to have essential or primary hypertension
. Patients with a specific etiology are said to have secondary
hypertension. It is important to consider specific causes in each
case, however, because some of them are amenable to definitive
surgical treatment: renal artery constriction, coarctation of
the aorta, pheochromocytoma, Cushing’s disease, and primary
aldosteronism.
Pheochromocytoma:
a small vascular tumor of the adrenal medulla, causing irregular secretion of epinephrine and norepinephrine, leading to attacks of raised blood pressure, palpitations, and headache.
Cushing's disease is a serious condition of an excess of the steroid hormone cortisol in the blood level caused by a pituitary tumor secreting adrenocorticotropic hormone (ACTH). ACTH is a hormone produced by the normal pituitary gland. ACTH stimulates the adrenal glands (located on top of the kidneys) to produce cortisol, commonly referred to as the stress hormone.
Both cardiac output and peripheral resistance have been reported to be elevated in Cushing’s syndrome
Primary aldosteronism, also known as primary hyperaldosteronism or Conn's syndrome, is excess production of the hormone aldosterone by the adrenal glands resulting in low renin levels. Often it produces few symptoms. Most people have high blood pressure which may cause poor vision or headaches.
Secondary to: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary
aldosteronism.

4. Hypertension Individuals
Hypertension Prevalence in Saudi Arabia
Hypertension is the most common cardiovascular disease.
The fourth‐ranked risk factor for disability‐adjusted life years (DALYs) in the Kingdom of Saudi Arabia in 2010.
In males > Females
In Obese > Non-obese
In Diabetic > Non-diabetic
Increase with age.
Varies by regions of Saudi Arabia.
90% diagnosed with primary hypertension whereas 10% with Secondary hypertension.
Uncontrolled & sustained arterial hypertension damages blood vessels in kidney, heart, and brain, and ultimately might leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke.
Hypertension Individuals
Prevalence (%)
Males
17.7%
Females
12.5%
Aged 65 or older
65.2%
Obese
26.4%
Non-Obese
10.2%
Diabetic
38.9%
Non-Diabetic
11.9%
The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death.
Source: Hypertension at a glance

5. Hypertension Complications
Heart diseases
Myocardial infarction (MI)
Heart failure
Angina pectoris
Kidney disease
Stroke

6. Regulation of Blood Pressure (BP)
BP is controlled mainly by CO, HR, SV, & peripheral resistance (PR), in which an increase in any of these can result in an increased BP.
Sympathoadrenal activity (adrenal medulla and sympathetic nervous system activity) increases BP by arteriole vasoconstriction & increased CO.
Kidney plays role in BP by regulating blood volume & thus stroke volume

7. Regulation of Blood Pressure (BP)
BP= CO X PR
Increase BP (hypertension)= increase CO X increase PR
-SV x HR
-EDV
-Contractility
-Blood viscosity
-Vessels diameter
(arteriolar)

8. Summary of the regulation of CO, HR and SV
Note: CO= SV x HR

9. BP regulation by Baroreceptor, Symp/Parasymp pathways
Barorecptor reflex control of BP Video:

10. Treatment of Hypertension

11. Sites of action of the major classes of antihypertensive drugs
I. Diuretics: bumetanide, furosemide, hydrochlorothiazide, spironolactone, triamterene
II. Sympathoplegic agents: methodopa, clonidine, guanfacine, thrimethaphan, guanethidine,
propranolol, reserpine, methoprolol, nadolol, carteolol, pindolol, labetalol, prazosin
III. Direct vasodilators: hydralazine, minoxidil, sodium nitroprusside, diazoxide
IV. ACE inhibitors and angiotensin receptor antagonists: captopril, enalapril, benazepril, quinapril,
losartan, valsartan, saralasin

12. Diuretic Mechanism of action
Water follows Na+
PCT reabsorbs 65 % of filtered Na, 20-25% of all Na is reabsorbed in the loop of Henle, 5-10% in distal convoluted tubule (DCT) & 3% in collecting ducts
If it can not be absorbed it is excreted with the urine
Diuretics act on the kidney to enhance sodium and water excretion  urine output by the kidney (i.e., promote diuresis)  blood volume preload
Reducing blood volume not only reduces central venous pressure, but even more importantly, reduces cardiac output
Side Effects: electrolyte losses [Na+ (hyponatremia) & K+ (hypokalemia)], fluid losses [dehydration], myalgia, N/V/D, Dizziness, hyperglycemia, hyperlipidemia, hypercalcemia
Example:
Thiazides: Chlorothiazide (Diuril®) & Hydrochlorothiazide (HydroDIURIL®)
Loop Diuretics: Furosemide (Lasix®), bumetanide (Bumex®)
Potassium Sparing Diuretics: Spironolactone (Aldactone®)

13. ACE inhibitors Mechanism of action. Therapeutic uses:
Dilate arteries and veins by blocking formation of angiotensin II (AII, a vasoconstrictor)  vasodilatation, thus reduces arterial pressure, preload and afterload on the heart
Promote renal excretion of sodium and water. This reduces blood volume, venous pressure and arterial pressure
Therapeutic uses:
Hypertension
Heart failure
Myocardial infarction (MI)
Diabetic and nondiabetic nephropathy
Adverse effects: Dry cough*, Angioedema, Hyperkalemia, Renal failure, Neutropenia, rashes, hypotension
Contraindications: Pregnancy - renal failure in infants, renal impairment.
Examples: Captopril (Capoten®), Enalapril (Vasotec®), Lisinopril (Prinivil® & Zestril®), Quinapril (Accupril®), Ramipril (Altace®), Benazepril (Lotensin®), Fosinopril (Monopril®)
This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase.
Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

14. Angiotensin Receptor Blockers (ARBs)
Mechanism of action:
ARBs are receptor antagonists that block type 1 angiotensin II receptors on blood vessels and other tissues such as the heart
Cause dilation of arterioles and veins
Decrease release of aldosterone
Increase renal excretion of sodium and water
Reduce excretion of potassium
These drugs have similar effects to ACE inhibitors
Can be used in certain conditions when ACEIs are contraindicated (angioneurotic edema, cough)
Therapeutic uses:
Hypertension, Heart failure,
Diabetic nephropathy, Myocardial infarction,
Stroke prevention, Migraine headache
Adverse effects: Angioedema, Fetal harm, Renal failure
Examples: Losartan (Cozaar), Valsartan (Diovan), Irbesartan, Candesartan, Telmisartan, Olmesartan
This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase.
Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

15. Example: Aliskiren (first-in-class oral renin inhibitor)
Renin Inhibitors
Mechanism of action:
Renin inhibitors produce vasodilation by inhibiting the activity of renin, which is responsible for stimulating angiotensin II formation
These drugs have similar effects to ACE inhibitors and ARBs and are used for the same indications (hypertension, heart failure)
Example: Aliskiren (first-in-class oral renin inhibitor)

16. Calcium Channel Blockers (CCBs) (cause vasodilation):
Mechanism of action.
These drugs bind to L-Type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes).
These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction.
Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilatation), decreased myocardial force contarction, decreased heart rate, and decreased conduction velocity within the heart, particularly at the atrioventricular node.
Therapeutic Uses: Angina pectoris, Tachycardia, Hypertension
Side Effects:
Cardiovascular: hypotension, palpitations & reflex tachycardia
Gastrointestinal: constipation & nausea
Other: rashes, facial flushing & peripheral edema
Examples: diltiazem (Cardizem®), verapamil (Calan®, Isoptin®), nifedipine (Procardia®, Adalat®), Amlodipine (Norvasc), Felodipine (Renedil)
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

17. Potassium Channel Openers (cause vasodilation): Mechanism of action.
These are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth muscle. Opening of these channels, hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium, leadings to muscle relaxation and vasodilatation, decreasing systemic vascular resistance and lowering blood pressure.
Examples: Nicorandil, minoxidil sulphate [Loniten®]
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

18. α1-Adrenoceptor Antagonists (α1-Blockers)
Mechanism of action.
These drugs block the effect of sympathetic nerves on blood vessels by binding to α-adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive antagonists to the binding of norepinephrine to the smooth muscle receptors
α-blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Thus, they decrease systemic vascular resistance (SVR) and lower blood pressure (BP).
Uses: Hypertension, Pheochromocytoma.
Adverse effects: Drowsiness, excitation, headache, tachycardia, and dizziness.
Examples: doxazosin (Cardura®), prazosin
(Minipress®), terazosin (Hytrin®)

20. β-Blockers : Mechanism of action.
β-blockers are drugs that bind to β-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Thus, drugs decrease heart rate, conduction velocity and force of contraction
The first generation of β-blockers were non-selective, meaning that they blocked both β1 and β2 adrenoceptors. Second generation b-blockers (β1-blockers) are more cardioselective in that they are relatively selective for β1 adrenoceptors.
Uses: Hypertension, angina, prevent MI, tachyarrythmias.
Adverse effects: Bronchospasm, sedation, reflex tachycardia, depression, and increased serum triglycerides.
Examples:
For non-selective β -blockers: Propranolol , carvedilol, Sotalol, timolol,
For selective β1 blockers: Atenolol, Metoprolol
β1 : Eye, Kidney, Heart, salivary glands
β2 : Lung, blood vessels, GIT, liver,
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

21. α2-Agonists (Centrally Acting Sympatholytics)
Mechanism of action.
Centrally acting sympatholytics block sympathetic activity by binding to and activating α2-adrenoceptors  inhibition of NE release.
This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility
Reduced sympathetic output to the blood vessels decreases sympathetic vascular tone, which causes vasodilatation and reduced systemic vascular resistance, which decreases arterial pressure
Therapeutic Uses: Hypertension. Migraine prophylaxis,
Adverse Effects: depression
Examples: Clonidine (Catapress®), Methylopa (Aldomet®)

22. Peripheral Vasodilators
Nitrovasodilators
NO release
Activate guanylyl cyclase and ↑cGMP
↓Intracellular calcium
Smooth muscle relaxation
Vasodilation
Preload and afterload reduction
Improved cardiac function

23. Hydralazine (Apresoline®): Reflex tachycardia, postural hypotension
Mechanism of action
Directly relaxes arteriole smooth muscle
Decrease systemic vascular resistance (SVR) = decrease afterload
Therapeutic Uses
Hypertension
Angina pectoris
Heart failure
Myocardial infarction
Peripheral vascular disease
Side effects:
Hydralazine (Apresoline®): Reflex tachycardia, postural hypotension
Sodium nitroprusside (Nipride®): Cyanide toxicity in renal failure, CNS toxicity = agitation, hallucinations, etc.
Example:
Hydralazine [Apresoline®]
Sodium Nitroprusside [Nipride®]
Diazoxide [Hyperstat®]

24. Renin-Angiotensin-Aldosterone system antagonists

26. Cont…

30. Thank you ?

31. Types and Names of Diuretics
Example
Sites of Action
Osmotic agents
Mannitol
PCT
Descending loop
Collecting duct
Carbonic anhydrase inhibitors.
Acetazolamide
Thiazides
Hydrochlorothiazide
DCT
Loop diuretic
Ethacrynic acid
Furosemide
Loop of Henle
K+ - sparing
Spironolactone
Amiloride
Collecting tubule