Antihypertensive Drugs Prof. Alhaider (1431H)

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AntihypertensiveDrugsProf. Alhaider (1431H)
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• Etiology of hypertension (HTN)
• 90 essential or primary while 10
  secondary (renal artery
• constriction, pheochromocytoma, Cushings
  disease, coarctation of the aorta)
• Causes of Essential Hypertension. Unknown but
• Weak epithelial elasticity ,genetics , stress,
  diet, environment play a role.
• Regulation of Blood Pressure
• BP CO X total peripheral vascular resistance
  (PVR)

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• Thus, hypertensive patients can be classified
  as
• Hyprereninemic (White, young) HTN because of ?
  renin
• Nor-or hyporenenemic (Black, elderly, obese)
• Salt sensitive (Black, elderly) increase
  Na influx into smooth muscles of blood vessel ?
  ?Ca influx ? vasoconstriciton

• Treatment of Hypertension
• Repeat Blood pressure measurement
• Start with low salt diet and look for
  any secondary causes.
• Look for age, race, lifestyle, etc

The goal of treatment with drugs is ?PVR
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• Classifications of Antihypertensive drugs
• Best classification that depends on mechanism of
  action
• and/or site of regulation
• 1) Drugs that alter sodium and water balance
  (Diuretics)
• 2) Drugs that inhibit sympathetic system
  (Sympatholytics)
• b-adrenergic Blockers
• a-adrenergic Blockers
• Centrally acting Blockers (a2-adrenergic
  agonists)
• 3) Direct vasodilators (calcium channel
  Blockers,
• Hydralazine, Minoxidil)
• 4) Drugs that block production or action of
  angiotensin II (ACE inhibitor)

Having many different types of drugs permit the
combination between them to increase the efficacy
or decrease toxicity (side effect)
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• A. Drugs that Alter Sodium and Water Balance
  (Diuretics)
• Examples Hydrochlorothiazide Indapamide
• Mechanism of Action
• Initially they increase sodium water excretion,
  this cause
• Reduction blood volume C.O. (less important)
• Late Reduce peripheral resistance via negative
  sodium
• Balance (more important)
• Indapamide has a direct vasodilating effect
• Clinical Pharmacology of Diuretics in
  Hypertension
• Blacks elderly patients best respond to this
  treatment (salt sensitive)

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• Contraindicated in arrhythmia and ischemic heart
  disease because of hypokalemia.
• In diabetes because they produce hyperglycemia.
• In pregnancy because of hypovolemia and ?
  perfusion to the fetus. In case of arrhythmia and
  ischemic heart disease

Adding K sparing diuretics to compensate for
hypokalemia
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• B. Drugs that Inhibit Sympathetic System
  (Sympatholytics)
• 1. b-adrenergic Blockers
• Examples Atenolol Metoprolol, Bisoprolol
  Esmilol
• Mechanism of Action and Side Effects
• (check the antiadrenergic lecture)
• Clinical Pharmacology of B-adrenergic blockers
• Discontinuation after prolong use? rebound
  tachycardia
• Propranolol is not used for HTN because
• Its nonselective.
• Short t1/2
• CNS side effects
• They can be used in heart failure
• Don not produce postural hypotension
• ß blockers can be used in patient with
  hyperthyroidism because hyperthyroidism induces
  tachycardia .
• ß blockers are used to treat hypertension in
  pregnant women .
• ß blockers are not used to treat hypertension in
  patient with asthma.
• Does ß blockers cause postural hypotension?
• No.

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bisoprolol atenolol Propranolol
Dose 5 Dose 100,50,25 Dose 40,80 mg
Once daily Once daily Three times daily
strongest More practical Not practical
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2- a- adrenergic Blockers e.g. non-selective
blockerslike phentolamine and phenoxybenzamine
selective like prazosin, terazosin Mechanism of
Action Dilation of arterial and venous
vessels 3. Centrally acting agents
(a2-adrenergic agonists) e.g Clonidine and
Methyldopa MOA and Side Effects (see
antiadrenergic lecture) Clinical Pharmacology of
centrally acting antihypertensive
agents Methyldopa used in pregnancy.
Advantages Side effects
?HDL 1st dose effect
Postural hypotension
Tolerance
Labetalol is used in pheochromocytoma and HTN
crisis.
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Side effects of centrally acting agents
Methyldopa clonidine
Sedation Sedation
Depression Rebound hypertension
Hypersensitivity Dry mouth
Hepatitis Fluid retention
Worsen heart failure
Hemolytic anemia
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• C. Direct vasodilators
• 1) Calcium Channel Blockers(CCB)
• e.g Nifedipine Amlodipine Diltiazem (not
  used in HTN) Verapamil (not used in HTN)
• Mechanism of Action
• There are two types of calcium channels T and L,
  the latter (L) is
• present in blood vessels.
• CCB block transmembrane voltage-dependent Ca
  channels mainly on arterial smooth muscles
  cardiac muscles.
• They have negligible effect on veins.
• Vascular smooth muscles are more sensitive to CCB
  than other smooth muscles e.g. (GI muscles,
  bronchioles)
• Skeletal muscles depend on intracellular Ca to
  contract so these drugs have no effect on them
• They have effect on cerebral blood vessels so
  they can be used in hemorrhagic stroke.
• Not contraindicated in asthma because they have
  no action on bronchiols

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We have to use ß blockers and diuretics with
vasodilator drugs to overcome the compensatory
mechanisms
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• Classification of Calcium channels Blockers
• 1) Dihydropyridine group (Amlodipine,
  Nicardipine, Nifedipine
• Nimodipine) are more selective as vasodilators
  and have less
• cardiac depressant effect (used for
  hypertension).
• 2. Non- Dihydropyridine group like Verapamil
  (antiarrythmic agent)
• has the greatest depressant effect on the
  heart and significantly
• decreases heart rate and cardiac output.
  While Diltiazem
• (antianginal agent) has intermediate
  action.
• Vascular Slectivity dose which produces
  cardiac effect
• dose which produces vasodilation

? dose that produce heart effect ? ?vascular
selectivity
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• Clinical Uses of Calcium channel Blockers
• Hypertension (Amlodipine, Nifedipine)
  especially in black, elderly, obese (salt
  sensitive)
• Angina (Diltiazem)
• Supraventricular tachycardia (Verapamil)
• For cerebral hemorrhage (nimodipine)
• Prophylactic of migraine (Nifedipine)
• Peripheral vascular diseases (Raynaud's
  Phenomenon)
• Nifedipine Amlodipine.
• Hyporenenemic and salt sensitive patient respond
  better to CCB
• They can be given to pregnant woman
• They do not require adding diuretics
• Generally, we add ACEI or ß blockers to prevent
  reflex tachycardia produced by the action of CCB

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• Side Effects of CCBs
• Reflex tachycardia mainly with short acting (like
  Nifedipine)
• less with long acting like (Amlodipine)
  while verapamil
• induces severe bradycardia
• Fatigue, headache.
• Constipation mainly with verapamil (very
  important)
• Ankle or peripheral edema (nifedipine), less
  edema with amlodipine

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• 2) Hydralazine
• Direct arterial vasodilator works via increasing
  c-GMP and NO.
• PK Given orally with 90 absorption but with
  significant 1st
• pass effect (via acetylation). Given 3 times
  daily (TDS)
• Side Effects
• Headache, sweating, flushing and Tachycardia
  (reflex) therefore, should not given alone
  (see Figure) (what figure ???)
• Systemic Lupus erthymatosus(SLE) like symptoms
  ( arthralgia, myalgia and fever without kidney
  involvement) .This occurs in slow
• Acetylator patients because slow acetylator ?
  ?hydralazine in blood ? SLE. Occurs more in women
  91.
• Hepatitis in fast acetylators. Fluid and salt
  retention

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• Which type of hypertensive patients can be given
  hydralazine?
• Hypertensive crisis
• In pregnancy induced Hypertension
• Essential hypertension (when patients have
  hyperkalemia)

• 3)Minoxidil
• Unique arterial vasodilator
• MOA enhance potassium outflow leading to
  hyperpolarization and arterial vasodilatation.
• Advantages Very potent arterial vasodilator
  used for refractory HTN
• (refractory means that HTN doesnt respond to
  normal drugs).
• Dose orally , 5-10mg , taken twice daily. Can
  be taken topically (treatment of
  alopecia by increasing the blood flow to the hair
  beds)

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• Disadvantage
• Produces salt and water retention and may
  precipitate
• pericardial effusion
• Tachycardia
• Hypertrichosis (increase hair length and
  density) can be used as a treatment for
  alopecia (hair loss) by increasing blood flow to
  the hair, leading to hair elongation.
• Not good for pregnant women .

• 4)Sodium Nitroprusside
• MOA by releasing the inside NO (see the drug
  structure in the next slide). Also, it releases
  cyanide (CN).
• PK
• sensitive to light and moisture.
• given IV only , short t1/2 (1-10 min) , used in
  hypertensive crisis
• CN will be converted to thiocyanate in the
  liver.
• Thyiocyanate will be eliminated in the kidney

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Accumulation of CN occurs in patient with liver
or renal impairment

• Side Effects of Sodium nitroprusside
• Accumulation of Cyanide lead to metabolic
  acidosis and
• arrhythmias low BP and coma.
• Accumulation of thiocyanate during prolonged
  administration or renal
  failure leads to weakness, disorientation,
  psychosis and muscle spasm and convulsion.
• Thiocyanate may inhibit iodide uptake by the
  thyroid (hypothyroidism)
• Methemoglobinemia during infusion may occur.

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• 5)Diazoxide
• Similar to thiazides diuretics with no diuretic
  activity.
• It causes water and salt retention
• Inhibits the release of insulin (via opening
  potassium
• channels), leading to severe hyperglycemia.
  Therefore, It is not now used for treatment of
  hypertension. Instead, it is used for
  hypoglycemia due to insulinoma (a tumor that
  produces insulin).

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• D. Drugs that block production or action of
  angiotensin II
• A.angiotensin converting enzyme
  inhibitors(ACEI)
• Examples Captopril Enalapril, Lisonopril,
  Fosinopril
• MOA see next slide.
• They decrease peripheral vascular resistance
  (PVR) ? (renal and venous action).
• PK
• They are long acting (taken once daily) Except
  captopril (TDS).
• All are pro-drugs, converted to the active
  agents by
• hydrolysis in the liver except Captopril.
• Enalaprilat is the active metabolite of enalapril
  and is available
• only for intravenous use for hypertensive
  emergency.
• All ACEI are distributed to all tissues except
  CNS.
• All ACEI are eliminated by the kidney except
• fosinopril moexpril

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• Clinical Uses of (ACEIs)
• More effective in treatment of hypertension in
• conditions associated with high plasma renin
  activity
• (young white people ), but we can get the same
• response with the majority.
• Safely used in patients with ischemic heart
  disease because
• They dont result in reflex sympathetic
  activation.
• They are drugs of first choice for patients with
  diabetic
• even without HTN, because they diminish
  proteinuria,
• and stabilize renal function.

Glomerulus
Afferent arteriole
Efferent arteriole
In diabetes efferent arteriole is constricted
result in ?GFR ? ?hydrostatic pressure ?
proteinuria
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ACEI
Glomerulus
Afferent arteriole
Efferent arteriole
With the use of ACEI efferent arteriole dilate
and proeinuria is thus treated

• Treatment of heart failure also used after
  myocardial infarction (MI) because they have an
  effect on veins and can also decrease renin
  (aldosteron) ? decreasing the load on heart
  muscles.
• They also can be given to non-hypertensive
  patients to
• Decrease proteinurea (nephrotic syndrome or
  other
• renal diseases)

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• Side Effects of ACEIs
• Severe hypotension at the beginning (start with
  low dose or start with captopril then use other
  ACEIs)
• Acute renal failure (in patients with bilateral
  renal arterial stenosis)
• Stenosis (afferent vasoconstriction) by using
  ACEI ? efferent vasoconstriction ?
• ?GFR? acute renal failure
• Hyperkalemia
• Dry cough, wheezing ,and angioedema (edema of
  the dermis and subcutaneous tissue due to ?
  secretion of bradykinin)
• Captopril in high doses may cause neutropenia,
• proteinuria, altered sense of taste, allergic
  skin rash, drug
• fever .
• Contraindications
• During the second and third trimesters of
  pregnancy
• because of the risk of fetal hypotension,
  anuria, renal failure.
• They may cause fetal malformations and death.
• Bilateral renal artery stenosis or stenosis of
  the artery of a solitary kidney.

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• B. Angiotensin Receptor Blockers (ARBs)
• Losartan Valsartan Candesartan Irbesartan
• Mechanism of action
• Block AT1 receptors.
• Advantages over ACEI
• They have no effect on the bradykinin system No
  cough, wheezing or angioedema.
• Complete inhibition of angiotensin action
  compared
• with ACEI
• Side Effects Are similar to ACE Inhibitors but
  with no cough or angioedema.

codiovan valsartan thiazide dieuretics We
use thiazide to treat hyperkalemia.
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????? ??????
You can use ACEI and CCB together or CCB and
diuretics. You cannot use ACEI with ß blockers
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Drugs Used for Hypertensive Crisis