Antihypertensive drugs (Elsevier Pharmacology George M. Brenner, Craig W. Stevens)

loop diuretics

1) more natriuresis than thiazides *but less effective in treating HTN 2) lead to hyponatremia

potassium sparing diuretic

1) little effect on natriuresis 2) prevent hypokalemia combine treatment with loop diuretics and thiazides

thiazide & thiazide-related diuretic

decrease peripheral vascular resistance mechanism of reduced PVR

1. sodium content reduced in arteriolar smooth muscle cells

*diet of sodium to resolve the natriuretic effect of thiazide*

thiazide

• Reduced BP (about 10-15mmHg)

• hydrochlorothiazide (most commonly use to treat HTN)

• indapamide (extra function as vasodilator)

• chlorthalidone

• offer protection to osteoporosis (it decreases excretion of calcium in the urine)

• use in combination with other anti HTN drugs

combination of indapamide (thiazide diuretics) and angiotensin inhibitor

1. effective In controlling BP

2. risk of stroke

3. MI

hydrochlorothiazide/ angiotensin inhibitor/ ccb

mild to moderate HTN

main function of diuretic

PREVENT compensatory fluid retention induce by other agents

Adverse drug (thiazide) reaction

1. hypokalemia induced-cardiac arrhythmia

2. muscle weakness

3. possibly elevate level of glucose, uric acid, lipids

4. cause hematologic toxicity

5. exacerbate hepatic disease

6. stimulate renin secretion (combination with angiotensin receptor to resolve the problems)

Loop diuretics

indications

1. poor renal function

2. serum creatinine greater than 2.3mg/dL

Potassium-sparing diuretic

drugs

1. amilorides

2. spironolactone

3. triamterene

K+sparing

mild Natriuretic prevent hypokalemia caused by thiazide and loop diuretics

mineral corticoid receptor antagonists

• spironolactone

• eplerenone

function :

*combination with other drugs show significant lowering bp

* treat HTN that can be controlled by three or more other drugs

*eplerenone similar to spironolactone but associate with less side effects *improve left ventricular hypertrophy in HTN *improve microalbuminuria in type 2 diabetes patient

Sympatholytic drug

adrenoreceptor antagonist

• a-adrenoreceptor antagonist (not suitable for initial treatment of high blood pressure)

• b-adrenoreceptor antagonist

• doxazosin,prazosin, erazosin (combine with diuretics)

• adverse drug effect -SNS reflex activation - causes elevated heart rate, NE, increased oxygen demand, fluid retention via RAAS, orthostatic HTN (first dose syncope)

central acting a-2 adrenoreceptor antagonist

Mechanism of action of b-adrenoreceptor antagonist-

1) block B1 receptor on renal juxtaglomerular cells -inhibit renin secretion -reduce sympathetic outflow -reduce formation of AII (via inhibition of renin) -reduce secretion of aldosterone

B-Blocker indication-

-coronary heart disease -MI

-heart failure

-diabetic (for people with PRE-EXTISITING cardiac condition) (use selective b1antagonist) benefits: reduce risk of myocardial infarction, reduce myocardial ischemia -cardioprotective (reduce ventricular arrhythmia, heart rate) -enhance symptoms and survival -improve cvs outcome in diabetic patients

side effect: 1) fatigue, sleep disturbances, sexual dysfunction, reduce exercise capacity due to decrease heart rate *in diabetic patient it may cause slight impaired in glycemic control (as a result of decreased insulin sensitivity), however CARVEDILOL will improve insulin sensitivity.

non-selective b blocker may delay the patient from recovering from hypoglycemia (by blocking b2-receptor- mediated GLYCOGENOLYSIS and hepatic glucose production)

indication for HTN without pre-existing heart condition

1. angiotensin inhibitor

2. Calcium channel blocker

3. diuretic

contraindication of non-selective b blocker

*asthma *copd

• may cause bronchospasms via b2 receptor blockade

so use selective B1-blocker in caution selective b1 blocker

atenolol (less lipophilic- more side effects on CNS) bisoprolol metoprolol nebivolol (third-generation)-nebivolol elevate nitric oxide release from endothelial cells (potent vasodilators), use to treat HTN patient with heart failure, diabetes, cardiac arrhythmias

non-selective b blocker

nadolol propranolol (more lipophillic) timolol a and b blocker

carvedilol (third generation) labetalol (chronic HTN/ in HTN emergency)

• carvedilol is antioxidant (protect vascular from free radical)

orthostatic hypertension emergency HTN, surgical HTN, ultra-short acting B1 blocker with IV administration

Centrally acting drugs

sympatholytic drug

• clonidine

• guanfacine

• methyldopa (convert to active metabolite (methyl -norepinephrine)

• should not be used with tricyclic antidepressant drugs (as it will block the effects of centrally acting drug)

function

Decrease sympathetic outflow from central vasomotor center to the blood circulation Alpha 2 adrenoreceptor is activated in the brain stem medulla Decrease blood pressure via reducing peripheral vascular resistance Less effect on heart rate and cardiac output

Clonidine

• more s/e than other anti HTN drugs

• not recommended for chronic HTN

• Used in outpatient urgency due to its effect on slow reduction of BP to a safe level (single oral dose)

• reduce SNS symptoms by alcohol, opioid/ nicotine withdrawal.

Methyldopa

• use in pregnant woman

• does not harm fetus

• immunologic effects (Coombs-positive hemolytic anemia, autoimmune hepatitis, organ dysfunction)

S/E

• sedation

• dry mouth

• impaired mental activity

• rebound HTN if stop abruptly

Discontinuations of methyldopa

• tapered gradually

• over 1 to 2 weeks

ejection fraction

% of blood ejected from the left ventricle during each systole

Angiotensin Inhibition

Angiotensin Inhibitors

• ACE inhibitors (-pril) (cerebroprotective)

• Angiotensin Receptor Blockers (-sartan) (cerebroprotective)

• Direct renin inhibitor (aliskiren)

Initial treatment of HTN

• ACE Inhibitor (MILD to SEVERE HTN acts by reducing PVR ,can decrease venous pressure )(decreased cardiac preload and afterload),

• little effect on Cardiac output & Blood volume)

Angiotensin receptor blocker

• effective in reducing risk of stroke

• renoprotective (decrease progression of renal failure & subsequent dialysis) effective for patient with diabetes (albuminuria, raised serum creatinine levels)

• or heart failure

• protective against MI

• enhance survival of left ventricular dysfunction (cardiac ejection fraction less than 40%)

ACE inhibitor Mechanism of action

1. bind to zinc atom in active site of enzyme

2. varying degree of first-pass hepatic inactivation

3. most ACE inhibitor (except captopril) actions is about 24h

4. drug administration: once/ twice daily (for HTN and others)

5. catalyze inactivation of bradykinin

6. hypotensive effect can be increased by increase renal prostaglandin production

7. compensatory elevated renin secretion is counteracted by direct renin inhibitor (aliskiren)

8. consequent of treatment: serum potassium levels increased by 0.5mEq/L

stimuli for renin secretion

1. decreased arterial pressure in renal afferent arterioles

2. decreased NaCl in dista renal tubule

3. SNS activation of B1-adrenoreceptors on renal juxtaglomerular cells

AT1 receptor activation

1. increased production of IP3

2. Increased production of arachidonic acid metabolites

3. Decreased formation of CAMP

Effects after activation of AT1 (angiotensin II receptor type I)

1. general vasoconstriction

2. aldosterone secretion from adrenal cortex

3. increased proximal tubule reabsorption of sodium

4. increased NE production from SNS nerves

5. stimulation of cell growth arteries and heart

AT2 (angiotensin II receptor type II)

1. CVS

2. involve in metabolism

adverse drug reactions,ACE inhibitor

1. FETAL & NEONATAL injury and death (2nd and 3rd trimesters)

2. renal failure in those with bilateral renal artery stenosis (dependent on AII)

S/E

1. dry cough (elevated bradykinin levels)

2. chronic bradykinin accumulation leads to angioedema (manifests as painful swelling of the lips, faces, throat)

sulfhydryl group -zinc binding moiety S/E

1. rash

2. abnormal taste sensation (Eg INDUCED BY captopril)

Augmentation of antiHTN

1)diuretics 2)CCB (calcium channel blocker)

Hyperkalemia caused by

potassium sparring diuretics, k+ supplements with ACE inhibitor

Lithium toxicity

1. lithium used in treatment of bipolar disorders

2. increased serum lithium by the ACE inhibitor

3. NSAID impedes the effect of ACE inhibitor and other antiHTN drugs

phosphoryl

fosinopril (ace inhibitor)

carboxyl

benazepril, enalapril, lisinopril, quinapril, ramipril

prodrug of ACE Inhibitor

all except captopril and lisinopril

PO (oral administration)

1) all except enalaprilat (active form of enalapril) IV 2) bioavailability is 25-75%

frequency of administration

1) captopril 2-3 times a day (shorter half life than others) 2) the rest twice a day

Angiotensin receptor blocker

selectively block AT1 receptor

• decrease vasoconstriction

• decrease aldosterone secretion

• decrease sodium reabsorption

• decrease NE released from SNS nerve terminal

effectiveness

• effective when used alone

• combination with calcium channel blocker

• combination with other anti HTN drugs

• combination of ACE inhibitor with Angiotensin receptor blocker for high risk diabetic nephropathy & others.

• as effective as ACE inhibitor but rarely cause dry cough as in with ACE inhibitor.

PO angiotensin receptor blocker

• candesartan

• irbesartan

• losartan

• telmisartan

• valsartan

losartan vs atenolol (similar blood pressure lowering effect)

• losartan effect- a greater reduction of left ventricular hypertrophy, reduce risk of stroke, reduce onset diabetes (new-onset diabetes)

telmisartan

• enhance insulin sensitivity

• via activation of peroxisome proliferator-activated receptor gamma (involve in glucose homeostasis and regulate adipocytes differentiation (negative regulator of macrophage activation) (expressed in adipose tissue, adrenal gland and spleen)

• same effectiveness as ramipril

• more powerful blood pressure lowering ability than ramipril

Advantages of angiotensin receptor blocker

1. does not increase serum glucose

2. does not increase uric acid

3. does not increase cholesterol level

s/e

1. hyperkalemia

2. neutropenia

3. elevated serum hepatic aminotransferase enzymes

Angiotensin receptor blocker contraindications

not to be used in pregnant women as it cause harm in fetus and death

Aliskiren- decrease plasma renin thereby Angiotensin I and AII

-protective against compensatory rise in AII induced by other anti HTN drug.

-equal to superior blood-pressure lowering effect than other drugs

-resemble placebo side effect profile

-contents : hydrochlorothiazide, amlodipine, valsartan

Vasodilators

• calcium channel blocker

• hydralazine

• minoxidil

• nitroprusside

Indications for calcium channel blocker

• HTN

• angina pectoris

• peripheral vascular disorder

• cardiac arrhythmias

Calcium Channel Blocker Mechanism of action

1. Inhibit Ca2+ channel on the Plasma membrane of vascular smooth muscles

2. Relaxation of vascular smooth muscle

3. Vasodilation

4. Greater effect on arteriolar smooth muscle than venous smooth muscles

5. Greater effect on reduction of PVR

6. less effect on venous capacitance, cardiac preload (cardiac filling pressure) and Cardiac output

7. has some effect of natriuresis

CCB such as Diltiazem and Verapamil

• significant effect on heart

• decrease heart rate

• decrease Cardiac output

CCB of dihydropyridine class

• amlodipine

• felodipine

• isradipine

• nicardipine

• nifedipine

Dihydropyridine vs (Diltiazem and verapamil)

• less effect on cardiac tissue

• evoke/ stimulate reflex tachycardia

CCB

• first line treatment of HTN

• combination with diuretics/ angiotensin system inhibitors

• protection against stroke, coronary heart disease, kidney disease

verapamil & diltiazem

• decrease protein excretion in patients with kidney disease

• combination with angiotensin receptor inhibitor and ACE inhibitor

adverse effect- no/ free

benefits

1. do not alter serum glucose

2. do not alter serum lipids

3. do not alter uric acid

4. do not alter electrolytes

5. HTN in asthma/ african

24-h BP control in HTN

1. amlodipine (long acting)

2. nifedipine (sustained release), gastrointestinal system

Vasodilators

• Hydralazine

• Minoxidil

to treat moderate to severe HTN

adverse drug reactions when used alone

• Evoke reflex tachycardia

• Cause fluid retention

• Exacerbate Angina

*counteract adverse drug reactions by drug combinations*

• diuretics+ B-adrenoreceptor antagonist/ sympatholytic agent

S/E hydralazine

lupus-like syndrome

S/E minoxidil

hypertrichosis (excessive hair growth in women)

minoxidil

• topical

• indicates for alopecia in men and women (Rogaine)

DRUG Reservation to overcome resistant anti HTN drug

• hydralazine

• minoxidil

Nitroprusside

• sodium nitroprusside (HTN emergency)

• IV administration

• Short-half life

• Rapid metabolization to cyanide in RBC (erythrocytes)

• cyanide can be converted to thiocyanate

• accumulation of thiocyanate & cyanide gradually (monitor BP and thiocyanate levels every 3 days to prevent potential toxicity

• duration of therapy limited to a few days

Fenoldopam

• Rapid-acting

• IV administration

• HTN emergency

• activates vascular dopamine D1 receptors

• promote vasodilation in coronary, renal (vasodilation of afferent and efferent arterioles- increased renal blood flow) and mesenteric vascular bed

• short half-life

• 5minutes half-life

• decrease serum potassium

• monitor every 6 h

single-drug therapy

1. preferred for initial treatment of mild HTN

2. eg: angiotensin inhibitor (preferred)

OR

1. CCB (Preferred)

2. thiazide diuretics (less favored)

3. b-blocker reservation for patient (with heart disease eg: angina pectoris)

benefit of combined drug treatment

1. lower doses

2. associated with less s/e

most common combined drug

CCB + Angiotensin blocker (amlodipine, valsartan) thiazide diuretic + ACE inhibitor/ CCB

HTN >65 years Initial treatment

1. dihydropyridine (CCB)

or

2. Angiotensin inhibitor

>70years

beta blocker decrease Cardiac output significantly -cardioprotective effect of b-blocker if well tolerated will be given

black elderly

1)diuretic or 2) CCB with or without angiotensin inhibitor

patient with IHD, angina pectoris, MI

1. treat with B blocker + ACE inhibitor/ angiotensin receptor blocker

2. b blocker protect against sudden death

diabetes mellitus

1. blood pressure controlled at < OR at 130/80mmHg

2. DECREASE the risk of progression of diabetic nephropathy to end-stage renal disease

3. ACE inhibitors / ARBs- anti HTN- ability to reduce the progression of diabetic nephropathy

B blocker (drug effect)

1. sequestered signs of hypoglycemia

2. block glycogenolysis

but can be managed easily

(non-selective) b-blocker contraindication

1. asthma (due to potential bronchoconstriction resulted from the drug action) (drug binds to b2-adrenoreceptor)

Hypertensive emergency

1. severe elevated bp (greater than 180/120mmHg)

2. organ dysfunction (encephalopathy, intracranial hemorrhage)

upper level stage 2 HTN

1. severe headache

2. SOB

3. severe anxiety

case presentation

Woman, 56y

medical hx of 8y type 2 diabetes, 5y HTN

medications taken

1)metformin (decrease glucose absorption from GI tract and formation in the liver, enhance insulin sensitivity) 2) thiazide diuretic for blood pressure (decrease insulin sensitivity)

investigation

1. bp 138/86mmHg

2. microalbuminuria (proteinuria) (50 micro/min over 24h)

new prescriptions

1. valsartan

2. amlodipine

3. glipizide

4. discontinued thiazide diuretics

new management

dietitian exercise counselor

type 2 diabetes & HTN

1. increased risk of proteinuria

2. increased risk of chronic kidney disease

Metformin with

1. glipizide

2. incretin mimetics (sitagliptin) (stimulate decrease in plasma glucose)

excess blood pressure reduction can

1. precipitate renal ischemia

2. precipitate cerebral ischemia

3. precipitate coronary ischemia

4. short-acting nifedipine no longer used in emergency setting

Blood pressure control in more systematic manner

1. bp no more than 25% in 1 h

2. target to 160/100mmHg next 2-6h

3. gradual BP reduction 24 to 48h

eclampsia

1)seizure not due to altered brain electrical activity

2) causes may be from Blood vessels, brain , nervous system, diet ,genes

3) induced by hydralazine

drugs used in emergency setting

1. fenoldopam

2. nicardipine

3. labetalol

4. sodium nitroprusside

acute coronary ischemia + HTN emergency

nitroglycerin

acute left ventricular failure

enalaprilat

aortic dissection + perioperative HTN

esmolol

pheochromocytoma

1. non malignant

2. tumor release catecholamine

3. tumor of the adrenal medulla

4. highly vascularized

5. hypertensive crisis

6. sudden (paroxysmal) /continuous release of epinephrine or norepinephrine

surgical removal of pheochromocytoma

1. pre-operative treatment with phenoxybenzamine (to induce long-lasting alpha adrenoreceptor blockade + b-blockers)

tyrosine hydroxylase

rate limiting enzyme involving catecholamine biosynthesis

metyrosine- tyrosine hydroxylase inhibitor

antiHTN

1. Diuretics

2. Vasodilator

3. Angiotensin-inhibitor

4. sympatholytic drug

thiazide diuretic :short-term effects

1. decrease blood volume

2. decrease cardiac output

thiazide diuretic :long-term effects

1. reduce total peripheral vascular resistance

sympatholytic drugs

1. alpha-adrenoreceptor antagonists (reduce peripheral vascular resistance)

2. b-adrenoreceptor antagonists (reduce cardiac output)

3. centrally-acting drug(reduce peripheral vascular resistance)

angiotensin inhibitors

1. ACE inhibitors (lisinopril)

2. Angiotensin receptor blocker (losartan)

3. direct renin inhibitor (aliskiren)

main functions

1. decrease PVR

2. decrease aldosterone levels

3. fewer effect on blood volume (for patient with no heart failure)

4. fewer effect on Cardiac output (for patient with no heart failure)

vasodilators

1. Calcium channel blocker

2. hydralazine (provoke fluid retention and reflex tachycardia)

3. minoxidil (provoke fluid retention and reflex tachycardia)

4. nitroprusside

Main drug functions

1. decrease PVR

#b-blocker &angiotensin system inhibitor : beneficial for patient with heart disease

#angiotensin receptor blocker protective effect on stroke

angiotensin system inhibitor : beneficial for patient with kidney disease

#GINGIVA enlargement caused by calcium channel blocker, phenytoin (for seizures)

, ciclosporin (immunosupressant- for transplant rejection and psoriasis)

2. irbesartan (angiotensin II inhibitor)

3. metoprolol (b-blocker)

1. doxazosin (alpha-blocker)

2. grape fruit increase the dose of the ccb (causing severe hypotension)

• inhibit cytochrome p450 3a4 (in the gut and liver)

• cytochrome p450 3a4 metabolise ccb

1. amlodipine and doxazosin do not affect insulin sensitivity

2. -thiazide diuretic cause a small decrease in insulin sensitivity