Dr. Florencia D. MunsayacDr. Florencia D. Munsayac

HYPERTENSIONHYPERTENSION "A state of abnormal arterial "A state of abnormal arterial

function and structure associated function and structure associated with endothelial dysfunction, with endothelial dysfunction, vascular smooth muscle vascular smooth muscle constriction or remodeling, constriction or remodeling, increased impedance to left increased impedance to left ventricular ejection and propensity ventricular ejection and propensity for atherosclerosis."for atherosclerosis."

Diagnosis:Diagnosis: repeated, reproducible measurements of repeated, reproducible measurements of

elevated BPelevated BP

Consequences:Consequences: damage to kidneys, heart & braindamage to kidneys, heart & brain

Diagnosis:Diagnosis: repeated, reproducible measurements of repeated, reproducible measurements of

elevated BPelevated BP

Consequences:Consequences: damage to kidneys, heart & braindamage to kidneys, heart & brain

Etiology:Etiology:

1. Abnormal cardiac & peripheral hemodynamics 1. Abnormal cardiac & peripheral hemodynamics 2. Impaired pressure natriuresis2. Impaired pressure natriuresis3. Baroreceptor resetting3. Baroreceptor resetting4. Abnormalities in the renin-angioitensin-4. Abnormalities in the renin-angioitensin-

aldosterone systemaldosterone system5. Abnormalities in other vasoregulatory systems 5. Abnormalities in other vasoregulatory systems

a. Endothelina. Endothelinb. Atrial Natriuresis peptide (ANP)b. Atrial Natriuresis peptide (ANP)c. Endothelium-derived relaxation factor (EDRF)c. Endothelium-derived relaxation factor (EDRF)

A. Primary HypertensionA. Primary Hypertension

1. Renovascular hypertension1. Renovascular hypertension2. Renal parenchymal diseases2. Renal parenchymal diseases

a. Altered excretory functiona. Altered excretory functionb. Altered renin-angiotensin-aldosterone b. Altered renin-angiotensin-aldosterone activityactivity

3. Endocrinologic causes3. Endocrinologic causesa. Oral Contraceptivesa. Oral Contraceptivesb. Mineralocorticosteroid excess syndromeb. Mineralocorticosteroid excess syndromec. Pheochromocytomac. Pheochromocytomad. Miscellaneous causes (Acromegaly, d. Miscellaneous causes (Acromegaly, Hyperparathyroidism, Hyperthyroidism, Hyperparathyroidism, Hyperthyroidism, Coarctation of the aorta)Coarctation of the aorta)

B. Secondary Hypertension

ABP = cardiac output x peripheral vascular resistance

• heart rate • arteriolar volume • contractility • blood volume • filling pressure • venous tone

Major Factors Influencing Blood Pressure

HYPERTENSION

Genetic influences + Environmental Factors

Defects in renal NA+

homeostasis

Functional vasoconstriction

Defects in vascular smooth muscle growth and structure

Inadequate Na+ secretion

Salt & water retention

Plasma & ECF volume

vascular reactivity

vascular wall thickness

cardiac output (autoregulation)

total peripheral resistance

Daytime: BP is controlled by sympathetic activityDaytime: BP is controlled by sympathetic activity

Sleep: BP lowestSleep: BP lowest sympathetic activity switch offsympathetic activity switch off renin level riserenin level rise BP control under RASBP control under RAS

Early Morning Waking: Early Morning Waking: BP rise as much as 30 mmHgBP rise as much as 30 mmHg

marked increased in sympathetic activity marked increased in sympathetic activity elevated levels of renin & elevated levels of renin &

angiotensin IIangiotensin II

Circadian Rhythm and Blood Pressure Circadian Rhythm and Blood Pressure VariabilityVariability

Physiological Changes Physiological Changes Associated With Early Associated With Early Morning BP ElevationMorning BP Elevation

Increase plasma cathecolamines Increase plasma cathecolamines && cortisol cortisol elevates myocardial oxygen demandelevates myocardial oxygen demand

Increase in platelet aggregability & vascular Increase in platelet aggregability & vascular tone; reduce myocardial oxygen supplytone; reduce myocardial oxygen supply

BPBP surge can cause rupture atherosclerotic surge can cause rupture atherosclerotic plaques in coronary arteriesplaques in coronary arteries

Promotes clot formation due to activation of Promotes clot formation due to activation of coagulation processcoagulation process

Excess sympathetic activation results in Excess sympathetic activation results in release of adrenaline, an arrhythmic promoterrelease of adrenaline, an arrhythmic promoter

Increase plasma cathecolamines Increase plasma cathecolamines && cortisol cortisol elevates myocardial oxygen demandelevates myocardial oxygen demand

Increase in platelet aggregability & vascular Increase in platelet aggregability & vascular tone; reduce myocardial oxygen supplytone; reduce myocardial oxygen supply

BPBP surge can cause rupture atherosclerotic surge can cause rupture atherosclerotic plaques in coronary arteriesplaques in coronary arteries

Promotes clot formation due to activation of Promotes clot formation due to activation of coagulation processcoagulation process

Excess sympathetic activation results in Excess sympathetic activation results in release of adrenaline, an arrhythmic promoterrelease of adrenaline, an arrhythmic promoter

Classification of Blood Pressure Classification of Blood Pressure for Adults >/= 18 years: JNC 7for Adults >/= 18 years: JNC 7

Pressure Category

SBP (mmHg) DBP (mmHg)

Normal < 120 < 80

Prehypertension 120 - 139 80 - 89

Hypertension

Stage 1 140 - 159 90 - 99

Stage 2 > / = 160 > / = 100

Management of Hypertension Management of Hypertension in Adults Aged > / = 18 Yearsin Adults Aged > / = 18 Years

Blood PressureClassification

LifestyleModification

Initial Drug Therapy

Without compellingindication

With compelling indication

Normal Encourage

Prehypertension Yes No antihypertensive drug indicated

Drug(s) for the compelling indications

Stage 1HTN Yes Thiazide-type diuretics for most; may consider ACE inhibitor' ARB, beta-blocker, CCB, or combination

Drug(s) for the compelling indications; other antihypertensive drugs (diuretics, ACE inhibitor, ARB, beta-blocker, CCB) as needed

Stage 2 HTN Yes 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or beta-blocker or CCB)

Drug(s) for the compelling indications; other antihypertensive drugs (diuretics, ACE inhibitor, ARB, beta-blocker, CCB) as needed

Classification of Antihypertensive Classification of Antihypertensive DrugsDrugs

A. DiureticsA. Diuretics1. Thiazides1. Thiazides2. Loop diuretics: Furosemide, Bumetanide2. Loop diuretics: Furosemide, Bumetanide3. Potassium Sparing diuretics: Triamterene, Spirinolactone, 3. Potassium Sparing diuretics: Triamterene, Spirinolactone, Amiloride Amiloride

B. Sympathoplegic AgentsB. Sympathoplegic Agents1. Centrally Acting Agents1. Centrally Acting Agents

a. Acting on alpha adrenoceptor (First Generation)a. Acting on alpha adrenoceptor (First Generation)- methyldopa, clonidine, guanabenz, guanfacine- methyldopa, clonidine, guanabenz, guanfacine

b. Acting on imidazoline receptor (Second Generation)b. Acting on imidazoline receptor (Second Generation)- moxonidine, rilmenidine- moxonidine, rilmenidine

2. Ganglionic Blocking Agent - Trimetaphan2. Ganglionic Blocking Agent - Trimetaphan3. Adrenergic Neuron Blocking Agents - reserpin, guanethidine, 3. Adrenergic Neuron Blocking Agents - reserpin, guanethidine, guanadrelguanadrel4. Beta-adrenergic Antagonists - propranolol; metaprolol, atenolol, 4. Beta-adrenergic Antagonists - propranolol; metaprolol, atenolol, pindolol, acebutolol, bisoprololpindolol, acebutolol, bisoprolol5. Alpha adrenergic Antagonists - prazocin, phenoxybenzamine, 5. Alpha adrenergic Antagonists - prazocin, phenoxybenzamine, phentolaminephentolamine6. Mixed Antagonists (Alpha 6. Mixed Antagonists (Alpha & & Beta) - labetalol, Beta) - labetalol, carvedilolcarvedilol

C. VasodilatorsC. Vasodilators1. Oral Vasodilators: hydralazine, minoxidil1. Oral Vasodilators: hydralazine, minoxidil2. Parenteral Vasodilators: nitroprusside, diazoxide, 2. Parenteral Vasodilators: nitroprusside, diazoxide,

fenoldepamfenoldepam3. Calcium Channel Blockers: Dihydropyridines - 3. Calcium Channel Blockers: Dihydropyridines -

nifedipine, amlodipine, felodipine. nimodipine, nifedipine, amlodipine, felodipine. nimodipine, nicardipine, isradipine, licidipine; Phenylalkylamines nicardipine, isradipine, licidipine; Phenylalkylamines --vcrapamil; Bcnzothiazcpincs - diltiazcm --vcrapamil; Bcnzothiazcpincs - diltiazcm

D. Inhibitors of Rcnin Aogiotcnsin System:D. Inhibitors of Rcnin Aogiotcnsin System:1. Angiotensin 11 Antagonists - saralasin, losartan, 1. Angiotensin 11 Antagonists - saralasin, losartan,

valsartanvalsartan2. ACE inhibitors - captopril, qiunapril, enalapril, 2. ACE inhibitors - captopril, qiunapril, enalapril,

pcrindopril, lisinoprilpcrindopril, lisinopril

Loop DiureticsLoop Diuretics

furosemide, bumetamide and furosemide, bumetamide and torsemidetorsemide

act primarily on the thick ascending act primarily on the thick ascending loop of Henle which reabsorbs 20-30% loop of Henle which reabsorbs 20-30% of the filtered load of NaClof the filtered load of NaCl

most potent diuretics in clinical usemost potent diuretics in clinical use Very steep dose-response natriuresis Very steep dose-response natriuresis

curve, termed high-ceiling diureticscurve, termed high-ceiling diuretics

FurosemideFurosemide

Rapidly absorbed from the GITRapidly absorbed from the GIT Binds avidly to plasma proteinsBinds avidly to plasma proteins Rapidly eliminated from the body, by Rapidly eliminated from the body, by

renal excretion (Proximal tubular renal excretion (Proximal tubular secretion)secretion)

Onset of action: 30-60 min after oral Onset of action: 30-60 min after oral administration or 2-5 min after IVadministration or 2-5 min after IV

Duration of action: PO-6 hours, 2-5 min IVDuration of action: PO-6 hours, 2-5 min IV

Thiazide DiureticsThiazide Diuretics

Low ceiling, flat dose responseLow ceiling, flat dose response Slow onset of effect, long duration of Slow onset of effect, long duration of

action (6-12 hours)action (6-12 hours) Reduce urine calciumReduce urine calcium Hydrochlorothiazide – sulfonamide Hydrochlorothiazide – sulfonamide

derivativederivative Indapamide – new thiazide like agent Indapamide – new thiazide like agent

with a significant vasodilating effect with a significant vasodilating effect

Potassium sparing diureticsPotassium sparing diuretics

Spirinolactone – aldosterone antagonist in the Spirinolactone – aldosterone antagonist in the collecting tubules has slow onset and offset collecting tubules has slow onset and offset of action (24-72 hours)of action (24-72 hours)

- direct inhibitor of aldosterone at steroid - direct inhibitor of aldosterone at steroid receptorreceptor

- Causes an increase in Na clearance & - Causes an increase in Na clearance & decrease in K excretiondecrease in K excretion

Amiloride and triamterene – inhibitors of Amiloride and triamterene – inhibitors of tubular potassium secretion, with 12-24 hrs tubular potassium secretion, with 12-24 hrs duration of actionduration of action

DIURETICS

Mechanism of Antihypertensive Effects of Diuretics

Decreased PVR

Reduction in body sodium

Decrease interstitial fluid volume

Fell in smooth muscle sodium concentration

Decrease in 1C calcium concentration

DIURETICS

Mechanism of Antihypertensive Effects of Diuretics

Decreased PVR

Reduction in body sodium

Decrease interstitial fluid volume

Fell in smooth muscle sodium concentration

Decrease in 1C calcium concentration

Diuretics and Potassium-Sparing AgentsAgent Daily Dosage

(mg)Duration of

Action(hour)

Thiazides

Bendroflumethiazide(Neturcun)

Benzthiazide (Aquata,Exna)

Chlorthiazide (Diuril)Cyclothiazide (Anhydron)

Hydrochlorothiazide(Esidrix, Hydrodiuril,

Oretic)Hydroflumethiazide

(Saluron)Methyclothiazide (Enduron)

Polythiazide (Renese)Trichlormethiazide

(Metahydrin Naqua)

2.5 - 5.0

12.5 - 50

125 - 5000.5 - 2

6.25 - 50

2.5 - 5.01 - 41 - 4

18

12 – 18

6 - 1218 – 24

12 – 18

18 – 24> 24

24 - 48

Related SulfonamidesCompounds

Chlorthalidone (Hygroton)Indapamide (Lozol)Metolazone (Zaroxolyn, Diulo)Quinethazone (Hydromox)

12.5 - 502.5

0.5 - 1024 - 100

24 - 722424

18 - 24

Loop Diuretics

Bumetanidc (Bumex)Ethacrynic acid (Edcecrin)Furosemide (Lasix)Torsemide (Demadex)

0.5 - 525 - 10040 - 480

5 - 40

4 - 6124.612

Potassuim-Sparing

Amiloride (Midamor)Spirinolactone (AIdactone)Triamterene (Dyrenium)

5 - 1024 - 10050 - 100

248 - 12

12

ToxicityToxicity

Potassium depletion (except K-sparing Potassium depletion (except K-sparing diuretics)diuretics)

Magnesium depletionMagnesium depletion Impair glucose toleranceImpair glucose tolerance Increase serum lipid concentrationIncrease serum lipid concentration Increase uric acid concentrationIncrease uric acid concentration

Rostral Ventrolateral

Medulla

Action of Centrally - Acting Antihypertensive AgentsAction of Centrally - Acting Antihypertensive Agents

Alpha-methyldopaGuanfacineGuanabenz

Clonidine MoxonidineRilmenidine

Alpha-adrenoceptor

Imidazoline receptor

SalivaryGlands

NucleusCoeruleus

NucleusTractus

Solitarius

SedationDry mouth

Inhibition of Sympathetic Nerve Activity

Inhibition of norepinephrine release

Decrease in vasoconstriction

Vasodilation

Lower Blood Pressure

MethyldopaMethyldopa

Mild to moderate hypertensionMild to moderate hypertension Decrease PVRDecrease PVR Extensive first pass metabolismExtensive first pass metabolism Effect 4-6 hours up to 24 hoursEffect 4-6 hours up to 24 hours Side effects: sedation, lactation, Side effects: sedation, lactation,

positive coombs testpositive coombs test

ClonidineClonidine Decrease cardiac output, HR and relaxation of Decrease cardiac output, HR and relaxation of

capacitance vessels, decrease PVRcapacitance vessels, decrease PVR Decrease renal vascular resistance & Decrease renal vascular resistance &

maintenance of RBFmaintenance of RBF 75% bioavailability75% bioavailability Half-life 8-12 hoursHalf-life 8-12 hours Lipid soluble, rapidly enters brain from Lipid soluble, rapidly enters brain from

circulationcirculation Toxicity: dry mouth, sedation, life threatening Toxicity: dry mouth, sedation, life threatening

HTN crisis in sudden withdrawalHTN crisis in sudden withdrawal

Ganglionic-blocking AgentsGanglionic-blocking Agents

Drugs that block stimulation of Drugs that block stimulation of postganglionic autonomic neurons by postganglionic autonomic neurons by AchAch

No longer available because of No longer available because of intolerable toxicities intolerable toxicities

Trimetaphan – prototype drug, given Trimetaphan – prototype drug, given IV, short-acting, that block the nicotine IV, short-acting, that block the nicotine receptorreceptor

Adrenergic Neuron Blocking Adrenergic Neuron Blocking AgentsAgents

Lower BP by preventing normal Lower BP by preventing normal physiologic release of norepinephrine physiologic release of norepinephrine from postganglionic sympathetic from postganglionic sympathetic neuronsneurons

GuanethidineGuanethidine BethanidineBethanidine GuanadrelGuanadrel DebrisoquinDebrisoquin reserpine reserpine

Reserpine Reserpine

Effective & safe for mild to moderate Effective & safe for mild to moderate HTNHTN

Enters BBBEnters BBB Causes depletion of central amines Causes depletion of central amines

sedation, mental depression & sedation, mental depression & parkinsonism symptomsparkinsonism symptoms

Lowers BP by decreased CO and PVRLowers BP by decreased CO and PVR Half-life 24-48 hoursHalf-life 24-48 hours

GuanethidineGuanethidine

Treatment of severe HTNTreatment of severe HTN MOA is associated with reduce CO due to MOA is associated with reduce CO due to

bradycardia & relaxation of capacitance bradycardia & relaxation of capacitance vesselsvessels

Half-life 5 days, bioavailability 3-50%Half-life 5 days, bioavailability 3-50% 50% cleared by the kidneys50% cleared by the kidneys Large volume of distributionLarge volume of distribution Too polar to enter the CNSToo polar to enter the CNS Has none of the central effectsHas none of the central effects toxicity: postural hypotension, retrograde toxicity: postural hypotension, retrograde

ejaculationejaculation

BETA – ADRENOCEPTOR BLOCKING DRUGSBETA – ADRENOCEPTOR BLOCKING DRUGS

Nonselective Selective With alpha-blocking ability

PindololPenbutololCarteololAlprenololDilevatolOxyprenolol

Nadolol PropranololTimololSotalolTetralol

AtenololEsmololMetoprololBevantololBisoprololBetaxolol

Acebutolol(Practolol)Celiprolol

LabetalolBucindololCarvedilol

PropranololPropranolol

Well absorbed orallyWell absorbed orally Extensive first pass metabolismExtensive first pass metabolism Rapidly distributed, large volume of Rapidly distributed, large volume of

distributiondistribution Half-life 3-6 hoursHalf-life 3-6 hours Dose: 80-480 mg/dayDose: 80-480 mg/day Toxicity: result from blockade of cardiac, Toxicity: result from blockade of cardiac,

vascular & bronchial beta receptorsvascular & bronchial beta receptors GIT side effectsGIT side effects Increase triglycerides & decrease HDLIncrease triglycerides & decrease HDL

Mechanism of ActionMechanism of ActionMechanism of ActionMechanism of Action

Decreased angiotensin II

Beta-adrenoceptor blockers

Decrease activation of B1 adrenoceptors on heart

Decreased cardiac output

Decreased Blood Volume

Decreased renin

Decrease aldosteroneDecrease PVR

Dec. Na+, H2O retention

Decreased Blood Volume

Decreased in Blood Pressure

Alpha-adrenergic AntagonistsAlpha-adrenergic Antagonists

Reduce arterial pressure by dilating both Reduce arterial pressure by dilating both resistance and capacitance vesselsresistance and capacitance vessels

Cause sympathetically mediated reflex Cause sympathetically mediated reflex increase in HR & plasma renin activityincrease in HR & plasma renin activity

Long-term therapy: vasodilatation persists, Long-term therapy: vasodilatation persists, but CO, HR & plasma renin activity return to but CO, HR & plasma renin activity return to normalnormal

Selective: prazosin, terazosin, doxazosinSelective: prazosin, terazosin, doxazosin Non-selective: phentolamine, Non-selective: phentolamine,

phenoxybenzamine phenoxybenzamine

Prazosin, terazosin, Prazosin, terazosin, doxazosindoxazosin Half-life 3-4 hrs (prazosin)Half-life 3-4 hrs (prazosin) Extensively metabolized but undergoes Extensively metabolized but undergoes

very little first-pass metabolism, half-life 12 very little first-pass metabolism, half-life 12 hours, given OD (terazosin)hours, given OD (terazosin)

Doxazosin has intermediate bioavailability, Doxazosin has intermediate bioavailability, half-life 22 hours, given once a day half-life 22 hours, given once a day

Toxicity: first dose phenomenon, dizziness, Toxicity: first dose phenomenon, dizziness, palpitation, headache & lassitude, positive palpitation, headache & lassitude, positive serum Antinuclear factor (prazosin)serum Antinuclear factor (prazosin)

Mechanism of Action-Mechanism of Action-VasodilatorsVasodilators

Inhibition of calcium influx into arterial Inhibition of calcium influx into arterial smooth muscle cells smooth muscle cells relax smooth muscle relax smooth muscle of arterioles of arterioles decreasing systemic vascular decreasing systemic vascular resistance resistance decrease arterial pressure decrease arterial pressure

direct arterial dilation triggers baroreceptor, direct arterial dilation triggers baroreceptor, svmpathetic activation resulting in svmpathetic activation resulting in tachycardia, increase cardiac output, increase tachycardia, increase cardiac output, increase myocardial oxygen demandmyocardial oxygen demand

cause significant fluid retentioncause significant fluid retention work best in combination with other work best in combination with other

antihypertensive drugs (anti-adrenergic & antihypertensive drugs (anti-adrenergic & diuretics) to overcome untoward effectsdiuretics) to overcome untoward effects

Oral Vasodilators Oral Vasodilators HydralazineHydralazine

dilate arterioles but not veinsdilate arterioles but not veins effective in severe HTNeffective in severe HTN well absorbed from GITwell absorbed from GIT systemic bioavailability is lowsystemic bioavailability is low half-life 1 hourhalf-life 1 hour duration of action 12 hoursduration of action 12 hours toxicity: immunological reactions, drug-toxicity: immunological reactions, drug-

induced lupus syndrome, serum sickness, induced lupus syndrome, serum sickness, hemolytic anemia, vasculitis & rapidly hemolytic anemia, vasculitis & rapidly progressive glomerulonephritisprogressive glomerulonephritis

MinoxidilMinoxidil

Metabolized by hepatic Metabolized by hepatic sulfotransferase to the active sulfotransferase to the active molecule, minoxidil N-O sulfatemolecule, minoxidil N-O sulfate

Well absorbedWell absorbed Half-life 3-4 hoursHalf-life 3-4 hours Duration of action 24 hours or longerDuration of action 24 hours or longer Toxicity: fluid and salt retention, Toxicity: fluid and salt retention,

hypertrichosishypertrichosis

Parenteral VasodilatorsParenteral VasodilatorsNitroprussideNitroprusside

Dilates both arterial and venous vesselsDilates both arterial and venous vessels Used in treating hypertensive emergencies, Used in treating hypertensive emergencies,

severe heart failuresevere heart failure Rapidly lowers BPRapidly lowers BP Given by IV infusionGiven by IV infusion Effects disappear within 1-10 min after Effects disappear within 1-10 min after

discontinuationdiscontinuation Eliminated by the kidneyEliminated by the kidney Toxicity: metabolic acidosis, arrhythmia, Toxicity: metabolic acidosis, arrhythmia,

hypotension, death, thiocyanate poisoning, hypotension, death, thiocyanate poisoning, delayed hypothyroidism, methemoglobinemiadelayed hypothyroidism, methemoglobinemia

DiazoxideDiazoxide

Arteriolar dilator – hyperpolarizes Arteriolar dilator – hyperpolarizes arterial muscle cells by activating ATP arterial muscle cells by activating ATP sensitive K channels, this cause sensitive K channels, this cause relaxation of the vascular smooth relaxation of the vascular smooth musclemuscle

Used to treat hypertensive Used to treat hypertensive emergenciesemergencies

Toxicity: hypotensionToxicity: hypotension

FenoldepamFenoldepam Newer peripheral arteriolar dilatorNewer peripheral arteriolar dilator Acts primarily as an agonist to dopamine Acts primarily as an agonist to dopamine

D1 receptors, resulting in dilatation of D1 receptors, resulting in dilatation of peripheral arteries and natriuresisperipheral arteries and natriuresis

Administered by IV infusionAdministered by IV infusion Half-life 10 minsHalf-life 10 mins Toxicity: reflex tachycardia, headache, Toxicity: reflex tachycardia, headache,

flushing, increased intraocular pressureflushing, increased intraocular pressure

Calcium Channel BlockersCalcium Channel Blockers

Dilate peripheral arteriolesDilate peripheral arterioles Dihydropyridines more selective as Dihydropyridines more selective as

vasodilatorvasodilator less cardiac depressant effectsless cardiac depressant effects Verapamil greatest effect on heart, Verapamil greatest effect on heart,

decrease heart rate and cardiac outputdecrease heart rate and cardiac output

Adverse EffectsAdverse Effects

Nifedipine: Nifedipine: 17 - 20% of patients 17 - 20% of patients

- hypotension, headache, peripheral edema- hypotension, headache, peripheral edema

Verapamil: Verapamil: 17 - 20% of patients 17 - 20% of patients

- cardiodepression (major), hypotension, - cardiodepression (major), hypotension, peripheral edema (moderate), headache, peripheral edema (moderate), headache, constipation (minor)constipation (minor)

Diltiazem: Diltiazem: 2 - 5% of patients 2 - 5% of patients

- hypotension, peripheral edema, AV block, - hypotension, peripheral edema, AV block, cardiodepressioncardiodepression

ANGIOTENSIN - CONVERTING ENZYME (ACE) INHIBITORS

Mechanism of Action

Reduction of circulating levels of Angiotensin II

Decrease aldosterone secretion; blunts increased in sympathetic activity

Direct inhibition of vascular hypertrophy

Enhance endothelium dependent relaxation

Inhibits the degradation of bradykinin – vasodilator, weak anti-aggregant peptide, enhances synthesis of vasodilatory prostaglandins

Vasodilation

Decrease peripheral vascular resistance

Decrease blood pressure

Various ACE inhibitorsVarious ACE inhibitorsDrug Dosage (min-

max)Administration Elimination

Benazepril 5 - 40 o.d. Renal

Captopril 12.5 - 150 t.i.d. Renal

Cilazapril 5 - 10 o.d. Renal

Enalapril 5 - 40 b.i.d. Renal

Fosinopril 10 - 40 o.d. Renal & hepatic

Lisinopril 5 - 40 o.d. Renal

Moexipril 7,5 - 30 o.d. Renal

Perindopril 1 - 16 o.d. Renal

Qninapril 5 - 80 o.d. Renal

Ramipril 1.25 - 20 o.d. Renal

Tandolapril 1 - 4 b.d. Renal

Spirapril 12.5 - 50 o.d. Hepatic

CaptoprilCaptopril

Rapidly absorbedRapidly absorbed Bioavalability 70% with fasting, 30-Bioavalability 70% with fasting, 30-

40% with food40% with food Half-life < 3 hoursHalf-life < 3 hours Metabolized to disulfide conjugatesMetabolized to disulfide conjugates Eliminated in kidneyEliminated in kidney HTN in DM – diminish proteinuria & HTN in DM – diminish proteinuria &

stabilize renal function stabilize renal function

ToxicityToxicity Severe hypotension Severe hypotension Acute renal failure Acute renal failure

Hyperkalemia Hyperkalemia Dry cough sometimes with wheezing & angioedemaDry cough sometimes with wheezing & angioedema

ContraindicationsContraindications 2nd & 3rd trimester of pregnancy2nd & 3rd trimester of pregnancy

Drug interactionDrug interaction Potassium supplements Potassium supplements

Potassium - sparing diureticsPotassium - sparing diuretics NSAIDsNSAIDs

ANGIOTENSIN II RECEPTOR -ANGIOTENSIN II RECEPTOR -BLOCKING AGENTSBLOCKING AGENTS

bind selectively to AT1 receptors and displace bind selectively to AT1 receptors and displace angiotensin II angiotensin II

blockers of the angiotensin II type 1 (AT1) blockers of the angiotensin II type 1 (AT1) receptorreceptor

1st drugs marketed: losartan, valsatran1st drugs marketed: losartan, valsatran candesartan, eprosartan, irbesartan, & candesartan, eprosartan, irbesartan, &

telmisartan - no effect on bradykinin telmisartan - no effect on bradykinin metabolism metabolism more selective blockers of more selective blockers of angiotensin effectsangiotensin effects

SE: similar to ACE inhibitors but less cough and SE: similar to ACE inhibitors but less cough and angioedemaangioedema