T herapy of hypertension1

Florencia G. dela Cruz-Munsayac, MD, FPSECP, MBA, RMT

Hypertension

most common cardiovascular disease

Prevalence: increases with advancing age

Causes pathological changes in the vasculature with endothelial dysfunction, hypertrophy of the LV & propensity for atherosclerosis

Principal cause of stroke

Major risk factor for coronary artery disease (MI & sudden cardiac death)

Major contributor to cardiac failure, renal insufficiency & dissecting aortic aneurysm

Hypertension

Defined as sustained increase in BP > 140/90 mmHg

Sustained arterial HTN damages blood vessels in heart, kidney & brain

Leads to incidence of renal failure, coronary disease, cardiac failure, & stroke

Normal Regulation of Blood Pressure

ABP = cardiac output x peripheral vascular resistance

Regulating the volume of intravascular fluid

Baroreflexes, act in combination with RAAS

Local release of vasoactive substances from vascular endothelium

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

Pressure Category SBP (mmHg) DBP (mmHg)

Normal < 120 < 80

Pre-hypertension 120 - 139 80 - 89

Hypertension Stage 1 140 - 159 90 – 99

Stage 2 > / = 160 > / = 100

Etiology of Hypertension

A. Primary HypertensionA. Primary Hypertension

1. Abnormal cardiac & peripheral hemodynamics 2. Impaired pressure natriuresis3. Baroreceptor resetting4. Abnormalities in the renin-angiotensin-

aldosterone system5. Abnormalities in other vasoregulatory systems

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

Etiology of Hypertension

B. Secondary Hypertension

1. Renovascular hypertension2. Renal parenchymal diseases

a. Altered excretory functionb. Altered renin-angiotensin-aldosterone activity

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

Genetic influences + Environmental FactorsDefects in renal Na+ Functional Defects in vascular hemostasis vasoconstriction smooth muscle

growth & structure

Inadequate Na+ excretion

Salt & H2O retention

Plasma & ECF vol vascular vascular wall thickness

reactivity Cardiac output

TPR

HYPERTENSION

Principles of Antihypertensive Therapy

Stage 1 HTN Weight reduction Restricting sodium intake Increasing aerobic exercise Moderating consumption of alcohol

Stage 2 HTN Non-pharmacological approach Drugs

Classification of Antihypertensive Drugs

A. Diuretics1. Thiazides & related agents (hydrochlorothiazide, chlorthalidone)2. Loop diuretics (Furosemide, Bumetanide, torsemide, ethacrynic acid)3. Potassium Sparing diuretics (Triamterene, Spirinolactone, Amiloride)

B. Sympatholytic Agents1. Centrally Acting Agents

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

guanfacineb. Acting on imidazoline receptor (Second Generation)

- moxonidine, rilmenidine2. Adrenergic Neuron Blocking Agents (reserpine, guanethidine, guanadrel)3. Beta-adrenergic Antagonists (propranolol, metaprolol, atenolol, pindolol, acebutolol, bisoprolol)4. Alpha-adrenergic Antagonists (prazocin, terazocin, doxazocin, phenoxybenzamine, phentolamine)5. Mixed Adrenergic Antagonists (labetalol, carvedilol)

Classification of Antihypertensive Drugs

C. Vasodilators1. Arterial (hydralazine, minoxidil, diazoxide, fenoldepam)2. Arterial & venous (nitroprusside)3. Calcium Channel Blockers

- Dihydropyridines - nifedipine, amlodipine, felodipine. nimodipine, nicardipine, isradipine, licidipine - Phenylalkylamines - verapamil- Benzothiazepines – diltiazem

D. Angiotensin Converting Enzyme Inhibitors (captopril, qiunapril, enalapril, perindopril, lisinopril, ramipril, benazepril, fosinopril, moexipril, trandolapril)

E. Angiotensin 11 Antagonists (losartan, valsartan, candesartan, irbesartan, telmisartan, eprosartan)

Diuretics: Mechanisms of Action & Hemodynamic Effects

Lower BP primarily by depleting body sodium stores

Initially: BP by reducing BV & CO; PVR may increase

After 6-8 weeks: normal CO; PVR

Effective in lowering BP by 10-15 mmHg

Provide adequate treatment for mild to moderate essential HTN

Diuretics: Mechanisms of Action & Hemodynamic Effects

Reduction in body sodium

Decreased interstitial Decreased IC Ca++ concentration fluid volume

Decreased BV Reduced vasoconstriction

Decrease PVR

Decrease BP

Diuretics: Benzothiadiazine & Related Compounds

Inhibit NaCl transport predominantly in the DCT

Slow onset of action, long duration of action (6-12 hours)

Chlorothiazide Not very lipid-soluble Available in parenteral administration

Chlorthalidone Slowly absorbed Has longer duration of action

Hydrochlorothiazide Prototype drug

Indapamide New thiazide like agent with a significant vasodilating effect

Diuretics: Benzothiadiazine & Related Compounds

Side effects & Precautions: K+ wasting Inhibition of uric acid excretion Inhibit renal Ca++ excretion Associated with some changes in plasma lipids

about 5-15% increase Impaired glucose tolerance Hyponatremia Impotence Allergic reactions

Diuretics: Loop diuretics

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

most potent diuretics in clinical use, in patients with severe edema & azotemia

Are frequently & inappropriately prescribed as once-a-day medication in the treatment of HTN, CHF & ascites → should be given twice a day

Furosemide & ethacrynic acid (phenoxyacetic acid derivative) – prototypical drugs

Bumetanide & torsemide – sulfonamide loop diuretics

Diuretics: Loop diuretics Pharmacokinetics:

Rapidly absorbed Torsemide – 1 hour Furosemide – 2-3 hours

Onset of action: Oral furosemide – 30-60 minutes I V furosemide – 2-5 minutes

Duration of action: Torsemide – 4-6 hours Furosemide – 2-3 hours; 2-5 minutes, I V

Eliminated by the kidney

Diuretics: Loop diuretics

Toxicity: Hypokalemia Ototoxicity Hyperuricemia Hypocalcemia Hypomagnesemia Allergic reactions

Diuretics: Potassium-sparing diuretics

Reduce Na+ absorption in the collecting tubules & ducts

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

- direct inhibitor of aldosterone at steroid receptor

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

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

Diuretics: Potassium-sparing diuretics

Adverse effects: BPH, impotence, gynecomastia & menstrual

irregularities (spirinolactone) Hyperkalemia Acute renal failure (triamterene + indomethacin) Kidney stone (triamterene)

Drug Interactions: K+ containing salt substitutes ACE inhibitors Angiotensin-receptor antagonists NSAIDs

Sympatholytic Agents – β-Adrenergic Receptor Antagonists

Mechanisms of Action:Beta-adrenoceptor blockers

Decrease activation of B1 adrenoceptors on heart decreased renin

Decreased cardiac output decreased angiotensin II

Decreased Blood Volume decreased PVR decreased aldosterone

Dec. Na+, H2O retention

Decreased Blood Volume

Decreased in Blood Pressure


BETA – ADRENOCEPTOR BLOCKING DRUGS

Nonselective

SelectiveWith alpha-blocking

ability

Nadolol PropranololTimololSotalolTetralol

PindololPenbutololCarteololAlprenololDilevatolOxyprenolol

AtenololEsmololMetoprololBevantololBisoprololBetaxolol

Acebutolol(Practolol)Celiprolol

LabetalolBucindololCarvedilol

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsPropranolol

Well absorbed orally

Extensive first pass metabolism

Rapidly distributed, large volume of distribution

Half-life: 3-6 hours

Dose: 80-480 mg/day

Toxicity: result from blockade of cardiac, vascular & bronchial beta receptors

GIT side effects

Increase triglycerides & decrease HDL

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsMetoprolol

50 – 100 fold less potent than propranolol

Its relative cardio-selectivity may be advantageous in treating hypertensive patients who also suffer from asthma, diabetes or peripheral vascular disease

T1/2: 3 – 7 hours

Bioavailability: 40%

Dose: 50 – 100 mg

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsNadolol, Carteolol, Atenolol, Betaxolol, & Bisoprolol

Nadolol & carteolol – non-selective beta receptor antagonists

Atenolol – beta1 selective blocker Not appreciably metabolized

Excreted in the urine

Betaxolol & bisoprolol – beta1 selective blockers Primarily metabolized in the liver

Have long half-lives

Administered once a day

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsPindolol, Acebutolol, & Penbutolol

Are partial agonists

Lower BP by decreasing vascular resistance, CO & HR less than other beta blockers → greater agonist than antagonist effects at beta2 receptors

Beneficial for patients with brady-arrhythmias, or peripheral vascular disease

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsLabetalol & Carvedilol

Labetalol is formulated as a racemic mixture of four isomers (S,S)- & (R,S)-isomers – are relatively inactive

(S,R) – is a potent blocker

(R,R) – is a potent β blocker → selective β2 agonist & non-selective β antagonist action

has 3:1 ratio of β: antagonism after oral dosing

BP is lowered by reduction of systemic vascular resistance without significant alteration in HR or CO

Effective in treating pheochromocytoma & hypertensive emergencies = 20-80 mg I V bolus

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsLabetalol & Carvedilol

Carvedilol - administered as racemic mixture S(-) isomer is a non-selective β-adrenoceptor blocker

both S(-) & R(+) isomers have equal blocking potency

Metabolized in the liver

Average t1/2: 7 – 10 hours

Sympatholytic Agents – β-Adrenergic Receptor AntagonistsEsmolol

Is a β1 selective blocker

Rapidly metabolized via hydrolysis by red blood cell esterases

Short t1/2: 9 – 10 minutes

Administered by constant I V infusion

Used for management of intra-operative & postoperative hypertension, associated with tachycardia


Pharmacological Effects: Effective as antihypertensive agents Drugs with ISA produces lesser decreases in HR &

CO

Adverse Effects & Precautions: Beta blockers without ISA - triglycerides &

HDL cholesterol SA or AV nodal dysfunction Asthma Produce withdrawal syndrome


Drug interactions: Indomethacin Epinephrine

Sympatholytic Agents – 1- Adrenergic Antagonists

Initially: reduce arteriolar resistance & venous capacitance → causes sympathetically mediated reflex in HR & plasma renin activity

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

Cause variable amount of postural hypotension & syncope (first dose effect)

Retention of salt occurs


reduce plasma concentrations of triglycerides & LDL cholesterol & HDL cholesterol

More effective when used in combination with beta blockers and diuretics

Attractive drugs for hypertensive patients with BPH


Prazosin (Minipress) Prototype drug Well absorbed after oral administration Bioavailability: 50-70% Plasma concentration: 1-3 hours Tightly bound to plasma proteins Extensively metabolized in the liver Excreted by the kidneys T1/2: 2-3 hrs; 6-8 hours (CHF) Duration: 7-10 hours


Terazosin (Hytrin)Less potent than prazosinBioavailability: 90%Half time of elimination: 12 hoursDuration: 18 hours

DoxazosinT1/2: 36 hoursMetabolites eliminated in the feces

Sympatholytic Agents – Non-selective Adrenergic Antagonists

Are useful in diagnosis & treatment of pheochromocytoma & other clinical situations associated with exaggerated release of catecholamines

Phenoxybenzamine Blocks alpha 1 & 2 receptors irreversibly T1/2: less than 24 hours

Phentolamine An imidazoline, a competitive alpha receptor

antagonist

Sympatholytic Agents – Centrally-Acting Agents

Mechanisms & Sites of Action:

MethyldopaGuanfacineguanabenz

clonidine MoxonidineRilmenidine

Alpha-adrenoreceptor

Imidazoliine receptor

NucleusTractus

solitarius

Salivary

glands

Dry mouth

Nucleuscoeruleu

s

Sedation

Rostral Ventrolatera

lmedulla

Inhibition of Sympathetic Nerve Activity

Inhibition of norepinephrine release

Decrease in vasoconstriction

Vasodilation

Lower BP

Sympatholytic Agents – Centrally-Acting AgentsMethyldopa

Analog of L-dopa

Converted to -methyldopamine & - methylnorepinephrine

→ stored in adrenergic nerve vesicle → released by nerve stimulation

Antihypertensive action: Acts in the CNS to inhibit adrenergic neuronal outflow

from the brainstem Acts as agonist at pre-synaptic alpha2 adrenergic

receptors attenuating NE release Reducing output of vasoconstrictor adrenergic signals to

the peripheral sympathetic NS


Pharmacological Effects: Reduces vascular resistance without causing much change

in CO, or HR in young patients

In older patients, CO may be as a result of HR & stroke volume → relaxation of veins & reduction in preload

Well tolerated during surgical anesthesia

Reduced renin secretion

Causes salt & water retention → overcome with concurrent use of a diuretic


Absorption, Metabolism, & Excretion: Metabolized in the brain

Absorbed by an active amino acid transporter orally

Peak plasma concentration: 2-3 hours

Peak effect: 6-8 hours (oral & I V)

T1/2: 2 hours; 4-6 hours in renal failure

Duration of action: 24 hours

Excreted in urine as sulfate conjugate


Adverse Effects & Precautions: Sedation Depression Dryness of the mouth Reduction in libido, parkinsonian signs,

hyperprolactenemia Severe bradycardia & sinus arrest Hepatotoxicity Hemolytic anemia Positive Coomb’s test

Sympatholytic Agents – Centrally-Acting AgentsClonidine, Guanabenz, & Guanfacine

Stimulate the 2A subtype of 2 adrenergic receptor in the brain stem → reduction in the sympathetic outflow from the CNS

Pharmacological Effects: Lower BP by an effect on both CO & peripheral

resistance in sympathetic tone → cardiac contractility & HR

Pharmacokinetics: Lipid-soluble, rapidly enters brain circulation Short t1/2 Preparation:

oral clonidine given b.i.d, transdermal preparation


Adverse Effects & Precautions: Sedation & xerostomia (dry nasal mucosa, dry eyes,

& parotid gland swelling & pain)

Postural hypotension & erectile dysfunction

Sleep disturbances with vivid dreams or night mares, restlessness & depression

Bradycardia

Contact dermatitis

Withdrawal syndrome


Drug Interactions:

Tricyclic antidepressants

Sympatholytic Agents – Adrenergic Neuron Blocking Agents

Lower BP by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons Guanethidine Bethanidine Guanadrel Debrisoquin Reserpine

Sympatholytic Agents – Adrenergic Neuron Blocking Agents Guanadrel

Pharmacokinetics: Rapidly absorbed Maximal plasma levels: 1-2 hours Maximum effect: 4–5 hours T1/2: 5-10 hours Administered b.i.d Excreted by renal & non-renal disposition

Adverse Effects: Hypotension Retrograde or delayed ejaculation Diarrhea

Sympatholytic Agents – Adrenergic Neuron Blocking Agents Guanadrel

Drug Interactions: Tricyclic antidepressant Cocaine Chlorpromazine Ephedrine Phenylpropanolamine Amphetamine

Sympatholytic Agents – Adrenergic Neuron Blocking Agents Reserpine

An alkaloid extracted from the root of Rauwolfia serpentina

Effective & safe for mild to moderate HTN

Pharmacological Effects: HR & renin secretion fall

Lowers BP by decreased CO and PVR

Causes depletion of central amines sedation, mental depression & parkinsonism symptoms

Half-life 24-48 hours

Sympatholytic Agents – Adrenergic Neuron Blocking Agents Reserpine

Pharmacokinetics:Enters BBB

Toxicity & Precautions:Sedation, inability to concentrate or performPsychotic depressionNasal stiffnessExacerbation of PUD

Sympatholytic Agents – Adrenergic Neuron Blocking Agents Guanethidine

Mainstay of outpatient therapy of severe hypertension

MOA is associated with reduce CO due to relaxation of capacitance vessels

Half-life: 5 days

Bioavailability: 3-50%

50% cleared by the kidneys

Too polar to enter the CNS

Has none of the central effects

Toxicity: postural hypotension, retrograde ejaculation

Angiotensin-Converting Enzyme Inhibitors

Mechanisms & Sites of Action: Na+ concentration in the distal tubule → release of

renin from kidney cortex → angiotensinogen → inactive decapeptide angiotensin I → endothelial ACE → octapeptide angiotensin II → angiotensin III (adrenal gland)

Angiotensin II – potent vasoconstrictor with sodium-retaining activity

Angiotensin II & III – stimulate aldosterone release

Inhibit the converting enzyme peptidyl dipeptidase that hydrolyses angiotensin I to angiotensin II & inactivates the bradykinin, a potent vasodilator → release of NO & prostacycline


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


Pharmacological Effects: Inhibit the conversion of the relatively inactive

angiotensin I to the active angiotensin II

Principal pharmacological & clinical effect: suppression of synthesis of angiotensin II

bradykinin levels → stimulates PG synthesis

circulating levels of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline → contribute to cardioprotective effects of ACE inhibitors


Clinical Pharmacology: Classified into 3 broad groups

Sulfhydryl-containing ACE inhibitors structurally related to captopril

Fentiapril, pivalopril, zofenopril, alacepril

Dicarboxyl-containing ACE inhibitors structurally related to enalapril

Lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, spirapril, perindopril, pentopril, cilazapril

Phosphorus-containing ACE inhibitors structurally related to fosinopril

fosinopril


Clinical Pharmacology: ACE inhibitors differ with regard to 3

properties: Potency

Whether ACE inhibition is primarily a direct effect of the drug itself or the effect of an active metabolite

Pharmacokinetics (extent of absorption, effect of food on absorption, plasma half-life, tissue distribution, & mechanisms of elimination)


Drug Dosage (min-max) Administration Elimination

Benazepril 5 - 40 o.d. RenalCaptopril 12.5 – 150 t.i.d. RenalCilazapril 5 - 10 o.d. RenalEnalapril 5 - 40 b.i.d. RenalFosinopril 10 – 40 o.d. Renal &

hepaticLisinopril 5 - 40 o.d. RenalMoexipril 7.5 – 30 o.d. Renal Perindopril 1 - 16 o.d. RenalQninapril 5 - 80 o.d. RenalRamipril 1.25 – 20 o.d. RenalTandolapril 1 - 4 b.i.d. RenalSpirapril 12.5 – 50 o.d. Hepatic


Drugs Metabolites Bioavailability Peak Plasma Concentration

Half-life

Captopril Disulfide dimers & cysteine disulfide

75% 1 hour 2 hours

Enalapril Enalaprilat 60% * 1 hrs / 3-4hrs 1.3 hrs / 11 hrs

Lisinopril-lysine analog of enalaprilat

25% * 7 hours 12 hours

Benazepril BenazeprilatGlucuronide conjugates

35% 0.5-1 hr / 1-2 hours

10-11 hours benazeprilat

Fosinopril FosinoprilatGlucoronide conjugate

3 hoursFosinoprilat

11.5 hoursFosinoprilat

Trandolapril Trandolaprilat 10% / 70% 4-10 hourstrandolaprilat

Quinapril Quinaprilat 1hour / 2 hours 2 hours / 25 hours

Pamipril Ramiprilat 1 hour / 3 hours

Moexipril Moexiprilat 13% 1.5 hours

Perindopril perindoprilat 75% / 35% * 3-7 hoursperindoprilat


All are prodrugs

All are absorbed from the GIT, reduced by food except: enalapril, lisinopril, perindropril

Enalapril, the only ACEI given I V

Converted to active agents by hydrolysis in the liver

Indications: chronic kidney disease, heart failure, post MI, reduce incidence of diabetes in patients with high

cardiovascular risk


Adverse Effects: Hypotension Cough Hyperkalemia Acute Renal Failure Fetopathic Potential Skin rash Proteinuria Angiodema Dysgeusia Neutropenia Glycosuria Hepatotoxicity


Drug Interactions: Antacids Capsaicin NSAIDs K+-sparing diuretics K+ supplements Digoxin & lithium Allopurinol

AT1 Angiotensin II Receptor Antagonists

Losartan Candesartan Irbesartan Valsatran Telmisartan Eprosartan Omesartan

These agents relax smooth muscle & thereby promote vasodilation, increase renal salt & water excretion, reduce plasma volume, & decrease cellular hypertrophy

Prevent ACE-mediated degradation of bradykinin & substance P


Pharmacological Effects: bind selectively to AT1 receptors and displace

angiotensin II

blockers of the angiotensin II type 1 (AT1) receptor

The rank-order of the AT1 receptor for ARBs is candesartan = omesartan > irbesartan = eprosartan > telmisartan = valsartan = EXP 3174 (active metabolite of losartan) > losartan


Drugs Peak Plasma Concentrati

on

Plasma Half-life

Metabolite Elimination

Candesartan Cilexetil

3-4 hours 9 hours Candesartan Renal & biliary

Eprosartan 1-2 hours 5-9 hours Glucuronide conjugate

Renal & biliary

Irbisartan 1.5-2 hours 11-15 hours Glucuronide conjugate

Renal & biliary

Losartan 1-3 hours 2.5 & 9 hours

EXP 3174 Renal & hepatic

Olmesartan medoxomil

1.4-2.8 hours

Between 10 & 15 hours

Olmesartan Renal & biliary

Telmisartan 0.5-1 hour 24 hours Biliary

Valsartan 2-4 hoours 9 hours liver


Adverse EffectsHypotensionHyperkalemia

Precautions:Reduced renal function pregnancy

Vasodilators Mechanisms & Sites of Action:

Relaxation of smooth muscle of arterioles decreasing systemic vascular resistance decrease arterial pressure

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

cause significant fluid retention

work best in combination with other antihypertensive drugs (anti-adrenergic & diuretics) to overcome untoward effects

Vasodilators

Hydralazine Causes direct relaxation of arteriolar

smooth muscle → may involve a fall in IC Ca++ concentration

Associated with powerful stimulation of the sympathetic NS, due to baroreceptor- mediated reflexes → results in HR, contractility, plasma renin activity & fluid retention

All of these counteract the antihypertensive effects of hydralazine

Vasodilators

HydralazinePharmacologic Effects:

The decrease in BP is associated with a selective decreases in vascular resistance in the coronary, & renal circulations, with a smaller effect in skin & muscle

Equally lowers BP in the supine & upright positions

Vasodilators

Hydralazine Absorption, Metabolism & Excretion:

Absorbed through GIT

Systemic bioavailability: less than 25%

T1/2: 1 hour

Peak plasma concentration: 30-120 minutes

Duration of action: 12 hours

Vasodilators

HydralazineToxicity & Precautions:

Headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, & angina pectoris

Salt retention, high-output congestive HF

Immunological reactions: drug-induced lupus syndrome, serum sickness, hemolytic anemia, vasculitis, & rapidly progressive glomerulonephritis

Vasodilators

K+ ATP Channel Openers: Minoxidil

Mechanisms of Action: Minoxidil N-O Sulfate, the active metabolite

relaxes vascular smooth muscle → activates ATP-modulated K+ channel → by opening K+ channels → permitting K+ efflux → hyperpolarization & relaxation of smooth muscle

Vasodilators


Pharmacological Effects: Produces arteriolar vasodilation

Increases blood flow to the skin, skeletal muscle, GIT, & heart more than to the CNS

Associated with reflex increase in myocardial contractility & CO

A potent stimulator of renin secretion, mediated by renal sympathetic stimulation & activation of the intrinsic renal mechanisms for regulation of renin release

Vasodilators


Absorption, Metabolism & Excretion: Well absorbed from the GIT

Peak concentration: 1 hour

20% is excreted unchanged in the urine

Main route of elimination is hepatic metabolism

Vasodilators


Adverse Effects & Precautions: Fluid & salt retention CV effects Hypertricosis

Vasodilators

Diazoxide An effective & relatively long-acting

parenterally administered arteriolar dilator

Results in rapid fall in systemic vascular resistance and mean ABP

Associated with tachycardia & CO

It prevents muscular smooth muscle contraction by opening K+ channels & stabilizing the membrane potential at the resting level

Vasodilators

Diazoxide Pharmacokinetics:

Bound extensively to albumin Partially metabolized T1/2: 24 hours Onset of action: 5 minutes Duration of action: 4-12 hours

Toxicity: Hypotension Inhibits insulin release Renal salt & water retention

Vasodilators

Fenoldepam A peripheral arteriolar dilator

Acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries & natriuresis

Rapidly metabolized

T1/2: 10 minutes

Administered by continuous I V infusion

Toxicities: reflex tachycardia, headache, flushing, increases IOP → should be avoided in glaucoma

Vasodilators

Sodium Nitroprusside Mechanism of Action:

Is a nitrovasodilator that acts by releasing NO → activates the guanylyl cylase-cyclic GMP-PKG pathway → vasodilation

Pharmacological Effects: Dilates both arteriolar & venules

Usually causes only modest in HR & reduction in myocardial O2 demand

Plasma renin activity increases

Vasodilators Sodium Nitroprusside

Absorption, Metabolism & Excretion: Decomposes under strongly alkaline conditions or when

exposed to sunlight

Given by continuous I V infusion

Onset of action: 30 seconds

Peak action: 2 minutes

When infusion is stopped, the effect disappears within 3 minutes

Metabolism is initiated by its reduction, followed by release of cyanide & NO. Cyanide is further metabolized in the liver rhodanase to thiocyanate → elimination half-time: 3 days

Vasodilators

Sodium Nitroprusside Toxicity & Precautions:

Hypotension Lactic acidosis Death thiocyanate poisoning delayed hypothyroidism methemoglobinemia

Vasodilators Calcium Channel Antagonists

MOA: inhibition of calcium influx into arterial smooth muscle cells

Dilate peripheral arterioles

Dihydropyridines: more selective as vasodilator

less cardiac depressant effects

Verapamil greatest effect on heart, decrease heart rate and cardiac output

Vasodilators

Calcium Channel Blocker: Pharmacokinetics

Absorption is nearly complete after oral administration

Reduced bioavailability → first pass hepatic metabolism

Effects are evident within 30 - 60 minutes of an oral dose, except slowly absorbed & longer acting agents (amlodipine, isradipine & felodipine); 15 minutes for I V verapamil

70-98% protein bound

Vasodilators

Calcium Channel Blocker: Pharmacokinetics

Elimination t1/2 – 1.3 - 64 hours

Major metabolite of diltiazem is desacetyldiltiazem, which has ½ of diltiazem’s potency as vasodilator

N-Demethylation of verapamil results in production of norverapamil (t1/2: 10 hours), which is biologically active but much less potent than the parent compound

Metabolites of dihydropyridines are inactive or weakly active

Vasodilators

Calcium Channel Antagonists Side Effects

Nifedipine: 17 - 20% of patients - hypotension, headache, peripheral edema

Verapamil: 17 - 20% of patients - cardiodepression (major), hypotension,

peripheral edema (moderate), headache, constipation (minor)

Diltiazem: 2 - 5% of patients - hypotension, peripheral edema, AV block,

cardio-depression

Calcium Channel Blocking DrugsDrugs Indication Dose Toxicity

Dihydropyridine group

Amlodipine Angina, HTN 5-10mg HA, peripheral edema

Felodipine HTN, CHF 5-10mg HA, dizziness

Isradipine HTN 2.5-10mg HA, fatigue

Nicardipine Angina, HTN, CHF 20-40mg Peripheral edema, HA, dizziness

Nifedipine Angina, HTN, migraine, CMP, Raynaud’s phenomenon

20-40mg q 8 hrs Hypotension, dizziness, flushing, edema, nausea, Constipation,

Nimodipine SAH, migraine 60mg q 4 hrs Headache, LBM

Nisoldipine HTN 20-40mg q 8 h Same as nifedipine

Niterndipine angina 20mg od/bid Same as nifedipine

Misc. Bepridil angina 200-400mg od Arrhythmia, nausea, dizziness

Diltiazem Angina, HTN 75-150ug/kg IV30-80mg q 6 hrs

Dizziness, flushing, nausea

Verapamil angina, HTN, arrhythmia, migraine, CMP

75-150ug/kg IV80-160mg q 8 hrs

Hypotension, cardiac depression, edema

Documents

T herapy of hypertension1