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T herapy of hypertension1
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Transcript of 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
Sympatholytic Agents – β-Adrenergic Receptor Antagonists
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
Sympatholytic Agents – β-Adrenergic Receptor Antagonists
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
Sympatholytic Agents – β-Adrenergic Receptor Antagonists
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
Sympatholytic Agents – 1- Adrenergic Antagonists
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
Sympatholytic Agents – 1- Adrenergic Antagonists
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
Sympatholytic Agents – 1- Adrenergic Antagonists
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
Sympatholytic Agents – Centrally-Acting AgentsMethyldopa
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
Sympatholytic Agents – Centrally-Acting AgentsMethyldopa
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
Sympatholytic Agents – Centrally-Acting AgentsMethyldopa
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
Sympatholytic Agents – Centrally-Acting AgentsClonidine, Guanabenz, & Guanfacine
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
Sympatholytic Agents – Centrally-Acting AgentsClonidine, Guanabenz, & Guanfacine
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
Angiotensin-Converting Enzyme 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
Angiotensin-Converting Enzyme Inhibitors
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
Angiotensin-Converting Enzyme 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
Angiotensin-Converting Enzyme Inhibitors
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)
Angiotensin-Converting Enzyme Inhibitors
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
Angiotensin-Converting Enzyme Inhibitors
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
Angiotensin-Converting Enzyme Inhibitors
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
Angiotensin-Converting Enzyme Inhibitors
Adverse Effects: Hypotension Cough Hyperkalemia Acute Renal Failure Fetopathic Potential Skin rash Proteinuria Angiodema Dysgeusia Neutropenia Glycosuria Hepatotoxicity
Angiotensin-Converting Enzyme Inhibitors
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
AT1 Angiotensin II Receptor Antagonists
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
AT1 Angiotensin II Receptor Antagonists
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
AT1 Angiotensin II Receptor Antagonists
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
K+ ATP Channel Openers: Minoxidil
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
K+ ATP Channel Openers: Minoxidil
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
K+ ATP Channel Openers: Minoxidil
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