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T herapy of hypertension1
 

T herapy of hypertension1

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    T herapy of hypertension1 T herapy of hypertension1 Presentation Transcript

    • Florencia G. dela Cruz-Munsayac, MD, FPSECP, MBA, RMT THERAPY OF HYPERTENSION
    •  
    •  
    • 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 Hypertension
      • 1. Abnormal cardiac & peripheral hemodynamics
      • 2. Impaired pressure natriuresis
      • 3. Baroreceptor resetting
      • 4. Abnormalities in the renin-angiotensin-aldosterone system
      • 5. Abnormalities in other vasoregulatory systems
      • a. Endothelin
      • b. Atrial Natriuresis peptide (ANP)
      • c. Endothelium-derived relaxation factor (EDRF)
    • Etiology of Hypertension
      • B. Secondary Hypertension
      • 1. Renovascular hypertension
      • 2. Renal parenchymal diseases
      • a. Altered excretory function
      • b. Altered renin-angiotensin-aldosterone activity
      • 3. Endocrinologic causes
      • a. Oral Contraceptives
      • b. Mineralocorticosteroid excess syndrome
      • c. Pheochromocytoma
      • d. Miscellaneous causes (Acromegaly, Hyperparathyroidism, Hyperthyroidism, Coarctation of the aorta)
    • Genetic influences + Environmental Factors
      • Defects 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. Diuretics
      • 1. Thiazides & related agents (hydrochlorothiazide, chlorthalidone)
      • 2. Loop diuretics (Furosemide, Bumetanide, torsemide, ethacrynic acid)
      • 3. Potassium Sparing diuretics (Triamterene, Spirinolactone, Amiloride)
      • B. Sympatholytic Agents
      • 1. Centrally Acting Agents
      • a. Acting on alpha adrenoceptor (First Generation)
      • - methyldopa, clonidine, guanabenz, guanfacine
      • b. Acting on imidazoline receptor (Second Generation)
      • - moxonidine, rilmenidine
      • 2. 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. Vasodilators
      • 1. 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
      • D ecrease 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 Selective With alpha-blocking ability Nadolol Propranolol Timolol Sotalol Tetralol Pindolol Penbutolol Carteolol Alprenolol Dilevatol Oxyprenolol Atenolol Esmolol Metoprolol Bevantolol Bisoprolol Betaxolol Acebutolol (Practolol) Celiprolol Labetalol Bucindolol Carvedilol
    • Sympatholytic Agents – β - Adrenergic Receptor Antagonists Propranolol
      • 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 Antagonists Metoprolol
      • 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 Antagonists Nadolol, 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 Antagonists Pindolol, 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 Antagonists Labetalol & 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 β 2 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 Antagonists Labetalol & 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 Antagonists Esmolol
      • Is a β 1 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 prazosin
        • Bioavailability: 90%
        • Half time of elimination: 12 hours
        • Duration: 18 hours
      • Doxazosin
        • T1/2: 36 hours
        • Metabolites 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:
      Methyldopa Guanfacine guanabenz clonidine Moxonidine Rilmenidine Alpha-adrenoreceptor Imidazoliine receptor Nucleus Tractus solitarius Salivary glands Dry mouth Nucleus coeruleus Sedation Rostral Ventrolateral medulla Inhibition of Sympathetic Nerve Activity Inhibition of norepinephrine release Decrease in vasoconstriction Vasodilation Lower BP
    • Sympatholytic Agents – Centrally-Acting Agents Methyldopa
      • 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 Agents Methyldopa
      • 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 Agents Methyldopa
      • 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 Agents Methyldopa
      • 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 Agents Clonidine, 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 Agents Clonidine, 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 Agents Clonidine, 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 perform
        • Psychotic depression
        • Nasal stiffness
        • Exacerbation 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. 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.i.d. Renal
      • Spirapril 12.5 – 50 o.d. Hepatic
    • Angiotensin-Converting Enzyme Inhibitors 3-7 hours perindoprilat 75% / 35% * perindoprilat Perindopril 1.5 hours 13% Moexiprilat Moexipril 1 hour / 3 hours Ramiprilat Pamipril 2 hours / 25 hours 1hour / 2 hours Quinaprilat Quinapril 4-10 hours trandolaprilat 10% / 70% Trandolaprilat Trandolapril 11.5 hours Fosinoprilat 3 hours Fosinoprilat Fosinoprilat Glucoronide conjugate Fosinopril 10-11 hours benazeprilat 0.5-1 hr / 1-2 hours 35% Benazeprilat Glucuronide conjugates Benazepril 12 hours 7 hours 25% * Lisinopril-lysine analog of enalaprilat 1.3 hrs / 11 hrs 1 hrs / 3-4hrs 60% * Enalaprilat Enalapril 2 hours 1 hour 75% Disulfide dimers & cysteine disulfide Captopril Half-life Peak Plasma Concentration Bioavailability Metabolites Drugs
    • 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
    • AT 1 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
    • AT 1 Angiotensin II Receptor Antagonists
      • Pharmacological Effects:
        • bind selectively to AT 1 receptors and displace angiotensin II
        • blockers of the angiotensin II type 1 (AT 1 ) receptor
        • The rank-order of the AT 1 receptor for ARBs is candesartan = omesartan > irbesartan = eprosartan > telmisartan = valsartan = EXP 3174 (active metabolite of losartan) > losartan
    • AT 1 Angiotensin II Receptor Antagonists liver 9 hours 2-4 hoours Valsartan Biliary 24 hours 0.5-1 hour Telmisartan Renal & biliary Olmesartan Between 10 & 15 hours 1.4-2.8 hours Olmesartan medoxomil Renal & hepatic EXP 3174 2.5 & 9 hours 1-3 hours Losartan Renal & biliary Glucuronide conjugate 11-15 hours 1.5-2 hours Irbisartan Renal & biliary Glucuronide conjugate 5-9 hours 1-2 hours Eprosartan Renal & biliary Candesartan 9 hours 3-4 hours Candesartan Cilexetil Elimination Metabolite Plasma Half-life Peak Plasma Concentration Drugs
    • AT 1 Angiotensin II Receptor Antagonists
      • Adverse Effects
        • Hypotension
        • Hyperkalemia
      • 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
      • Hydralazine
        • Pharmacologic 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
      • Hydralazine
        • Toxicity & 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 Drugs Hypotension, cardiac depression, edema 75-150ug/kg IV 80-160mg q 8 hrs angina, HTN, arrhythmia, migraine, CMP Verapamil Dizziness, flushing, nausea 75-150ug/kg IV 30-80mg q 6 hrs Angina, HTN Diltiazem Arrhythmia, nausea, dizziness 200-400mg od angina Misc. Bepridil Same as nifedipine 20mg od/bid angina Niterndipine Same as nifedipine 20-40mg q 8 h HTN Nisoldipine Headache, LBM 60mg q 4 hrs SAH, migraine Nimodipine Hypotension, dizziness, flushing, edema, nausea, Constipation, 20-40mg q 8 hrs Angina, HTN, migraine, CMP, Raynaud’s phenomenon Nifedipine Peripheral edema, HA, dizziness 20-40mg Angina, HTN, CHF Nicardipine HA, fatigue 2.5-10mg HTN Isradipine HA, dizziness 5-10mg HTN, CHF Felodipine HA, peripheral edema 5-10mg Angina, HTN Amlodipine Dihydropyridine group Toxicity Dose Indication Drugs
    •