Drugs Used for Hypertension

1
Drugs Used for Hypertension

• Philip Marcus, MD MPH

2
Clarifying the Diagnosis Good News and Bad News
Sometimes the Diagnosis is Obvious
3
Hypertension Epidemiology

• Elevation in Blood Pressure
• High Prevalence in US population
• Affects up to 24 of adults
• Over 50 million people affected in US
• Untreated in a large percentage
• Only 53 treated
• Lack of treatment may result in irreversible
  damage

4
Primary (Essential) Hypertension

• No identifiable cause
• Accounts for 95/- of cases
• Clusters in families
• Chronic and progressive
• Populations at risk
• Elderly
• Postmenopausal females
• African-Americans
• Obese
• Drug therapy lowers BP
• Does not eliminate underlying pathology
• Treatment generally lifelong
• Smoking and Obesity are cofactors

5
Primary Hypertension Pathophysiology

• Increased sympathetic activity
• Increased production of sodium retaining hormones
  and vasoconstrictors
• Long term sodium intake
• Inadequate potassium/calcium intake
• Increased renin secretion
• Deficiency of endogenous vasodilators
• Prostaglandin, Prostacyclin
• Nitric Oxide
• Obesity and Insulin resistance

6
Classification of Hypertension
Category Systolic Diastolic
Optimal lt120 lt80
Normal lt130 lt85
High Normal 130-139 85-89
Stage I 140-159 90-99
Stage II 160-179 100-109
Stage III 180-209 110-119
Stage IV gt210 gt120
7
Secondary Hypertension

• Chronic Renal Disease 4
• Renovascular Disease 2
• Coarctation of Aorta 0.3
• Primary Aldosteronism 0.2
• Cushings Syndrome 0.1
• Oral Contraceptive Use 1
• Pheochromocytoma 0.1
• Sleep Apnea
• 50 have significant hypertension

8
Consequences of Hypertension

• Untreated hypertension leads to increase in
  morbidity and mortality
• Heart Disease
• LV Hypertrophy and Congestive Heart Failure
• Coronary Artery Disease
• Renal Disease
• Increased prevalence despite available treatment
• Retinal Disease
• Cerebral Vascular Disease
• Stroke

9
Benefits of Antihypertensive Treatment

• Greater in elderly than in younger patients over
  short term (5 years)
• Older persons at higher immediate and absolute
  risk of developing cardiovascular events
• Prevalence of preexisting cardiovascular disease
  greater
• Systolic hypertension is associated with greater
  cardiovascular risk than diastolic
• Systolic hypertension more prevalent in elderly
• Smoking less common in older persons
• Smokers respond less well to antihypertensive
  treatment
• Most large trials involving elderly are more
  recent than those involving younger patients
• Use treatment regimens with fewer adverse effects
• Benefits of therapy increase over time
• Long-term benefits may be greater in younger
  patients

10
(No Transcript)
11
Non-Drug Management of Hypertension Lifestyle
Modification

• Weight reduction
• Sodium restriction
• Alcohol restriction
• Smoking cessation
• Exercise
• Maintenance of dietary potassium(gt100 mEq/day)
  and calcium intake
• Dietary Approaches to Stop Hypertension (DASH)
• Reductions in BP in persons on diet rich in
  fruits, vegetables, and low-fat dairy products
• Lowered BP in all subgroups
• Appel, et al, NEJM 1997 3361117

12
Physiologic Control of Blood Pressure

• BP C.O. x SVR
• C.O. H.R. x Stroke Volume
• Factors to be considered
• Heart Rate
• Blood Volume
• Contractility
• Arteriolar Constriction

13
HR x SV
Arterial Pressure
Cardiac Output
Peripheral Resistance

X
1. Heart Rate 2. Contractility 3.
Blood Volume 4. Venous Return
Arteriolar Constriction
14
Mechanisms Regulating Blood Pressure

• Sympathetic Nervous System
• Baroreceptors
• Medullary vasomotor center
• Renin Angiotensin System
• Angiotensinogen
• a-2 globulin
• Activated by Renin
• Produced by JG cells
• Increased by decreased renal blood flow
• Increased with b-1 stimulation
• Observed clinically with renal artery stenosis,
  hypotension

15
Mechanisms Regulating Blood Pressure

• Renin Angiotensin System
• Angiotensin I
• Product of renin action on angiotensinogen
• Converted by Angiotensin-Converting Enzyme
• Primarily in vasculature and lung
• Angiotensin II
• Acts on Angiotensin Receptors (AT1)
• Causes vasoconstriction
• Causes release of Aldosterone
• Converted to Angiotensin III in adrenal
• Aldosterone
• Results in Na retention and K loss
• Expands extracellular fluid volume
• Action of Angiotensin II and Aldosterone results
  in decrease in renin secretion

16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
Sites of Antihypertensive Drug Action

• Central Nervous System
• Vasomotor center
• Suppresses sympathetic outflow
• Cardiac
• Resistance Vessels (arterioles)
• Results in
• Reduction in Heart Rate
• Decrease in Contractility
• Vasodilatation
• Typical drugs
• Clonidine,
• Methyldopa

22
Sites of Antihypertensive Drug Action

• Sympathetic Ganglia
• Ganglionic blockade reduces sympathetic
  stimulation to heart and blood vessels
• Cause vasodilatation and reduction in HR
• Rarely used anymore
• Trimethaphan last remaining agent
• Adrenergic Nerve Terminals
• Decreases NE release
• Results in decreased stimulation of heart and
  blood vessels
• Guanethidine, reserpine

23
Sites of Antihypertensive Drug Action

• Cardiac b-1 Receptors
• Results in decrease in HR and contractility
• Vascular a-1 Receptors
• Results in vasodilatation
• Prazosin, Terazosin, Labetalol
• SA node and myocardium
• Calcium channel blockers
• Verapamil and Diltiazem
• Renal tubules
• Diuretic agents
• Furosemide, Hydrochlorothiazide

24
Diuretics Used in the Treatment of Hypertension
25
Sites of Antihypertensive Drug Action

• b-1 Receptors on juxtaglomerular cells
• Reduces renin release
• Vascular Smooth Muscle
• Direct vasodilators
• Hydralazine
• Angiotensin-Converting Enzyme Inhibitors
• Decreases formation on Angiotensin II
• Captopril, Enalapril
• Angiotensin II Receptor Blockers
• Results in blockade of AT1 receptors
• Losartan, Candesartan
• Similar in action to ACE inhibitors
• D1 (dopamine) Receptor Agonists

26
Hypertensive Crisis

• Severe Increase in BP
• Diastolic BP gt 120
• Rate of rise more important than absolute BP in
  determining need for EMERGENCY treatment
• Usually occurs in noncompliant or under-medicated
  patients
• In absence of evidence of acute or ongoing target
  organ damage, no need for acute, aggressive BP
  reduction

27
Hypertensive Crisis What constitutes the
Hypertensive Emergency?

• Encephalopathy
• Myocardial Infarction or Unstable Angina
• Congestive Heart Failure
• Subarachnoid hemorrhage, stroke or intracerebral
  hemorrhage
• Dissecting Aortic Aneurysm
• Cocaine overdose
• Acute renal insufficiency
• Post-operative hypertension

28
Centrally Acting Antiadrenergic Agents

• Act in CNS to reduce firing of sympathetic
  neurons
• Effects are the result of decreased stimulation
  of a b receptors in periphery
• Stimulate central inhibitory a-2 receptors
• Acts on post-synaptic receptors
• Exerts inhibitory influence on regions of brain
  that regulate sympathetic nervous activity
• Primary site of action in medulla

29
Centrally Acting Antiadrenergic Agents

• Clonidine (Catapres )
• 2-imidazoline derivative
• Results in decrease in BP, HR and CO
• Decreases renal vascular resistance
• Renal blood flow unchanged
• Lipid soluble
• Enters CNS
• Side effects common
• Dry mouth, dizziness, drowsiness
• Gynecomastia, rebound hypertension
• Oral and Transdermal route
• Also used in drug, alcohol and nicotine withdrawal

30
Centrally Acting Antiadrenergic Agents

• Clonidine HCl
• Recently introduced in epidural form
• Useful in this formulation for neuropathic pain
• Primarily used in patients with neoplastic
  disease
• Produces analgesia at presynaptic and
  postjunctional a-2 adrenergic receptors in the
  spinal cord
• Prevents pain signal transmission to the brain
• Pain relief additive to morphine
• Duraclon

31
Centrally Acting Antiadrenergic Agents

• Methyldopa (Aldomet )
• Analog of L-dopa
• Action similar to clonidine
• Requires uptake into CNS neurons
• Converted to methyl-norepinephrine
• Results in decrease in BP with little cardiac
  effects
• Large 1st pass effect
• Low bioavailability
• Oral and IV administration
• Side Effects
• Positive Coombs test, Hemolytic Anemia
• Hepatotoxicity
• Sedation, Lactation

32
(No Transcript)
33
Adrenergic Neuron Blocking Agents

• Act in presynaptic location to reduce NE release
  from sympathetic neurons
• Rarely used in therapy because of side effects
• Previously major agents used in treatment
• Reserpine and Guanethidine

34
Rauwolfia serpentina
35
Reserpine

• Rauwolfia alkaloid
• Causes depletion of NE from postganglionic
  sympathetic neurons
• Decreases stimulation of all adrenergic receptors
• Effects resemble a b blockade
• Blocks uptake of dopamine into vesicles which
  prevents NE synthesis
• Interferes with ATP and Mg dependent uptake
• Displaces NE from vesicles causing degradation of
  NE by MAO
• Acts peripherally and in CNS

36
Reserpine

• Physiologic Effects
• Bradycardia
• Decreased Cardiac Output
• Vasodilatation
• End result is reduction in Blood Pressure
• Side Effects
• Sedation and Depression
• Nasal stuffiness
• Orthostatic hypotension
• Extrapyramidal effects
• GI hypersecretion
• Diarrhea, cramps, Increased gastric Acid

37
Guanethidine

• Acts presynaptically to inhibit the release of NE
  from sympathetic neurons
• Must first be taken up into terminals of
  sympathetic nerves
• Uptake via active transport for NE
• After uptake, will prevent further NE release
• Can promote NE release initially
• Polar compound
• Highly basic Nitrogen
• Does NOT enter CNS
• Oral route, t1/2 5 days

38
Guanethidine

• Physiologic Effects
• Bradycardia
• Decreased Cardiac Output
• Vasodilatation
• Side Effects
• Resemble those of pharmacologic sympathectomy
• Orthostatic Hypotension
• Diarrhea
• Defective ejaculation
• Effects decreased by compounds that interfere
  with uptake
• Tricyclic Antidepressants
• Cocaine
• Phenothiazine drugs

39
a-1 Adrenergic Blockers

• Useful in hypertension and pheochromocytoma
• Selective inhibitors of a-1 receptor
• Contrast with phenoxybenzamine and phentolamine
• Cause blockade of a-1 a-2 receptors
• Used also for urinary obstruction in BPH
• Alternative to surgery
• Results in decrease in tone in smooth muscle of
  bladder neck and prostate
• Improves urine flow

40
a-1 Adrenergic Blockers

• Physiologic Effects
• Decrease peripheral vascular resistance
• Relax arterial and venous smooth muscle
• Results in decrease in Blood Pressure
• Minimal changes in Cardiac Output, renal blood
  flow and GFR
• Used orally

41
a-1 Adrenergic Blockers

• Side Effects
• Orthostatic Hypotension
• Results from blockade of venous a receptors
  causing pooling when upright
• Reflex tachycardia, generally not long-term
• Nasal Congestion
• Impotence
• Interference with ejaculation
• Sodium retention and edema
• Frequently used with a diuretic
• First-dose effect
• Exaggerated hypotensive effect
• Results in syncope
• Adjust first dose to 1/3 to ¼ usual dose at
  bedtime

42
a-1 Adrenergic Blockers

• Prazosin (Minipress )
• Initial agent
• Short half-life
• Terazosin (Hytrin )
• Longer acting
• Half-life 12 hours
• Doxazosin (Cardura )
• Longest half-life, 20 hours

Tamsulosin Flomax
43
Vasodilators

• Direct Vasodilators
• Hydralazine
• Minoxidil
• Angiotensin-Converting Enzyme Inhibitors
• Angiotensin II Receptor Blockers

44
Vasodilators

• Traditionally not used as primary drugs for
  hypertension
• Produce relaxation of vascular smooth muscle,
  predominantly arteriolar
• Decreases SVR
• Decreases Blood Pressure
• Result in reflex tachycardia and increased
  contractility
• May precipitate angina
• Increase myocardial oxygen consumption
• Also result in increase in plasma renin
  concentration
• Sodium and water retention

45
(No Transcript)
46
Hydralazine (Apresoline )

• Hydrazine derivative
• Direct arteriolar smooth muscle dilator
• Rapidly and almost totally absorbed from GI tract
• Significant 1st-pass effect
• Peak levels in ½ to 2 hours
• Correlates with peak hypotensive effects
• t-1/2 2-4 hours, duration of action 6-8 hours
• Acetylation
• Slow vs. Fast acetylators
• 87 protein-bound

47
Hydralazine (Apresoline )

• Side Effects
• Headache
• Nausea, vomiting
• Tachycardia, dizziness
• Fluid retention
• Lupus syndrome
• Occurs in up to 10 of patients
• Generally with gt400 mg/day
• Generally reversible upon discontinuation

48
Minoxidil

• Selective arteriolar dilator
• ? Effect on opening of K channels
• Antagonizes action of intracellular cAMP on K
  channels
• Opens K channels causing relaxation of muscle
• No effect on capacitance vessels (veins)
• Rapidly and completely absorbed
• Extensive metabolism
• Eliminated in urine
• Hypertrichosis
• Occurs in 80 receiving drug gt 4 weeks
• Used topically to stimulate hair growth
  (Rogaine)
• Reserved for use in severe hypertension

49
Sodium Nitroprusside (Nipride )

• Causes arterial and venous smooth muscle
  relaxation
• Decreases preload and afterload
• Action more pronounced in upright patient
• Increased venous pooling occurs
• Renal blood flow and GFR maintained
• Increased plasma renin activity
• No tachycardia occurs
• Mechanism similar to nitrates
• Results in increase in cGMP

50
Sodium Nitroprusside
51
Sodium Nitroprusside (Nipride )

• Used exclusively via intravenous infusion
• Onset of action with 1 to 2 minutes
• t1/2 of minutes
• Used for hypertensive emergencies and severe CHF
• Used also for aortic dissection

52
Sodium Nitroprusside (Nipride )

• Fe reacts with SH compounds in RBC
• CN- produced
• Reduced to SCN- in liver (rhodanase)
• Sodium thiosulfate (S donor) facilitates
  metabolism of CN-
• Hydroxy-cobalamin also combines with CN-
  (cyanocobalamin)
• SCN- excreted in urine
• Half-life 3 to 4 days
• May accumulate after prolonged use
• Causes toxic psychosis
• Predisposing factors include renal disease and
  hyponatremia
• Monitor levels gt3 days 0.1 mg/ml
• Acute toxicity
• Excess vasodilatation and hypotension

53
Diazoxide

• Thiazide compound
• No diuretic effect
• Selective arteriolar dilator
• Results in decrease in SVR and BP
• Compensatory increase in HR and contractility
• Increase Na and water retention
• Pharmacokinetics
• Administer via bolus IV injection
• Extensively bound to albumin
• Effects in minutes, half-life 24 hours
• Adverse Effects
• Hyperglycemia
• Suppresses insulin release
• Hyperuricemia
• Decreases renal uric acid excretion

54
Fenoldopam mesylate (Corlopam)

• Selective D1 dopamine receptor agonist
• D1 receptors located on smooth muscle of renal,
  coronary, cerebral and mesenteric arteries
• Vasodilator effect strongest in renal arteries
• Causes diuresis and natriuresis
• Maintains renal perfusion
• D2 peripheral receptors located on presynaptic
  adrenergic nerve terminals and on sympathetic
  ganglia
• Inhibit norepinephrine release
• Used via intravenous infusion
• Used in hypertensive emergencies
• Adverse effects related to excess vasodilatation
• Flushing
• hypotension

55
Angiotensin-Converting Enzyme Inhibitors

• Block action of angiotensin-converting enzyme
  (ACE)
• Inhibit cleavage of Angiotensin I
• Prevents formation of Angiotensin II
• Interfere with bradykinin degradation
• Via inhibition of kininase II
• Bradykinin stimulates PG synthesis
• Causes vasodilatation by
• Decreased amounts of Angiotensin II
• Increased amounts of bradykinin
• Decreased secretion of aldosterone

56
(No Transcript)
57
Angiotensin-Converting Enzyme Inhibitors

• Causes decrease in SVR
• Results in decrease in Blood Pressure
• Causes venodilation in CHF
• Relatively selective action on renal vasculature
• Decreases afferent and efferent arteriolar
  resistance
• Decreases glomerular capillary hydrostatic
  pressure
• No effect on cardiovascular reflexes
• Minimal orthostatic hypotension
• No CNS effects
• Effects enhanced by diuretic/Na restriction

58
Angiotensin-Converting Enzyme Inhibitors
Therapeutic Use

• Hypertension
• Useful for initial therapy
• Most effective in younger patients and elderly
• Efficacy enhanced with diuretics
• Congestive Heart Failure
• Decrease in rate of sudden death and progressive
  heart failure
• Left ventricular dysfunction
• May lead to regression of LV hypertrophy
• Following myocardial infarction
• To improve survival, particularly with LV
  dysfunction
• Administer with 24 hours of MI
• Diabetic nephropathy

59
Assessment of LV Function (Echocardiogram,
Radionuclide Ventriculogram)
EF lt 40
Assessment of Volume Status
Signs and Symptoms of Fluid Retention
No Signs and Symptoms of Fluid Retention
ACE Inhibitor
Diuretic (Titrate to Euvolemic State)
Digoxin
B-Blocker
Recommended Approach to the Patient with Heart
Failure
60
Angiotensin-Converting Enzyme Inhibitors
Chemical Classification

• Peptide structure
• Direct-acting ACE inhibitors
• Captopril, lisinopril, enalaprilat
• Prodrugs
• De-esterified in liver to active diacid forms
• Three subgroups
• Sulfhydryl-containing
• Captopril
• Di-carboxyl-containing
• Enalapril
• Phosphorus containing
• Fosinopril

61
Angiotensin-Converting Enzyme Inhibitors

• Captopril (Capoten)
• Initial agent in class
• Only agent available generically
• 70 bioavailable
• Reduced to 40 in presence of food
• Half-life 3 hours
• Primarily excreted in urine
• 40 to 50 unchanged
• Active metabolites eliminated by kidney

62
Angiotensin-Converting Enzyme Inhibitors

• Remainder of agents differ in terms of
• Half-life
• Duration of action
• Protein binding
• Route of elimination
• Fosinopril
• Renal hepatic elimination
• Captopril, Lisinopril (enalaprilat derivative)
  active forms
• Benazepril, Enalapril, Moexipril, Ramipril
  require de-esterification

63
Angiotensin-Converting Enzyme Inhibitors Adverse
Reactions

• Rash
• Dysgeusia
• Angioedema
• Potentially fatal
• Macroglossia typical
• Also, swelling of mouth, pharynx, larynx
• Seen with all ACE inhibitors
• May be related to increase in kinin levels
• Susceptible patients may have subclinical
  deficiency of complement 1-esterase inactivator
• Urticaria

64
Angiotensin-Converting Enzyme Inhibitors Adverse
Reactions

• Cough
• Dry, hacking cough develops in 3 to 20
• Usual begins within 1 to 2 weeks of therapy
• Women affected more than men
• Resolves within one week after discontinuation,
  can take up to 4 weeks
• Recurs upon repeat challenge
• Not more frequent in asthmatics
• Mechanism unknown
• Worse in supine position
• Neutropenia

65
Angiotensin-Converting Enzyme Inhibitors Adverse
Reactions

• Hypotension
• More prominent in patients with hypovolemia
• Begin with low doses
• Acute Renal Failure
• Most severe in bilateral renal artery stenosis
• Also occurs in hypertensive nephrosclerosis and
  polycystic kidney disease
• ACEI relax efferent arteriole, cause lowering of
  intraglomerular pressure and reduce GFR
• Angiotensin II levels rapidly reduced
• Serum creatinine rises within few days of therapy

66
Angiotensin-Converting Enzyme Inhibitors Adverse
Reactions

• Hyperkalemia
• Results from reduction in aldosterone secretion
• Impairs efficiency of urinary K excretion
• Incidence approaches 10
• Proteinuria
• Primarily with underlying renal disease
• Seen with high doses of Captopril

67
Angiotensin-Converting Enzyme Inhibitors Use in
Pregnancy

• Not teratogenic in first trimester
• Category C
• Discontinue as soon as pregnancy discovered
• Fetopathic in second and third trimesters
• Category D
• Causes fetal injury
• Skull hypoplasia
• Anuria
• Renal failure (Reversible/Irreversible)
• Oligohydramnios
• Intrauterine growth retardation

68
Angiotensin II Receptor Antagonists

• Saralasin
• Peptide analog of Angiotensin II
• Partial agonist
• Parenteral administration
• Short duration of action
• Not used clinically
• New agents introduced first in 1995
• Non-peptide selective blockers of binding of
  Angiotensin II to type 1 (AT1) angiotensin
  receptors on cell membrane
• Primarily imidazole compounds
• Represent third class of agents that antagonize
  renin-angiotensin-aldosterone system

69
Angiotensin II Receptor Antagonists

• Blockade of action of Angiotensin II leads to
  elevations in plasma levels of
• Renin
• Angiotensin I
• Angiotensin II
• Agents block effects of Angiotensin II
• Vasoconstrictor
• Aldosterone secretion
• Build-up of precursors does not overwhelm
  receptor blockade
• Comparative efficacy in hypertension to ACEI

70
Angiotensin II Receptor Antagonists

• Losartan (Cozaar )
• Irbesartan (Avapro )
• Candesartan (Atacand )
• Telmisartan (Micardis )
• Valsartan (Diovan )
• Eprosartan (Teveten )
• Olmesartan (Benicar )
• Agents differ in half-life, duration of action,
  bioavailability and metabolic fate
• Approved only for use in hypertension

71
Angiotensin II Receptor Antagonists Side Effects

• Generally well tolerated
• May cause changes in renal function
• Effects in pregnancy same as for ACEI
• Category C first trimester
• Category D second and third trimesters
• No cough noted
• Hyperkalemia

72
Lifestyle Changes Weight Reduction Sodium
Restriction Alcohol Restriction Exercise
Smoking Cessation
Inadequate Response
Continue Lifestyle Changes and initiate drug
therapy Preferred Initial Drug Diuretic
or b-blocker Alternative Initial Drug ACE
inhibitor or calcium channel blocker,
a-1-blocker or a, b blocker
Inadequate Response
Increase drug dose or Substitute another
drug Or Add a second drug from a different class
73
Recycling at its Best
74
(No Transcript)