Dr. Florencia D. Munsayac
HYPERTENSION
 "A state of abnormal arterial
function and structure associated
with endothelial dysfunction,
vascular smooth muscle
constriction or remodeling,
increased impedance to left
ventricular ejection and propensity
for atherosclerosis."
 Diagnosis:
 repeated, reproducible measurements of
elevated BP
 Consequences:
 damage to kidneys, heart & brain
Etiology:
A. Primary Hypertension
1. Abnormal cardiac & peripheral hemodynamics
2. Impaired pressure natriuresis
3. Baroreceptor resetting
4. Abnormalities in the renin-angioitensinaldosterone system
5. Abnormalities in other vasoregulatory systems
a. Endothelin
b. Atrial Natriuresis peptide (ANP)
c. Endothelium-derived relaxation factor (EDRF)
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)
Major Factors Influencing
Blood Pressure
ABP = cardiac output x peripheral
vascular resistance
•
•
•
•
•
•
heart rate
arteriolar volume
contractility
blood volume
filling pressure
venous tone
Genetic influences + Environmental Factors
Defects in renal
NA+
homeostasis
Functional
Defects in
vascular
smooth muscle
growth and
structure
 vascular
reactivity
 vascular wall
thickness
vasoconstriction
Inadequate Na+
secretion
Salt & water
retention
 Plasma & ECF
volume
 cardiac
output
 total
peripheral
resistance
(autoregulation)
HYPERTENSION
Circadian Rhythm and Blood Pressure
Variability
 Daytime: BP is controlled by sympathetic activity
 Sleep: BP lowest
sympathetic activity switch off
renin level rise
BP control under RAS
 Early Morning Waking:
BP rise as much as 30 mmHg
marked increased in sympathetic activity
elevated levels of renin & angiotensin II
Physiological Changes
Associated With Early Morning
BP Elevation
 Increase plasma cathecolamines & cortisol
elevates myocardial oxygen demand
 Increase in platelet aggregability & vascular
tone; reduce myocardial oxygen supply
 BP surge can cause rupture atherosclerotic
plaques in coronary arteries
 Promotes clot formation due to activation
of coagulation process
 Excess sympathetic activation results in
release of adrenaline, an arrhythmic
promoter
Classification of Blood Pressure
for Adults >/= 18 years: JNC 7
Pressure
Category
SBP (mmHg)
DBP (mmHg)
< 120
< 80
120 - 139
80 - 89
Stage 1
140 - 159
90 - 99
Stage 2
> / = 160
> / = 100
Normal
Prehypertension
Hypertension
Management of Hypertension
in Adults Aged > / = 18 Years
Blood Pressure
Classification
Lifestyle
Modification
Initial Drug Therapy
Without compelling
indication
Normal
With compelling indication
Encourage
Prehypertension
Yes
No antihypertensive drug
indicated
Drug(s) for the compelling
indications
Stage 1HTN
Yes
Thiazide-type diuretics
for most; may
consider ACE
inhibitor' ARB, betablocker, CCB, or
combination
Drug(s) for the compelling
indications; other
antihypertensive drugs
(diuretics, ACE
inhibitor, ARB, betablocker, CCB) as needed
Stage 2 HTN
Yes
2-drug combination for
most (usually
thiazide-type diuretic
and ACE inhibitor or
ARB or beta-blocker
or CCB)
Drug(s) for the compelling
indications; other
antihypertensive drugs
(diuretics, ACE
inhibitor, ARB, betablocker, CCB) as needed
Classification of Antihypertensive
Drugs
A. Diuretics
1. Thiazides
2. Loop diuretics: Furosemide, Bumetanide
3. Potassium Sparing diuretics: Triamterene, Spirinolactone,
Amiloride
B. Sympathoplegic 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. Ganglionic Blocking Agent - Trimetaphan
3. Adrenergic Neuron Blocking Agents - reserpin, guanethidine,
guanadrel
4. Beta-adrenergic Antagonists - propranolol; metaprolol,
atenolol, pindolol, acebutolol, bisoprolol
5. Alpha adrenergic Antagonists - prazocin, phenoxybenzamine,
phentolamine
6. Mixed Antagonists (Alpha & Beta) - labetalol, carvedilol
C. Vasodilators
1. Oral Vasodilators: hydralazine, minoxidil
2. Parenteral Vasodilators: nitroprusside,
diazoxide, fenoldepam
3. Calcium Channel Blockers: Dihydropyridines nifedipine, amlodipine, felodipine.
nimodipine, nicardipine, isradipine, licidipine;
Phenylalkylamines --vcrapamil;
Bcnzothiazcpincs - diltiazcm
D. Inhibitors of Rcnin Aogiotcnsin System:
1. Angiotensin 11 Antagonists - saralasin,
losartan, valsartan
2. ACE inhibitors - captopril, qiunapril, enalapril,
pcrindopril, lisinopril
Loop Diuretics
 furosemide, bumetamide and
torsemide
 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
 Very steep dose-response natriuresis
curve, termed high-ceiling diuretics
Furosemide
 Rapidly absorbed from the GIT
 Binds avidly to plasma proteins
 Rapidly eliminated from the body, by
renal excretion (Proximal tubular
secretion)
 Onset of action: 30-60 min after oral
administration or 2-5 min after IV
 Duration of action: PO-6 hours, 2-5
min IV
Thiazide Diuretics
 Low ceiling, flat dose response
 Slow onset of effect, long duration of
action (6-12 hours)
 Reduce urine calcium
 Hydrochlorothiazide – sulfonamide
derivative
 Indapamide – new thiazide like agent
with a significant vasodilating effect
Potassium sparing diuretics
 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
Mechanism of Antihypertensive Effects of Diuretics
Decreased PVR
Reduction in body sodium
Decrease interstitial fluid volume
Fell in smooth muscle sodium concentration
Decrease in 1C calcium concentration
Diuretics and Potassium-Sparing Agents
Agent
Daily Dosage
(mg)
Duration of
Action
(hour)
2.5 - 5.0
18
12.5 - 50
12 – 18
125 - 500
0.5 - 2
6 - 12
18 – 24
6.25 - 50
12 – 18
2.5 - 5.0
1-4
1-4
18 – 24
> 24
24 - 48
Thiazides
Bendroflumethiazide
(Neturcun)
Benzthiazide (Aquata,
Exna)
Chlorthiazide (Diuril)
Cyclothiazide (Anhydron)
Hydrochlorothiazide
(Esidrix, Hydrodiuril,
Oretic)
Hydroflumethiazide
(Saluron)
Methyclothiazide (Enduron)
Polythiazide (Renese)
Trichlormethiazide
(Metahydrin Naqua)
Related Sulfonamides
Compounds
Chlorthalidone (Hygroton)
Indapamide (Lozol)
Metolazone (Zaroxolyn, Diulo)
Quinethazone (Hydromox)
12.5 - 50
2.5
0.5 - 10
24 - 100
24 - 72
24
24
18 - 24
0.5 - 5
25 - 100
40 - 480
5 - 40
4-6
12
4.6
12
5 - 10
24 - 100
50 - 100
24
8 - 12
12
Loop Diuretics
Bumetanidc (Bumex)
Ethacrynic acid (Edcecrin)
Furosemide (Lasix)
Torsemide (Demadex)
Potassuim-Sparing
Amiloride (Midamor)
Spirinolactone (AIdactone)
Triamterene (Dyrenium)
Toxicity
 Potassium depletion (except K-sparing
diuretics)
 Magnesium depletion
 Impair glucose tolerance
 Increase serum lipid concentration
 Increase uric acid concentration
Action of Centrally - Acting Antihypertensive Agents
Alphamethyldopa
Guanfacine
Guanabenz
Alphaadrenoceptor
Salivary
Glands
Dry mouth
Clonidine
Moxonidine
Rilmenidine
Imidazoline
receptor
Nucleus
Tractus
Solitarius
Rostral
Ventrolateral
Medulla
Nucleus
Coeruleus
Sedation
Inhibition of Sympathetic
Nerve Activity
Inhibition of norepinephrine release
Decrease in vasoconstriction
Vasodilation
Lower Blood Pressure
Methyldopa





Mild to moderate hypertension
Decrease PVR
Extensive first pass metabolism
Effect 4-6 hours up to 24 hours
Side effects: sedation, lactation,
positive coombs test
Clonidine
 Decrease cardiac output, HR and relaxation
of capacitance vessels, decrease PVR
 Decrease renal vascular resistance &
maintenance of RBF
 75% bioavailability
 Half-life 8-12 hours
 Lipid soluble, rapidly enters brain from
circulation
 Toxicity: dry mouth, sedation, life
threatening HTN crisis in sudden
withdrawal
Ganglionic-blocking Agents
 Drugs that block stimulation of
postganglionic autonomic neurons by
Ach
 No longer available because of
intolerable toxicities
 Trimetaphan – prototype drug, given
IV, short-acting, that block the
nicotine receptor
Adrenergic Neuron Blocking
Agents
 Lower BP by preventing normal
physiologic release of norepinephrine
from postganglionic sympathetic
neurons
 Guanethidine
 Bethanidine
 Guanadrel
 Debrisoquin
 reserpine
Reserpine
 Effective & safe for mild to moderate
HTN
 Enters BBB
 Causes depletion of central amines 
sedation, mental depression &
parkinsonism symptoms
 Lowers BP by decreased CO and PVR
 Half-life 24-48 hours
Guanethidine
 Treatment of severe HTN
 MOA is associated with reduce CO due to
bradycardia & relaxation of capacitance
vessels
 Half-life 5 days, bioavailability 3-50%
 50% cleared by the kidneys
 Large volume of distribution
 Too polar to enter the CNS
 Has none of the central effects
 toxicity: postural hypotension, retrograde
ejaculation
BETA – ADRENOCEPTOR BLOCKING DRUGS
Nonselective
Nadolol
Propranolol
Timolol
Sotalol
Tetralol
Pindolol
Penbutolol
Carteolol
Alprenolol
Dilevatol
Oxyprenolol
Selective
Atenolol
Esmolol
Metoprolol
Bevantolol
Bisoprolol
Betaxolol
With alpha-blocking
ability
Acebutolol
(Practolol)
Celiprolol
Labetalol
Bucindolol
Carvedilol
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
Mechanism of Action
Beta-adrenoceptor blockers
Decrease activation of B1
adrenoceptors on heart
Decreased renin
Decreased cardiac output
Decreased angiotensin II
Decreased Blood Volume
Decrease PVR
Decrease aldosterone
Dec. Na+, H2O retention
Decreased Blood Volume
Decreased in Blood Pressure
Alpha-adrenergic
Antagonists
 Reduce arterial pressure by dilating both
resistance and capacitance vessels
 Cause sympathetically mediated reflex
increase in HR & plasma renin activity
 Long-term therapy: vasodilatation persists,
but CO, HR & plasma renin activity return
to normal
 Selective: prazosin, terazosin, doxazosin
 Non-selective: phentolamine,
phenoxybenzamine
Prazosin, terazosin,
doxazosin
 Half-life 3-4 hrs (prazosin)
 Extensively metabolized but undergoes
very little first-pass metabolism, half-life
12 hours, given OD (terazosin)
 Doxazosin has intermediate
bioavailability, half-life 22 hours, given
once a day
 Toxicity: first dose phenomenon,
dizziness, palpitation, headache &
lassitude, positive serum Antinuclear
factor (prazosin)
Mechanism of ActionVasodilators
 Inhibition of calcium influx into arterial
smooth muscle cells  relax smooth muscle
of arterioles  decreasing systemic vascular
resistance  decrease arterial pressure
 direct arterial dilation triggers baroreceptor,
svmpathetic 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
Oral Vasodilators
Hydralazine







dilate arterioles but not veins
effective in severe HTN
well absorbed from GIT
systemic bioavailability is low
half-life 1 hour
duration of action 12 hours
toxicity: immunological reactions, druginduced lupus syndrome, serum sickness,
hemolytic anemia, vasculitis & rapidly
progressive glomerulonephritis
Minoxidil
 Metabolized by hepatic
sulfotransferase to the active
molecule, minoxidil N-O sulfate
 Well absorbed
 Half-life 3-4 hours
 Duration of action 24 hours or longer
 Toxicity: fluid and salt retention,
hypertrichosis
Parenteral Vasodilators
Nitroprusside
 Dilates both arterial and venous vessels
 Used in treating hypertensive emergencies,
severe heart failure
 Rapidly lowers BP
 Given by IV infusion
 Effects disappear within 1-10 min after
discontinuation
 Eliminated by the kidney
 Toxicity: metabolic acidosis, arrhythmia,
hypotension, death, thiocyanate poisoning,
delayed hypothyroidism,
methemoglobinemia
Diazoxide
 Arteriolar dilator – hyperpolarizes
arterial muscle cells by activating ATP
sensitive K channels, this cause
relaxation of the vascular smooth
muscle
 Used to treat hypertensive
emergencies
 Toxicity: hypotension
Fenoldepam
 Newer peripheral arteriolar dilator
 Acts primarily as an agonist to
dopamine D1 receptors, resulting in
dilatation of peripheral arteries and
natriuresis
 Administered by IV infusion
 Half-life 10 mins
 Toxicity: reflex tachycardia, headache,
flushing, increased intraocular
pressure
Calcium Channel Blockers
 Dilate peripheral arterioles
 Dihydropyridines more selective as
vasodilator
 less cardiac depressant effects
 Verapamil greatest effect on heart,
decrease heart rate and cardiac output
Adverse 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,
cardiodepression
ANGIOTENSIN - CONVERTING ENZYME
(ACE) INHIBITORS
Mechanism of Action
Reduction of circulating levels of Angiotensin II
Decrease aldosterone secretion; blunts increased in
sympathetic activity
Direct inhibition of vascular hypertrophy
Enhance endothelium dependent relaxation
Inhibits the degradation of bradykinin – vasodilator, weak anti-aggregant
peptide, enhances synthesis of vasodilatory prostaglandins
Vasodilation
Decrease peripheral vascular resistance
Decrease blood pressure
Various ACE inhibitors
Drug
Dosage (minmax)
Administration
Elimination
Benazepril
5 - 40
o.d.
Renal
Captopril
12.5 - 150
t.i.d.
Renal
Cilazapril
5 - 10
o.d.
Renal
Enalapril
5 - 40
b.i.d.
Renal
Fosinopril
10 - 40
o.d.
Renal & hepatic
Lisinopril
5 - 40
o.d.
Renal
Moexipril
7,5 - 30
o.d.
Renal
Perindopril
1 - 16
o.d.
Renal
Qninapril
5 - 80
o.d.
Renal
Ramipril
1.25 - 20
o.d.
Renal
Tandolapril
1-4
b.d.
Renal
Spirapril
12.5 - 50
o.d.
Hepatic
Captopril
 Rapidly absorbed
 Bioavalability 70% with fasting, 3040% with food
 Half-life < 3 hours
 Metabolized to disulfide conjugates
 Eliminated in kidney
 HTN in DM – diminish proteinuria &
stabilize renal function
 Toxicity
 Severe hypotension
 Acute renal failure
 Hyperkalemia
 Dry cough sometimes with wheezing & angioedema
 Contraindications
 2nd & 3rd trimester of pregnancy
 Drug interaction
 Potassium supplements
 Potassium - sparing diuretics
 NSAIDs
ANGIOTENSIN II RECEPTOR BLOCKING AGENTS
 bind selectively to AT1 receptors and
displace angiotensin II
 blockers of the angiotensin II type 1 (AT1)
receptor
 1st drugs marketed: losartan, valsatran
 candesartan, eprosartan, irbesartan, &
telmisartan - no effect on bradykinin
metabolism  more selective blockers of
angiotensin effects
 SE: similar to ACE inhibitors but less cough
and angioedema