Pharmacologic

Management of
Hypertension and Angina
Prepared by:
Abraham Daniel C. Cruz, MD
Instructor A, Department of Pharmacology, FEU-NRMF
Associate Member, Philippine Society of Experimental and Clinical
Pharmacology
Candidate, Master of Science in Pharmacology, UP College of
Medicine
ANTIHYPERTENSIVE
AGENTS
HYPERTENSION
Blood pressure elevation on repeated,
reproducible measurements
Specific cause: 10-15% of patients
SECONDARY HYPERTENSION
Renal artery stenosis
Coarctation of the aorta
Pheochromocytoma
Primary aldosteronism
Essential/PRIMARY hypertension
(multifactorial)
Antihypertensives
(JNC 6) Hypertension : with SBP of
140 or greater and DBP of 90 or
greater

Relationship of blood pressure (BP) &

cardiovascular disease (CVD)
MI & stroke

4
JNC 7 CLASSIFICATION
Stage SBP DBP
Normal <120 <80
Pre-HPN 120 139 80 89
Stage I 140 159 90 99
Stage II 160 100

5
BLOOD PRESSURE

BP = CO X PVR
H STROK
R E
VOLUM
E PRELOAD
CONTRACTILIT
Y
AFTERLOAD
PRELOAD = filling volume of the heart
AFTERLOAD = the resistance the
ventricles face on ejection of blood;
tension the ventricle develops during
contraction
CONTRACTILITY = efficiency and vigor
of contraction of the heart muscle
 Determinants
LV Preload or LV end diastolic pressure
Blood volume and pulmonary vein pressures,
along with venous tone and rate or return
Contractility
amount of cytosolic Ca++ released during the
excitation sequence (major), condition of cardiac
muscle
LV Afterload or LV end systolic pressure
Aortic pressure, peripheral vasular resistance
(arterioles)
Blood Pressure Regulation
Coordination of
Neural mechanisms-
Baroreflexes
(carotid/aortic sinus)
Humoral mechanisms
Renin-Angiotensin-
Aldosterone System
Local hormone
release
Nitric oxide
Endothelin-1
Blood Pressure Regulation
Blood Pressure Regulation
Kidney long-term blood pressure
control
DEC RENAL PERFUSION
PRESSURE

Redistribution Dec Pressure in

of Renal Blood renal arterioles,
Flow-- Inc sympathetic
reabsorption of activity
salt and water RENIN
Angiotensin II
Inc
Aldosterone
Blood Pressure Regulation
In hypertensive patients, BP control
systems are set at a higher level of
blood pressure.

Antihypertensive drugs
Interfere with normal mechanisms of BP
control
Act at one or more of four anatomic
sites
arterioles, venules, heart, kidney
ANTIHYPERTENSIVE AGENTS

BP = CO X PVR
H STROK
R E
VOLUM
Epreload
contractility
afterload
Choice of Antihypertension
depends:
Stage of hypertension
Physical factors( cardiac, renal
complications)
Individualized
prescribed on a trial basis

14
Common Side Effects of
Antiypertensives
Hypotension

Bradycardia
except hydralazine (Apresoline)

15
ANTIHYPERTENSIVE AGENTS
1. Diuretics
2. Sympathoplegic agents
3. Vasodilators
4. Angiotensin antagonists
Initial Therapy Options
Thiazide diuretics
Good first choice and cost effective
Beta-adrenergic blockers review ANS
drugs
Decreased sympathetic outflow
Hypertension with angina, post-myocardial
infarction, and certain arrythmias
Calcium channel blockers (CCB)
Hypertension with diabetes or coronary risk
Cardioselective >>>vasoselective
Verapamil > diltiazem > nifedipine

17
DIURETICS
Act by reduction of blood volume and
direct vascular effects
Deplete body sodium stores
Often provide adequate treatment
for mild to moderate
hypertension
In more severe hypertension
combined with sympathoplegic and
vasodilators
DIURETICS
Thiazide diuretics
Loop diuretics
Potassium-sparing diuretics
Thiazides
Prototype: hydrochlorothiazide
One of the first-line agents for
hypertension
Inhibit Na/Cl transporter
predominantly in the distal
convoluted tubule
Reduces blood volume and
cardiac output initially
Eventually, normal cardiac
output, PVR (due to depleted
sodium stores)
Thiazide toxicity
Hypokalemic metabolic alkalosis
Hyperuricemia
Impaired carbohydrate tolerance
Hyperlipidemia (5-15% increase in serum
cholesterol and LDL)
Hyponatremia
Hypercalcemia
Allergic reactions (cross-reactivity in
sulfonamide-sensitive patients,
photosensitivity, hemolytic anemia,
thrombocytopenia)
Loop Diuretics
Prototype: furosemide
Most potent diuretics
available
Inhibit NaCl reabsorption in
the thick ascending loop of
henle (Na+/K+/2Cl-
transporter)
Do not reduce PVR to the
same extent as thiazides
Commonly used in patients
with fluid overload
FUROSEMIDE TOXICITY
Hypokalemic metabolic alkalosis
Ototoxicity- dose related, usually
reversible
Hyperuricemia
Hypomagnesemia
Skin rash, eosinophilia, interstitial
nephritis
Cross-reactivity in patients sensitive
to sulfonamide
Potassium-sparing diuretics
Inhibit Na reabsorption (and
K+ and H + excretion) in the
distal and collecting tubules
Limited natriuretic activity
Usually given to reduce K loss
Amiloride, triamterene
inhibits Na+ influx through
ion channels (Na/K
transporters) in the luminal
membrane
Spironolactone, eplerenone -
competitive ALDOSTERONE
antagonists
Sympathoplegic Agents
block the actions of endogenous
neurotransmitters
(Epinephrine/Norepinephrine) or
other sympathomimetics
Decrease PVR
Inhibits cardiac function
Increase venous pooling in
capacitance vessels (decrease
preload)
Signal Transduction by 2 - and - Adrenergic
Receptors
Sympathoplegic Agents
1. Centrally acting
sympathoplegic drugs
Clonidine, Methyldopa
Reduce sympathetic outflow
from vasopressor centers in
the brainstem
Activates Alpha-2 receptors
Sedation, mental depression,
sleep disturbances
Methyldopa

2 agonist diminishes
adrenergic outflow
Reduces PVR, variable reduction
in CO and HR
Additional toxicities: lactation,
positive Coombs test, rarely
hemolytic anemia, hepatitis
Discontinuation of drug prompt
reversal
Methyldopa (Aldomet)
DOC of hypertension in pregnant
women
Useful for px w/ renal insufficiency
SIDE EFFECTS: hypotension, GI
symptoms: nausea, vomiting,
diarrhea
Sudden cessation may cause severe
rebound hypertension

33
Methyldopa (Aldomet)
CONTRAINDICATIONS:
liver disease, dialysis patients, blood
dyscrasias, older adults

INTERACTIONS:
Levodopa (CNS effects & psychosis)
lithium
NSAIDs, tricyclics, sympathomimietics
(inc. BP)
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Clonidine
Decreased CO due to decreased
Clonidine
adrenergic output decreased
HR, relaxation of capacitance
vessels, decreased PVR
Severe hyp0tension can
complicate overdosage
Withdrawal can result to life-
threatening hypertensive crisis-
rebound hypertension
CLONIDINE ( Catapres)
INDICATIONS:
For hypertension
For nicotine/opiate withdrawal
vascular headaches
glaucoma
ulcerative colitis
Tourettes Syndrome
severe pain in cancer patients

36
Sympathoplegic agents
2. Adrenoceptor Antagonists
Beta-blockers
Alpha 1-blocker
Beta Blockers
Competitive antagonists of beta
adrenergic receptors
Either selective for the Beta-1
receptor or non-selective
Selectivity is relative; higher doses
will also block beta-2 receptors
Decrease CO or PVR depending on
cardioselectivity and partial agonist
activity
Relative selectivity of B-blockers

RECEPTOR
AFFINITY
Propranolol, Beta1 = Beta2
carteolol, penbutolol,
pindolol, timolol
Metoprolol, Beta1>>>Beta2
acebutolol, atenolol,
esmolol, alprenolol,
betaxolol
Labetalol, carvedilol Beta1=Beta2alpha1
>alpha2
Beta-blockers
Non-selective (1 and 2)
Negative chronotropic and inotropic
effects (1 )
Stimulation of renin production (beta-1
receptors)
May also act on peripheral presynaptic
beta receptors

Prototype: Propranolol
Propranolol
First to be shown
effective in
hypertension and
ischemic heart disease
Shown to reduce
mortality and morbidity
Prevents reflex
tachycardia induced
by direct vasodilators
Beta-blockers
Selective (1)
Less likely to cause bronchospasmmetoprolol
Safer in patients with
asthma/COPD, diabetes,
peripheral vascular disease
Metoprolol, atenolol

atenolol
plus Alpha-blocking
properties
Vasodilatation
Labetalol, carvedilol
 Plus intrinsic sympathomimetic
properties (not pure antagonists)
Less likely to cause bradycardia,
bronchospasm, vasoconstriction,
decrease cardiac output
Acebutolol, Pindolol
Beta blockers
Two Categories (Pharmacokinetic
properties):
1. Eliminated by hepatic metabolism
and relatively short half-lives
(Propranolol, Metoprolol)
2. Eliminated unchanged by the
kidneys with longer half-lives
(Atenolol)
Beta Blockers
Most beta antagonists Esmolol
have half-lives in the range
of 3-10 hours; major
exception is esmolol (beta-
1 selective), with a half-life
of 10-15 minutes
Short half-life relates to the
rapid metabolism of drug by
blood and hepatic esterases
Beta Blockers- Toxicity
RESULT FROM BLOCKADE OF
CARDIAC, VASCULAR, OR BRONCHIAL
RECEPTORS
ADVERSE EFFECTS:
bronchoconstriction;
bradycardia, hypotension
fatigue, sedation, depression, insomnia
(highly lipophilic drugs)
impaired exercise tolerance,
exacerbation of peripheral vascular
disease, impotence
increased triglycerides, hyperglycemia
Alpha-1 Blockers
Prototype: Prazosin Prazosin
Blocks 1 receptors in arterioles
and venules (peripherally acting)
Reduce arterial pressure by
dilating both resistance and
capacitance vessels
Less reflex tachycardia than non-
selective alpha antagonists
More effective when used in
combination with other agents
(Beta blocker/diuretic)
Signal transduction by Post-synaptic
Alpha-1 and Alpha-2 receptors
Alpha-1 Blockers
first-dose phenomenon
precipitous drop in standing BP
First dose should be small and
administered at bedtime
Toxicities: dizziness, palpitations,
headache; positive ANA
(asymptomatic)
Direct Vasodilators
Decrease PVR, arteriolar resistance
Increase capacitance
Elicit compensatory responses
Baroreceptors/sympathetic nervous
system
Renin-angiotensin-aldosterone
Does not cause orthostatic
hypotension
Direct Vasodilators
1. Oral vasodilators: hydralazine,
minoxidil
2. Parenteral vasodilators:
nitroprusside, hydralazine,
diazoxide, fenoldopam
3. Calcium channel blockers
Mechanism of action of
vasodilators
Release of nitric oxide from drug or
endothelium
Hyperpolarization of vascular smooth
muscle through opening of
potassium channels
Reduction of calcium influx
Activation of dopamine1 receptors
Hydralazine
Dilates arteries and arterioles but not
veins
Low and variable (fast vs slow
acetylators) bioavailability due to
first pass metabolism
Avidly binds to vascular tissue
Adverse Effects: headache, nausea,
palpitations, sweating, flushing
Lupus-erythematosus-like syndrome
(arthralgia, myalgia, skin rashes,
HYDRALAZINE
Usu. Administered with propranolol to
counter the reflex tachycardia and diuretic
to decrease sodium retention
INDICATION:
Moderate to severe hypertension esp with CHF,
preeclampsia
SIDE EFFECTS:
tachycardia, orthostatic hypotension, edema &
weight gain

55
HYDRALAZINE
CONTRAINDICATION:
SLE
renal disease
coronary artery disease
pregnancy ( except in preeclampsia)

56
Sodium Nitroprusside
In hypertensive emergencies
Dilates both arterial and venous
vessels
Activation of guanylyl cyclase via
release of nitric oxide or direct
stimulation of the enzyme
Toxicity: excessive blood pressure
lowering; accumulation of cyanide
Calcium channel blockers
Inhibit L-type calcium channels in cardiac
and smooth muscle
 Decreased contractility
Decreased PVR arterial muscle
relaxation
Decreased heart rate (non-
dihydropyridines)
Classes
Dihydropyridines (DHPs): nifedipine,
amlodipine, felodipine, nicardipine
Non-DHPs- Verapamil, Diltiazem
DHPs (versus non-
DHPs)
Prototype: Nifedipine
more selective as vasodilators
(peripheral and coronary
artery)
less cardiac depressant effect
Do not affect cardiac
conduction
Reflex sympathetic
tachycardia
Short-acting DHPs NOT
recommended for long-term
Non-DHPs
Diphenylalkylamine
(Verapamil) and
Benzothiazepine
(Diltiazem)
Specificity for the heart
tissue
Slow AV node
conduction
Verapamil, greatest
depressant effect on the
heart (decrease heart
rate and cardiac output)
Adverse Effects
TOXICITY most important toxic
effects: direct effects of therapeutic
action; i.e. , cardiac depression and
cardiac arrest, bradycardia, AV block,
heart failure; GI complaints and
fatigue
DHPs flushing, peripheral edema,
hypotension, headache; reflex
tachycardia
Agents that block production or action of Angiotensin
Agents that block production or
action of Angiotensin
Decrease PVR
(potentially) Decrease blood volume
(preload)
REMEMBER: Renin release stimulated by
Reduced renal arterial pressure
Sympathetic neural stimulation > blocked by
BLOCKERS
Reduced sodium delivery
Increased sodium concentration at the distal
tubule
Antihypertensives
ACE inhibitors (ACEI)
Decrease vasoconstriction

Angiotensin receptor blockers (ARB)

Similar to ACE inhibitors as they block
vasoconstriction, but at different sites

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ACE INHIBITORS
Block conversion of Angiotensin I to
Angiotensin II
Vasodilatation and decreased sodium
retention
Blocks bradykinin breakdown
Additional vasodilatation
Cough, angioedema
Absence of reflex tachycardia (downward
resetting of baroreceptors/enhanced
parasympathetic activity)
Angiotensin-Converting Enzyme Inhibitors
(ACEI)

captopril (Capoten) enalapril (Vasotex)

lisinopril (Zestril)

Decrease vasoconstriction

Useful in patient with other conditions like

heart failure, diabetes, renal disease and
cerebrovascular disease
Drug of choice for hypertensive patients with
nephropathy because they slow the
progression of the renal disease

70
ACE Inhibitors

All ACEIs except Fosinopril and

moexipril are eliminated primarily by
the kidneys
ACE Inhibitors
Captopril
Half-life= 2.2 h
Enalapril prodrug converted to
enalaprilat (peak at 3-4 hr; half-
life=11 hr)
Lysinopril lysine derivative of
enalaprilat
TOXICITY
Severe hypotension after initial doses
Acute renal failure in patients with
bilateral renal artery stenosis
Rash or photosensitivity
Hyperkalemia
Dry cough, angioedema (bradykinin-
mediated)
Contraindicated during second and third
trimester of pregnancy
ACEI INTERACTIONS
Diuretics
Vasodilators
Potassium Sparing Diuretics
NSAIDs
Antacids
Digitalis
Lithium

74
ACEI Contraindications
Collagen Disease
Heart Failure*
Angioedema
Pregnancy, lactation, children

75
Angiotensin-Receptor Blockers
Competitive angiotensin II receptor
antagonists
Effect same as ACEIs
Vasodilatation and decreased sodium retention
Do not block bradykinin metabolism
Same efficacy with ACEIs; more expensive
For those unable to tolerate ACEIs
Losartan, Valsartan - first marketed AT1
receptor blocker
Angiotensin II Receptor Blockers
(ARB)
losartan (Cozaar); telmisartan
(Micardis); Valsartan (Diovan)

Low incidence of cough, rash or

taste disturbance

Blocks the effects of angiotensin

II, decreasing BP without marked
change in heart rate

77
Angiotensin II Receptor
Blockers
SIDE EFFECTS:
Dizziness, URTI, hyperkalemia

CONTRAINDICATIONS:
Renal impairment, heart failure
Pregnancy, lactation, children

INTERACTIONS: Same with ACEII

78
DRUGS for HYPERTENSION
Based on determinants of Blood
Pressure
ACT ON SITES OF BP CONTROL AND
REGULATION
1. DIURETICS (Thiazides, loop, K
sparers, aldosterone antagonists)
2. SYMPATHOPLEGICS (Beta-blockers,
alpha-1 blockers, centrally acting
alpha-2 agonists)
3. Direct vasodilators (CCBs,
hydralazine)
4. Agents that block production or
PATIENT EDUCATION

Immediate reporting of any adverse side

effects, especially slow or irregular
heartbeat, dizziness, weakness, breathing
difficulty, gastric distress and numbness or
swelling of extremities
Taking medication on time as prescribed
by the physician, not skipping a dose or
doubling a dose, NOT discontinuing the
medication, even, if the patient is feeling
well, without consulting the physician first

80
PATIENT EDUCATION
Rising slowly from reclining position to
reduce lightheaded feeling,
Taking care in driving a car or operating
machinery if medication causes
drowsiness.
Potentiation of adverse side effects by
alcohol, esp dizziness, weakness,
sleepiness and confusion,
Reduction or cessation of smoking to help
lower blood pressure

81
PATIENT EDUCATION
Importance of diet in control of blood
pressure , following the physicians
instructions regarding appropriate diet for
the individual, which may include a low-
salt diet or low sodium or weight reduction
diet if indicated.
Avoiding hot rubs and hot showers, which
may cause weakness or fainting.
Mild exercise on a regular basis as
approved by the physician.

82
PATIENT EDUCATION
Always swallowing the extended-release
products intact, Quick release of the
medication into the system can cause the
blood pressure to drop suddenly causing
loss of consciousness and possible shock.
Avoiding grapefruit juice while taking
calcium channel blockers which can
increase the risk of hypotension and other
adverse cardiac effects.

83
DRUGS FOR
ANGINA PECTORIS
Angina pectoris
Definition
Severe chest pain occurring when
coronary blood flow is inadequate to
supply the Oxygen required by the heart
Causes
1. Obstruction to coronary flow
(atheromatous, classic angina)
2. Spasm (angiospastic, variant
angina- vasospastic or variant
angina)
Unstable angina change in character,
frequency, duration of chest pain
(formation of labile, non-occlusive
thrombi in fissure or ulcerated plaque)

IN THEORY, correction may be made by

1. Decreasing O2 demand
2. Increase delivery by increasing
coronary flow
Determinants of Myocardial Oxygen
Consumption
Myocardial fiber tension
Diastolic factors
Blood volume
Venous tone
Systolic factors
Peripheral resistance
Heart rate
Contractility
Ejection time
 Physical exercise and sympathetic
discharge precipitate angina in
patients with obstructive coronary
disease
Principles of Therapy for
Angina
1. Modification of risk factors for coronary
atherosclerosis, smoking, hypertension,
dyslipidemia
2. Reduction of myocardial O2
demand and increase coronary
blood flow to restore balance
3. Prevent myocardial infarction (MI) with
antiplatelet and lipid-lowering agents;
Angiotensin converting enzyme (ACE)
inhibitors
ANTIANGINALS
NITRATES
Long acting
Intermediate
VASODILATORS acting
Short acting

CALCIUM BLOCKERS

CARDIAC
DEPRESSANTS

BETA BLOCKERS
ANTIANGINALS
1. NITRATES
2. CALCIUM CHANNEL BLOCKERS (CCBs)
3. BETA-BLOCKERS

. Decrease myocardial O2 requirements

(heart rate, volume, blood pressure,
contractility)
. Nitrates and CCBs may reverse
coronary arterial spasm
NITRATES AND NITRITES
Mainstay of therapy; provide
immediate relief
Simple nitric and nitrous acid esters
of polyalcohols
Nitroglycerin is the prototype of this
group
Used as dynamite, but formulations
used in medicine are not explosive
All therapeutically active agents in
the nitrate group have identical
Pharmacokinetics
Difference: Pharmacokinetic factors
(determine choice of agent and mode of
therapy)
Highly metabolized in the liver (first pass
effect)
Oral bioavailability of traditional nitrates
(nitroglycerin and isosorbide dinitrate) is
very low (<10-20%)
Sublingual route is preferred
Total duration of effect 15-30 minutes; oral
preparation available for a longer duration
of action
NITRATE PREPARATIONS
NITROGLYCERIN:
nitrostat, nitrolungual , transderm
nitro ( tabs, spray and patch)
ISORBIDE DINITRATE:
Tabs Sl, tabs caps, tabs ER
ISOSORBIDE MONONITRATE Monoket,
Ismo, Imdur (SR) tabs

95
 Nitroglycerin metabolites (two
dinitroglycerins and two mononitro
forms)
Dinitro derivatives significant
vasodilator ; most of the therapeutic
effect of orally administered
nitroglycerin
5-mononitrate metabolite of isosorbide
dinitrate; active; clinically available as
isosorbide mononitrate; 100%
bioavailable
Excretion: glucoronide derivatives of
Pharmacodynamics
Nitroglycerin denitrated by
glutathione S-transferase free
nitrite ion is released
nitric oxide increase in cGMP
smooth muscle relaxation

Production of prostaglandin E and

prostacyclin (PGI2) and
hyperpolarization may also be
involved
 TOLERANCE important consideration in
the use of nitrates; partially caused by
decrease in tissue sulfhydryl groups

ORGAN SYSTEM EFFECTS

- Relaxes all types of smooth muscle
irrespective of the cause of preexisting
muscle tone
- Practically no direct effect on cardiac or
smooth muscle
Nitrates
1. Vascular Smooth Muscle all
segments from large arteries
through large veins relax; veins
respond at lowest concentrations,
arteries at slightly higher ones
* Primary direct effect: increased
venous capacitance and decreased
ventricular preload
Nitrates: Side Effects
Dilation of large arteries (aorta);
temporal artery pulsations and
throbbing headache due to
meningeal artery pulsations

INDIRECT EFFECTS : due to

compensatory responses
(baroreceptors and hormonal
mechanisms) tachycardia and
increased cardiac contractility; salt
and water retention; contribute to
 May redistribute coronary flow from
normal to ischemic areas
2. Relaxation of smooth muscle of the
bronchi, GIT, GUT (brief duration)
NITRATES

CONTRAINDICATIONS: glaucoma, GI
hypermotility , severe anemia,
hypotension

INTERACTIONS: alcohol,
phosphodiesterase inhibitors
( Sildenafil) potentiate dec. BP

103
TOXICITY AND TOLERANCE
ACUTE ADVERSE EFFECTS direct extensions of
therapeutic vasodilation: orthostatic
hypotension, tachycardia, and throbbing
headache; contraindicated in increased
intracranial pressure

TOLERANCE with use of long-acting

preparations (oral, transdermal), or continuous
IV infusion for more than a few hours without
interruption
e.g. factory workers exposed to high levels of
nitrates in the chemical industry
Nitrate and Nitrite drugs used in angina
Drug Dose Duration of
action
Short-acting
Nitroglycerin, sublingual 0.15-1.2 mg 10-30 min
Isosorbide dinitrate, sublingual 2.5-5 mg 10-60 min
Amyl nitrite, inhalant 0.18-0.3 mL 3-5 min
Long-acting
Nitroglycerin, oral sustained- 6.5-13 mg q 6- 6-8 h
action 8h
Nitroglycerin, 2% ointment, 1 -1.5 in q 4 h 3-6 h
transdermal
Nitroglycerin, slow-release 10-25 mg q 24 8-10 h
patch, transdermal h
Isosorbide dinitrate, sublingual 2.5-10 mg per 1.5-2 h
2h
Isosorbide dinitrate, oral 10-60 mg q 4-6 4-6 h
h
CALCIUM CHANNEL BLOCKERS
Calcium influx is necessary for the
contraction of smooth and cardiac
muscle
Discovery of the Calcium channels
paved the way for the development
of clinically useful blocking drugs (L-
type channel blockers)
CALCIUM CHANNEL BLOCKERS
CALCIUM CHANNEL
BLOCKERS
1. Decrease myocardial oxygen requirement
Decrease myocardial contractile force
Decrease arteriolar tone and systemic vascular
resistance (SVR)
Decrease arterial and intraventricular pressure
Decrease wall stress
Decrease Heart rate (verapamil, diltiazem)
2. Prevent primary cause of variant angina
*focal coronary artery spasm
*most effective prophylactic treatment
CALCIUM CHANNEL
BLOCKERS
DIHYDROPYRIDINES (DHP) VERSUS
NON-DIHYDROPYRIDINES (non-DHP)
Dihydropyridines greater ratio of
vascular smooth muscle effects; e.g.,
Nifedipine (prototype), Felodipine
Nondihydropyridines block
tachycardias in Ca++ - dependent
cells (e.g. AV node) more selectively;
e.g., verapamil and diltiazem
CALCIUM CHANNEL
BLOCKERS
TOXICITY most important toxic
effects: direct effects of therapeutic
action; i.e. , cardiac depression and
cardiac arrest, bradycardia, AV block,
heart failure
Non-specific sympathetic antagonism
Most marked in Diltiazem, much less
in verapamil
Nifedipine none; significant reflex
tachycardia
Diltiazem and verapamil
Supraventricular
tachycardia
BETA-BLOCKERS
REMEMBER?
Antagonizes the effects of
catecholamines at beta-
adrenoreceptors; some have partial
agonist effect
Hemodynamic effects
Decreased heart rate, BP, contractility
Decreased myocardial O2 requirement
Increased diastolic perfusion time
Relief of angina and improved
exercise tolerance

BETA-BLOCKERS
Remember?

Metabolism

Selectivity
ANTIANGINALS
1. NITRATES
2. CALCIUM CHANNEL BLOCKERS
(CCBs)
3. BETA-BLOCKERS

. Decrease myocardial O2
requirements
. Increase oxygen delivery
Nitrates and CCBs may reverse
coronary arterial spasm
PATIENT EDUCATION FOR NITRATES

Administer fast acting preparations (SL or

spray) while sitting down because the
patient may become lightheaded,
Rising slowly from a reclining position.
NOT drinking alcohol or taking PDE inhibitors
while taking those medicines, which can
cuase serious drop in BP.
Using time-released capsules or tablets to
prevent attacks,

115
PATIENT EDUCATION
Taking timed-release capsules or tablets
on an empty stomach with a full glass of
water.
Allowing sublingual tablets, to dissolve
under the tongue or in the cheek pouch
and not chewing or swallowing them
Repeated sublingual, tablets or spray in 5-
10 minutes for a maximum of three tablets
or sprays (if no relief of chest pain within
15-30 min, call the physician at once,

116
PATIENT EDUCATION
Not discontinuing medication suddenly if
administered for several weeks,
Sensations to be expected, including facial
flushing, headache for a short time,
lightheadness upon rising too suddently.
Preventing attacks of angina by
adminsitering a SL tabor spray before
physical exertion or emotional stress,

117
Summary: drug therapy
for hypertension and
angina
HYPERTENSION
 Antihypertensive Drug
Groups
Hypertension has severe, often fatal
sequelae
Stroke
Myocardial infarction
Renal failure
4 major drug groups
Diuretics
Sympathoplegics
Vasodilators
Angiotensin antagonists
 Diuretics
Lower BP by at least 2 mechanisms
Reduction of blood volume
Alteration of vascular smooth muscle tone
Thiazides (HCTZ)
Adequate for mild and moderate HTN
oral
Loop diuretics (furosemide)
For severe HTN; pulmonary congestion
Oral or parenteral (depends on situation)
Malignant HTN (severe HTN with rapidly progressing
organ damage) IV route
Decrease sympathetic discharge or its effects on the CVS

SYMPATHOPLEGIC DRUGS
Centrally-acting sympathoplegics

Clonidine and methyldopa (active

metabolite: methylnorepinephrine)
Mild to moderate HTN
activate 2 receptors in the brainstem
and reduce sympathetic outflow
reduce cardiac output and peripheral
resistance (to a lesser extent)
 Centrally-acting
sympathoplegics
Clonidine active as given
Methyldopa converted to methylnorepinephrine in
the CNS stored in vesicles in noradrenergic neurons
and released slowly
Duration of action
Clonidine
Oral 8 12 hrs; transdermal 7 days
Oral methyldopa 12 24 hrs
Toxicities
Clonidine minimal in antihypertensive doses BUT sudden
cessation may cause severe rebound HTN
Methyldopa sedation, bradycardia, hemolytic anemia (rare)
 Ganglion Blockers
Trimethaphan (rarely used)
Nicotinic cholinoceptor antagonist
Parenteral agent for the rapid reduction 0f
severely elevated BP; induction of controlled
hypotension (useful in some types of surgery)
Blocks the nicotinic channel in autonomic
ganglion cells and prevents synaptic transmission
Administered via constant IV infusion
Duration of action: 1 3 minutes
Toxicities: marked orthostatic hypotension,
blurred vision, constipation, urinary retention
Postganglionic sympathetic neuron blockers

Reserpine
Guanethidine
Postganglionic sympathetic neuron blockers

Alter the storage and release of NE and other

amine neurotransmitters (rarely used)
Reserpine
Blocks the uptake of catecholamines and 5-
hydroxytryptamine (5-HT) into storage vesicles
deplete transmitter stores in the nerve endings
Orally active; duration 12 48 hours
Guanethidine
Prevents the release of transmitter vesicles and
also depletes norepinephrine stores
Used orally; duration several days
 Postganglionic sympathetic neuron
blockers
Toxicities
Reserpine
May cause severe psychiatric depression
(limit use; NOT for clinically depressed
patients)
Diarrhea, nasal stuffiness, sexual
dysfunction
Guanethidine
Does not enter CNS
Causes same peripheral toxicities as
reserpine
Marked orthostatic hypotension and salt and
 Adrenoreceptor blockers
Prazosin, doxazosin, terazosin
 Adrenoreceptor blockers
Used for mild to moderate
hypertension
Selectively block 1 receptors,
causing a decrease in peripheral
resistance
Orally active; duration: 10 24 hrs
Toxicities:
Occasional marked first-dose
hypotension, mild tachycardia, salt and
water retention
 Adrenoreceptor blockers
Important as monotherapy for mild
hypertension and as part of
polypharmacy for moderate and
severe hypertension
 Adrenoreceptor blockers
Multiple subgroups
1 selective agents atenolol,
metoprolol
Drugs with reduced CNS effect atenolol
Partial agonist blockers pindolol
blockers lacking in local anesthetic
effects timolol
Drugs with some vasodilating action
carvedilol
blockers with a very short duration
esmolol (15 minutes)
 Adrenoreceptor blockers
Esmolol
Used for hypertensive emergencies and acute
arrhythmias
Except for esmolol (IV only), the blockers are
orally active
Duration of action varies from 6 to 24 hours
Toxicities
Asthma, bradycardia, atrioventricular blockade, heart
failure
Less dangerous toxicities:
Mental lassitude, sleep disturbances, sexual responses,
blunting of the response to hypoglycemia
Important as part of polypharmacy for severe hypertension
Calcium channel blocker subgroup is also used in
monotherapy for mild to moderate hypertension

VASODILATORS
 Hydralazine
Orally active; duration of action 4
8 hrs
Toxicities
Moderate compensatory tachycardia
(prevent with reserpine or a blocker)
Salt and water retention (prevent with a
thiazide or loop diuretic)
Reversible systemic lupus
erythematosus
 Minoxidil
Orally active; converted to active
metabolite (minoxidil sulfate);
duration of action: 4 5 hours
Causes severe compensatory
tachycardia (prevent with blocker)
and salt and water retention (prevent
with loop diuretic)
Causes hirsutism exploited in a
hair-restoring lotion preparation
(Rogaine)
 Calcium channel blockers
Verapamil and diltiazem
Balanced cardiac and vascular L-type
CCB with similar efficacy in depressing
cardiac and vascular smooth muscle
Orally active; half-lives of 6 7 hours
Toxicities
Bradycardia, AV block, heart failure,
constipation, edema
 Calcium channel blockers
Vasoselective calcium channel blockers
Dihydropyridines (nifedipine)
Produce greater L-type calcium channel
blockade in vessels than in heart
Orally active; half-lives of 6 24 hours
Toxicities
Immediate release nifedipine causes a sudden
drop in blood pressure and compensatory
sympathetic discharge
Constipation, edema, bradycardia (rare), AV block,
heart failure
 Parenteral drugs for
hypertensive emergencies
Nitroprusside
Diazoxide
 Parenteral drugs for
hypertensive emergencies
Nitroprusside
Spontaneously releases nitric oxide in the blood; used
more frequently
Duration of action few seconds (constant IV infusion
required)
Toxicities: hypotension, tachycardia, accumulation of
metabolites (cyanide and thiocyanate)
Diazoxide
Potassium channel opener
Duration of action several hours given by intermittent
injection
Toxicities: tachycardia, salt and water retention,
hyperglycemia
Angiotensin-converting enzyme (ACE inhibitors)
Angiotensin-receptor inhibitors

ANGIOTENSIN
ANTAGONISTS
 ACE inhibitors
Captopril, enalapril
Useful as monotherapy in mild and
moderate hypertension
Beneficial in heart failure and diabetes
MOA: block ACE reduce synthesis of
angiotensin II from angiotensin I
Also inhibit breakdown of bradykinin
(vasodilator peptide)
 ACE inhibitors
Orally active; may be given once
daily; half-lves of 1 2 hours
Toxicities: cough, renal damage in
nondiabetic renal vascular disease,
renal dysgenesis in the fetus
(absolutely contraindicated in
pregnancy
 Angiotensin-receptor
inhibitors
Used in patients who cannot tolerate ACE
inhibitors
Block angiotensin II AT1-type receptors in
the heart, blood vessels, adrenal cortex,
and kidneys
Orally active; duration of action: 4 10 hrs
Toxicities: cause less cough than ACE
inhibitors, can lead to renal damage in the
fetus, absolutely contraindicated in
pregnancy
 PHARMACOLOGIC
MANAGEMENT OF
HYPERTENSION
Patients with primary or essential
HPN are initially given monotherapy,
usually a thiazide, blocker, calcium
channel blocker, or ACE inhibitor
Escalated to polypharmacy if
monotherapy is unsuccessful
Drug choice should maximize efficacy
and minimize toxicity (diuretic plus
sympathpplegic plus vasodilator)
 PHARMACOLOGIC
MANAGEMENT OF
HYPERTENSION
Emergency or malignant HPN is
associated with the risk of imminent
myocardial infarction or stroke
Treated with a parenteral vasodilator,
blocker, and loop diuretic (in patient)
Pressure is reduced gradually over a
period of several hours, not suddenly, to
prevent ischemic effects of reduced
perfusion
ANGINA PECTORIS
 Types of Angina
Angina recurrent, severe, crushing pain in the
chest, neck or shoulder and arm
Results from myocardial ischemia caused by coronary
blood flow that is inadequate for the needs of the heart.
Often atypical in women
Effort angina occur when oxygen demand
increases
Variant angina coronary artery vasospasm
Acute coronary syndrome (unstable angina)
signals an impending myocardial infarction
MEDICAL EMERGENCY
 Nitrates
Nitroglycerin, isosorbide dinitrate,
other organic nitrates
For effort and variant angina
Venodilators
Act through the release of nitric oxide
in smooth muscle of blood vessels
Reduce venous return (preload,
end-diastolic pressure), cardiac size,
and diastolic myocardial oxygen
consumption
 Nitrates
Formulations: sublingual, oral, transdermal
Toxicities:
Tachycardia, orthostatic hypotension, and
headache
Transdermal nitroglycerin patch therapy is
subject to development of marked tolerance if
patch is allowed to remain on the skin for more
than 12 hours
NITRITES are rarely used in angina but have
found a medical application as antidotes for
cyanide poisoning
 Calcium Channel Blockers
Verapamil, diltiazem, and nifedipine
and other dihydropyridines cause
smooth muscle relaxation and
cardiac depression
Used for prophylaxis of effort or
variant angina, but have little or no
benefit in acute coronary syndrome
Act in effort angina by causing
peripheral vasodilation (reduced
afterload) and reduction of cardiac
 Calcium Channel Blockers
Prevent coronary vasospasm
Toxicities:
Excessive cardiovascular effect
(hypotension, AV blockade, and
bradycardia), constipation, and edema
 Blockers
adrenoreceptor blockers
(propranolol) prevent angina by
reducing blood pressure and cardiac
work
Not effective in variant angina, but
are very important in effort angina
and acute coronary syndrome