CVS Pharmacology 1

CVS Pharmacology
The study of drug effect on CVS( heart, blood
vessels).
Approximately 5 liters of blood that the blood
vessels transport.
Responsible for transporting oxygen, nutrients,
hormones, and cellular waste products throughout
the body.
 CV system is powered by the body’s hardest-
working organ — the heart.
Common CV disorders are:
HTN, CHF, Arrhythmias, Angina pectoris

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 Definition of HTN
Actual level of pressure for hypertensive is
difficult to define.
Because it depends on:
 Patient’s age, sex, race, and lifestyle.
As a working definition, many cardiovascular
treatment centers consider that a DBP of 90 mm
Hg or higher or a SBP of 140 mm Hg or higher
represents hypertension.

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 Definition of HTN cont’d
 Persistent (repeated & reproducible) elevation of
arterial blood pressure(BP).
 Patients with diastolic blood pressure (DBP)
values <90 mm Hg and systolic blood pressure
(SBP) values >140 mm Hg have isolated systolic
hypertension.
 A hypertensive crisis (BP >180/120 mm Hg)
may be categorized as either;
– A hypertensive emergency (malignant HTN): extreme
BP elevation with acute or progressing target organ
damage (heart, brain or kidney) or
– A hypertensive urgency: severe BP elevation without
acute or progressing target organ injury.
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 BP Classification cont’d

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 Mechanisms of hypertension

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 Regulation of Blood Pressure
1. Expansion of intravascular volume
• Initially results in CO which → ABP(arterial BP).
– To maintain constant blood flow, auto
regulation in vascular beds (kidney, brain) will
result in PVR & CO reduces while ABP remains
elevated.
• Intra vascular volume expansion results from:
Excess intake of NaCl.
Impaired excretion of NaCl due to:
Intrinsic renal disease, i.e. renal failure or
Increased amount of mineralocorticoid.

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 2. Autonomic Nervous System
• Responds to Pressure, volume, and chemoreceptor
signals.
• The three endogenous catecholamines;
norepinephrine, epinephrine, and dopamine, play
important roles in tonic and phasic cardiovascular
regulation.

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Adrenergic receptors:α1 ,α2, β1, β2
 α1R: located on postsynaptic cells in smooth
muscle and elicit vasoconstriction.
 α2R: localized on presynaptic membranes of
postganglionic nerve terminals that synthesize
norepinephrine.
 Act as negative feedback controller.
 β1R; Cardiac: result in increased myocardial
contractility→ increased COP.
 Renal: lead to release of renin.
 β2R: vasodilatation when activated.

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3. Renin Angiotensin Aldosterone System (RAAS)
 Contributes to the regulation of arterial pressure
primarily via the vasoconstrictor properties of
angiotensin II and the sodium-retaining
properties of aldosterone.
Primary stimuli for renin secretion:
Decreased NaCl transport in the thick
ascending limb of the loop of Henle
Decreased pressure or stretch within the renal
afferent arteriole
Sympathetic nervous system stimulation of
renin-secreting cells via β1 adrenoreceptors.

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 liver

lungs

kidney

Adrenal medulla Vasoconstriction

Sodium & water retention
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Aldosterone:
Increases sodium reabsorption

Water reabsorption

K and H are exchanged for Na.

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 Etiology
Based on the cause HTN broadly classified into
two;
1. Primary (Essential)
2. Secondary (non-essential)

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 Essential HTN (hyperpiesia)
 HTN with no definable etiology.
 90-95% of hypertensive patients.
 Multifactorial;
Age
Genetics: e.g. family history
 15 – 35% of heritability
Environmental
Urbanization
Psychological stress
Dietary factors:
 Increased saturated fat, alcohol & salt intake
 Low dietary intakes of Ca++ & K+.
Obesity: 60% of hypertensives are overweight by > 20%
Physical inactivity.
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 Factors affecting the course of HTN
 Race: blacks have 4x risk of HTN related mortality
compared to whites.
 Age: the younger onset, the greater the reduction of life
expectancy
 Gender: females fare better up to 65yr.
 DBP: Persistently > 115mmHg →poor prognosis.
 Smoking

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 Secondary HTN (symptomatic)
• Results from a specific cause;
 Endocrine disease: Cushing's disease or
Phaeochromocytoma or 1º
hyperaldosteronism.
 Kidney disease: renal artery stenosis.
 DM
• Accounts for only 5-10% of cases.
• Identifying patients is important b/c;
Correction of the cause may be curative.
Provide insight into essential HTN.

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1. Life style measures (Non Pharmacologic)
 Reduce BP and enhance drug therapy.
 Recommendation includes:
1. Weight reduction (maintain normal body wt).
2. Diet: reduce calorie for obese. Rich in fruits
& vegetables, low fat & dairy products (DASH)
3. Salt restriction.
4. Physical activity: e.g. Brisk walking for 30
minutes or more.
5. Limit alcohol intake.
6. Smoking cessation.
7. Psychological methods (relaxation, meditation etc.)

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 2. Pharmacologic therapy
• Should be individualized.
• Indications:
 Stage 1 HTN
 Stage 2 HTN
• Treat DM, dyslipidemia and other co-
morbidities optimally.

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 Drug categories
 Drug selection based on:
a. Age
b. Comorbidities/TOD
c. Side effects
d. Cost of the drug

Anti hypertensive drugs:

a. Diuretics: Thiazides
First line agents
b. ACEI/ARB
c. Beta blockers
d. CCB
e. Vasodilators
f. Renin inhibitor (aliskiren)
g. Central alpha-2 agonists
h. Alpha-1 blockers
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CVS Pharmacology 21
 Thiazide Diuretics
Mechanism: inhibit Na/Cl pumps in the
Veins distal convoluted tubule (DCT).
Examples:
Hydrochlorothiazide 12.5-25 mg daily.
Thiazides

Chlorthalidone 12.5-50 mg daily.

Effective first line agent and provides
synergistic benefit.
As single agent more effective if CrCl
>30 ml/min.
Compelling indications: HF, High CAD
risk, Diabetes, Stroke.
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 Loop Diuretics
Mechanism: Inhibit Na/K/2Cl ATPase
Veins in thick ascending loop of henle (TALH).
Examples:
Furosemide 20 mg BID.
Typically only beneficial in patients with
resistant HTN and evidence of fluid.
Loops

Effective if CrCl <30 ml/min.

Administer AM and lunch time???

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 Aldosterone Receptor Antagonists
Mechanism: inhibit aldosterone’s
Veins
effect, reducing Na and water retention.
Examples:
Spironolactone 25 mg daily.
Aldosterone Antagonists

Can provide as much as 25 mmHg BP

reduction.
Monitor SCr and K.
Compelling indications: HF.

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 Nitrates
Mechanism: Direct venodilation by
release of nitric oxide (NO).
Veins
Examples:
Isosorbide dinitrate 10 mg TID.
In renal patients with resistant
Nitrates

hypertension addition to 3-4 drug

regimen may help get patient to goal.
Provide 8hr nitrate free interval
daily???
Compelling indications: Angina.

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 ACEI/ARBs
Mechanism: inhibit vasoconstriction by
inhibiting synthesis or blocking action of
Veins angiotensin II; provides balanced
vasodilation.
Examples:
Enalapril 2.5-40 mg daily –BID.
ACEI/ARBs

Lisinopril 5 – 40 mg daily.
Irbesartan 150-300 mg daily.
Losartan 25-100 mg daily – BID.
Monitor: SCr, K
Compelling indications: HF, post-MI,
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High CAD risk, Diabetes, CKD, Stroke. 26
 Beta Blockers (BB)
Mechanism: Competitively inhibit the
binding of catecholamines to beta-
Heart
adrenergic receptors.
Examples:
Atenolol 25-100 mg PO daily.
Beta Blockers

Metoprolol 25 -100 mg PO daily or BID.

Carvedilol 6.25-25 mg PO BID.
Monitor: HR, Blood Glucose in DM.
Compelling indications: HF, post-MI, High
CAD risk, Diabetes.

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Non dihydropyridine CCBs (Diltiazem & Verapamil)
Mechanism: Decrease calcium influx into
Heart cells of vascular smooth muscle &
myocardium.
Examples:
Diltiazem 60-480mg q6h to daily.
Nondihydropyridine

Verapamil 60-480 q8h to daily.

Monitor: HR
CCBs.

Verapamil causes constipation.

Relatively contraindicated in HF.
Compelling indications: DM, High CAD
risk.
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 Dihydropyridine Calcium Channel Blockers
Mechanism: decrease calcium influx into
cells of vascular smooth muscle 
Arteries vasodilation…
Examples:
Amlodipine 2.5-10 mg PO daily.
Dihydropyridine CCBs

Felodipine2.5-10 mg PO daily.
Do not use immediate release
nifedipine ???
Monitor: Peripheral edema, HR (can cause
reflex tachycardia).
Good add on agent if cost is not an issue.
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 Alpha2 Agonists: Central Acting Agents
Mechanism: false neurotransmitters;
Heart reduce sympathetic outflow reducing
sympathetic tone.
Examples:
Via Central Mechanism:

Clonidine 0.1-0.6 mg PO BID-TID;

patch
Clonidine

Methyldopa, Guanabenz, Guanfacine

Monitor: HR
Side effects often limiting: dry mouth,
orthostasis, sedation.

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 Vasodilators
Mechanism: direct vasodilation of
arteries.
Arteries Examples:
Hydralazine 20-400 mg BID-QID.
Minoxidil 2.5-40 mg PO daily-BID.
Hydralazine

Monitor: HR (can cause reflex tachycardia),

Minoxidil

Na/Water retention.
Hydralazine is an alternative in HF if ACEI
contraindicated.
Consider minoxidil in refractory patients on
multi-drug regimens.

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 Alpha1 Blockers
Mechanism: Inhibit peripheral post-
synaptic alpha1 receptors causing
Arteries
vasodilation.
Examples:
Terazosin 1 – 20 mg daily.
Alpha1 Blockers

Doxazosin 1 – 16 mg daily.
Cause marked orthostatic hypotension,
give dose at bedtime.
Can be beneficial in patients with BPH.

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 ACEI/ARBs
Mechanism: inhibit vasoconstriction by
inhibiting synthesis or blocking action of
Arteries angiotensin II; provides balanced
vasodilation.
Examples:
ACEI/ARB

Enalapril 2.5-40 mg daily –BID

Lisinopril 5 – 40 mg daily
Irbesartan 150-300 mg daily
Losartan 25-100 mg daily - BID
Monitor: SCr, K
Compelling indications: HF, post-MI, High CAD
risk, Diabetes, CKD, Stroke.
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CVS Pharmacology 34
 Heart Failure
Progressive inability of the heart to
supply adequate blood flow to vital
organs.
Classically accompanied by
significant fluid retention.
Leading cause of mortality and
morbidity.
Common symptoms
 Shortness of breath (SOB)
 Edema
 Fatigue

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CVS Pharmacology 36
 Infections
 Arrhythmias
 Physical, Dietary, Fluid, Environmental, and
Emotional Excesses.
 Myocardial infarction
 Pulmonary embolism
 Anemia
 Thyrotoxicosis and pregnancy
 Aggravation of hypertension
 Infective endocarditis

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 STAGE DISABILITY
CLASS 1 No symptoms- Can perform ordinary
MILD activities without any limitations

CLASS 2 Mild symptoms - occasional

MILD swelling Somewhat limited in ability
to exercise or do other strenuous
activities
CLASS 3 Noticeable limitations in ability to
exercise or participate in mildly
strenuous activities
MODERATE
Comfortable only at rest

CLASS 4 Unable to do any physical activity

SEVERE without discomfort Some HF
symptoms at rest
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 Drugs for CHF

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 Drugs for CHF
Vasodilators – α-adrenergic blockers ,ACEI,
direct smooth-muscle relaxants (e.g. hydralazine)
Diuretics
Beta blockers
Cardiac Inotropes – Digoxin, Dobutamine,
Milrinone.

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 Drugs for CHF
Vasodilators
ACE Inhibitors :
Captopril, Lisinopril, Enalapril, Ramipril, Quinapril.

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ACE Inhibitors:
 Reduction in arterial resistance (afterload).
 Reduction in venous tension (preload).
 Reduction in aldosterone secretion.
 Inhibition of cardiac and vascular remodeling.

 Dry irritating persistent cough,

 Hyperkalemia,
Adverse effect
 Angioedema,
 Fetal toxicity, CI in pregnancy.

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 Drugs for CHF…
AT-1 receptor blockers (ARB):
Losartan, Valsartan, Irbesartan, Candesartan
Competitive antagonists of ATII (AT-1).
No inhibition of ACE or Cough. (do not affect
bradykinin metabolism).

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Beta Blockers (BB):
Inhibiting the sympathetic nervous system.
Anti-arrhythmic properties.
Carvedilol and Metoprolol-most commonly used
for CHF amongst BB.
Cardiac glycosides: Digoxin:
Inhibition of Na/K ATPase pump increase
intracellular Na conc.=>increase cytosolic Ca.
Restores the vagal tone and abolishes the
sympathetic over activity.
Digoxin-first-line drug in patients with CHF who
are in AF
..\Mechanism of action of digoxin.mp4
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 In therapeutic dose leads to partial inhibition
of Na+/K+ ATPase enzyme

K+
 Na +

ca++

ATPase Na + /ca + + ca++

exchange

Na+ ca ++ ca
++
ca++ ca++ ca++
Na +
Na +
ca++ ++ ca++
Na+ ca troponin
Na +
Na +
Na+
 intracellular Na+ resulting in:
 ca++ caca
++ ca
++ ++

sarcoplasmic reticulum Actin Myosin

 Force Of Contractility
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 Drugs for CHF…
Digoxin: Adverse effects / Precautions :
NV, gynecomastia, visual disturbances and
psychosis.
 AV block and bradycardia
Toxicity Rx:
With higher than normal doses of potassium.????
Digoxin antibody (digibind) is used specifically to
treat life-threatening digoxin overdose.

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Drugs used in the treatment of Angina pectoris

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Definition
 Angina pectoris is severe retrosternal chest pain due to
myocardial ischemia.
 It occurs when coronary blood flow is inadequate to supply
oxygen required by the heart.
 The immediate cause of angina pectoris imbalance b/n
cardiac work and myocardial oxygen demand & coronary
blood flow and oxygen supply.
 Pain radiating to the left shoulder, left arm, jaw, or
epigastrium.
 Increased myocardial oxygen demand
•Determined by Ventricular wall tension, HR,
contractility.
Decreased myocardial oxygen supply
•Determined by coronary blood flow (CBF), oxygen-
carrying capacity of the blood.

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 Types of Angina
1.Stable /exertional, typical, classic.../ Angina

Underlying Pathology – atherosclerosis in large coronary

arteries.
Episodes precipitated by exercise, cold, stress, emotion,
eating.
Treatment principles: Decrease cardiac load (pre-& after
load), increase myocardial blood flow.
2. Vasospastic/Variant, prinzmetal’s.../ Angina
 Cause: transient vasospasm of coronary vessels.
 Associated: underlying atheromas.
 Pain can occur at rest.
 Treatment principles: ed Vasospasm of
coronary Vessels.

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3. Unstable /preinfarction, crescendo.../ Angina
 Cause: recurrent episodes of small platelet
clots.
Site: ruptured atherosclerotic plague
Precipitated: local Vasospasm
Association: change in character, frequency &
duration of Angina (Stable) and prolonged
episodic angina.
Treatment principles: inhibit platelet
aggregation & thrombus formation, decrease
cardiac load, Vasodilate coronary arteries.

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 Drugs used to treat angina pectoris
The aim of drug therapy is:
• Improve blood delivery to the heart muscle by
dilating coronary blood vessels.
 Increasing the supply of oxygen.
• Improve blood delivery to the heart muscle by
decreasing the work of the heart (↓HR,)
Decreasing the demand for oxygen.

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1. Organic nitrates
 These agents are simple nitric and nitrous acid
esters of polyalcohols.
a. Nitroglycerin (Glycerol trinitrate) is the
prototype of the group.
Due to this sublingual route the preferred
method as it avoids first pass effect and results
a rapid onset of action.
Isosorbide mononitrate has 100%
bioavailability.

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MOA:
Release nitrates → converted to nitric oxide
(NO) → activate guanylyl cyclase → ↑cGMP →
Smooth muscle relaxation.
Adverse effects:
 orthostatic hypotension,
 tachycardia, and
 throbbing headache.
Contra indication:
 elevated intracranial pressure.
 use with phosphodiesterase-5 blockers.

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2. Ca++ channel blockers

3. ß-adrenergic antagonists
Tappering off

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