Drugs act on

cardiovascular
system
 Patho-physio-pharmacology
of CV functions
CNS BR

α2 β1 Heart
Sympathetic BP
Nerve
BV Ca++
α1
Ag Retention
Kidney
Na & water
β1 Renin
A-I A-II Aldosteron
ACE
 The Renin-Angiotensin system in
the development of high blood pressure
Non-ACE pathways ACE pathways
Angiotensinogen Kininogen
Non-renin
enzymes Renin Kallikrein

Angiotensin I Bradykinin
CAGE
t-PA Chymase ACE
Cathepsin G Cathepsin G
Chymase
Angiotensin II Inactive
Cathepsin G
peptides

AT1 AT2 NO
PG
• vasoconstriction • Vasodilation (?)
vasodilation
• aldosterone release, Na • Bradykinin, NO and
and fluid retention cGMP release
• cell proliferation, • Antiproliferation,
hypertrophy apoptosis stimulation,
• Sympathetic activation tissue regeneration
CAGE= Chymotrypsin like
Adapted from Hollerberg NK. Am J Med Care,1998;A(suppl7)5384-5387
Angiotensin Generating Enzyme
 Adrenergic Agents
Mechanism of Action
Direct-acting sympathomimetic:
 Binds directly to the receptor and causes a
physiologic response
Indirect-acting sympathomimetic:
 Causes the release of catecholamine from the
storage sites (vesicles) in the nerve endings
 The catecholamine then binds to the receptors
and causes a physiologic response
Mixed-acting sympathomimetic
Sympathetic Receptor Types
Receptor Effects
Alpha 1 • In walls of blood vessels leading to places other than
skeletal muscles, brain & lungs. Not on heart (cardiac
muscle)
• Excites (constricts) certain blood vessels & in spincters
directing blood to skeletal muscles
• Dilates pupils.
Alpha 2 • On membranes of platelets.
• Promotes blood clotting
Beta 1 • On heart (cardiac muscle) & kidneys
• Cardiac Muscle increases heart rate & strength
Beta 2 • On coronary arteries, bronchioles & on smooth muscle
walls of digestive & urinary systems
• Depresses (dilates) smooth muscle in bronchioles &
coronary arteries increasing blood flow to heart and air
flow to lungs.
 Adrenergic Receptor Responses
to Stimulation
Organ Location Receptor Response
Cardio- Blood vessels alpha1 Constriction
vascular beta2 Dilatation
Cardiac beta1 Increased
muscle contractility
AV Node beta1 Increased
SA Node beta1 Increased
Respiratory Bronchial beta2 Dilatation/
muscles Relaxation
 Adrenergic Receptor Agonists and
Antagonists
-AR non selective -AR nonselective
• Agonists: I > E > NE • Agonists: E > NE > > Iso,
• Antagonists: Propranolol, Clonidine, Oxymetazoline
Nadolol, Timolol • Antagonists: Dibenamine,
Phenoxybenzamine,
Phentolamine, Tolazoline
1-AR
• Agonists: Dobutamine, Dopamine
• Antagonists: Atenolol, Esmolol,
1-AR
Metoprolol • Agonists: Phenylephrine,
Methoxamine
• Antagonists: Doxazosin,
2-AR Prazosin, Terasin,
• Agonists: Albuterol, Ritodrine,
Tertbutaline, Salmeterol,
• Antagonists: Butoxamine
2-AR
• Agonists: a-methyldopamine
• Antagonists: Yohimbine
Stimulation of beta1-adrenergic
receptors on the myocardium,
AV node, and SA node results
in CARDIAC STIMULATION
 Increased force of contraction
(positive inotropic effect)
 Increased heart rate
(positive chronotropic effect)
 Increased conduction through the AV node
(positive dromotropic effect)
 Mechanism of action
Beta Blocker

↓ activation of
Beta Blocker β1 receptor in ↓ CO
heart

↓ Renin ↓ angiotensin II ↓PR ↓BP

↓ aldosteron

↓ Na and
water ↓ blood
retention volume
 What are -blockers used for?
Current Uses
 Treatment
– Angina pectoris (chest pain associated with lack of oxygen
to the heart)
– Arrhythmias (irregular heart rhythms)
– Heart attack
– Heart failure
– Hypertension (high blood pressure)
 Prevention
– Protects the heart in people who have coronary artery
disease
– Reduces risk of stroke
– Protective prior to non-cardiac surgery in persons at high
risk of complications
Beta Blockers
10. Drug interaction -
blockers with other CV
agents
First-line antihypertensive drugs
Diuretics

β– blockers ACE inhibitors

α1–blockers Ca antagonists

Angiotensin II antagonists
 Blood Pressure Regulation

Cardiac output X Peripheral Resistence

LOCAL
CARDIAC Heart rate Ionic
BARORECEPTOR Auto reg
Contractility
NERVOUS
SYMPATHETIC
RENAL FLUID VOLUME
• Sodium
Constrictor Dilator
• Minerolcorticoid
alpha beta
HUMORAL

VASOLIDATOR VASOCONSTRICTOR
Prostaglandins, KININ ANGIOTENSIN, Catechols
 Low concentrations of drug

1 >   2 > 1 > 1 and D1

reflex 1-slight inc 1-strong inc 1-slight inc

D1- vasodil
Renal and
Inc. 2-vasodil 2-vasodil mesenteric blood
vessels
 Different Pharmacological Profiles
of Beta-Blockers Studied in
Heart Failure
β1- β2- α1- Ancillary
β1- blocker properties
blockade blockade blockade ISA
Propranolol +++ +++ 0 0 0
Metoprolol +++ 0 0 0 0
Bisoprolol +++ 0 0 0 0
Bucindolol +++ +++ +(0) +(0) 0
Carvedilol +++ +++ +++ 0 +++(*)

*Antioxidant and antiproliferative.

 Pathophysiology of Angina Pectoris

Oxygen Demand
Double product = (Heart Rate) (Systolic Blood Pressure)
anti-ischemic effects of
β-blocker
Beta Blockers: Therapeutic Uses
 Anti-angina:
– decreases demand for myocardial oxygen
 Cardioprotective:
– inhibits stimulation by circulating
catecholamines
 Class II antidysrhythmic
 Antihypertensive
 Treatment of migraine headaches
 Glaucoma (topical use)