Drugs act on cardiovascular

system

CNS

Heart

BV

SympatheticNerve

β1

α1

Kidney

β1 Renin

Ag

A-I A-IIACE

Ca++

Aldosteron

RetentionNa & water

BR

α2 BP

Patho-physio-pharmacologyof CV functions

The Renin-Angiotensin system in the development of high blood pressure

Angiotensinogen

Non-reninenzymes

CAGEChymaseCathepsin G

t-PACathepsin G

ACE

Renin

ACE pathwaysNon-ACE pathways

AT2

Angiotensin I

Adapted from Hollerberg NK. Am J Med Care,1998;A(suppl7)5384-5387CAGE= Chymotrypsin like

Angiotensin Generating Enzyme

Angiotensin II

AT1

• vasoconstriction• aldosterone release, Na

and fluid retention• cell proliferation,

hypertrophy• Sympathetic activation

• Vasodilation (?)• Bradykinin, NO and

cGMP release• Antiproliferation,

apoptosis stimulation, tissue regeneration

Kallikrein

NOPG

Kininogen

Bradykinin

Inactivepeptides

vasodilation

ACE

ChymaseCathepsin G

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 endingsThe catecholamine then binds to the receptors

and causes a physiologic response

Mixed-acting sympathomimetic

Sympathetic Receptor TypesReceptor 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 Responsesto Stimulation

Organ Location Receptor Response

Cardio-vascular

Blood vessels alpha1 Constriction

beta2 Dilatation

Cardiac muscle

beta1 Increased contractility

AV Node beta1 Increased

SA Node beta1 Increased

Respiratory Bronchial muscles

beta2 Dilatation/Relaxation

Adrenergic Receptor Agonists and Antagonists

-AR non selective• Agonists: I > E > NE• Antagonists: Propranolol,

Nadolol, Timolol

1-AR • Agonists: Dobutamine, Dopamine• Antagonists: Atenolol, Esmolol,

Metoprolol

2-AR• Agonists: Albuterol, Ritodrine,

Tertbutaline, Salmeterol, • Antagonists: Butoxamine

-AR nonselective• Agonists: E > NE > > Iso,

Clonidine, Oxymetazoline• Antagonists: Dibenamine,

Phenoxybenzamine, Phentolamine, Tolazoline

1-AR• Agonists: Phenylephrine,

Methoxamine• Antagonists: Doxazosin,

Prazosin, Terasin,

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)

Beta Blocker↓ activation of β1 receptor in

heart ↓ CO

↓ Renin ↓ angiotensin II

↓ aldosteron

↓ Na and water

retention↓ blood volume

↓PR

Mechanism of action Beta Blocker

↓BP

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

α1–blockers

ACE inhibitors

Angiotensin II antagonists

Ca antagonists

Blood Pressure Regulation

Cardiac output X Peripheral Resistence

CARDIAC Heart rate

Contractility

LOCALIonicAuto reg

NERVOUSSYMPATHETIC

Constrictoralpha

Dilatorbeta

RENAL FLUID VOLUME• Sodium• Minerolcorticoid

HUMORAL

VASOLIDATOR VASOCONSTRICTOR

BARORECEPTOR

Prostaglandins, CatecholsKININ ANGIOTENSIN,

Low concentrations of drug

1 >

Inc.

reflex

2-vasodil

1-slight inc

2 > 1 >

2-vasodil

1-strong inc

1 and D1

1-slight inc

D1- vasodil

Renal and mesenteric blood

vessels

Different Pharmacological Profilesof Beta-Blockers Studied in

Heart Failure

β1- blockerβ1-

blockadeβ2-

blockadeα1-

blockade ISAAncillary

properties

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 DemandDouble 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)