201103-fkg-Drugs act on cardiovascular system

Drugs act on cardiovascular  system

Patho-physio-pharmacology of CV functions BR

CNS

2

1

Heart

BP

Sympathetic Nerve

1 BV

1

Retention Na & water 

Ag

Kidney

Ca++

Renin A-I

A-II ACE

Aldosteron

The

Renin-Angiotensin system in the development of high blood pressure Non-ACE pathways

ACE pathways Angiotensinogen

Non-renin

Kininogen Kallikrein

Renin

enzymes

Angiotensin I t-PA Cathepsin G

CAGE

ACE

Chymase Cathepsin

Bradykinin

G

Angiotensin II

AT1

AT2

Chymase Cathepsin

G

Inactive peptides

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

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

Cardiovascular 

Response

Adrenergic Receptor Agonists and Antagonists F-AR non selective Agonists: I > E > NE Antagonists: Propranolol, Nadolol, Timolol

F1-AR Agonists: Dobutamine, Dopamine Antagonists: Atenolol, Esmolol, Metoprolol

F2-AR Agonists: Albuterol, Ritodrine, Tertbutaline, Salmeterol, Antagonists: Butoxamine

E-AR nonselective Agonists: E > NE > > Iso, Clonidine, Oxymetazoline Antagonists: Dibenamine, Phenoxybenzamine, Phentolamine, Tolazoline

E1-AR Agonists: Phenylephrine, Methoxamine Antagonists: Doxazosin, Prazosin, Terasin,

E2-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  1 receptor in heart

Beta Blocker 

 Renin

 CO

 angiotensin II

 aldosteron  Na and water  retention

 blood volume

PR

BP

What

are F-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 Fblockers with other CV agents

First-line

antihypertensive drugs Diuretics

± blockers

1±blockers

ACE inhibitors

Ca

Angiotensin II antagonists

antagonists

Blood Pressure Regulation

Cardiac Heart

CARDIAC

BARORECEPTOR

output X Peripheral Resistence LOCAL Ionic Auto reg

rate

Contractility

NERVOUS

RENAL FLUID VOLUME Sodium Minerolcorticoid

SYMPATHETIC Constrictor 

alpha

Dilator  beta

HUMORAL

VASOLIDATOR Prostaglandins, KININ

VASOCONSTRICTOR ANGIOTENSIN, Catechols

Low concentrations of drug E1 > F

F2 > E1

F>E

F1 and D1

reflex

F1-slight inc

F1-strong inc

F1-slight inc

D1- vasodil

Inc.

F2-vasodil

F2-vasodil

Renal and mesenteric blood vessels

Different Pharmacological Profiles of Beta-Blockers Studied in Heart Failure 





1211- blocker  blockade blockade blockade

ISA

Ancillary 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

Demand Double product = (Heart Rate) (Systolic Blood Pressure)

anti-ischemic effects of  -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)