Pharmacology of vasoactive drugs

How the drug acts on the body

• Chemical/physical - e.g. laxatives or antacids
• Binding to a receptor - (majority)

Actions of drugs at the receptor site:

• Agonist: stimulates
• Antagonist: blocks

The simplest analogy to describe this by the action is: the lock and key theory.

It can be more complicated then this

• Different types of agonists (full, partial and inverse)
• Different types of antagonists (competitive, non-competitive, reversible and irreversible).

OBJECTIVES

• Address principles behind pharmacology and drug targets

• Heart Function - and contributing factors

• Review Autonomic Nervous System and Renin-angiotenisin system

• Look at types of receptor targets in cardiovascular system

• Learn about vasoactive drugs and their pharmacological action.

Pharmacology of Vasoactive Drugs

Heather Weerdenburg

Pharmacist

Pharmacodynamics

Lock & Key Theory

Analogy to simply describe how a substrate (e.g. drug) fits into the target receptor e.g. an enzyme.

What happens when CO is low?

Use of Inotropes

Phosphodiesterade III Inhibitors

"inodilators''

Tissue hypoperfusion and subsequent hypoxia.

Metabolism switches from aerobic to anaerobic = building up lactic acid.

If left untreated = multi-organ failure and death.

Conditions when CO is low:

• Cardiogenic shock following MI
• Acute decompensated heart failure
• Post cardiac surgery.

Alters the force of the heart contraction to increase CO and HR

Maintain perfusion to vital organs and tissues

Positive inotropes: Increase for of contraction

Negative inotropes: Decrease force of contraction

Endogenous:

Dopamine, Noradrenaline, Adrenaline

Exogenous:

Drug therapy

Problems

Long term use: Evidence inotropes increases mortality.

Short half life

Compatability and administration issues

Phosphodiesterase - III (PDE3)

Enzyme found in cardiac and smooth muscle cells

Breaks down cyclic-AMP by PDE3

Ideal drug target when down regulation possible e.g. chronic heart failure.

Inhibition = increased calcium = vasodilation and myocardial contraction

PDE3 inhibitors:

Milrinone (most common) and amrinone

Half life: 2 hours

Autonomic Nervous System

Part of the peripheral nervous system

Mainly unconscious control

Innervates different parts of the body including:

• Heart e.g. heart rate
• Lungs e.g. respiration
• Gut e.g. digestion
• Blood vessels e.g. constriction/dilatation
• Bladder e.g. urination
• Eyes: pupil dilation

2 types:

Sympathetic and Parasympathetic

Receptor Signaling

Not a direct effect but activating a chain of events to result in the desired effect on the target

The Heart

Dopamine Receptors

An efficient heart perfuses all body tissues

Tissue perfusion is dependent on Mean Arterial Pressure (MAP)

MAP = Cardiac Output (CO) x Systemic Vascular Resistance (SVR)

SVR = Resistance to blood flow or 'afterload'

CO = Heart rate + stroke volume

Contributors to MAP:

• Autonomic Nervous System &
• Neurohormonal Nervous System

D1 receptors:

• Found in the renal and splanchnic vessels
• Stimulation leads to vasodilation and increased diuresis

D2 receptors:

• Found presynapticically on sympathetic nerve terminals
• Activation results in decreased release of noradrenaline (vasodilation).

Endogenous Inotropes

Sympatheric Nervous System

Alpha 2 receptors

Receptor Targets

• Abundant in cutaneous blood vessels

• Coupled mainly to Gi protein cascade (different to alpha 1 inhibits vasodilation)

• Results in potassium channel conductance = depolarization and vasocontriction

• More limited in distribution than alpha 1 receptors

• adrenaline > noradrenaline

'Fight or Flight"

Neurotransmitters: Noradrenaline (NA) and ACH

Receptors: Alpha & Beta receptors

Beta2-adrenoceptors

Location: smooth muscle cells of blood vessels, bronchi and uterus

Activated by adrenaline > noradrenaline

Gs protein coupled.

Activation results in vasodilation

Alpha1 - receptors

Abundant in blood vessels and myocardium

• Activated by endogenous catecholines: noadrenaline > adrenaline

• Gq coupled cascade

Activation of the receptor =

• Peripheral smooth muscle: vasoconstriction
• Heart: increase force of contraction

Other Inotropes

Beta1-adrenoceptors

Most dominant receptor in the heart

• Gs protein coupled

Stimulation:

• increased heart rate (both atria and ventricles)
• increased force of contraction
• increase the rate of discharge from th SA node
• increased AV conduction
• increased relaxation of the myocardium (lusitropy)

Agonists: Noradrenaline > adrenaline

Antagonists:

Endogenous Inotropes (2)

SUMMARY OF RECEPTORS

Parasympathetic Nervous System

"Rest & digest" and "Feed & breed"

• Neurotransmitter: acetylcholine (ACH)
• Receptors: Nicotinic (N) and Muscarinic (M)

Cardiospecific role:

• Slows the heart rate, and contraction of the atria

• M2 receptors located in atria and SA and AV node. (Less/sparse in the ventiricles = less effect)

• Endurance athletes: increase in tone activity = bradycardia

RECEPTOR PERIPHERAL ACTION HEART ACTION

Alpha 1 Vasoconstriction Inotropy

Alpha 2 Vasoconstriction

Beta 1 Increase force &

rate

Beta 2 Vasodilation

Dopamine 1 Vasodilation

Dopamine 2 Vasodilation

NORADRENALINE

• Predominately alpha 1 agonst (peripheral vasoconstiction) but also has affinity for beta receptors.
• Can be used as an antihypotensive agent (vasopressor) to increase SVR and maintain MAP
• Give via large vein: extravasation and necrosis risk
• Side effects: headache, taccycardia, bradycardia and hypertension

ADRENALINE

• Activity on all receptors (beta at low dose and alpha at high dose)
• Not specific receptor agonist
• Uses: cardiac arrest for inotropic/chronotropic effect + higher dose vasoconstriction and maintains BP due to beta 2 stimulation
• Side effects: tacycardia, arrythmias, anxiety, headache, cold extremities, cerebral haemorrhage and pulmonary oedema

Renin-angiotenisin System

DOPAMINE - COMPLICATED!

Dose dependent action

Low doses - 1-5mcg/kg/min: Stimulation of dompamine receptors

Medium dose - 5-10 mcg/kg/min: predominately beta 1 effects (+ve inotropy)

High doses - 10-20 mcg/kg/min: alpha 1 effects (vasoconstriction and increased BP)

• Has a diuresis effect as increases renal blood flow

Problems

High doses: reduced renal blood flow (monitor BP, ECG and urinary flow)

Side effects: nausea and vomiting, hypertension (high doses), taccycardia, dysrhythmia, angina

MAOI interaction (e.g. selegiline, moclobemide) - reduced metabolism so dose needs to be cut by 1/10th!

Inactivated by alkaline solutions e.g. sodium bicarbonate

Stimulation in juxtaglomerular cell causes the release of renin which causes the chain of events ultimately causing the release angiotensin II

Causes for renin release:

• Beta receptor stimulation: vasodilation
• low blood pressure
• Reduced sodium reabsorption in the kidney

Angiotensin II Role:

• Increases secretion of NA
• Stimulates aldosterone release (Causes renal sodium and water retention)
• Causes smooth muscle vascular vasoconstriction ( 40 x more potent then NA)
• Vasopressin release (increases periperal vascular resistance and increases water retention)
• Bradykinin breakdown (inflammatory mediators that cause vasodilation)
• Cardiac remodelling - acts as a growth signal (hyperplasia &hypertropy)

Drugs that affect the RAS = ACE inhibitors!

ACTION OF AN ACEi

ACE Inhibitors

ACE: Angiotensin Converting Enzyme

• Target for preventing conversion to Angiotensin II
• Causes vasodilation and reduces afterload
• Possible effects on cardiac remodelling

Dobutamine

• Predominately beta 1 thus +ve inotropic effect + HR
• Also agonist for Beta 2 = vasodilation and reduced SVR
• Doesn't bind to D receptors = No diuresis effect

Side effects: arrythmias, tachycardia, raised myocardial oxygen demand

Infusions last max 24 hours before degrade

Isoprenaline

• Relatively pure beta 2 stimulant
• beta 1>beta 2
• Positive inotrope effect + vasodilatory effect

Side effects: tachycardia (more than dobutamine) and arrythmias, possible decrease in diastolic BP, headache, tremor and sweating

Can be used for bradycardic patients requiring inotropic support.

Dopexamine

Synthetic dopamine analog

D1 agonist = vasodilation of coronary smooth muscle arteries

Stimulates sympathetic nervous system

beta 2 agonist

Examples of ACEI "....pril"

• E.g. Captopril, Enalapril (pro-drug), lisinopril (water soluble)
• Use: hypertension (preventing ang II and aldosterone), cardiomyopathy, primary left ventricular function
• Fact: Captopril is 30 000x greater affinity to ACE then angiotensin I!!

Side effects

• COUGH
• Reduced BP
• Renal impairment
• Hyperkalaemia
• Neutropaenia (with captopril - rare)

Test dose (requires monitoring of BP, HR and renal function) then increase with monitoring to desired dose

Angiotensin II Receptor Blockers (ARB's)

• Side effect for ACEI: dry cough - irritating
• Due to bradykinin buildup
• Bradykinin causes bronchoconstriction in lungs
• Can switch to alternative angiotensin II blocker
• Still block action of Angiotensin II
• Different mechanism - receptor blocker on muscles around the blood vessels.
• E.g. Losartan

Beta - Blockers

• Negative inotropic effects
• Reduce oxygen demand to the heart
• Many types but different !

Intrinsic sympathomimetic activity (ISA)

• partial agonist activity - stimulate as well as to block adrenergic receptors e.g. Oxprenolol and celiprolol
• Cause less bradycardia
• Possible less coldness of the extremities.

Water soluble

• Don't cross BBB = Less nightmares
• Care in renal impairment
• E.g. atelolol, nadolol, sotalol

All can cause bronchospasm - beta receptors in lungs avoid in asthmatics if possible