Download Cardiovascular Pharmacology

Drugs for Heart failure
& Angina
Department of pharmacology
Liming zhou
2010,3
Q. Importance of Heart Failure
A common & fatal cardiovascular (CV)
diseases.
20% die within 1 year of diagnosis & 50%
within 5 years
Increases with age- more men and more risk if
high BP.
Decline in death from other CV diseases since
1980 – but not heart failure ?
Q. What is heart failure ?
INABILITY OF THE VENTRICLES TO
PUMP ENOUGH BLOOD TO MEET
METABOLIC DEMANDS
Not a distinct disease – associated with several
disorders
No cure for Heart failure (HF): prevent, treat &
remove underlying cause.
Effective drug treatment removes symptoms &
prolong life.
Q. What are the disorders
associated with heart failure ?
DISEASE
Mitral stenosis
DESCRIPTION
mitral valve fault
Myocardial infarction
arteries
clot in coronary
Chronic hypertension
high blood pressure
Coronary artery disease atherosclerosis
DEVELOPMENT OF ATHERO-SCLEROTIC PLAQUES
Q. What is the Physiological
consequence of Heart Failure ?
In HF myocardium weakened – heart cannot
reject all blood it receives
Weakening on left side: blood accumulates in
left ventricle – walls thicken- blood backs-up
to lung
cough & shortness of breath
Weakening of right side: blood backs-up to
peripheral veins – odema of feet/ankles/liver
Or failure on both sides
Q. What are the common
Symptoms of heart failure ?
Progressive chronic disorder
Anxiety/Restlessness
Persistent cough
Rapid breathing
Fast Heart Rate
Edema of lower limbs
Skin cyanotic & clammy
General Anatomy
of the human
Circulatory System
Heart
Atrium: receives
blood returning
Ventricle:pumps
blood out
IN HEART FAILURE
ATTEMPT TO
MAINTAIN
HOMEOSTASIS
Arteries carry
blood away from
heart
Valves
Ensure
Blood flows
in one direction
Veins return
Blood to heart
Right side of heart receives blood from tissues & sends to lungs for
oxygenation
Left side of heart receives newly oxygenated blood from lungs & pumps to tissues.
Non-Pharmacological Therapy
In early stages
stop smoking & limit alcohol
limit sodium intake – food rich in k+ & Mg2+
exercise plan
understand how to reduce stress
reduce weight to optimal
limit caffeine
Q. What drug classes are used for
HF ?
1. Cardiac Glycosides
2. Angiotensin Converting Enzyme Inhibitors
3. Vasodilators & Diuretics
4. Phosphodiesterase Inhibitors
5. Beta- Adrenergic Blockers
Cardiac Glycosides: Digoxin
Known for 2000 years – from Digitalis
Still widely described for lung
congestion/peripheral edema
Mode of action: Inhibits Na/K ATPase & effects
resting membrane potential, Na+ accumulates &
Ca2+ stays in cytosol - more forceful contractions
  Cardiac Output  urine ↓ blood vol.
Adverse: Heart- Dysrhythmias
Digestive system – nausea, vomiting
Nervous system – blurred vision
TOXIC & MANY DRUG-DRUG
INTERACTIONS
DIGITALIS GLYCOSIDES
• Increase the force of the heart’s
contractions.
• Derived from digitalis which is a substance
that occurs naturally in foxglove plants and
certain toads.
• Digoxin most frequently used.
DIGITALIS GLYCOSIDES
• Pharmacokinetics:
• Absorption varies according to form;
distributed widely throughout the body;
bound extensively to skeletal muscles; small
amount is metabolized by the liver; excreted
by the kidneys unchanged.
DIGITALIS GLYCOSIDES
• Pharmacodynamics:
• Used to treat heart failure by increasing
intracellular calcium at the cell membrane
making the heart contractions stronger.
• Also used to treat supraventricular
arrhythmias because it acts on the CNS to
slow the heart rate.
DIGITALIS GLYCOSIDES
• Pharmacotherapeutics:
• Also used to treat paroxysmal atrial
tachycardia.
• Because of a long half-life, a loading dose
must be given in this situation.
DIGITALIS GLYCOSIDES
• Drug interactions:
• Many drugs can interact with digoxin.
• Amphotericin B, potassium-wasting
diuretics, and steroids taken with digoxin
may cause hypokalemia and increase the
risk of dig toxicity.
DIGITALIS GLYCOSIDES
• Adverse reactions:
• Because of a narrow therapeutic index,
monitoring blood levels are required to
prevent dig toxicity.
PDE INHIBITORS
• Used for short-term management of heart
failure or long-term management for
patients awaiting a transplant.
• Include the drugs inamrinone lactate(Inocor)
and milrinone (Primacor).
PDE INHIBITORS
• Pharmacokinetics:
• Both drugs are administered IV; distributed
rapidly; metabolized by the liver; excreted
by the kidneys.
PDE INHIBITORS
• Pharmacodynamics:
• Improve cardiac output by strengthening
contractions by moving calcium into the
cardiac cell.
PDE INHIBITORS
• Pharmacotherapeutics:
• Used for the management of heart failure
when patients haven’t responded
adequately to treatment with dig, diuretics,
or vasodilators.
PDE INHIBITORS
• Drug interactions:
• Because they reduce serum potassium levels,
when taken with potassium-wasting
diuretics may cause hypokalemia.
PDE INHIBITORS
• Adverse reactions:
• Uncommon but the risk increases with
prolonged use.
Angiotensin Converting Enzyme inhibitors;
Lisinopril
Commonly used for slow progressive
Heart failure (Hf)
Replaced digoxin as first line drugs in
chronic Hf
Mechanism:
Inhibit ACE = reduced water/sodium retention
decreased peripheral vascular
resistance
Dilate veins returning blood = ↓ peripheral odema
Decrease heart workload & allow it to function
more efficiently
Adverse: cough ( bradykinin) electrolyte
imbalance, taste disturbances
The renin –angiotensin –aldosterone pathway
Vasodilators: Isosorbide dinitrate
(organic nitrate)
Minor role in HF therapy
Mechanism: Release NO &  cGMP (direct
venodilation) =
↓ cardiac workload &  cardiac output
Also dilates coronary arteries =  oxygen to myocardium
Adverse: headache, hypotension, tachycardia
SERIOUS HYPOTENSION CONTRAINDICATION
WITH VIAGRA
Phosphodiesterase Inhibitor
Milrinone
Inhibitor to ‘heart’ specific phosphodiesterase
III given intravenously in Advanced HF
Actions:  force of contraction & cardiac
output.
 vasodilation
by cAMP = increasing amount of calcium
for myocardial contraction
Adverse: Serious (chest pain. Bronchospasm,
tremor) 
for patients not responding to ACE inhibitors
+ Ventricular Dysrhythmia in 10%
patients
(ECG monitored during drug infusion)
Cardiac Glycosides
L-type calcium channels
Phosphodiesterase
Inhibitors
Beta-Adrenergic Blocker
Carvedilol
Only a few registered for HF. Not first-line.
Mechanism: blocks 1 & 2 (& 1) adrenergic
receptors
= reduction in heart-rate & bp.
= ↓ bp reduces workload on heart.
Adverse:
Dose monitored – worsen heart failure
by reducing contractility !
Q. What is Angina pectoris ?
Symptoms: sharp /moving chest/left arm pain
on physical excretion or emotional stress
- produces many symptoms of heart attack
More frequently in women – over 70.
Cause: atherosclerosis - myocardial ischemia
Types: Stable- predictable in
frequency/duration
Unstable: severe & at rest
Variant:
Prognosis: rarely fatal
Q. How do you treat Angina ?
Life Style changes
(obvious)
&
Surgical Procedures
(bypass graft or
angioplasty)
Drug treatment
3 classes of drugs
1. Organic nitrates
2. Beta-adrenergic
blockers
3. Calcium channel
blockers
Q. What are the pharmacological
goals of angina treatment ?
Reduce the frequency of angina episodes &
terminate acute anginal pain
- reduce myocardial demand for oxygen
- increase oxygen to myocardium
1.Slow heart-rate
2.Reduce blood to heart by dilating veins
(reduce preload)
3.Cause heart to contract with less force
4. Lower blood pressure – less resistance in
heart to pushing blood from chambers (reduce
after-load)
Organic Nitrates
Properties known since 1857: mainstay
treatment for stable angina.
Mode of action: a) relax arterial & venous
smooth muscle
by release of NO &
stimulation by cGMP.
b) increase blood flow to
coronary artery
Types: a) short-acting. Nitroglycerin
sub-lingually for acute attack.
B) long-acting. Isosorbide dinitrate
orally/dermal patch for decreasing
frequency & severity of episodes
Adverse: Tolerance with long-acting drugs
Case Study: Nitroglycerin
Many Routes: Sub-lingually reaches plasma
levels in 4 mins.- rapid relief of pain by dilating
vessels.
If chest pain does not respond myocardial infarction ?
Adverse: Headache (vessel dilation)
Reflex tachycardia (not common)
Calcium Channel Blockers
Mode of action
Acts on L-type calcium channels. Reduces
myocardial oxygen demand by lowering bp &
slowing heart-rate
- inhibit calcium uptake & relax blood vessels
Vasodilation will increase oxygen supply.
Adverse
Related to vasodilation: headache, dizziness, edema
(ankles& feet)
Beta-Adrenergic Blockers
Why for Angina ?
reduce workload on heart – angina
prophylaxis
How ?
Slow heart rate & reduce contractility
What types ?
Cardioselective beta1 blockers & mixed
beta1 –beta2 blockers.