ANGINA (with hypercholesterolemia )

U Han, 70 years old man complaint of transient left sided chest pain. He claims
that getting chest pain is worse by walking up stairs and strenuous work. On
examination, his blood pressure was 150/90 mmHg. ECG and Chest X-ray showed
normal. Lipid profile showed total cholesterol-240 mg/dl and high-density
lipoprotein (HDL) cholesterol-40 mg/dl. He was diagnosed as angina with
hypercholesterolemia. If you are DR. Hla Thaung, SAMA-333444 & Assistant
Surgeon at YGH, Ph No: 0999 22110, describe the drug therapy that you would
prescribe for this patient, giving reason for your choice of drugs according to
"WHO six steps rational prescribing practice

Step 1 - Problem identification

Problem identification – 70 year old male H/o IHD get chest pain climbing
upstairs with hypercholesterolemia
P/D Acute attack of exertional angina with underlying IHD
2. Pathogenesis
-angina pain is the severe pressing substernal pain radiating to left shoulder along
the flexor surface of the arm(due to advanced arthrosclerosis- it is induced by
stress, exercises, cold weather etc.)
-temporary and relative myocardial ischemia – either decreased blood
supply(coronary atherosclerosis) or increased supply (increased cardiac workload)
-i.e. imbalance between the supply and demand

Step 2 Objectives
(1) to relieve the acute attack of angina ( short acting nitrite and nitrate)
(2) to prevent the further attack of angina (long acting nitrite and nitrate ,CCB,
Beta blocker)
(3) To reduce lipid level

Step 3 Drug Therapy

Drugs to relieve the acute attack of angina ( short acting nitrite and nitrate)
 Glyceryl trinitrate (GTN) and isosorbide di nitrate
 Route – Sublingual or IV

Choice of drug for acute attack (Suitability)

 To relieve the acute attack of pain.

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Drugs can be used for acute attack include short acting nitrite & nitrate with
immediate onset
Glyceryl trinitrate is the treatment of choice. It is short acting nitrates .
Appropriate route for immediate onset - IV or sublingual route
It can be used in the acute attack of angina.

Efficacy
 Organic nitrites and nitrates
Mechanism of action
release NO which activate guanylate cyclase → increase cGMP → stimulate protein
kinase → dephosphorylation of light chain myosin → relaxation of vascular smooth
muscle (Vasodilation)
 Pharmacological Actions
- increased supply due to dilatation of large coronary vessels
( redistribution to ischaemic area)
- decreased demand due to peripheral vasodilatation
venodilatation → decreased preload
arterial dilatation with high dose → decreased afterload
 It can relieve chest pain & also reduce BP
Duration – to take GTN for life- long if required. It has very rapid onset of action.
Peak concentration reaches at 4 mins.
 Patient should be warned to get hypotension, throbbing headache,
palpitation, and flushing, impaired vision. Long term used can cause tolerance.

Safety (Warning and precautions)

 due to excessive vasodilatation- throbbing headache (common and can be severe),
flushing of face, postural hypotension (with high dose), reflex tachycardia, cerebral
ischaemia, drug rash, impaired vision
 high dose can produce methaemoglobinaemia (pseudocyanosis, tissue hypoxia)

Instructions
- when severe throbbing headache occur during GTN, it can be swallowed or
split it as soon as the pain is relieved or can be prevented by NSAID
- hypotension and reflex tachycardia can occur
- Apart from that, there is no serious S/E.
- it is important to take the drugs regularly to control the pain
- it is suitable because it is easily available and rapid onset of action.

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Suitability
Suitability- it has rapid onset of action and the patient has no history of anemia

Dose, Route, Interval, Duration

 Glyceryl trinitrate, 0.5 mg tab, sublingual, p.r.n, with 5 minutes interval,
maximal 3 consecutive times per attack

For objective (2)

To prevent further attack of angina. Drugs with sustained effect are used.
Drug can be used for objective 2 include
long acting nitrite & nitrate (GTN , isosorbide 5 mononitrate)
CCB (Verapamil, amlodipine) and
beta blocker ( propranolol , atenolol)

Long-acting nitrite & nitrate (isosorbide 5 mononitrate) is drug of choice for

prevention of further attack
Pharmacological action – Long- acting nitrate can prevent angina by increase
myocardial Supply as well as reduce demand (reduce preload & Afterload.
- Nitrate can also reduce BP.

Objective 3 - to reduce hypercholesterolemia

Drugs can be used for lipid lowering -- Statins, Clofibrate, Cholestyramine, niacin,
Ezetimibe ,Fish oil, Mipomersen, Lomitapide, Evolocumab

Drug of choice for this patient is Statins (Rosuvastatin)

Mechanism of action
- Block cholesterol synthesis in liver: by inhibiting HMG Co A reductase
All compete effectively to inhibit HMG CoA reductase, the rate-limiting step in
cholesterol synthesis. By inhibiting de novo cholesterol synthesis, they deplete the
intracellular supply of cholesterol.
- Increase in LDL receptors: Depletion of intracellular cholesterol causes
hepatocytes to increase the number of specific cell-surface LDL receptors
that can bind and internalize circulating LDLs.
- Therapeutic benefits include atherosclerotic plaque stabilization,
improvement of coronary endothelial function, inhibition of platelet
thrombus formation, and anti-inflammatory activity.

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Efficacy
- reduction of LDL cholesterol (dose related); Rosuvastatin is more potent &
effectively dose related lipid lowering effects than other Statins
- reduction of VLDL, IDL and increase HDL

Warning,Precautions & instructions

Generally well tolerated
- GI symptoms, headache, rash,
- elevations of serum aminotransferase activity (up to three times normal)
- Myopathy which refers to a broad spectrum of muscle complaints, ranging
from mild muscle soreness or weakness (myalgia) to life-threatening
rhabdomyolysis.
- (The risk of muscle adverse effects increases in proportion to statin dose
and plasma concentrations)
- cataract (very high dose)
- teratogenic
- Contraindication
- pregnancy and lactation
Dose , Route, Interval, Duration – Rosuvastatin 10 mg PO OD x 10 days

Step 4. Prescription

Patient Data
Date

Glyceryl trinitrate, 0.5 mg tab, sublingual, p.r.n, with 5 minutes interval,

maximal 3 consecutive times per attack followed by
isosorbide 5 mononitrate 20 mg, bd for 10 days
Rosuvastatin 10 mg PO OD x 10 days

Instruction --- important to take these drugs regularly , can cause throbbing
headache , Come back after 10 days and important to take these drugs regularly

Doctor data
Singature & SAMA

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Step 5
Information,Warning
Patient should be warned of hypotension & throbbing headache
palpitation, and flushing, impaired vision. Long term used can cause tolerance by
nitrate.

Step 6
Monitoring & stopping of drug
Patient should be taken drug regularly
Follow up regularly, recheck ECG, Chest X ray & Lipid profile
Regularly Blood pressure Check up
Monitor clinically improvement and also side effect of drugs

CHRONIC STABLE HEART FAILURE

U Thet Oo, 57 years, live in Lanmadaw Township, came in with dyspnoea on exertion
and oedema on the lower limb. His BP was 160/100 mmHg and chest X ray showed
enlargement of the heart. His condition was diagnosed as congestive heart failure
due to hypertension. Describe the drug therapy for that patient and give reasons
for your choice of drugs.

Step 1. Problem identification

Chief complaint : Breathlessness & tiredness on daily routine works
History of known case of moderate hypertension with heart failure
Provisional Diagnosis (P/D) → Early stage of Heart Failure due to Hypertension

Pathophysiology
- Longstanding H/T may cause increase TPR and increase cardiac workload lead to
hypertrophy of cardiac m/s. Counter regulatory responses implicate with
neurohumoral system; renin-angiotensin-aldosterone axis (angiotensin II),
sympathetic nervous system, various inflammatory cytokines (e.g., tumor necrosis
factor-α), and local mediators such as endothelin which make the situation worse,
not better.
- These mediators activate biochemical pathways that induce myocyte
hypertrophy, apoptosis, collagen production, fibrosis, and other effects that lead
to cardiac remodeling and loss of ventricular function.

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- Cardiac or ventricular remodeling, is characterized by cardiac dilatation,
ventricular wall thinning, interstitial fibrosis, and wall stiffness. These changes
impair the ability of the heart to relax or contract.

Step 2 - Objectives
To relieve Symptoms by To ↓Cardiac Workload
Reduction of BP
Maintenance of BP within normal range

Step 3 – Suitability of drug treatment

Since the pt: has both hypertension & heart failure, therapy should be directed
for these 2 conditions.
It is a known case of moderate degree of essential hypertension & pt has been
taking antihypertensive treatment irregularly will make a complication like heart
failure.
Therefore, reduction of BP is most important part of therapy for him.
After that BP should be maintained within normal limit by taking antihypertensive
drug regularly which may be Life-long.
Hypertensive heart failure (one of the complications of hypertension) is prevented
by regular antihypertensive treatment.
 Drugs can be used for chronic heart failure – Enalapril, Losartan, Carvedilol,
Spironolactone
For achieving above objectives: ACEI is drug of choice among this patient
of hypertensive heart failure.
ACEI (ENALAPRIL) not only lowers BP but also reduces cardiac workload.
CONCEPTS in treatment of Heart failure;
Cardiac function can be improved by (1) increasing myocardial contractility
(2) optimizing preload & decreasing after load
Drug therapy directed at noncardiac targets (↓preload & after load) is more
valuable in long-term treatment of heart failure than positive inotropic agents such
as digitalis.

Efficacy (ENALAPRIL)
- ACEI
- Inhibits angiotensin converting enzyme (ACE) causes decrease formation of
angiotensin II which is potent vasoconstrictior & promotes synthesis & secretion
of aldosterone

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 - ↓Ag II --- vasodilatation of both arteries and veins resulting in reduce preload &
afterload of the heart & reduced sodium & water retension.
Relieve dyspnoea & tiredness --- also falls in BP and reduce complications
-in heart failure, ACEI reduce ventricular dilatation and tend to restore the heart
to its normal elliptical shape
ACE inhibitors may reverse ventricular remodeling via changes in
preload/afterload,
by preventing the growth effects of angiotensin II on myocytes, and/or
by attenuating aldosterone-induced cardiac fibrosis.

Dose, Route, interval , duration

Initial dose 2.5 mg, gradually increases the dose to 5 mg orally
Maintenance dose: 10 -20 mg/day orally

Safety (Instructions & Warnings)

Check this side effects for Safety, if patient get this side effect & cannot
tolerate these effects, dose adjustment or change another drug
ACEI may cause first dose hypotension & so 1st dose should be taken at bed time.
Drugs should be taken regularly.
It may cause dry cough, urticaria and angioedema (painful swelling which can be
life-threatening if it involves the airway), wheezing, rashes, hyperkalaemia,
hyponatremia & dysgeusia (loss of taste) . If these side effects develop, pt:
informs to doctor.

Suitability (Check this contraindication for Suitability)

ACEI is contraindicated in pregnancy & bilateral renal artery stenosis.
Before giving ACEI check renal function of patient and monitor every 6 month
during treatment.

If not controlled with ACEI alone

To ↓Cardiac Workload and BP (ACEI combined with Carvedilol)
Carvedilol --- 3.125 mg po bd
- third-generation β1- and β2-blocker that also produces vasodilation via α1-
receptor blockade.
- reduce renin secretion from kidneys
- reduce myocardial contractility, HR and CO causing decreased BP
- tranqulizing & central sympathoplegic action (reduced central sympathetic out
flow)

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- β blocker reduce the sympathetic nervous system in cardiac remodeling and the
progression of heart failure.
Sympathetic activation of cardiac β-receptors → tachycardia,↑oxygen demand →
↑ infarct size and the propensity for cardiac remodeling in persons with myocardial
infarction.
Sympathetic activation → ↑ activation of the RAA system, which has role in
cardiac remodeling
Chronic stimulation of cardiac β-receptors → myocyte hypertrophy and apoptosis
that contributes to cardiac dilatation and ventricular wall thinning
Activation of the sympathetic system → ↑ production of cardiac cytokines,
including tumor necrosis factor-α and interleukins→ myocyte hypertrophy and
apoptosis and produce alterations in the intracellular matrix that contributes to
fibrosis and ventricular wall stiffness.
The benefits of therapy with β-blockers are caused by the ability of these drugs
to reduce excessive sympathetic stimulation of the heart and circulation in
patients with heart failure.
Carvedilol is a third-generation β1- and β2-blocker that also produces vasodilation
via α1-receptor blockade. In addition, carvedilol and its metabolites have
antioxidant properties and it also exhibits anti-inflammatory and anti-apoptotic
properties that can contribute to its beneficial effects in heart failure. For these
reasons, carvedilol has been called a multiple-action neurohumoral antagonist.
Carvedilol reduces both hospitalization and mortality in persons with heart
failure when it is added to a standard treatment regimen.

Dose, route, interval , Duration

Carvedilol PO 3.125 mg bd x 10 days

[ If sign & symptom of heart failure not controlled, Add diuretic and /or nitrate
vasodilator (or symptom of oedema occur + add diuretic)
* Diuretics (Thiazide diuretics) Xipamide po 20 mg OD cm
It acts on luminal side in early distal tubules → inhibit Na+-Cl- symport → ↓Active
reabsorption of Na+ (5-10%) ↑Salt & water loss →DIURESIS →↓blood volume
(Relieve oedema) →↓ excessive venous filling pressure→ ↓BP and cardiac workload →
relieve symptoms
It lowers BP at sub diuretic dose due to vasodilatation ]

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Step 4 -- Prescription
U Thet Oo, 57 years, male
Lanmadaw Township,
Date:
Enalapril po 5 mg od × 10 days
Carvedilol po 3.125 mg bd x 10 days

Instructions: 1st dose must be taken at bed time. Takes the drug regularly.
Please come back after 10 days.

Doctor’s Name
Clinic Address
Contact Phone No:
Signature
SAMA

Step 5 Instructions & Warnings, Precaution

ACEI may cause first dose hypotension & so 1st dose should be taken at bed time.
Drugs should be taken regularly.
It may cause dry cough, urticaria and angioedema (painful swelling which can be
life-threatening if it involves the airway), wheezing, rashes occur change ARB

Check K+ level, renal function & BP regularly

Step 6 -- Monitoring & Stopping of drug

Monitor patient symptoms of heart failure (Oedema, dyspnoea, congestion)

Dose adjustment of the drugs, lifestyle modification, restrict salt intake, salt &
water retention drugs also drug interactions of patients.