Product Manual Chronic

Aldactone
It is a synthetic 17-lactone drug that is a aldosterone antagonist in a class

of pharmaceutical called mineralocorticoid receptor antagonist, used
primarily to treat heart failure, ascites in patients with liver disease, as
well as high blood pressure.
Mechanism of action
Spironolactone inhibits the effect of aldosterone by competing for
intracellular MR receptor.
MR receptors are located at various places hence spironolactone offers
multiple benefits.
Role
Role of
of Aldactone
Aldactone
Aldactone
Aldactone
MR
Heart
Heart Vascular
Vascular Kidney
Kidney Brain
Brain
Prevents
Prevents Reduces
Prevents
Prevents arterial
arterial Lowers
Lowers volume
volume overload
overload Reduces the
the risk
risk
worsening
worsening of
of HF.
HF. of
stiffness
stiffness &
& lowers
lowers BP
BP of stroke
stroke
Regresses
Regresses LVH
LVH
Pharmacokinetic:
• Absorption Well absorbed
• Time to reach peak 1-3h
plasma levels
• Bioavailability 91%
• Plasma protein 90%
binding
• Plasma half life (t1/2) 1.3 to 1.4h
• Elimination Mainly in urine
CV effects of Aldosterone:
• Endothelial dysfunction
• Vascular inflammation
• Myocardial ischemia
• Necrosis
• Increase collagen synthesis
• Increase in PAI – 1 activity
• Decrease in baroreceptor sensitivity
• Increase in ROS
• Increased cardiocyte apoptosis
Indication & Dosage
– Essential Hypertension: 50-100mg/day OD or Div. Doses

– CHF & other oedematous states:100 -200mg/day
– Cirrhosis: 100 - 400mg/day
– Nephrotic syndrome: 100-200mg/day
Adverse Effects
– Gynaecomastia - dose dependent-- reversible
– G.I. - nausea, vomiting, diarrhoea
– Irregular menses
– Drowsiness, Lethargy, headache
What is the role of Aldactone in Heart failure?
 Spironolactone acts as a diuretic as well as an aldosterone antagonist. As a

diuretic, its advantage over other diuretics lies in the fact that it spares
potassium and so does not cause hypokalemia. Hypokalemia may lead to
arrhythmias, which may be life-threatening causing sudden cardiac death.
 Aldosterone was originally thought to be important in the pathophysiology of
heart failure only because of its ability to increase sodium retention and
potassium loss. However, in the recent past, research has shown that
aldosterone also causes fibrous tissue formation in the myocardium
(cardiac remodeling), leading to progressive worsening of heart failure.
ACE inhibitors block the RAAS, but do not completely stop aldosterone
synthesis (aldosterone escape phenomena). Since aldosterone remains
in circulation, only the presence of an aldosteone blocker will completely
stop the effects of aldosterone. Aldactone, by blocking the effects of
aldosterone prevents myocardial fibrosis, thus reducing the mobidity and
mortality in heart failure.
 Spironolactone, in a dosage of up to 25mg day may be used in combination
with ACE-inhibitors & other standard therapy, without risk of hypokalemia /
hyperkalemia .The efficacy & safety of this combination has been proven in
the RALES trial.
What is the role of Aldactone in ascites?
Ascites is the most common complication of cirrhosis. Management of ascities is

dietary salt restriction and diuretic therapy. The diuretic of choice is Aldactone,
since secondary hyperaldosteronism (high levels of aldosterone) is an important
cause of sodium and water retention in such patients. Even if patients require
additional diuretics, spironolactone should be continued. Response is measured
by monitoring daily reduction in body weight.
The initial dose of Aldactone is usually 50mg per day. The dose may be
increased to as much as 400mg per day. If maximal doses of Aldactone do not
cause an adequate diuresis, a thiazide diuretic can be added. If diuresis is still
inadequate, a loop diuretic can be given instead of the thiazide while Aldactone is
continued.
Removal of ascitic fluid by drainage is often necessary in patients with cirrhosis.
This procedure is called paracentesis. Aldactone given after paracentesis
decreases the recurrence of ascites.
What is the role of Aldactone in hypertension?

Mechanism of action:
Inhibit aldosterone receptors in distal convulated tubule (DCT) & collecting duct
(CT) of nephron
Diuresis with K+ retention
Blood volume ↓
Cardiac output (CO) ↓
Blood Pressure (BP) ↓
To be effective as an antihypertensive agent, Aldactone (mild diuretic) is

combined with another diuretic, generally a thiazide diuretic. The dosage of
Aldactone in hypertension is 50-100 mg/day.
What is the role of Aldactone in the management of nephrotic syndrome?

Aldactone is used as a diuretic to reduced sodium and water retention in this
condition.
Conventional diuretics are commonly used in the treatment of patients with
nephrotic oedema. Spironolactone may prevent or correct diuretic induced
hypokalemia and may have an additive diuretic effect when administered
concomitantly. However Spironolactone should not be used in patients with renal
failure because of risk of hyperkalemia. The dosage of Spironolactone in this
condition is 100-200mg/day.
The Randomized Aldactone Evaluation Study

Objective - The Effect of Spironolactone on Morbidity and Mortality in Patients
with Severe Heart Failure.
Design - The Randomized Aldactone Evaluation Study (RALES) was designed

to test the hypothesis that daily treatment with 25 mg of spironolactone would
significantly reduce the risk of death from all causes among patients who had
severe heart failure as a result of systolic left ventricular dysfunction and who
were receiving standard therapy, including an ACE inhibitor, if tolerated.
Design-
– No. of patient- 1663
– Patient type - Diagnosed for HF in last six weeks times.
– Patient NYHA class- 3 &4
– Ejection fraction- 35%
– Treatment - ACEI, Diuretic, Digitalis
– Duration- 36 months
Results
– The trial was discontinued early because an interim analysis
determined that spironolactone was efficacious.
– There was 30 percent reduction in the risk of death among patients

in the spironolactone group.
– In addition, patients who received spironolactone had a significant

improvement in the symptoms of heart failure, as assessed on the
basis of the New York Heart Association functional class.
Conclusions
– Blockade of aldosterone receptors by spironolactone, in addition to
standard therapy, substantially reduces the risk of both morbidity
and death among patients with severe heart failure. (N Engl J Med
1999:341:709-17.)
Role play for Aldactone:
Aldactone in post MI
TBM: Doctor if you allow me I would like to know whether Aldactone forms a
part of your optimal therapy after MI?
DR: Yes I Rx it as a diuretic for hypervolemic patients.
TBM: First of all thanks for selecting Aldactone as a part of your optimal therapy
for patients after MI. But sir if you allow me I would like to throw some light on
effects of Aldactone beyond a diuretic.
• Doctor as you are well aware that 16-40% of MI patients subsequently
develop HF, so cardio protection becomes a major concern for these
patients
Dr: For that I prescribe ACEI. So cardio protection is taken care of.
TBM: Doctor as you may be well aware that ACE Inhibitor were given to the
patients in RALES trial but still there was worsening of cardiac symptoms or
hospitalization of patients. RALES showed that when Aldactone was added to
the therapy which included ACE inhibitors, Aldactone gave 30% additional
benefit over ACE inhibitors.
Dr: but that may be due to decrease in blood volume or the diuretic effect of
Aldactone.
TBM: Dr., here I would like to add the dose of Aldactone used in RALES trial
was 25mg which had minimal diuretic effect which was confirmed as a Sodium
retention scores in RALES trial. Thus Dr., NEJM article logically concludes that
decrease in subsequent hospitalization or worsening of HF may be attributed to
cardio protection conferred by Aldactone.
Doctor would you not like to pass on this additional 30%
cardioprotective benefit to your patients?
Aldactone & incidences of hyperkalemia
TBM : Doctor I would like to learn from you that for a patient of Post MI or HF
how often do you prescribe my Aldactone?
Dr: Yes I do prescribe after MI or in HF patients for at least 3 months.
TBM : Doctor I am sure you know that there is definite advantage of prescribing
Aldactone to your HF patients as it decreases the cardiac mortality by 30% and
hospitalization by 35% which was evident from RALES trial, so Sir if you allow
me may I know why you prefer Aldactone for short span of time?
Dr: I’ am worried about life threatening hyperkalemia associated with use of
Aldactone.
TBM: Doctor I really appreciate your concern for the safety of your patients, but
here I would like to bring to your notice certain facts about Aldactone.
• Doctor I would like to share with you the fact according to RALES trial the
increase in the potassium level was only 0.3 mEq/L & the average
baseline K level in the group was 4.5 mEq/L. Thus hyperkalemia was not
regular observation in RALES trial. In fact Sir following the RALES trial
because of Aldactones benefit the prescription increased 5 times whereas
the incidences of hyperkalemia did not increase in the same ratio which
indicates a poor co relation between use of Aldactone & incidences of
hyperkalemia. Also Sir NEJM article in Aug 2004 says that donot withhold
the patients from the benefits of spironolactone.
• Instead the concurrent Rx which would leads to hyperkalemia should be

reduced, regular K levels should be monitored. Sir I’ am sure your patient
if properly educated about the symptoms of Hyperkalemia would prefer to
monitor his K levels rather than have worsening of symptoms &
subsequent hospitalization.
Dr: That is true but I’ am apprehensive about prescribing it as there are reports of
hyperkalemia with spironlactone.
TBM: Sir if you would not mind I would like to bring to your observation that there
are reports which suggest that prescribing plain NSAIDs may also give
hyperkalemia which is more pronounced than spironolactone. But Drs still
continue to prescribe it as the benefits far out way the disadvantages associated
with NSAID. Similarly sir with my Aldactone the benefits what you have with
regards to decreased CV mortality & morbidity outweigh risk of hyperkalemia.
Doctor, based on this safety data, do you think my Aldactone will find wider
usage among your patients with HF/MI?
• OR
Thus Doctor in this new light of evidence can I get assurance for your
continuous patronage for every patient of yours having HF/MI (Quantify if
required, depending upon RCPA)
Aldactone & HF
TBM: Doctor, being an eminent Consulting Physician in my region, I would like to

learn something from you, so can I have the privilege to ask a few questions?”
Dr: Ok go ahead.
TBM: Doctor do you prescribe Aldactone in all your patients of HF?
Dr: See normally I prescribe when I’ am having patient with severe HF i.e. NYHA
class 3 or 4. It is a good drug for those kinds of patients.
TBM:Thanks doctor for considering my Aldactone, but may I learn from you what
are the criteria’s you consider when you exclude NYHA class 1 & 2 from
prescribing my Aldactone.
Dr: Spironolactone is recommended for class 3 & 4 where Ejection Fraction is
less than 35%. Being a CP I don’t get many class 3 & 4 patients to prescribe your
product.
TBM: Doctor here with your permission I would like to add as you are precisely
aware that RALES trial had shown prescribing Aldactone can prevent the
worsening of symptoms of HF and also may decrease the CV morbidity risk
which was seen by patients in class 3 & 4 moving into class 1 or 2. Also Sir
Braunwald Heart suggests that Aldactone can be prescribed even in mild to
moderate HF since it may slow the progression of HF and decrease the chance
of sudden death.
Doctor, based on this efficacy & safety data, do you think my Aldactone will find
wider usage among your patients with even class 1 & 2 HF/MI?
FAQ:
1. What is the communication objective of the brand?

Ans: Resistant Hypertension: Add years to life
Heart Failure: Add years to life
Diabetic proteinuria: Add years to life
Ascites due to liver cirrhosis: The diuretic of choice, Removes fluid,
Adds life
2. Who are your target audience (Doctor) and the patient profile in which
the brand is to be prescribed?
Ans: Physician: Resistant Hypertension
Cardiologist: Heart Failure
Diabetologist: Nehropathy, Diabetic Proteinuria
Gastrologist: Ascites due to liver cirrhosis
3. Explain the positioning of the specific product?

Ans: Resistant Hypertension: Add years to life
Heart Failure: Add years to life
Diabetic proteinuria: Add years to life
Ascites due to liver cirrhosis: The diuretic of choice, Removes fluid, Adds
life.
4. Role of Aldactone in case of Diabetic proteinuria
Ans: - Dr, proteinuria considered to be nephrotoxic. Aldactone reduces

development of glomerulosclerosis, modulates the vascular tone, retards renal
disease progression, inhibits formation of renal cortical ROS and reduction of
proteinuria from 15 to 45% .
5. Role of Aldactone in case of Ascites due to liver cirrhosis
Ans: Doctor Aldactone is the diuretic of choice as Aldactone reduces the portal
hypertension and reduces weight and volume overload
Aldactone prevents the early recurrence of ascites and is the valuable therapy in
refractory and severe ascites.
Dr the recommended initial dose of Aldactone is 100 mg per day in single or
divided doses and after 5 days adjust dose to a max of 400 mg/day.
6. Why Aldactone in case of resistant hypertension
Ans: Hypertension is called resistant if a person's blood pressure remains above

goal despite their taking three medications to lower it. High blood pressure that is
under control, but requires four or more medications to treat it is also considered
resistant to treatment. Resistant hypertension requires special consideration in
terms of evaluation and treatment." Diuretics are often underused in people with
resistant hypertension, and some patients may benefit from adding
mineralocorticoid receptor antagonists (MRAs) to their treatment regimens.
Dr, in resistant hypertension prescribe Aldactone that add years to life
Aldactone lowers blood pressure, improve endothelial function, reduces arterial
stiffness and is safe and well tolerated
7. How Aldactone works to reduce the edema of the body?
Ans:Aldactone blocks the aldosterone receptors of distal convoluted tubule &

collecting duct of the kidney and thus reduces the reabsorption of sodium &
water, increasing the rate & formation of urine. Thus excessive fluid is thrown out
of the body.
8. How Aldactone works in CHF (Congestive heart failure)?
There are multiple mechanisms of action in CHF

It reduces the load on heart by throwing excess fluid out of the body, reducing
the load on the heart
It blocks the aldosterone receptors of the heart, thereby reducing cardiac
remodeling (changes in cardiac structure & function)
It improves the endothelial dysfunction (function of the inner lining of the blood
vessels)
It improves electrolyte balance like Magnesium thus reducing the chances of
sudden death because of the arrhythmia
9. What is the management of Gynaecomastia?
Ans:Gynaecomastia, a benign enlargement of the male breast as a result of

proliferation of the glandular component, is common, being present in 30-50% of
healthy men. It may be an incidental finding, an acute unilateral or bilateral
tender breast enlargement or a progressive painless enlargement of the male
breast.
The management of Gynaecomastia can be done medically, surgically or by
radiation depending upon the cause. Androgens, anti-oestrogens, aromatase
inhibitors and danazol have all been used to treat gynaecomastia
10. What is the management of Hyperkalemia?

Ans:- Hyperkalemia is defined as a potassium level greater than 5.5 mEq/L.
Ranges are as follows:
• 5.5-6.0 mEq/L - Mild condition

• 6.1-7.0 mEq/L - Moderate condition
• 7.0 mEq/L and greater - Severe condition
Patients may be asymptomatic or report the following:
o Generalized fatigue
o Weakness
o Paresthesias (Tingling & altered sensations in the body)
o Paralysis
o Palpitations (irregular heart beats in the body)
A patient with known hyperkalemia or renal failure with suspected hyperkalemia

should have intravenous access established and should be placed on a cardiac
monitor. In the presence of hypotension or marked QRS widening (ECG changes
seen in hyperkalemia), intravenous bicarbonate, calcium, and insulin given
together with 50% dextrose may be appropriate. Calcium may be avoided if
digoxin toxicity is suspected. Magnesium sulfate (2 g over 5 min) may be used
alternatively in the face of digoxin-toxic cardiac arrhythmias
What are the main obstacle with regards to Knowledge, skill, & attitude which
restrict the desired return on investment?
11. What specific competitor brands / molecules are you going to target?
Ans: All Digoxin prescriber. The brand name are as follows
Lanoxin
Dixin
Cardin
Digoxin
Co-prescription with ACEI and ARB
SPIROMIDE
Each tablet contains:
Frusemide: 20mg
Spironolactone: 50mg
Frusemide
Frusemide is a loop or high ceiling diuretic and are one of the potent diuretics
Mechanism of action
Frusemide:
Frusemide inhibits Na+/K+/Cl- cotransport in the tubular uses in the ascending
loop of Henle and decrease Na+/K+ /Cl- reabsorption. Sine 30-40% of Na+
load in tubular fluid is reabsorbed here, inhibition of it causes increased
amount of Na+ to be retained in tubular fluid, which cannot be reabsorbed at
the distal sites.
Frusemide is very potent diuretic and acts even in case of decrease
glomerular filtration rate (poor renal function), in which other diuretics fail.
Spironolactone:
Spironolactone is an aldosterone receptor antagonist.
Pharmacokinetics
Frusemide:
Bioavailability - 60-64%
Half life - 2hrs
Onset of action - within 1 hour
Peak of action - 1-2 hrs
Duration of action - 6-8hrs
Spironolactone:
Bioavailability - > 90%
Half life - 20hrs
Onset of action - 24-48hrs
Peak plasma levels- 48-72hrs
(Of action)
Duration - 48-72 hrs
Rationale for combination

Long term diuretic therapy constitutes an important treatment option in
hypertension and certainly in edema. Thiazides and loop diuretics are most
commonly employed. Thiazides are known to be associated with
hypokalemia, hyperuricemia, impaired glucose tolerance and altered lipid
profile. Frusemide, a loop diuretic having similar effects, also causes
hypokalemia. Hypokalemia (may lead to ventricular arrhythmias and sudden
cardiac death in CHF) is the main undesirable side effect of thiazides and
Frusemide. Potassium salt supplementation is not well tolerated by GI tract.
Hence, K+-sparing diuretics like spironolactone are preferable. They also give
added natriuresis, thus allowing lower dose of the other diuretic. The lower
dose minimizes hypokalemia and risk of hyperuricaemia and impaired
glucose tolerance too.
Frusemide and spironolactone combination has been shown to be effective in
hypertension and CHF.
Spironolactone adds to the diuretic efficacy of Frusemide, spares potassium
and magnesium and prevents electrolyte imbalances associated with long
term diuretic therapy. Spironolactone has antihypertensive action, counters
aldosteronism (cause of hypertension), and diuretic refractoriness ensuring
long term efficacy. Because of its longer half-life, it can be administered once
daily. Spiromide can also be given once daily improving therapy compliance.
Indications
Managing disorders with abnormal fluid retention (edema) as in

• Congestive heart failure
• Hepatic cirrhosis with ascites
• Nephrotic syndrome
In hypertension diuresis causes reduction in blood volume leading to
reduction in blood pressure
• Congestive Cardiac failure
As already explained in congestive cardiac failure due to falling cardiac output

there is congestion of lungs, liver etc leading to breathlessness (pulmonary
oedema) and decreased exercise tolerance (capacity). Due to activation of
RAAS and sympathetic overactivity there is abnormal salt and water retention
worsening the condition.
Spiromide by causing extreme diuresis it promptly relieves pulmonary

oedema and decrease venous pressure.
• Hepatic cirrhosis - This is a disease of liver, in which normal parenchyma is

damaged and by fibrous tissue, distorting the normal architecture of liver.
Etiology - Chronic alcoholism induced liver damage

- Hepatitis B and infection
Due to anatomical distortion portal blood cannot bypass liver causing increased
portal venous pressure and filtration of fluid in peritoneal cavity causing ascites.
Due to decreased liver function adequate amount of proteins are not
synthesised, decreasing the osmotic pressure of blood, favouring development of
ascites.
Collection of fluid in abdomen cause decreased blood volume and decreased
blood pressure leading to abnormal salt and water retention (↑RAAS).
Aldosterone levels are abnormally increased. Frusemide and Spironolactone
decrease fluid overload and antagonise aldosterone respectively.
Nephrotic syndrome
This is a disease of renal tubules due to variety of causes in which abnormal

quantities of protein and water are excreted. In cases of nephrotic syndrome due
to decreased osmotic pressure of blood (due to decrease proteins) fluid seeps
into interstitial tissue/oedema formation) leading to activation of RAAS and
abnormal salt and water retention. Spiromide reverses these abnormal changes.
Dosage
1-4 tablets in single or divided doses.
Competitors:
Aquamide Sun
Fruselac Lupin
Lasilactone Sanofi Aventis
Amifru Elder
Lasiride Sanofi Aventis
1. What is DCM ?
Ans- Dilated cardiomyopathy or DCM is a condition in which the heart becomes
weakened and enlarged, and cannot pump blood efficiently. The decreased heart function
can affect the lungs, liver, and other body systems.
DCM is one of the cardiomyopathy, a group of diseases that primarily affect the
myocardium (the muscle of the heart). Different cardiomyopathies have different causes
and affect the heart in different ways. In DCM a portion of the myocardium is dilated,
often without any obvious cause. Left or right ventricular systolic pump function of the
heart is impaired, leading to progressive cardiac enlargement and hypertrophy, a process
called remodeling.
2. What is VPC?
Ans- A Premature Ventricular Contraction (PVC), also known as a premature
ventricular complex, ventricular premature contraction (or complex or complexes)
(VPC), ventricular premature beat (VPB), or extrasystole, is a relatively common
event where the heartbeat is initiated by the heart ventricles rather than by the SA node,
the normal heartbeat initiator. The electrical events of the heart detected by the ECG
allow a PVC to be easily distinguished from a normal heart beat.
A PVC may be perceived as a "skipped beat" or felt as palpitation in the chest. In a

normal heartbeat, the ventricles contract after the atria have helped to fill them by
contracting; in this way the ventricles can pump a maximized amount of blood both to the
body and to the lungs. In a PVC, the ventricles contract first, which means that
circulation is inefficient.
3. What is VT?
Ans- Ventricular tachycardia (V-tach or VT) is a tachycardia, or fast heart rhythm, that
originates in one of the ventricles of the heart. This is a potentially life-threatening
arrhythmia because it may lead to ventricular fibrillation and sudden death.
Classification
Ventricular tachycardia can be classified based on its morphology:
• Monomorphic ventricular tachycardia means that the appearance of all the

beats match each other in each lead of a surface electrocardiogram (ECG).
• Polymorphic ventricular tachycardia, on the other hand, has beat-to-beat
variations in morphology. This most commonly appears as a cyclical progressive
change in cardiac axis, previously referred to by its French name torsades de
pointes ("twisting of the points"). However, nowadays, the term torsades is
reserved for polymorphic VT occurring in the context of prolonged resting QT
interval
Demator
Demator (Torsemide) is a pyridine-sulfonyl urea type loop diuretic mainly

used in the management of edema associated with congestive heart failure. It
is also used at low doses for the management of hypertension.
Mechanism of action
Torsemide inhibits Na+/K+/Cl- cotransport in the tubular uses in the ascending

loop of Henle and decrease Na+/K+ /Cl- reabsorption. Sine 30-40% of Na+
load in tubular fluid is reabsorbed here, inhibition of it causes increased
amount of Na+ to be retained in tubular fluid, which cannot be reabsorbed at
the distal sites.
Torsemide is very potent diuretic and acts even in case of decrease
glomerular filtration rate (poor renal function), in which other diuretics fail.
Pharmacokinetic data :
 Bioavailability : 80-90%
 Protein binding : 99%
 Metabolism :80%(hepatic)
 Half life :3.5hr
:7-8hr in cirrhosis
Therapeutic considerations:
 Category :C
 Routes : Oral/ I.V
Advantages of Demator over frusemide
► Torsemide is more potent than frusemide on a weight per weight basis.

10-20 mg of torsemide produces effects equivalent to that of 40 mg of
frusemide.
► Torsemide has a fast onset of action and produces intense diuresis, which
is comparable to that of frusemide. However, unlike frusemide, which is
short acting, torsemide has a more sustained diuretic action.
► Torsemide has a more predictable absorption profile and better

bioavailability than frusemide. Frusemide has an erratic and highly
variable bioavailability, which leads to unpredictability of response. This
may affect the overall outcomes with frusemide.
► Torsemide is potassium sparing in nature: this is attributable to its

aldosterone-inhibiting property. Torsemide also prevents calcium loss.
► Studies have shown that in congestive heart failure, torsemide-treated

patients were less likely to be readmitted for heart failure and for all
cardiovascular causes. Torsemide is also associated with decreased
mortality rates. It also results in reduced overall costs.
► Torsemide is excreted mainly via the hepatic route; hence high doses up
to 100-200 mg in advanced chronic renal failure may be used. Frusemide,
on the other hand, accumulates in renal failure and causes toxicity.
► Torsemide has been used in combination with spironolactone in cirrhosis
of liver with ascites. This decreases potassium loss and further imbalance
of electrolytes. Frusemide on the other hand causes potassium loss and
adds to imbalance of electrolytes.
► Torsemide is the first loop diuretic indicated for the treatment of

hypertension. Doses required are sub-diuretic doses (2.5 to 5 mg) and do
not have any biochemical or electrolyte adverse effects. Torsemide may
be used alone or in combination with other drugs for hypertension
DOSAGE AND ADMINISTRATION
► Congestive Heart Failure

 The usual initial dose is 10 mg or 20 mg of once-daily oral or
intravenous DEMATOR. If the diuretic response is inadequate, the
dose should be titrated upward by approximately doubling until the
desired diuretic response is obtained. Single doses higher than 200
mg have not been adequately studied.
► Chronic Renal Failure

 The usual initial dose of DEMATOR is 20 mg of once-daily oral or
intravenous DEMATOR. If the diuretic response is inadequate, the
dose should be titrated upward by approximately doubling until the
desired diuretic response is obtained. Single doses higher than 200
mg have not been adequately studied.
► Hepatic Cirrhosis
 The usual initial dose is 5 mg or 10 mg of once-daily oral or
intravenous DEMATOR, administered together with an aldosterone
antagonist or a potassium-sparing diuretic. If the diuretic response
is inadequate, the dose should be titrated upward by approximately
doubling until the desired diuretic response is obtained. Single
doses higher than 40 mg have not been adequately studied.
 Chronic use of any diuretic in hepatic disease has not been studied
in adequate and well-controlled trials.
► Hypertension
 The usual initial dose is 5 mg once daily. If the 5 mg dose does not
provide adequate reduction in blood pressure within 4 to 6 weeks,
the dose may be increased to 10 mg once daily. If the response to
10 mg is insufficient, an additional antihypertensive agent should be
added to the treatment regimen.
Side effects
► Dizziness, Headache, Nausea, Weakness, Vomiting, Hyperglycemia,

Excessive urination, Hyperurecemia , Hypokalemia
Excessive thirst, Hypovolemia Impotence Esophageal hemorrhage, and
dyspepsia
DRUG INTERACTIONS
► Patients receiving high doses of salicylates may experience salicylate
toxicity when DEMATOR is concomitantly administered.
► The natriuretic effect of DEMATOR (like that of many other diuretics) is
partially inhibited by the concomitant administration of indomethacin.
► Co administration of probenecid reduces secretion of DEMATOR into the
proximal tubule and thereby decreases the diuretic activity of DEMATOR.
Toric study
 TORIC (Torsemide in Congestive Heart Failure)
 No of patients =1377 with NYHA class II-III CHF
 Diuretic therapy with torsemide 10 mg or frusemide 40 mg or other
diuretics in addition to their existing standard CHF therapy for 12
months.
Outcome:
Mortality was significantly lower in the torsemide (2.2%) than in the
frusemide/other diuretics group (4.5%).
Torsemide treatment was associated with a significantly lower total
mortality and cardiac mortality.
Also, a significantly greater proportion of patients in the torsemide group
showed improvement in the NYHA class compared to patients treated with
frusemide or other diuretics.
TORIC study throw up the exciting possibility that torsemide, by its specific
pharmacological profile & anti-aldosterone effect , might provide additional
benefits in CHF, which are beyond its pure diuretic effect
Use of demator to decrease fibrosis:
TORIC study has already established the anti-aldosterone effect of Torsemide.
As we all know that increased level of aldosterone is associated with increased
production of MMP & increased synthesis of collagen which leads to cardiac
remodeling. Aldosterone by decreasing NO bioactivity leads to endothelial
damage & also causes increased production of endothelin & inactivation of
bradykinin which also contributes to endothelial damage. Torsemide by virtue of
its anti-aldosterone effect plays an important role in the management of arterial
fibrosis & cardiac remodeling.
Competitors:
Diurator Elder
Dytor Cipla
Tide Torrent
Toride Ranbaxy (cv)
Torsinex Micro (cv)
LOSATEC
Each tablet contains:
Losartan Potassium: 25mg/ 50mg
LOSATEC
Losatec, the first of the selective AII receptor antagonists to be
approved by US FDA for clinical use on 14th April 1995, indicates
that this approach is efficacious in all grades of hypertension and offers
a more attractive and acceptable tolerability profile than other forms of
antihypertensive medications. Clinical trial data indicate that Losatec
beneficial in heart failure in older patients.
Mechanism of action
Losatec acts by inhibiting aangiotensinn II (AT1) receptor. Removal of

angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity. Even with increases in plasma renin activity leading to
increases in angiotensin II in plasma, antihypertensive activity and
suppression of plasma aldosterone concentration are maintained indicating
effective angiotensin II receptor blockade by Losatec.
Pharmacokinetics
Bioavailability 33%
Half life 6-9 hours
Onset of action within 1 hour
Peak of action 1-2 hrs
Duration of action 6-8hrs
Protein binding 99%
Indications
Losatec is indicated for the treatment of hypertension; it may be used alone or

in combination with other antihypertensive agents. Losatec is indicated in
diabetic nephropathy.
Dosage of Losatec
Usual starting dose is 50 mg once daily.

Losatec can be administered with or without food once or twice daily with total
daily doses ranging from 25 to 100 mg.
In patients with possible depletion of intravascular volume; patients on
diuretics or with a history of hepatic impairment or in some sensitive elderly
the starting dose should be 25 mg once daily.
Contraindications
Hypersensitivity to Losatec or any ingredients of this product.
Adverse Drug Reaction
Treatment with Losatec is usually well tolerated. The overall incidence of

adverse effects was similar to placebo in clinical studies. Discontinuation of
therapy because of clinical adverse experiences was 2.3% with Losatec and
2% with placebo. The reported adverse effects include diarrhoea, dyspepsia,
myalgia, back pain, muscle cramps, leg pain, dizziness, insomnia, and upper
respiratory tract infection. The incidence of dry cough with Losatec was not
significantly different than placebo. Anxiety, angina, arrhythmias, angio-
edema and photosensitivity have been rarely reported.
The USPs of Losatec
• First angiotensin II receptor blocker

• Selective A II receptor (Type AT1) antagonist
• Patients with/ susceptible to cough on ACEIs
• No change in heart rate unlike Calcium Channel blockers

• Reduction of mortality and left ventricular mass
• Reduction in the risk of stroke
• Reno – protection in diabetics

•
Competitor :
Cosart Cipla Losar Unichem
Covance Ranbaxy Repace Sun
Losacar Zydus Tozaar Torrent
Losagard Lupin
LOSATEC-H
Introduction
It is a combination of first non-peptide angiotensin II receptor (type AT1)

antagonist i.e. Losartan and thiazide diuretic, hydrochloro-thiazide.
Losartan -50mg
Hydrochlorthiazide -12.5mg
Mechanism of action
Losartan
Losatec acts by inhibiting aangiotensinn II (AT1) receptor. Removal of

angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity. Even with increases in plasma renin activity leading to
increases in angiotensin II in plasma, antihypertensive activity and
suppression of plasma aldosterone concentration are maintained indicating
effective angiotensin II receptor blockade by Losatec.
Hydrochlorthiazide
Hydrochlorothiazide belongs to the thiazide class of diuretics, acting on the
kidneys to reduce sodium (Na) reabsorption in the distal convoluted tubule.
This increases the osmolarity (what is this) in the lumen, causing less water to
be reabsorbed from the collecting ducts. This leads to increased urinary
output.
Pharmacokinetics
Losartan:
Bioavailability 33%
Half life 6-9 hours
Onset of action within 1 hour
Peak of action 1-2 hrs
Duration of action 6-8hrs
Protein binding 99%
Hydrochlorthiazide:
Bioavailability : Variable
Half life : 5.6-14.8hours
Excretion : Unchanged through urine
Adverse Drug Reaction
The reported adverse effects include dizziness, upper respiratory tract infection,
back pain, skin rash, palpitation and edema/swelling.
Following additional side effects reported with hydrochlorothiazide may occur
with the combination. Hydrochlorothiazide may cause electrolyte imbalance
(hyponatraemia and hypokalemia), glycosuria, hyperglycaemia, hyperuricaemia
and weakness.
Indications
The fixed dose combination is indicated for treatment of hypertension (not for
initial therapy) – what is meant by this?
Dosage
• The usual dosage recommended is 1 tablet once daily.

• The maximum dose is 2 tablets once daily for most patients with or without
food. The maximal hypertensive effect is attained about 3 weeks after
initiation of therapy.
• The usual total daily dosage recommended for the treatment of
hypertension is 25-100mg Losartan and 12.5-100mg once daily
hydrochlorothiazide respectively. The combination can be given at doses
of 12.5 to 25mg hydrochlorothiazide.
• No initial dosage adjustment is necessary for elderly.
• No initial dosage (adjustment necessary in mild renal impairment and is
not recommended in moderate to severe renal impairment.
Contraindications
Hypersensitivity to Losartan or hydrochlorothiazide or to any components of the

product or other sulfonamide-derived drugs, and anuria..
Presentation
Losatec-H – Each tablet contains Losartan Potassium 50mg +

Hydrochlorothiazide 12.5mg
Strip of 10 tablets
The Usps (capital) of Losatec-H
• Better BP control than monotherapy.

• High patient responses
LIFE STUDY
Losartan Intervention for Endpoint Reduction in Hypertension Study

LIFE Study
Double-blind, randomized trial to compare the effects of losartan and atenolol on
cardiovascular morbidity and mortality in high-risk patients with hypertension and left
ventricular hypertrophy (LVH).
Population
• 9,193 patients (55 to 80 years old) from 945 sites in 7 countries
– previously treated or untreated essential hypertension (systolic BP 160–
200 mmHg or diastolic BP 95–115 mmHg)
– ECG LVH
• 1,195 patients (13%) had diabetes at baseline

Primary Endpoint
• Composite of cardiovascular mortality, fatal and non-fatal myocardial infarction,
and fatal and non-fatal stroke
Other predefined endpoints
– total mortality
– angina pectoris†
– heart failure†
– coronary or peripheral revascularization procedures
– resuscitated cardiac arrest
– new-onset diabetes mellitus
LIFE Study Summary
• Losartan-based compared with atenolol-based
Antihypertensive therapy was associated with:
– A reduction in the combined primary endpoint of cardiovascular death,
stroke or MI (-13%)
– Fewer strokes (-25%)
– similar blood pressure reduction
• Losartan reduced the rate of new-onset diabetes (-25%)
• In the diabetic subgroup, losartan reduced the rate of:
– Combined endpoint of cardiovascular death, stroke and MI (-25%)
– All-cause mortality (-39%)
Conclusions
• Losartan reduced the combined risk of cardiovascular morbidity and mortality
compared to atenolol with benefits not explained by blood pressure reduction
• Losartan reduced the rate of new-onset diabetes
• Losartan was significantly better tolerated than atenolol
• Among diabetics, losartan reduced cardiovascular morbidity and mortality
RENAAL STUDY
RENAAL stands for Reduction of Endpoints in Non-insulin dependent diabetes

mellitus with the Angiotensin II Antagonist Losartan.
Objective
The RENAAL study was undertaken to find out if COZAAR® (losartan
Potassium)––a medication indicated for the treatment of hypertension has
an effect of slowing down the progression of renal disease
in people with type 2 diabetes (non-insulin dependent diabetes mellitus),
suffering from hypertension or not, in other words, independent of its effect on
hypertension. The question addressed by this study is: does taking losartan
reduce the progression of kidney disease in patients with type 2 diabetes
and established kidney disease?
Design
RENAAL is a multicentred, international, double-blind, placebo-controlled,
randomized trial with a total of 1,513 patients enrolled.
Male and female patients between the ages of 31 to 70 diagnosed with type 2
diabetes and established kidney disease with or without hypertension were
recruited for the study.
Recruitment began in June, 1996 and the study ended in February, 2001.
Patients were randomly assigned to one of two groups, one taking COZAAR®
(50 mg or 100 mg once daily), and the other taking a placebo. Those with
hypertension also continued their usual antihypertensive therapy that could
include diuretics, vasodilators, calcium channel blockers and/or beta blockers,
but could not include ACE (angiotensin-converting enzyme) inhibitors and
other AIIAs (angiotensin II antagonists). Maintaining adequate and equal blood
pressure control (target: 140/90 mmHg) in both groups was essential.
Endpoints (results assessment)

Primary endpoint
To determine the impact of losartan on the progression of kidney disease as
assessed by the length of time it takes for doubling serum creatinine (the level
of creatinine in the blood is an indirect measure of how well the kidneys are
functioning), to reach end-stage renal disease, or death.
Secondary endpoints
To assess the effect of losartan compared to placebo on:
 D ecreasing sickness and death caused by cardiovascular (heart and
circulation-related) disease;
Slowing down the progression of renal disease;
Reducing protein in the urine;
Safety and tolerability
Results-
Losartan treatment was associated with:
• 28% risk reduction of ESRD over a mean of 3.4 years (P = 0.002)

• 25% risk reduction of a doubling of the serum creatinine concentration (P =
0.006)
• 35% decrease in the level of proteinuria (P < 0.001)
• 32% risk reduction in the rate of first hospitalization for heart failure (P < 0.005)
The benefits exceeded those attributable to changes in blood pressure. Morbidity from
cardiovascular causes was similar in the two groups, as was all-cause mortality.
Conclusion---Losartan conferred significant renal benefits in patients with type 2
diabetes and was generally well tolerated.
Competitor :
Cosart -H Cipla Losar -H Unichem
Covance -D Ranbaxy Repace-H Sun
Vida-H Lupin Tozaar -H Torrent
TOPDIP
INTRODUCTION
TOPDIP contains Amlodipine besylate is second generation

dihydropyridine calcium channel blockers. Being long acting it has distinct
advantages over other members of the family e.g. verapamil, diltiazem,
nifedipine etc.
Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist
or slow-channel blocker) that inhibits the transmembrane influx of calcium
ions into cardiac muscle & hence reduces the force of contraction & rate of
contraction of heart & lowers the blood pressure.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular
smooth muscle to cause a reduction in peripheral vascular resistance and
reduction in blood pressure.
TOPDIP
↓ Coronary artery ↓ Myoplasmic ↓ Peripheral arterial

spasm calcium ion influx vascular tone
↓ Coronary
artery tone ↓ Muscle cell ↓Systemic vascular
contraction resistance
↓ Coronary vascular
resistance
↓ After load
↓ Overall Cardiac
↑ Myocardial output
blood flow
PHARMACOKINETICS
• Bioavail (%): 64-90

• Onset (min): 30-60
• Protein Binding: 93
• Half-life (h): 40 h
• Tmax (h): 6-12
INDICATIONS
I. Hypertension
Used alone or in combination with other antihypertensive agents
II. Chronic Stable Angina
Alone or in combination with other antianginal agents
III. Vasospastic Angina (Prinzmetal or Variant Angina)
Alone or in combination with other antianginal agents
RECOMMENDED DOSAGE
Hypertension
Usual dose is 5-10mg once daily. In small, fragile or elderly patients or patients
with hepatic insufficiency or when used with other antihypertensive agent, the
dose is 2.5mg once daily.
Angina
Usual dose is 10mg. For elderly patients and patients with hepatic insufficiency.
CONTRAINDICATIONS
Amlodipine is contraindicated in patients with a known sensitivity to
dihydropyridines and cardiac conduction defects.
ADVERSE DRUG REACTIONS

The most common side effects are headache and edema.
Other adverse reactions are fatigue, nausea, somnolence and abdominal pain.
Amlodipine has not been associated with clinically significant changes in routine
laboratory tests. No clinically relevant changes were noted in serum potassium,
serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid,
blood urea nitrogen, creatinine or liver function tests.
DRUG INTERACTIONS
Amlodipine has no effect on the protein binding of drugs like digoxin, phenytoin,
warfarin and indomethacin.
Co-administration with cimetidine does not alter pharmacokinetics of amlodipine
Co-administration with warfarin does not change the warfarin prothrombin
response time.
Amlodipine can be safely administered with thiazide diuretics, beta blockers,
ACE inhibitors, long acting nitrates, sublingual nitroglycerin, digoxin, wafarin,
NSAIDs, antibiotics and oral hypoglycemic drugs.
WARNINGS
Rarely, patients with severe obstructive coronary artery disease have developed
increased frequency, duration and severity of angina or acute MI on starting
amlodipine or with increase in the dose.
PRECAUTIONS
Caution should be exercised when co-administered with other peripheral
vasodilators particularly in patients with severe aortic stenosis.
Use with caution in patients with CHF

When used along with beta blocker, withdrawal of the latter should be by gradual
reduction of its dose.
Use in Patients with impaired Hepatic Function

Since amlodipine is extensively metabolised by the liver and plasma half-life is 56
hours in patients with impaired hepatic function, caution should be exercised in
such patients when administering amlodipine.
Use in Renal Failure

Changes in amlodipine plasma concentrations are not correlated with degree of
renal impairment. Amlodipine may be used at normal doses in such patients.
Amlodipine is not dialyzable.
PRESENTATIONS
Topdip 2.5mg - Each uncoated tablet contains Amlodipine 2.5mg
Topdip 5mg - Each uncoated tablet contains Amlodipine 5mg
Topdip 10mg - Each uncoated tablet contains Amlodipine 10mg
USPs of TOPDIP
• Smooth onset of action
• Aids patient compliance with OD dosing
• Effective as monotherpy and in combination with diuretics, ACEIs and beta
blockers
• Useful in hypertensive patients of all ages with concomitant diseases viz.
asthma, hyperlipidemia, diabetes, CHD and renal disease
Competitor :
Amdepin Cadila Amlogard Pfizer Amlong Micro
Amlopres Cipla Stamlo DRL Amlovas Macleods
Amlopin USV Amlosafe Aristo
TOPDIP AT
INTRODUCTION
Topdip AT contains calcium channel blocker amlodipine besylate and beta

blcoker atenolol.
Mechanism of Action
Amlodipine
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or
slow-channel blocker) that inhibits the transmembrane influx of calcium ions into
cardiac muscle & hence reduces the force of contraction & rate of contraction of
heart & lowers the blood pressure.
Atenolol
Atenolol is water-soluble β 1 selective betablocker. Atenolol being selective
blocker causes negative ionotropic (decrease force of construction)
negative chronotropic (decrease heart rate) and negative dromotropic
effect (decrease conduction velocity).
This causes decrease in cardiac output. Atenolol also decreases plasma renin
levels and antagonise the sympathetic stimuli. All these contribute reduction in
blood pressure.It also decreases the myocardial oxygen consumption by
decreasing the work done by the heart.Thus atenolol is very effective in
treatment of hypertension and stable angina (exertional angina).
PHARMACOKINETICS
Amlodipine:
• Bioavail (%): 64-90
• Onset (min): 30-60
• Protein Binding: 93
• Half-life (h): 40 h
• Tmax (h): 6-12
Atenlol:
• Absorption: 50%
• Bioavailability: 50 - 60%
• Half-life: 6-9 hours
• Protein binding: 16%
• Excreted: 50% unchanged in feces
• Does not cross blood brain barrier - Low lipid solubility
RECOMMENDED DOSAGE OF ATENOLOL
Hypertension
Initial 50 mg OD either alone or in conjunction with a diuretic
Dosage can be increased to 100 mg/day
Angina
Initial 50 mg OD, Increase to 100 mg OD
In MI and Supra Ventricular Arrhythmia : intravenous formulations used
ADVERSE DRUG REACTIONS OF ATENOLOL
Poor exercise tolerance (fatigue) and cold extremities. Bradycardia, diarrhoea,

constipation, and impotence CVS side effects are less compared to lipophilic
beta-blockers (propranolol) since hydrophilic atenolol does not cross blood brain
barrier.
Atenolol – Summary
• Decreased BP and decreased oxygen demand by blocking positive isotropic

and chronotropic action of catecholamines
• Cardioselective (i.e. selective beta 1blocker)
• No unwanted (β 2) bronchoconstrictor effect
• Antagonise β 1 at 50 - 100 times less dose than required for β 2
• Least lipid solubility than other selective blockers (metoprolol, esmolol,
acebutolol); very hydrophilic, hence low incidence of CNS side effects than
propranolol
• Useful in diabetics hypertensives (receiving insulin / oral hypoglycaemics),
since little effect on carbohydrate metabolism
• Hypertension 50 mg OD, increased to 100 mg after several weeks
• Efficacious with diuretics, in elderly
• Well tolerated in elderly
• In all grades of hypertension
• In painful and silent ischaemia, decreased frequency of attacks and use of
Nitroglycerine at 50-100 mg/day depending on severity
• Long duration of action lasting upto 24 hours allowing once daily dosing
• Compared to non-selective beta-blockers, atenolol is preferred in asthmatic
and diabetic patients
• It reduces both resting and exercise heart rates
• Narrow dose response range obviates need for highly individualised dose
titration.
PRESENTATION:
Strip of 10 tablets
USPs of TOPDIP AT:
• Improvement of patients compliance due to once daily dosing

• Better clinical response with lesser side effects due to reduction in the doses
of the individual drugs
• Enhancement of antihypertensive and antianginal action
• At high doses, β 1 selectively is lost. Since in combination, lower doses are
used, selectivity is retained.
• Alteration (reduction) of adverse effects viz. Amlodipine may inhibit alpha
adrenergic mediated vasoconstriction caused by atenolol
Competitor :
Amdepin- Cadila Amlodac- Zydus Amlong-A Micro
AT AT
Amlopres- Cipla Stamlo- DRL Amlovas- Macleods
AT Beta AT
Amlopin USV Amlosafe- Aristo
-AT AT
ACEDIP
INTRODUCTION
ACE inhibitor (Lisinopril 5 mg) added to calcium channel blocker (Amlodipine 5
mg) decrease vasodilatation induced activation of RAAS by latter. The
antihypertensive actions are complimentary to each other.
Mechanism of Action
Amlodipine
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or
slow-channel blocker) that inhibits the transmembrane influx of calcium ions into
cardiac muscle & hence reduces the force of contraction & rate of contraction of
heart & lowers the blood pressure.
Lisinopril:
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and
animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of
angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also
stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of
lisinopril in hypertension and heart failure appear to result primarily from
suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE
results in decreased plasma angiotensin II which leads to decreased vasopressor
activity and to decreased aldosterone secretion. The latter decrease may result
in a small increase of serum potassium.
INDICATIONS:
Hypertension
Lisinopril is indicated for the treatment of hypertension. It may be used alone as
initial therapy or concomitantly with other classes of antihypertensive agents.
Heart Failure
Lisinopril is indicated as adjunctive therapy in the management of heart failure in
patients who are not responding adequately to diuretics and digitalis.
Acute Myocardial Infarction

Lisinopril is indicated for the treatment of hemodynamically stable patients within
24 hours of acute myocardial infarction, to improve survival. Patients should
receive, as appropriate, the standard recommended treatments such as
thrombolytics, aspirin and beta-blockers.
ADVERSE DRUG REACTIONS

Cough, nausea, fatigue, asthenia, hypotension, diarrhea, rash and angioedema.
CONTRAINDICATIONS
Lisinopril is contraindicated in patients who are hypersensitive to this product and
in patients with a history of angioedema related to previous treatment with an
angiotensin converting enzyme inhibitor and in patients with hereditary or
idiopathic angioedema.
DRUG INTERACTIONS
Agents Increasing Serum Potassium: ACE inhibitors cause decreased

aldosterone production which may lead to increased potassium retention by the
kidney. When combined with agents such as potassium-sparing diuretics
(Aldactone, triamterene or amiloride), potassium supplements or potassium-
containing salt substitutes, severe hyperkalemia may occur.
Alpha-blocking Agents: Patients taking ACE inhibitors may experience an

exaggerated hypotensive response to the first dose of an alpha-blocker (e.g.,
doxazosin, prazosin, terazosin).
Hypotension — Patients on Diuretic Therapy: Patients on diuretics and

especially those in whom diuretic therapy was recently instituted, may
occasionally experience an excessive reduction of blood pressure after initiation
of therapy with lisinopril.
Non-Steroidal Anti-Inflammatory Agents: Coadministration of lisinopril may

result in further deterioration of renal function.
RECOMMENDED DOSAGE
1 tablet once daily
USPs of Acedip
1. Potentiation (addition or synergism) of antihypertensive effect when two

antihypertensive gents are combined.
2. Lower doses of each drug required, leading to better clinical response with less
side effect.
3. Due to their long elimination half life, they can be administered once daily,
hence improved patient's compliance and better clinical response.
4. Reinforcement of antihypertensive effect of ACE inhibitor by the negative
sodium balance caused by calcium channel locker.
5. Calcium channel blockers activates sympathetic nervous system. ACE
inhibitors counterbalance this effect by decreasing sympathetic outflow.
6. Angiotensin converting enzyme inhibits bradykinin. ACE inhibitors by
inhibiting ACE increase the levels of bradykinin, nitric oxide and prostacyclin
and thus provides vasoprotection.
Calcium channel blockers reduce contraction and facilitate relaxation of the
myocardium. Also, they inhibit the effect of platelet derived growth factor, thus
exhibiting antiproliferative effect.
7. Hypertension is a disease that required life long treatment in most patients.
With combination the number of tablets to be administered are reduced and
moreover due to their long action, number of doses are reduced too. This
leads to increased patient's convenience.
ACCOMPLISH TRIAL
The Avoiding Cardiovascular Events through Combination Therapy in Patients
Living with Systolic Hypertension
Designed to challenge current guidelines in defining the optimal therapeutic
strategy for achieving blood pressure control and preventing CVD events in high-
risk patients
– First trial to randomize to initial antihypertensive combination
therapy (amlodipine besylate / benazepril vs benazepril HCTZ)
Methods: Randomized, double-blind trial, multicenter

No. of patients: 11,506 patients with hypertension who were at high risk for
cardiovascular events to receive treatment with either benazepril plus amlodipine
or benazepril plus hydrochlorothiazide.
• Only 37.5% of patients were controlled to <140/90 mmHg
Primary end point: Composite of death from cardiovascular causes, nonfatal

myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation
after sudden cardiac arrest, and coronary revascularization.
Secondary end points: were a composite of cardiovascular events, defined as
the primary end point excluding fatal events, and a composite of death from
cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction.
Results: It was stopped early because treatment with antihypertensive

combination therapy--the ACE inhibitor benazepril plus the calcium-channel
blocker amlodipine--was more effective than treatment with the ACE inhibitor
plus diuretic.
Investigators report that combination treatment with benazepril plus amlodipine
reduced cardiovascular morbidity and mortality, defined as cardiovascular death,
fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for unstable angina, and
coronary revascularization, by 20%, compared with those treated with
benazepril plus a diuretic.
Competitor:
Amlace USV Amlodac-L Zudus
Amlopres-L Cipla Amlovas-L Macleods
Amtas-LP Intas Primodil-L Medley
Arpitor
Arpitor is Atorvastatin. Atorvastatin is a potent synthetic HMG CoA-reductase

inhibitor. It lowers plasma cholesterol levels by inhibiting endogenous cholesterol
synthesis. Atorvastatin also has additional beneficial effects on arterial structure
and function i.e., anti-atherosclerotic and antithrombotic effects.
Mechanism of action:
HMG CoA Reductase

HMG CoA Reductase Inhibitor
Arpitor
Mevalonic Acid
Cholestero
l
The formation of mevalonate is the rate-limiting step in endogenous
cholesterol synthesis. This is catalyzed by the enzyme HMG CoA reductase.
Atorvastatin selectively & competitively inhibits HMG CoA reductase. By
decreasing the production of mevalonate, Atorvastatin reduces hepatic
cholesterol biosynthesis
Pharmacokinetic:
• Absorption : Rapidly absorbed on oral administration;
• Peak plasma levels: within 1-2 hours.
• Protein binding: 98%
• Its’ long-acting inhibitory effect is due to the presence of active
metabolites (Ortho and Para hydroxylated derivatives). 70 % of
inhibitory action is due to the metabolites. This is responsible for the
high potency of the drug
• Half-life : 14 hours
Indication:
Atorvastatin is indicated to reduce
• Total-Cholesterol
• LDL cholesterol
• Apolipoprotein B
• Triglycerides
in patients with Hypercholesterolemia and combined hyperlipidemia.
Dosage:
o Initial dose 10mg/day
o Dose range 10 to 80mg/day.
o Atorvastatin can be administered as single dose at any time
of the day.
o Atorvastatin can be administered with or without food
Side effects:
Atorvastatin is generally well tolerated, with mild and transient reactions.Most
commonly reported side effects are
o Constipation
o Dyspepsia
o Flatulence
o Myalgia
o Allergy &
o Abdominal pain
Pleiotropic effects of statins: Statins have been shown to modulate vascular

function by increasing expression of nitric oxide synthase and enhancing nitric oxide
production. Increases in nitric oxide reduce endothelial dysfunction, attenuate leukocyte-
endothelium interactions, and decrease platelet aggregation. Statins have also been
demonstrated to scavenge reactive oxygen species, decrease endothelial cell apoptosis,
and produce antithrombotic effects. Statins exert antiinflammatory effects that contribute
to atherosclerotic plaque stability. In addition, statins reduce vascular smooth muscle
proliferation in response to injury and may contribute to a decrease in the incidence of
restenosis after percutaneous coronary intervention.7 The direct cardioprotective effects
of statins may be particularly important in disease states (e.g., diabetes mellitus) in
which endogenous signal transduction responsible for normal protection against
ischemic injury is impaired.
↓ Platelet activation
↓ Coagulation
Endothelial function
↓ Reactive oxygen species
NO bioactivity
↓ AT1 receptor
↓ Effects on collagen
↓ MMPs
↓ Endothelin
How is Atorvastatin superior to Simvastatin?
 More prolong inhibition of HMG -CoA reductase

 Leading to greater reduction in LDL-C, TG, Apo-B and TC
Arpitor Simvastatin
T 1/2 14 hrs 2-3 hrs
Metabolites Active Less active
Atorvastatin exhibited more potent cholesterol lowering activity, as it was

more difficult to displace the drug from the microsomal HMG CoA
reductase
 Greater reduction in LDL-C, TG, Apo-B and TC2

Arpitor Simvastatin
LDL-C -39% -30%
Triglyceride -27% -15%
Total Cholesterol -30% -24%
% Patient achieved 76% 58%

Target LDL-C levels
• Atorvastatin 10 mg produced LDL-C reductions comparable or greater than
Simvastatin 10, 20 and 40 mg
 Effect seen from starting dose

Arpitor Simvastatin
Median Response Time 170 days 353 days
 The maximum gain in life expectancy was achieved with Atorvastatin

• 36 % reduction in cardiovascular complication in CAD patient compared to
patients undergoing angioplasty.
• Ensures patients compliance.
• Cost effective therapy.
Comparative study:
Statin Daily Dose % reduction Total
cholesterol
Simvastatin 40mg 31%
Simvastatin 80mg 35%
Atorvastatin 10mg 32%
Atorvastain 80mg 47%
Rosuvastatin 5mg 33%
Effects of Statins on Lipids
Statin LDL-C % change HDL-C % change TG % change
Rosuvastatin (10 mg) 52 +14 -10
Atorvastatin (10 mg) -39 +6 -19
Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med
1999;341:498–511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-
409.
,
Ssimvastatin (20 mg) -33 +8 -19
Pravastatin (20 mg) -32 +2 -11
Fluvastatin (20 mg) -22 +3 -12
Summary of Drug Choice:
Lipid First choice Additional Remarks

abnormality type
↑ LDL Statin Ezetimibe Myopathy ↑
↑ TG Fibrate Niacin ↓ CHO intake
↓ HDL Niacin Fibrate Exercise
↑ LDL + ↑ TG Statin + Fibrate Niacin Myo risk ↑ ↑
↑ LDL + ↓ HDL Statin + Niacin Fibrate Exercise
↑ TG + ↓ HDL Fibrate + Niacin Statin Exercise
↑ LDL + ↑ TG + ↓ Statin + Fibrate E, N, BA, FO Myo risk ↑ ↑ ↑
HDL
Effect of lipid-modifying therapies on lipids

Therapy TC LDL HDL TG Patient
tolerability
Bile acid Down Down Up Neutral or Poor
sequestrant 20% 15–30% 3–5% up
s
Nicotinic Down Down Up Down Poor to

acid 25% 25% 15–30% 20–50% reasonable
Fibrates Down Down Up Down Good

15% 5–15% 20% 20–50%
Probucol Down Down Down Neutral Reasonable

25% 10–15% 20–30%
Statins* Down Down Up Down Good

19–37% 25–50% 4–12% 14-29%
Ezetimibe ------- Down Up Down Good
18% 8%
Competitor :
SERENACE
Serenace is an antipsychotic product useful for different types of psychotic

illnesses. It belongs to the group called Typical/Older/1 st generation Antipsychotic
or Neuroleptic. Chemically it belongs to butyrophenone group (Chlorpromazine
belongs to Phenothiazine group).
Composition of Serenace:
Serenace is available as tablets, liquid and injection.
Serenace 0.25
Each tablet contains
Haloperidol I.P. 0.25mg
Serenace 1.5
Haloperidol I.P. 1.5 mg
Serenace 5
Haloperidol I.P. 5 mg
Serenace 10
Serenace 20
Serenace injection (1 ml ampoule)

Each ml contains
Serenace liquid (15 ml bottle)

Each ml contains
Serenace is indicated :
Serenace is used in the following conditions:
1. Schizophrenia
2. Acute psychoses
3. Delirium
4. Manic states
5. Anxiety states
Mode of action:
Schizophrenia occurs as a result of excess activity of dopaminergic systems in

the brain. Serenace is a very potent dopamine D2 receptor antagonist. By
blocking these receptors, Serenace controls thought disorders and reduces
hyperactivity and mania.
Pharmacokinetic profile
The onset of sedation :1 h after intravenous dosing

Peak serum levels : within 20 min and 2 to 6 h with intramuscular and oral
dosing, respectively;
Approximately 60% to 70% of an oral dose is absorbed
Protein binding : Approximately 90%;
Volume of distribution : 1300 L;
Elimination half-life : 13 to 35 h;
Metabolism : hepatic metabolism
Exctetion: 33% to 40% excreted in the urine within the first 5 days; an additional
15% is excreted in the feces.
What are antipsychotic drugs?
Antipsychotic drugs are the drugs used in the treatment of psychotic illnesses like
schizophrenia. They are classified into two major groups as follows:
Older/Typical Antipsychotics
Ex: Chlorpromazine, Haloperidol
Newer/Atypical Antipsychotics
Ex: Clozapine, Risperidone, Olanzapine, Ziprasidone, Qutiapine
How do typical and atypical antipsychotics differ from one another?
With typical antipsychotics, there are always a chance of getting EPS (Extra-
Pyramidal Syndrome). But as far as efficacy of typical agents is concerned, they
are highly efficacious molecules. Serenace is well known for its established
efficacy in the treatment of schizophrenia as well as acute conditions like
agitation. On the other hand, atypical antipsychotics usually do not cause EPS,
but in high dose, there can be EPS with these drugs also (like olanzapine,
risperidone). As far as efficacy is concerned, it is said that these agents control
negative symptoms in addition to positive symptoms (because of their additional
action on 5-HT receptors; Serenace blocks only Dopamine receptors). But there
is very less evidence for this claim.
It has been observed that atypical antipsychotics are capable of causing weight
gain and this has been already proved in all the clinical trials for these drugs. The
drugs which cause weight gain are clozapine, olanzapine, risperidone and
qutiapine. This is a very serious concern in the minds of the doctors, because
this may lead to obesity, glucose intolerance, diabetes mellitus, dyslipidemia,
atherosclerosis, etc.
Because of above mentioned problems (weight gain liability), many doctors

have already shifted back to older (typical) agents like Serenace. Please
note that this is the most important point for the promotion of Serenace.
How do doctors make a choice of antipsychotic agents?
Typical antipsychotic drugs like Haloperidol are very potent inhibitors of

Dopamine receptors, thus very efficacious drugs. They have one common side
effect, i.e., Extra-Pyramidal Reactions.
Atypical antipsychotics are also effective agents, but their binding with Dopamine
receptors is not firm. Thus they are dissociated from the receptors faster than
typical agents. Therefore chances of getting EPS with these drugs are less. But
recent clinical evidence shows that atypical antipsychotic agents like olanzapine
and clozapine are capable of causing weight gain. They can also cause glucose
intolerance, diabetes mellitus, dyslipidemia, etc, which are of extreme concern in
cardiovascular patients, especially those suffering from diabetes mellitus.
Taking this consideration, many doctors still prefer to start therapy with
Haloperidol (Serenace) in newly diagnosed cases of schizophrenia. Once the
patient is stabilized on Haloperidol, it is continued as long as it is tolerated and
does not cause EPS, especially TD (Tardive Dyskinesia). If it causes EPS, then
atypical agents are preferred.
If the patient shows agitation or irritability, then the preferred choice is typical
agent like Haloperidol, because it is very potent drug and it effectively controls
agitation. For this purpose, either injection or liquid preparation is preferred.
The choice of therapy also depends on the associated conditions like pregnancy,
diabetes mellitus, cardiac disease, osteoporosis, sexual dysfunction, treatment-
refractory cases, etc.
What is the commonest side effect of Serenace?
The commonest side effect of Serenace is Extra-Pyramidal Syndrome (EPS).

What is EPS? What are the different types of extrapyramidal reactions?
When we treat a case of schizophrenia, the drug is supposed to block the

Dopamine receptors (D2R) in mesolimbic pathway (which is responsible for
emotions). Thus Serenace gives antipsychotic action by blocking these
receptors. Since dopamine receptors (D2R) are also present in nigrostriatal
pathway (which is responsible for movements), Serenace will block D2R here
also. This leads to movement disorders called EPS. This usually happens when
Dopamine receptor occupancy crosses 80%.
These reactions are manifested in various ways. There are many kinds of EPS.
But here we are describing important EPS. There are three main types of EPS.
They are Acute dystonia, Parkinsonism and Tardive dyskinesia.
Acute dystonia
It is characterized by sudden tonic contraction of muscles of tongue, neck, back,

mouth and eyes. It is common in young males, early in treatment and the
incidence is 10%.
Parkinsonism
It is characterized by muscular rigidity (stiff muscles), bradykinesia (poverty of

movements like shuffling gait) and tremors. It is more common in women, >40
years of age, early in treatment and the incidence is 15%.
Tardive dyskinesia
It is a late onset (Tardive) movement disorder (dyskinesia). It is characterized by

abnormal movement of muscles of head, limbs and trunk. It is common in older
patients, but rare in early stages.
What is the recommended dose of Serenace?
Tablets and Liquid:
Adults: Normally treatment may be started at 10-15 mg daily and increased until
satisfactory control is achieved. When maximum improvement is reached the
dose should be gradually reduced to the lowest effective maintenance dose
which for many patients will be 1-10 mg/day.
Children: 0.05mg per kg body weight per day. Where control is not urgent,
treatment may be initiated at half the above level working upto the maintenance
dosage. Serenace is not recommended for children under three years of age.
Injection:
Adults: For rapid emergency control upto 30 mg (a dose of 10mg will normally
be adequate) may be given by intramuscular injection. Further doses may be
repeated every 6 hours until control is achieved, when oral dosage may be
substituted in diminishing doses. The intravenous route may be used if required.
Children: 0.05mg per kg body weight per day. Where control is not urgent,
treatment may be initiated at half the above level working upto the maintenance
dosage. Serenace is not recommended for children below 3 years of age.
In adults, therapy may be started at 2 or 3 times the maintenance dosage, and

may be combined with anti-Parkinsonian drugs.
The dosage range can vary between 1mg and over 200mg per day depending on
the condition and the individual’s response to treatment. Dosage should be
titrated to clinical efficacy and then reduced to the lowest effective level. Safety of
prolonged administration of high dosage has not been demonstrated by
controlled clinical trials. Children and debilitated or geriatric patients may be more
sensitive to haloperidol and require adjustment of the starting dose. The
maximum dose and maintenance doses are generally lower for these patients.
Why do doctors use liquid and injection?
Rapid neuroleptization: Liquid and injection formulation is used when patients

show agitation or acute psychotic symptoms for rapid neuroleptization. Cmax
after IM injection is achieved in 30 minutes, whereas that after oral administration
takes 1.5 hours. Therefore when it is the question of rapid action, injection is
preferred for control of acute psychotic symptoms. Hourly IM doses are given till
control is achieved.
Compliance: With liquid preparation, patient compliance is more than tablets.

Patients sometimes suffer from delusion of persecution (someone is trying to
poison me). Liquid can be mixed with fruit juice and administered.
How does haloperidol differ from chlorpromazine?
Phenothiazines like chlorpromazine causes some side effects which haloperidol

does not cause like postural hypotension, weight gain, fluid retention,
sedationand hypothermia.
SERENACE 0.25 mg
What is Serenace? Which group does it belong to? What is the
composition?
Serenace is an antipsychotic product useful for different types of psychotic

illnesses. It belongs to the group called Typical/Older/1st generation
Antipsychotic or Neuroleptic. Chemically it belongs to butyrophenone group
(Chlorpromazine belongs to Phenothiazine group). Serenace contains
Haloperidol. It is available as Serenace 0.25mg/1.5mg/5mg/10mg/20mg tablets
and also as liquid (2mg/ml) and Injection (5mg/ml).
Serenace 0.25
Each tablet contains Haloperidol I.P. 0.25mg
What is Serenace 0.25 mg indicated for?
Serenace 0.25 mg is used as an anxiolytic.
How does Serenace 0.25 mg act?
The mechanism of action is not known.
What are the key features in the pharmacokinetics of Serenace?
Following oral administration the drug is rapidly and almost completely absorbed.
Peak plasma concentrations are attained 2-6h after oral administration.
Approximately 60% to 70% of an oral dose is absorbed; protein binding is
approximately 90%; volume of distribution is 1300 L; elimination half-life is 13 to
35 h; hepatic metabolism to inactive metabolites is followed with 33% to 40%
excreted in the urine within the first 5 days; an additional 15% is excreted in the
feces.
What are the side effects of Serenace 0.25 mg?
The side effects of Serenace 0.25 mg are rare but Extra-Pyramidal Syndrome
(EPS) can occur. No sedition, no drug dependence like Benzodiazepines.
What is the recommended dose of Serenace 0.25 mg?
Three times daily.
What are the USPs of Serenace 0.25 mg?

Relives anxiety rapidly
No sedition
No drug dependence
No tolerance development
Does not interfere with patients’ reflexes
Preferred when mental alertness is essential
PRESENTATION
Each tablet contains Haloperidol 0.25mg- Blister pack of 10 tablets
CLINICAL TRIAL EVIDENCE
Clinical study of haloperidol and diazepam in anxiety states: A double blind

trial.
Channabasavanna SM, Jayram SS, Kodandaram P
Ninety five patients suffering from anxiety were treated with diazepam or
haloperidol, of which 80 completing 4 weeks of treatment were assessed (1)
subjectively, and (2) objectively, by Hamilton Rating Scale. The results at the end
of 2 weeks and 4 weeks of therapy showed that haloperidol is as effective as
diazepam in controlling anxiety. They were also found to be equieffective in both
public and private setups. Any differences were not statistically significant. The
side effects were minimal and transient for both groups, although the incidence of
drowsiness in the diazepam treated group was higher.
-Curr.Therap. Resea.1978;24:381-386.
A study of a recognized antipsychotic agent as a tranquillizer in general

practice.
Donald JF
A double-blind trial was undertaken to compare the effects of haloperidol

(Serenace 0.25mg), 0.75 mg a day, and chlordiazepoxiede (Librium10mg), 30mg
a day, in patients presenting in general practice with anxiety. The results
recorded demonstrate a superior response to haloperidol, which was statistically
significant.
-The Practitioner 1969; 203:684-687.
Methods of assesment in a trial of haloperidol in anxiety neurosis

-Indian J. Psychiat. (1971), 13, 131-136
S. S. JAYARAM, P. K. RAM, M.A. D.M. & S.P.
SERENACE Depot
Generic Name: Haloperidol

Dosage Form: Injection
SERENACE Depot Description

SERENACE Depot (Haloperidol decanoate) is the decanoate ester of the
butyrophenone, haloperidol. It has a markedly extended duration of effect. It is
available in sesame oil in sterile form for intramuscular (IM) injection. The
structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-
fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is:
Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in

most organic solvents.
Each mL of SERENACE Depot 50 mg for IM injection contains 50 mg haloperidol
(present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2%
(w/v) benzyl alcohol as a preservative.
SERENACE Depot - Clinical Pharmacology
SERENACE Depot 50 mg is the long-acting forms of SERENACE Depot

(Haloperidol). The basic effects of SERENACE Depot are no different from those
of SERANACE (Haloperidol) with the exception of duration of action. Haloperidol
blocks the effects of dopamine and increases its turnover rate; however, the
precise mechanism of action is unknown.
Administration of haloperidol decanoate in sesame oil results in slow and
sustained release of haloperidol. The plasma concentrations of haloperidol
gradually rise, reaching a peak at about 6 days after the injection, and falling
thereafter, with an apparent half-life of about 3 weeks. Steady state plasma
concentrations are achieved after the third or fourth dose. The relationship
between dose of haloperidol decanoate and plasma haloperidol concentration is
roughly linear for doses below 450 mg. It should be noted, however, that the
pharmacokinetics of haloperidol decanoate following intramuscular injections can
be quite variable between subjects.
Indications and Usage for SERENACE Depot

SERENACE Depot 50 mg are indicated for the treatment of schizophrenic
patients who require prolonged parenteral antipsychotic therapy.
Contraindications
Since the pharmacologic and clinical actions of SERENACE Depot 50 mg are
attributed to SERANACE (Haloperidol) as the active medication,
CONTRAINDICATIONS, WARNINGS, and additional information are those of
SERENACE (Haloperidol), modified only to reflect the prolonged action.
SERENACE Depot is contraindicated in severe toxic central nervous system
depression or comatose states from any cause and in individuals who are
hypersensitive to this drug or have Parkinson's disease.
Warnings
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been
reported in patients receiving haloperidol. Higher than recommended doses of
any formulation and intravenous administration of haloperidol appear to be
associated with a higher risk of QT-prolongation and Torsades de Pointes.
Although cases have been reported even in the absence of predisposing factors,
particular caution is advised in treating patients with other QT-prolonging
conditions (including electrolyte imbalance [particularly hypokalemia and
hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities,
hypothyroidism, and familial long QT-syndrome). SERENACE Depot MUST NOT
BE ADMINISTERED INTRAVENOUSLY.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic
movements may develop in patients treated with antipsychotic drugs. Although
the prevalence of the syndrome appears to be highest among the elderly,
especially elderly women, it is impossible to rely upon prevalence estimates to
predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their
potential to cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will
become irreversible are believed to increase as the duration of treatment and the
total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after
relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia,
although the syndrome may remit, partially or completely, if antipsychotic
treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress
(or partially suppress) the signs and symptoms of the syndrome and thereby may
possibly mask the underlying process. The effect that symptomatic suppression
has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a
manner that is most likely to minimize the occurrence of tardive dyskinesia.
Chronic antipsychotic treatment should generally be reserved for patients who
suffer from a chronic illness that 1) is known to respond to antipsychotic drugs,
and 2) for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate. In patients who do require chronic
treatment, the smallest dose and the shortest duration of treatment producing a
satisfactory clinical response should be sought. The need for continued treatment
should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on
antipsychotics, drug discontinuation should be considered. However, some
patients may require treatment despite the presence of the syndrome. (For
further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic
Malignant Syndrome (NMS) has been reported in association with antipsychotic
drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered
mental status (including catatonic signs) and evidence of autonomic instability
(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac
dySRhythmias). Additional signs may include elevated creatine phosphokinase,
myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In
arriving at a diagnosis, it is important to identify cases where the clinical
presentation includes both serious medical illness (e.g., pneumonia, systemic
infection, etc.) and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis
include central anticholinergic toxicity, heat stroke, drug fever and primary central
nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2)
intensive symptomatic treatment and medical monitoring, and 3) treatment of any
concomitant serious medical problems for which specific treatments are
available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The
patient should be carefully monitored, since recurrences of NMS have been
reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex,
have also been reported with SERENACE Depot.
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including SERENACE Depot (haloperidol). It has been
postulated that lethargy and decreased sensation of thirst due to central inhibition
may lead to dehydration, hemoconcentration and reduced pulmonary ventilation.
Therefore, if the above signs and symptoms appear, especially in the elderly, the
physician should institute remedial therapy promptly.
Although not reported with SERENACE Depot, decreased serum cholesterol
and/or cutaneous and ocular changes have been reported in patients receiving
chemically-related drugs.
Precautions
SERENACE Depot 50 mg should be administered cautiously to patients:
– with severe cardiovascular disorders, because of the possibility of
transient hypotension and/or precipitation of anginal pain. Should
hypotension occur and a vasopressor be required, epinephrine should not
be used since SERENACE Depot (haloperidol) may block its vasopressor
activity, and paradoxical further lowering of the blood pressure may occur.
Instead, metaraminol, phenylephrine or norepinephrine should be used.
– receiving anticonvulsant medications, with a history of seizures, or with

EEG abnormalities, because SERENACE Depot may lower the convulsive
threshold. If indicated, adequate anticonvulsant therapy should be
concomitantly maintained.
– with known allergies, or with a history of allergic reactions to drugs.
– receiving anticoagulants, since an isolated instance of interference

occurred with the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued
after SERENACE Depot 50 mg is discontinued because of the prolonged action
of haloperidol decanoate. If both drugs are discontinued simultaneously,
extrapyramidal symptoms may occur. The physician should keep in mind the
possible increase in intraocular pressure when anticholinergic drugs, including
antiparkinson agents, are administered concomitantly with haloperidol
decanoate.
In patients with thyrotoxicosis who are also receiving antipsychotic medication,
including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or
talk) may occur.
When SERENACE Depot is used to control mania in bipolar disorders, there may
be a rapid mood swing to depression.
Information for Patients

Haloperidol decanoate may impair the mental and/or physical abilities required
for the performance of hazardous tasks such as operating machinery or driving a
motor vehicle. The ambulatory patient should be warned accordingly.
The use of alcohol with this drug should be avoided due to possible additive
effects and hypotension.
Drug Interactions
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and FBS) followed by irreversible brain damage has
occurred in a few patients treated with lithium plus SERENACE Depot. A causal
relationship between these events and the concomitant administration of lithium
and SERENACE Depot has not been established; however, patients receiving
such combined therapy should be monitored closely for early evidence of
neurological toxicity and treatment discontinued promptly if such signs appear.
As with other antipsychotic agents, it should be noted that SERENACE Depot
may be capable of potentiating CNS depressants such as anesthetics, opiates,
and alcohol.
In a study of 12 schizophrenic patients coadministered oral haloperidol and
rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean
scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5
other schizophrenic patients treated with oral haloperidol and rifampin,
discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol
concentrations. Thus, careful monitoring of clinical status is warranted when
rifampin is administered or discontinued in haloperidol-treated patients.
Carcinogenesis, Mutagenesis, and Impairment of Fertility

No mutagenic potential of haloperidol decanoate was found in the Ames
Salmonella microsomal activation assay. Negative or inconsistent positive
findings have been obtained in in vitro and in vivo studies of effects of short-
acting haloperidol on chromosome structure and number. The available
cytogenetic evidence is considered too inconsistent to be conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats
(dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at
up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal
in all dose groups, reducing the number of rats at risk for developing tumors.
However, although a relatively greater number of rats survived to the end of the
study in high-dose male and female groups, these animals did not have a greater
incidence of tumors than control animals. Therefore, although not optimal, this
study does suggest the absence of a haloperidol related increase in the
incidence of neoplasia in rats at doses up to 20 times the usual daily human dose
for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or
resistant patients, there was a statistically significant increase in mammary gland
neoplasia and total tumor incidence; at 20 times the same daily dose there was a
statistically significant increase in pituitary gland neoplasia. In male mice, no
statistically significant differences in incidences of total tumors or specific tumor
types were noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third
of human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients.
An increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available
evidence is considered too limited to be conclusive at this time.
Usage in Pregnancy
Pregnancy Category C. Rodents given up to 3 times the usual maximum human
dose of haloperidol decanoate showed an increase in incidence of resorption,
fetal mortality, and pup mortality. No fetal abnormalities were observed.
There are no adequate and well-controlled studies in pregnant women. There are
reports, however, of cases of limb malformations observed following maternal
use of SERENACE Depot along with other drugs which have suspected
teratogenic potential during the first trimester of pregnancy
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed
during drug treatment with haloperidol decanoate.
Pediatric Use
Safety and effectiveness of haloperidol decanoate in children have not been
established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified
differences in responses between the elderly and younger patients. However, the
prevalence of tardive dyskinesia appears to be highest among the elderly,
especially elderly women
Adverse Reactions
Adverse reactions following the administration of SERENACE Depot 50 mg are
those of SERENACE Depot (haloperidol). Since vast experience has
accumulated with SERENACE Depot, the adverse reactions are reported for that
compound as well as for haloperidol decanoate. As with all injectable
medications, local tissue reactions have been reported with haloperidol
decanoate.
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT
prolongation and/or ventricular arrhythmias have also been reported, in addition
to ECG pattern changes compatible with the polymorphous configuration of
torsade de pointes, and may occur more frequently with high doses and in
predisposed patients .
Cases of sudden and unexpected death have been reported in association with
the administration of SERENACE Depot. The nature of the evidence makes it
impossible to determine definitively what role, if any, SERENACE Depot played
in the outcome of the reported cases. The possibility that SERENACE Depot
caused death cannot, of course, be excluded, but it is to be kept in mind that
sudden and unexpected death may occur in psychotic patients when they go
untreated or when they are treated with other antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of SERENACE Depot (haloperidol) have been
reported frequently, often during the first few days of treatment. EPS can be
categorized generally as Parkinson-like symptoms, akathisia, or dystonia
(including opisthotonos and oculogyric crisis). While all can occur at relatively low
doses, they occur more frequently and with greater severity at higher doses. The
symptoms may be controlled with dose reductions or administration of
antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl
hydrochloride USP. It should be noted that persistent EPS have been reported;
the drug may have to be discontinued in such cases.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of
treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes
progressing to tightness of the throat, swallowing difficulty, difficulty breathing,
and/or protrusion of the tongue. While these symptoms can occur at low doses,
they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute
dystonia is observed in males and younger age groups.
Withdrawal Emergent Neurological Signs

Generally, patients receiving short-term therapy experience no problems with
abrupt discontinuation of antipsychotic drugs. However, some patients on
maintenance treatment experience transient dyskinetic signs after abrupt
withdrawal. In certain of these cases the dyskinetic movements are
indistinguishable from the syndrome described below under "Tardive Dyskinesia"
except for duration. Although the long-acting properties of haloperidol decanoate
provide gradual withdrawal, it is not known whether gradual withdrawal of
antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent
neurological signs.
Tardive Dyskinesia
As with all antipsychotic agents SERENACE Depot has been associated with
persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially
irreversible, involuntary, dyskinetic movements, may appear in some patients on
long-term therapy with haloperidol decanoate or may occur after drug therapy
has been discontinued. The risk appears to be greater in elderly patients on high-
dose therapy, especially females. The symptoms are persistent and in some
patients appear irreversible. The syndrome is characterized by rhythmical
involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue,
puffing of cheeks, puckering of mouth, chewing movements). Sometimes these
may be accompanied by involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson
agents usually do not alleviate the symptoms of this syndrome. It is suggested
that all antipsychotic agents be discontinued if these symptoms appear. Should it
be necessary to reinstitute treatment, or increase the dosage of the agent, or
switch to a different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an
early sign of tardive dyskinesia and if the medication is stopped at that time the
full syndrome may not develop.
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been
reported. Tardive dystonia is characterized by delayed onset of choreic or
dystonic movements, is often persistent, and has the potential of becoming
irreversible.
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient
leukopenia and leukocytosis, minimal decreases in red blood cell counts,
anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely
been reported to have occurred with the use of SERENACE Depot, and then only
in association with other medication.
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of
photosensitivity and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities,
gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and
hyponatremia.
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and
vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia,
an inherited disorder of ammonia excretion, following treatment with SERENACE
Depot.
Overdosage
While overdosage is less likely to occur with a parenteral than with an oral
medication, information pertaining to SERENACE Depot (haloperidol) is
presented, modified only to reflect the extended duration of action of haloperidol
decanoate.
SERENACE Depot: Dosage and Administration

SERENACE Depot 50 mg should be administered by deep intramuscular
injection. A 21 gauge needle is recommended. The maximum volume per
injection site should not exceed 3 mL. DO NOT ADMINISTER
INTRAVENOUSLY.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
SERENACE Depot 50 mg are intended for use in schizophrenic patients who
require prolonged parenteral antipsychotic therapy. These patients should be
previously stabilized on antipsychotic medication before considering a conversion
to haloperidol decanoate. Furthermore, it is recommended that patients being
considered for haloperidol decanoate therapy have been treated with, and
tolerate well, short-acting SERENACE Depot (haloperidol) in order to reduce the
possibility of an unexpected adverse sensitivity to haloperidol. Close clinical
supervision is required during the initial period of dose adjustment in order to
minimize the risk of overdosage or reappearance of psychotic symptoms before
the next injection. During dose adjustment or episodes of exacerbation of
symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented
with short-acting forms of haloperidol.
The dose of SERENACE Depot 50 mg should be expressed in terms of its
haloperidol content. The starting dose of haloperidol decanoate should be based
on the patient's age, clinical history, physical condition, and response to previous
antipsychotic therapy. The preferred approach to determining the minimum
effective dose is to begin with lower initial doses and to adjust the dose upward
as needed. For patients previously maintained on low doses of antipsychotics
(e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that
the initial dose of haloperidol decanoate be 10–15 times the previous daily dose
in oral haloperidol equivalents; limited clinical experience suggests that lower
initial doses may be adequate.
Initial Therapy
Conversion from oral haloperidol to haloperidol decanoate can be achieved by
using an initial dose of haloperidol decanoate that is 10 to 20 times the previous
daily dose in oral haloperidol equivalents.
In patients who are elderly, debilitated, or stable on low doses of oral haloperidol
(e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15
times the previous daily dose in oral haloperidol equivalents is appropriate for
initial conversion.
In patients previously maintained on higher doses of antipsychotics for whom a
low dose approach risks recurrence of psychiatric decompensation and in
patients whose long-term use of haloperidol has resulted in a tolerance to the
drug, 20 times the previous daily dose in oral haloperidol equivalents should be
considered for initial conversion, with downward titration on succeeding
injections.
The initial dose of haloperidol decanoate should not exceed 100 mg regardless
of previous antipsychotic dose requirements. If, therefore, conversion requires
more than 100 mg of haloperidol decanoate as an initial dose, that dose should
be administered in two injections, i.e. a maximum of 100 mg initially followed by
the balance in 3 to 7 days.
Maintenance Therapy
The maintenance dosage of haloperidol decanoate must be individualized with
titration upward or downward based on therapeutic response. The usual
maintenance range is 10 to 15 times the previous daily dose in oral haloperidol
equivalents dependent on the clinical response of the patient.
SERENACE Depot Dosing Recommendations

Monthly
Patients 1st Month Maintenance
Stabilized on low daily oral
10–15 × Daily Oral 10–15 × Previous Daily Oral
doses
Dose Dose
(up to 10 mg/day)
Elderly or Debilitated
10–15 × Previous Daily Oral
High Dose 20 × Daily Oral Dose
Dose
Risk of relapse
Tolerant to oral haloperidol
Close clinical supervision is required during initiation and stabilization of
haloperidol decanoate therapy. Haloperidol decanoate is usually administered
monthly or every 4 weeks. However, variation in patient response may dictate a
need for adjustment of the dosing interval as well as the dose
Clinical experience with haloperidol decanoate at doses greater than 450 mg per
month has been limited.
How is SERENACE Depot Supplied

SERENACE Depot® (Haloperidol Decanoate) 50 for IM injection, 50 mg
haloperidol as 70.52 mg per mL haloperidol decanoate—NDC 0045-0253, 10 × 1
mL ampoules and 3 × 1 mL ampoules.
Store at controlled room temperature (15°–30° C, 59°–86° F). Do not refrigerate
or freeze.
Protect from light.

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