Tarka

Uses

Trandolapril is a prodrug of an ACE inhibitor used to treat hypertension, congestive heart failure, and to improve survival following a myocardial infarction.

For the treatment of mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure (CHF), to improve survival following myocardial infarction (MI) in individuals who are hemodynamically stable and demonstrate symptoms of left ventricular systolic dysfunction or signs of CHF within a few days following acute MI, and to slow progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

Verapamil Tablet:

• Essential hypertension
• Angina pectoris and prevention of re-infarction
• Supraventricular arrhythmias

Verapamil Injection:

• Tachycardias such as: Paroxysmal supraventricular tachycardias
• Atrial fibrillation with rapid ventricular response (except WPWS)
• Atrial flutter with rapid conduction
• Extrasystoles
• Acute hypertension
• Acute coronary insufficiency

For the prophylaxis and / or therapy of ectopic arrhythmias (predominantly ventricular extrasystoles) in halothane anaesthesia and in the application of adrenaline in halothane anaesthesia respectively.

Tarka is also used to associated treatment for these conditions: Diabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Left Ventricular Systolic DysfunctionChronic Stable Angina Pectoris, Cluster Headache, Heart Rate, High Blood Pressure (Hypertension), Paroxysmal Supraventricular Tachycardia, Supra-ventricular Tachyarrhythmias, Unstable Angina Pectoris, Vasospastic Angina

How Tarka works

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Trandolaprilat, the active metabolite of trandolapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Trandolaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit,Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus.

Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina.

Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia.

Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type).

Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors.

Dosage

Tarka dosage

Verapamil Tablet:

• The dose of Verapamil should be individualized by titration and the drug should be administered with food.
• For essential hypertension the initial dose should be given 180 mg in the morning. If adequate response is not obtained with 180 mg of Verapamil then the dose may be titrated by following manner: 240 mg each morning. 180 mg each morning plus 180 mg each evening. 240 mg every 12 hourly.
• For angina the usual dose is 80 mg to 120 mg three times a day.
• For arrythmias in digitalized patients, Verapamil should be given 240 mg to 360 mg in divided doses, depending on the severity of the condition. Divided doses up to 180 mg/day may occasionally be needed.

Verapamil Injection:

Adults

: 5 mg slowly intravenously, in tachycardias and hypertensive crises, if necessary repeat after 5 to 10 minutes. Drip infusion to maintain the therapeutic effect: 5-10 mg/hour in physiological saline, glucose, laevulose or similar solutions, on average up to a total dose of 100 mg/day.

Children

:

• Newborn: 0.75-1 mg (= 0.3-0.4 ml)
• Infants: 0.75-2 mg (= 0.3-0.8 ml)
• Children age 1-5 years: 2-3 mg (= 0.8-1.2 ml)
• Age 6-14 years: 2.5-5 mg (= 1-2 ml)

of Verapamil, given intravenously, depending on age and action. The injection should be made slowly under electrocardiographic control and only until onset of the effect. Intravenous infusion in hypertensive crises: initially 0.05-0.1 mg/kg/hour; if the effect proves to be insufficient, the dose is increased at 30-60 minute intervals until twice the dose or more is reached. Average total dose up to 1.5 mg/kg/day.

Side Effects

Verapamil is generally well tolerated. The following reaction to orally administered Verapamil appeared clearly drug related or occurred at rates greater than 1% in clinical trials with approximately 5000 patients.

• Digestive system: Constipation, nausea;
• Cardiovascular system: Hypotension, edema, CHF, pulmonary edema, bradycardia, AV block;
• Respiratory system: Upper respiratory tract infections;
• Nervous system: Dizziness, headache, fatigue;
• Skin: Rash, flashing;
• Hepatic: Elevated liver enzyme.

Toxicity

Most likely clinical manifestations of overdose are symptoms of severe hypotension. Most common adverse effects include cough, headache and dizziness. The oral LD₅₀ of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.

Verapamil's reported oral TDLo is 14.4 mg/kg in women and 3.429 mg/kg in men. The oral LD₅₀ is 150 mg/kg in rats and 163 mg/kg in mice.

As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i.e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion.

Precaution

Care should be taken in 1st degree AV block, bradycardia <50 beats/minutes, hypotension <90 mm Hg systolic pressure, atrial fibrillation/flutter and simultaneous pre-excitation syndrome e.g. WPW syndrome, heart failure (previous compensation with cardiac glycosides/diuretics required).Verapamil may impair ability to drive or operate machinery, particularly in the initial stages of treatment and with concomitant consumption of alcohol. Verapamil markedly slows down the elimination of alcohol and prolongs the duration of the effects of alcohol.Verapamil should be given as a slow intravenous injection over at least 2 minutes under continuous ECG and blood pressure monitoring. Intravenous injection should only be given by the physician. In atrial fibrillation and simultaneous WPW syndrome there is a risk of inducing ventricular fibrillation

Interaction

May increase plasma level with CYP3A4 inhibitors (e.g. erythromycin, ritonavir), cimetidine. May decrease plasma level with CYP3A4 inducers (e.g. rifampicin), phenobarbital, sulfinpyrazone. Increased risk of bleeding with aspirin. May increase bradycardic and hypotensive effect with telithromycin. Increased AV blocking effect with clonidine. May increase plasma level of cardiac glycosides (e.g. digoxin, digitoxin), β-blockers (e.g. propranolol, metoprolol), α-blockers (e.g. terazosin, prazosin), immunosuppressants (e.g. sirolimus, ciclosporin, tacrolimus, everolimus), lipid lowering agents (e.g. lovastatin, simvastatin, atorvastatin), colchicines, quinidine, carbamazepine, imipramine, glibenclamide, doxorubicin, midazolam, buspirone, almotriptan, theophylline. May potentiate hypotensive effect with diuretics, antihypertensives, vasodilators. May increase neurotoxic effect of lithium.

Volume of Distribution

• 18 L

Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer.

Elimination Route

~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14%

More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. T_max) between 1-2 hours following administration, whereas sustained-release formulations tend to have a T_max between 6 - 11 hours.

AUC and C_max values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC_0-24h and C_max values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively.

Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state.

Half Life

The elimination half lives of trandolapril and trandolaprilat are about 6 and 10 hours, respectively, but, similar to all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase that involves a small fraction of administered drug. This likely represents drug binding to plasma and tissue ACE. The effective half life of elimination for trandolaprilat is 16-24 hours.

Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours.

Clearance

• 52 L/h [After approximately 2 mg IV doses]

Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil.

Elimination Route

After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces.

Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug.

Pregnancy & Breastfeeding use

Verapamil carries the potential to produce fetal hypoxia associated with maternal hypotension. Verapamil should not be administered intravenously during the first six months of pregnancy. There are no data on use in the first and second trimester. Verapamil should not be used in the final trimester unless the benefits clearly outweigh the risks. Verapamil should not be administered intravenously during lactation. If a nursing mother requires intravenous Verapamil, breast feeding should be discontinued for the duration of treatment.

Contraindication

• Severe left ventricular dysfunction
• Hypotension or cardiogenic shock
• Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
• Second or third-degree atrioventricular (AV) block (except in patients with a functioning artificial pacemaker)
• Patients with atrial flutter or atrial fibrillation and an accessory by pass tract (eg. Wolff-Parkinson-White, Lown-Ganong-Levine syndrome)
• Patients with known hypersensitivity to verapamil hydrochloride
• Verapamil injection should not be administered intravenously to patients on beta-blockers (except in an intensive care setting) and known hypersensitivity to Verapamil hydrochloride.

Acute Overdose

Treatment of overdose should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solution may increase calcium ion flux across the slow channel and have been used in the treatment of overdose with Verapamil. Verapamil cannot be removed by haemodialysis.

Innovators Monograph

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