TARKA CAPSULES

Indications

• Hypertension
• Supraventricular arrhythmias
• Angina pectoris

Dosage

Children: Not licensed for use in children. Consult the BNF for Children for any potential off-label uses and specific dosing recommendations.

Adults: For hypertension, the usual starting dose is 80 mg to 120 mg daily, which can be adjusted based on blood pressure response. The maintenance dose may range up to 240 mg daily. For supraventricular arrhythmias, initial intravenous doses can vary. Refer to specific product literature for detailed dosing.

Mechanism of action

Verapamil hydrochloride selectively inhibits L-type calcium channels in the cardiac and vascular smooth muscle. By blocking these channels, it reduces intracellular calcium concentrations, leading to decreased myocardial contractility, heart rate, and vascular resistance. This mechanism is crucial in managing conditions like hypertension and arrhythmias.

Pharmacodynamics

Verapamil produces a dose-dependent decrease in heart rate and myocardial contractility. It also causes vasodilation, which contributes to its antihypertensive effects. The drug can have varying effects on peripheral vascular resistance and may influence the autonomic nervous system, particularly through its impact on heart rate.

Pharmacokinetics

Verapamil is well absorbed from the gastrointestinal tract, but undergoes extensive first-pass metabolism in the liver, resulting in lower bioavailability. It is highly protein-bound, primarily to albumin. The drug is metabolized by the liver, with a half-life ranging from 3 to 7 hours. Its metabolites are excreted via the kidneys. Dosage adjustments may be necessary in patients with hepatic impairment.

Contra-indications

• Cardiogenic shock
• Severe aortic stenosis
• Severe hypotension
• Pregnancy with multiple gestations

Adverse effects

• Constipation
• Malaise
• Oedema
• Allergic reactions
• Angioedema

Interactions

• Caution with other calcium channel blockers
• Increased risk of serious hypotension when used with antihypertensives

Precautions

• Monitor blood pressure and heart rate regularly
• Use with caution in hepatic and renal impairment
• Consider dose adjustment in severe impairment

Pregnancy

May inhibit labor and is not recommended in multiple pregnancies due to risks of severe maternal hypotension and fetal hypoxia.

Breast-feeding

Manufacturer advises avoidance as it is present in breast milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets
• Modified-release capsules

Indications

• Hypertension
• Heart failure
• Prophylaxis after myocardial infarction
• Left ventricular dysfunction

Dosage

Children: For paediatric patients, dosing should be based on

Adults: The usual starting dose for adults is 0.5 mg to 1 mg once daily, which may be adjusted based on response. The maximum recommended dose is 4 mg once daily.

Mechanism of action

Trandolaprilat, the active metabolite of trandolapril, inhibits the activity of angiotensin-converting enzyme (ACE), which is responsible for converting angiotensin I (ATI) to angiotensin II (ATII). By reducing ATII levels, trandolaprilat decreases vasoconstriction and aldosterone secretion, leading to lower blood pressure and decreased fluid retention. Additionally, the inhibition of ACE increases plasma renin activity due to the loss of ATII's feedback inhibition on renin release.

Pharmacodynamics

As a prodrug, trandolapril is metabolized to trandolaprilat, which is approximately eight times more potent as an ACE inhibitor. The drug's primary action is through the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure, fluid balance, and electrolyte homeostasis. By interfering with this system, trandolapril effectively lowers systemic vascular resistance and facilitates better cardiac output.

Pharmacokinetics

Trandolapril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after oral administration. The bioavailability of the active form, trandolaprilat, is significantly affected by liver metabolism, leading to variable plasma levels based on hepatic function. The elimination half-life of trandolaprilat is approximately 6 to 12 hours, and it is excreted primarily via the kidneys. Dose adjustments may be necessary in patients with renal impairment.

Contra-indications

• Hypersensitivity to trandolapril or any component of the formulation
• History of angioedema associated with previous ACE inhibitor therapy
• Hereditary or idiopathic angioedema
• Severe renal impairment (creatinine clearance less than 10 mL/min)
• Pregnancy

Adverse effects

• Hypotension
• Dizziness
• Cough
• Hyperkalemia
• Angioedema
• Rash
• Fatigue
• Gastrointestinal disorders

Interactions

• Potassium-sparing diuretics and potassium supplements may lead to hyperkalemia
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Lithium levels may increase when used in conjunction with ACE inhibitors
• Diuretics may enhance the hypotensive effect of trandolapril

Precautions

• Monitor renal function, especially in patients with renal impairment
• Use with caution in patients with a history of heart failure or severe aortic stenosis
• Pregnancy should be avoided due to potential fetal harm
• Caution is advised in patients undergoing surgery or anesthesia

Pregnancy

Trandolapril is contraindicated during pregnancy due to the risk of fetal harm, particularly in the second and third trimesters.

Breast-feeding

Not recommended; alternative treatments with better established safety during breastfeeding should be considered.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Trandolapril 500 microgram capsules
• Trandolapril 1 mg capsules
• Trandolapril 2 mg capsules
• Trandolapril 4 mg capsules
• Trandolapril oral suspension

Indications

• Hypertension
• Angina pectoris
• Supraventricular tachycardias
• Atrial fibrillation or flutter (rate control)

Dosage

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated. Common dosing includes 80-240 mg daily in divided doses for hypertension, and for

Mechanism of action

Verapamil inhibits L-type calcium channels by binding to the alpha-1 subunit (Cav1.2), which is prevalent in vascular smooth muscle and myocardial tissue. This binding occurs in a voltage- and frequency-dependent manner, increasing as the membrane potential decreases and with excessive depolarization. The inhibition of calcium influx prevents muscle contraction and promotes relaxation of blood vessels, thus lowering systemic vascular resistance and blood pressure. Additionally, it affects electrical conduction through the AV node, which can lower heart rate.

Pharmacodynamics

Verapamil exhibits antiarrhythmic, antianginal, and antihypertensive properties. It is classified as a negative inotropic agent, meaning it reduces myocardial contractility. Due to this effect, it is contraindicated in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy, as it may exacerbate these conditions. Immediate-release forms require multiple daily doses, while extended-release options facilitate once-daily administration.

Pharmacokinetics

Verapamil is well-absorbed from the gastrointestinal tract, but it undergoes extensive first-pass metabolism in the liver, which significantly reduces its bioavailability. The drug is metabolized primarily by the liver enzymes CYP3A4 and CYP2C8. Its half-life varies depending on the formulation, with immediate-release forms having a shorter half-life compared to extended-release forms. The drug is primarily excreted in urine as metabolites, with only a small fraction eliminated unchanged.

Contra-indications

• Severe left ventricular dysfunction
• Hypertrophic cardiomyopathy
• Known hypersensitivity to verapamil or any of its components

Adverse effects

• Constipation
• Dizziness
• Headache
• Nausea
• Bradycardia
• Hypotension
• Peripheral edema

Interactions

• Severe: amiodarone (increases risk of cardiodepression)
• Severe: non-selective beta-blockers (increases risk of cardiovascular adverse effects)
• Severe: intravenous dantrolene (increases risk of acute hyperkalaemia and cardiovascular collapse)
• Severe: grapefruit juice (increases exposure)
• Moderate: miconazole (increases exposure)
• Moderate: bictegravir (increases exposure)
• Moderate: panobinostat (increases exposure)
• Moderate: thrombin inhibitors (increases exposure)
• Moderate: dabigatran (increases exposure)
• Unknown: enzalutamide (decreases exposure)

Precautions

• Caution in patients with renal impairment
• Caution in patients with liver impairment
• Monitor heart rate and blood pressure regularly during treatment
• Consider alternative therapies in patients with severe cardiac conditions

Pregnancy

Verapamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines for specific recommendations.

Breast-feeding

Verapamil is excreted in breast milk. Caution should be exercised when administering to nursing women.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Immediate-release tablets
• Extended-release tablets
• Injection solution

Mechanism of action

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.

Pharmacodynamics

Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure via a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention.

Mechanism of action

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. Calcium antagonists inhibit excitation-contraction coupling in myocardial and smooth muscle by blocking the transmembrane carrier of calcium. This results in decreased myocardial contractility and in vasodilatation. ... /Salt not specified/ Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of verapamil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures; 2) Ligand binding studies showed that the binding of (3)H-verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel-independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-)-verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated

Pharmacodynamics

Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions.