COVERSYL

Indications

• Urea cycle disorders
• Hyperammonaemia types I and II
• Citrullinaemia
• Arginosuccinic aciduria
• Deficiency of N-acetyl glutamate synthetase
• Acute hyperammonaemia in carbamylphosphate synthetase deficiency
• Acute hyperammonaemia in ornithine transcarbamylase deficiency

Dosage

Children: Neonate: 100–300 mg/kg daily in 3–4 divided doses; Child (body-weight up to 40 kg): 6 mg/kg/hour; Child (body-weight 40 kg and above): 4 mg/kg/hour.

Adults: Refer to BNF for specific dosing based on condition; typically administered as 5–50 mg/kg twice daily, adjusted according to plasma ammonia concentration.

Mechanism of action

Arginine serves as a substrate for the synthesis of nitric oxide (NO), a crucial signaling molecule, and contributes to the urea cycle, facilitating the detoxification of ammonia in the liver.

Pharmacodynamics

As a precursor for nitric oxide, arginine plays a vital role in vasodilation and modulating blood flow. It also aids in protein synthesis and supports metabolic processes in the body.

Pharmacokinetics

Arginine is absorbed from the gastrointestinal tract and is distributed throughout the body. It undergoes hepatic metabolism, primarily via the urea cycle, and its half-life is influenced by renal function.

Pregnancy

Use only if clearly needed; consult specialist.

Breast-feeding

Use with caution; benefits should outweigh risks.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• L-Arginine 500 mg tablets
• L-Arginine 1 gram tablets
• L-Arginine powder for solution
• L-Arginine 500 mg capsules
• L-Arginine 21% concentrate for solution for infusion

Indications

• Hypertension
• Heart failure
• Prevention of cardiovascular events in patients with coronary artery disease

Dosage

Adults: The usual

Mechanism of action

Perindoprilat, the active metabolite of perindopril, binds to and inhibits the activity of the somatic isoform of angiotensin-converting enzyme (ACE), particularly the C-domain, which plays a crucial role in blood pressure regulation. By inhibiting ACE, perindoprilat decreases the levels of angiotensin II (ATII), thereby reducing blood pressure and promoting vasodilation. Additionally, the inhibition of ATII leads to increased plasma renin activity due to the loss of feedback inhibition.

Pharmacodynamics

Perindopril is a nonsulfhydryl prodrug that undergoes first-pass metabolism and systemic hydrolysis to produce perindoprilat. This active form lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS), which is involved in regulating blood pressure and fluid balance. By inhibiting the actions of ATII, perindoprilat reduces aldosterone secretion, leading to decreased sodium and water reabsorption in the kidneys. This results in increased urine output and a decrease in blood volume, further contributing to its antihypertensive effects.

Pharmacokinetics

After oral administration, perindopril is rapidly absorbed, with a bioavailability of approximately 62%. It undergoes extensive first-pass metabolism in the liver to form its active metabolite, perindoprilat, which has a half-life of about 17 hours. Perindoprilat is primarily excreted by the kidneys, and its pharmacokinetics may be altered in patients with renal impairment. The peak plasma concentration of perindoprilat is reached within 3 to 4 hours after administration.

Contra-indications

• History of hypersensitivity to perindopril or any other ACE inhibitor
• History of angioedema associated with previous ACE inhibitor therapy
• Hereditary or idiopathic angioedema
• Severe renal impairment (creatinine clearance less than 30 mL/min)
• Pregnancy

Adverse effects

• Cough
• Hyperkalemia
• Hypotension
• Dizziness
• Fatigue
• Renal impairment
• Angioedema

Interactions

• Potassium supplements or potassium-sparing diuretics may increase the risk of hyperkalemia
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect of perindopril
• Lithium levels may increase when used concurrently with perindopril
• Other antihypertensive agents may have additive effects leading to hypotension

Precautions

• Monitor renal function before and during treatment
• Use with caution in patients with aortic stenosis or hypertrophic cardiomyopathy
• Consider monitoring potassium levels in at-risk populations
• Caution in patients with a history of angioedema

Pregnancy

Perindopril is contraindicated during pregnancy due to potential harm to the fetus, particularly in the second and third trimesters.

Breast-feeding

Caution is advised as perindopril is excreted in breast milk; consult a healthcare professional before use.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets: 2 mg, 4 mg, 8 mg

Mechanism of action

Many of supplemental L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3,'5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium. All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid^would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, supplemental L-arginine could enhance endothelial-dependent vasodilation and NO production.

Pharmacodynamics

Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

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. Perindoprilat, the active metabolite of perindopril, 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. Perindopril 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

Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect 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 using 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 sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure.