Introduction

Drotaverine (INN, also known as drotaverin) is an antispasmodic drug, structurally related to papaverine. Drotaverine is a selective inhibitor of phosphodiesterase 4, and has no anticholinergic effects. Drotaverine has been shown to possess dose-dependant analgesic effects in animal models. One small study has shown drotaverine to be eliminated mainly nonrenally.

PHYSICAL PROPERTIES
MOLECULAR WEIGHT MONOISOTOPIC PHYSICAL STATE MELTING POINT BOILING POINT DENSITY ASSAY LOSS ON DRYING pH STORAGE TEMP. SOLUBILTY STABILITY INCOMPATIBLE MATERIALS DECOMPOSITION PRODUCTS POLYMERIZATION NFPA RATINGS HAZARD NOTES EYE SKIN INGESTION INHALATION 433.97g/mol 397.225308485 yellowish and greenish shade crystalline powder 208 - 211 C

564 c at 760 mmhg 1.097 g/cm3

98.5 - 100.5% 5.0% max 3.0 - 5.5 20C Freezer Moderately soluble in water, soluble in alcohol (96%) , easily soluble in chloroform. Stable under normal conditions. May discolor on exposure to light. Strong oxidizing agents Carbon monoxide, Carbon dioxide, Nitrogen oxides, Hydrogen chloride Has not been reported Health:2 , Flammability:0 , Reactivity:1 Harmful if swallowed. Target organ(s): Smooth muscle. May cause eye irritation. May be harmful if absorbed through skin. May cause skin irritation. Harmful if swallowed. Harmful if inhaled. Material may be irritating to mucous membranes and respiratory tract. http://chemicalland21.com/specialtychem/nd/DROTAVERIN%20HYDROCHLORIDE.htm

Structure

Chemical Formula C24H31NO4 IUPAC Name Absorption Protein binding Metabolism Half life Dosage form Oral Adult Child (1Z)-1-[(3,4-diethoxyphenyl)methylidene]-6,7-diethoxy-1,2,3,4tetrahydroisoquinoline Bioavailability is highly variable 80 to 95% Hepatic 7 to 12 hours
Tablet 40mg, Injection 40mg/2ml

Antispasmodic 40-80mg 8 hourly 1-6 yr: 20 mg 3-4 times daily; >6 yr: 40 mg tid.

Indication: Control and prevention of pain & dysfunction caused by smooth muscle spasm. Billary and renal colics; cholecystopathy associated with spastic symptoms, cholelithiasis, Cholecystitis, nephrolithiasis, Peptic ulcer, spastic constriction, colitis, tenesmus, smooth muscle spasm provoked by instrumental diagnostic procedures, in uterine irritability & obstetrics to relax the constriction of osuteri.

Pharmacokinetics Rapidly and completely is absorbed in gastro-intestinal tract. Following oral

administration bioavailability of drotaverine is close to 100%, elimination half-life is 12 minutes. Drotaverine is uniformly distributed in tissues, penetrates smooth muscles. The preparation is excreted in the urine. Pharmacodynamics: Its chemical structure and pharmacological properties are close to those of papaverine, but the effect is stronger and more durable. It decreases the influx of active calcium into smooth muscles due to inhibiting of phosphodiesterase and intracellular increase of cAMP level. The preparation decreases the tone of smooth muscles in visceral organs, reduces intestinal peristalsis, dilatates blood vessels thereby relieving smooth muscle spasm and pain. It does not have an impact on vegetative nervous system, does not cross blood-brain barrier. The preparation increases minute blood volume. Mechanism of action: Drotaverine inhibits phosphodiesterases hydrolysing cAMP, thereby increasing cAMP concentration, decreasing Ca uptake of the cells and changing the distribution of calcium among the cells. It may also have minor allosteric calcium channel blocking properties. http://www.drugbank.ca/drugs/DB06751 Food(before/after) Adverse/Side Effects May be taken with or without food. Drotaverine is usually well tolerated. Occasionally arrhythmia, arterial hypotension, palpitations, allergic dermatitis, constipation, sweating, flushing may occur. Exercise caution in patients with renal/hepatic/cardiac dysfunction. Pregnacy, lactation. May attenuate the action of levodopa. Concurrent use of analgesics, antimuscarinics or benzodiazepines. Additive beneficial effect with concurrent use of analgesics, antimuscarinics or benzodiazepines.

Special Precautions Drug Interactions

Pregnancy and Lactation Caution when used during pregnancy and lactation; also in patients with marked coronary atherosclerosis. Contraindication Hypersensitivity to drotaverine; significant hepatic, renal, and cardiac insuffiency, II - III degree atrioventricular block, cardiogenic shock, arterial hypotension, children under 1 year of age.

Table 1: Drug-Excipients Ratios in Trials

Ingredients Drotaverine HCl Trial-1 83.33 Trial-2 83.33 Trial-3 83.33

Lactose monohydrate Ethyl cellulose Butyl Hydroxy toluene IPA Methylene Chloride Ac-Di-Sol Cross Povidone Aerosil-200 Stearic Acid
Average weight

43.49 4.0 1.0 q.s q.s 2.82 2.82 0.71 2.82

141.00

42.67 4.0 1.0 q.s q.s 3.50 3.50 1.0 2.0

141.00

39.97 4.0 1.0 q.s q.s 5.64 4.23 0.71 2.11

141.00

Coating materials HPMC 5cps Titanium dioxide Purified talc Ferric oxide yellow Dibutyl Phthalate IPA Methylene chloride Average weight

7.00 1.12 0.94 0.25 0.70 q.s q.s 151.00

7.00 1.12 0.94 0.25 0.70 q.s q.s 151.00

7.00 1.12 0.94 0.25 0.70 q.s q.s 151.00

*Formulation and In-vitro Evaluation of Immediate release tablets of Drotaverine HCl---A.K. Tiwari1, H. Shah1, A. Rajpoot1*, Manmohan Singhal2. Journal of Chemical and Pharmaceutical Research J. Chem. Pharm. Res., 2011, 3(4):333-341

Composition: 1 tablet contains drotaverin hydrochloride 0.04 g (40 mg) calculated as 100% substance; excipients: potato starch, GranuLac-70 (lactose monohydrate), medicinal low molecular polyvinylpyrrolidone, calcium stearate.

Cholelithiasis is the medical term for gallstone disease. Gallstones are concretions that form in the biliary tract. Choledocholithiasis refers to the presence of one or more gallstones in the common bile duct. Allosteric -pertaining to an effect on the biological function of a protein, produced by a compound not directly involved in that function (an allosteric effector) or to regulation

of an enzyme involving cooperativity between multiple binding sites (allosteric sites).

Nephrolithiasis A kidney stone is a solid mass made up of tiny crystals. One or more stones can be in the kidney or ureter at the same time Tenesmus is the urge to pass stool. This feeling can arise even if the bowels are already empty. Tenesmus most commonly involves straining, pain or cramping. This condition arises due to the inflammation of the bowels. The inflammation can be a consequence of any kind of infection or can occur as a part of any other motility disorder of the intestine. People who suffer from Tenesmus generally strain and push hard to pass stool.. Obstetrics (from the Latin obstare, "to stand by") is the medical specialty dealing with the care of all women's reproductive tracts and their children during pregnancy (prenatal period), childbirth and the postnatal period. Osuteri The vaginal opening of the uterus.