No-shpa forte, tablets 80 mg 10 pcs

Drotaverine is an isoquinoline derivative with chemical structure and pharmacological properties similar to papaverine, but with stronger and more prolonged action. It has a powerful antispasmodic effect on smooth muscles by inhibiting the enzyme FDE. PDE enzyme is necessary for hydrolysis of cAMP to AMP.

PDE inhibition leads to an increase in the concentration of cAMP, which triggers the following cascade reaction: high concentrations of cAMP activate cAMP-dependent phosphorylation of myosin light chain kinase (CLKM).

Phosphorylation of CLSM leads to a decrease in its affinity for the Ca²⁺-calmodulin complex; as a result, the inactivated form of CLSM maintains muscle relaxation. In addition, cAMP affects cytosolic Ca²⁺ ion concentration by stimulating Ca²⁺ transport into the extracellular space and the sarcoplasmic reticulum. This decreasing Ca²⁺ ion concentration effect of drotaverine via cAMP explains the antagonistic effect of drotaverine with respect to Ca²⁺.

In vitro, drotaverine inhibits the FDE4 isoenzyme without inhibiting the FDE3 and FDE5 isoenzymes. Therefore, the effectiveness of drotaverine depends on the concentration of FDE4 in tissues (FDE4 content varies in different tissues). FDE4 is most important for inhibition of contractile activity of smooth muscles, therefore selective inhibition of FDE4 may be useful for treatment of hyperkinetic dyskinesias and various diseases accompanied by spastic state of GIT.

The hydrolysis of CAMP in the myocardium and vascular smooth muscle occurs primarily through the FDE3 isoenzyme, which explains the fact that with high antispasmodic activity, drotaverine has no serious cardiovascular side effects and no pronounced cardiovascular effects.

Intake

In comparison with papaverine, drotaverine is more rapidly and completely absorbed from the gastrointestinal tract when taken orally. Absorption is 100%. After metabolism during “first passage” through the liver, 65% of the administered dose of drotaverine enters the systemic bloodstream. C_max in plasma is reached after 45-60 min.

Distribution

In vitro drotaverine is highly bound to plasma proteins (95-98%), especially to albumin, β- and γ-globulins.

Drotaverine is evenly distributed in tissues and penetrates smooth muscle cells. It does not penetrate through the HEB. Drotaverine and/or its metabolites are able to slightly penetrate through the placental barrier.

Metabolism

In humans, drotaverine is almost completely metabolized in the liver by O-deletion. Its metabolites rapidly conjugate to glucuronic acid. The main metabolite is 4′-dezethyldrotaverine, in addition to which 6-dezethyldrotaverine and 4′-dezethyldrotaveraldine have been identified.

Excretion

T_1/2 is 8-10 h.

Drotaverine is almost completely eliminated from the body within 72 hours. More than 50% of drotaverine is excreted by the kidneys and about 30% through the intestines (excretion into the bile). Drotaverine is mainly excreted as metabolites, unchanged drotaverine is not detected in the urine.

Drotaverine is effective for smooth muscle spasms of both neurogenic and muscular origin. Regardless of the type of autonomic innervation, drotaverine relaxes the smooth muscles of the gastrointestinal tract, biliary tract, and urogenital system.

Due to its vasodilator effect, drotaverine improves blood supply to tissues.

Indications

Spasms of smooth muscles in diseases of the biliary tract: cholecystolithiasis, cholangiolithiasis, cholecystitis, pericholecystitis, cholangitis, papillitis;
spasms of smooth muscles of the urinary system: nephrolithiasis, urethrolithiasis, pyelitis, cystitis, bladder spasms.

As an adjuvant therapy:

for spasms of smooth muscles of the gastrointestinal tract: peptic ulcer of the stomach and duodenum, gastritis, spasms of the cardia and pylorus, enteritis, colitis, spastic colitis with constipation and irritable bowel syndrome with flatulence;
tension headaches;
algodismenorrhea.

Pharmacological effect

Drotaverine is an isoquinoline derivative, similar in chemical structure and pharmacological properties to papaverine, but with a stronger and longer-lasting effect. It has a powerful antispasmodic effect on smooth muscles due to inhibition of the PDE enzyme. The enzyme PDE is necessary for the hydrolysis of cAMP to AMP.

Inhibition of PDE leads to an increase in cAMP concentration, which triggers the following cascade reaction: high concentrations of cAMP activate cAMP-dependent phosphorylation of myosin light chain kinase (MLCK).

Phosphorylation of MLCK leads to a decrease in its affinity for the Ca2+-calmodulin complex, as a result of which the inactivated form of MLCK maintains muscle relaxation. In addition, cAMP affects the cytosolic concentration of the Ca2+ ion by stimulating the transport of Ca2+ into the extracellular space and the sarcoplasmic reticulum. This lowering Ca2+ ion concentration effect of drotaverine through cAMP explains the antagonistic effect of drotaverine towards Ca2+.

In vitro, drotaverine inhibits the PDE4 isoenzyme without inhibiting the PDE3 and PDE5 isoenzymes. Therefore, the effectiveness of drotaverine depends on the concentration of PDE4 in tissues (the content of PDE4 in different tissues varies). PDE4 is most important for suppressing the contractile activity of smooth muscles, and therefore selective inhibition of PDE4 may be useful for the treatment of hyperkinetic dyskinesias and various diseases accompanied by a spastic state of the gastrointestinal tract.

The hydrolysis of cAMP in the myocardium and vascular smooth muscle occurs mainly with the help of the PDE3 isoenzyme, which explains the fact that with high antispasmodic activity, drotaverine has no serious side effects on the heart and blood vessels and no pronounced effects on the cardiovascular system.

Suction

Compared with papaverine, drotaverine, when taken orally, is absorbed faster and more completely from the gastrointestinal tract. Absorption is 100%. After first-pass metabolism through the liver, 65% of the administered dose of drotaverine enters the systemic circulation. Cmax in blood plasma is reached after 45-60 minutes.

Distribution

In vitro, drotaverine is highly bound to plasma proteins (95-98%), especially albumin, β- and γ-globulins.

Drotaverine is evenly distributed in tissues and penetrates smooth muscle cells. Does not penetrate the BBB. Drotaverine and/or its metabolites are able to slightly penetrate the placental barrier.

Metabolism

In humans, drotaverine is almost completely metabolized in the liver by O-desethylation. Its metabolites quickly conjugate with glucuronic acid. The main metabolite is 4′-desethyldrotaverine, in addition to which 6-desethyldrotaverine and 4′-desethyldrotaveraldine have been identified.

Removal

T1/2 is 8-10 hours.

Within 72 hours, drotaverine is almost completely eliminated from the body. More than 50% of drotaverine is excreted by the kidneys and about 30% through the intestines (excretion into bile). Drotaverine is mainly excreted in the form of metabolites; unchanged drotaverine is not detected in the urine.

Drotaverine is effective against smooth muscle spasms of both neurogenic and muscular origin. Regardless of the type of autonomic innervation, drotaverine relaxes the smooth muscles of the gastrointestinal tract, biliary tract, and genitourinary system.

Due to its vasodilating effect, drotaverine improves blood supply to tissues.

Special instructions

When using the drug in patients with arterial hypotension, increased caution is required.

Each tablet of No-shpa® forte contains 104 mg of lactose. When taken according to the recommended dosage regimen, up to 156 mg of lactose (1.5 tablets of No-shpa® forte) can be delivered with each dose, which can cause gastrointestinal disorders in patients suffering from lactose intolerance. This form of the drug is not suitable for patients with lactase deficiency, galactosemia or glucose/galactose malabsorption syndrome.

Impact on the ability to drive vehicles and operate machinery

When taken orally in therapeutic doses, drotaverine does not affect the ability to drive vehicles or perform work that requires increased concentration.

If any adverse reactions occur, the issue of driving and operating machinery requires individual consideration. If dizziness occurs after taking the drug, the patient should avoid engaging in potentially hazardous activities, such as driving vehicles and operating machinery.

Active ingredient

Drotaverine

Composition

1 tab. contains drotaverine hydrochloride 80 mg;

Contraindications

Severe renal failure;
severe liver failure;
severe heart failure (decreased cardiac output);
breastfeeding period;
childhood (no clinical studies have been conducted in children);
hereditary lactose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome (due to the presence of lactose in the tablets);
hypersensitivity to drotaverine and/or auxiliary components of the drug.

Use the drug with caution in case of arterial hypotension and pregnancy.

Side Effects

The following side effects, which in clinical studies were considered to be at least possibly related to drotaverine, are listed according to the following frequency of occurrence: very common (≥1/10), common (≥1/100, <1/10); rare (≥1/1000, <1/100); sometimes (≥1/10,000, <1/1000); very rare, including isolated reports (< 1/10,000); frequency unknown (it is impossible to determine the frequency of occurrence from the available data).

From the nervous system: sometimes – headache, dizziness, insomnia.

From the cardiovascular system: sometimes – rapid heartbeat, decreased blood pressure.

From the digestive system: sometimes – nausea, constipation.

From the immune system: sometimes – allergic reactions (itching, rash, urticaria, angioedema).

Interaction

When used simultaneously with drotaverine, it is possible to reduce the antiparkinsonian effect of levodopa, i.e. increased rigidity and tremor.

When used simultaneously, drotaverine enhances the antispasmodic effect of papaverine, bendazole and other antispasmodics (including m-anticholinergics).

With simultaneous use, drotaverine reduces the spasmogenic activity of morphine.

With simultaneous use, phenobarbital enhances the severity of the antispasmodic effect of drotaverine.

Overdose

Drotaverine overdose has been associated with cardiac rhythm and conduction disturbances, including complete bundle branch block and cardiac arrest, which can be fatal.

Treatment: In case of overdose, patients should be under medical supervision. If necessary, symptomatic treatment aimed at maintaining the basic functions of the body should be carried out.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C.

Manufacturer

Hinoine Pharmaceutical and Chemical Plant, Hungary