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General Description:

Propiverine, identified by CAS number 60569-19-9, is a notable compound with significant therapeutic applications. Propiverine is a widely used antimuscarinic drug with a mixed mode of action in the treatment of symptoms associated with overactive bladder (OAB) . Overactive bladder (OAB) is a chronic condition of the lower urinary tract characterized by urinary urgency, increased frequency of urination, and nocturia (frequent waking during the night to urinate). OAB has a negative impact on quality of life and may lead to leakage and inconvenient urinary accidents , . Overactive bladder syndrome affects millions of elderly individuals in the United States and shows equal prevalence in men and women. The impact of OAB on quality of life is sometimes devastating, especially to elderly patients with other medical conditions . Propiverine hydrochloride is a bladder detrusor muscle relaxant drug with dual antimuscarinic and calcium-modulating properties for the treatment of OAB .

Indications:

This drug is primarily indicated for: Indicated for symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder (OAB) . Propiverine may also be used in patients with neurogenic bladder as a result of spinal cord injury . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Propiverine undergoes metabolic processing primarily in: The major metabolites were found to be as follows; 4-piperidyl diphenylpropoxyacetate (DM-P-4), 1-methyl-4-piperidyl benzilate (Dpr-P-4) and 1-methyl-4-piperidyl diphenyl-(2 carboxy) ethoxyacetate (ω-COOH-P-4) in the liver, Dpt-p-4, DM-P-4 in the kidney, and DM-P-4, DPr-P-4 in the lung . In the same pharmacokinetic study, All pharmacologically active compounds such as the unchanged compound, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N→O)), Dpt-p-4 and 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (P-4 (N→O)) were present in the urinary bladder, a target organ for P-4, at higher concentrations than in the plasma . Propiverine is metabolized by both intestinal and hepatic enzymes. The main metabolic pathway involves the oxidation of the _piperidyl-N _and is mediated by _CYP 3A4_ and _flavin-containing monooxygenases (FMO) _1 and 3 and results in the formation of the second main metabolite M-5, the plasma concentration of which is greater in concentration that of the parent substance propiverine. Four metabolites have been identified in the urine following propiverine ingestion; 3 them are pharmacologically active metabolites that may contribute to its therapeutic effect (M-5, M-6, M-23) . The mean absolute bioavailability of propiverine IR 15 mg is 40.5% . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Propiverine are crucial for its therapeutic efficacy: Propiverine is rapidly absorbed from the gastrointestinal tract with maximum plasma concentrations attained after 2.3 hours. the mean absolute bioavailability of mictonorm 15 mg tablets (propiverine) is 40.5 %. It undergoes heavy first-pass metabolism in the liver . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Propiverine is an important consideration for its dosing schedule: In three studies including a total of 37 healthy volunteers mean elimination half-life was 14.1, 20.1 and 22.1 hours, respectively . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Propiverine exhibits a strong affinity for binding with plasma proteins: 90-95% for the parent compound and about 60% for the main metabolite . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Propiverine from the body primarily occurs through: Following the ingestion of 30 mg propiverine, 60% radioactivity was recovered in urine and 21% was recovered in feces within 12 days. Less than 1% of an oral dose is excreted unchanged in the urine . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Propiverine is distributed throughout the body with a volume of distribution of: In one study, the volume of distribution was calculated in 21 healthy volunteers after intravenous (IV) administration of propiverine hydrochloride was measured to range from 125 to 4731 (average 2791) indicating, that a large amount of available propiverine is distributed to peripheral compartments . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Propiverine is a critical factor in determining its safe and effective dosage: Mean total clearance after single dose administration of 30 mg is 371 mL/min (191 – 870 mL/min) . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Propiverine exerts its therapeutic effects through: Propiverine hydrochloride inhibits abnormal contractions of bladder smooth muscle in vivo through not only its anticholinergic activity but also its concurrent calcium antagonistic activity . Through the above-mentioned mechanism, propiverine is able to relieve the symptoms of overactive bladder. In animal models, this administration of this drug leads to a dose-dependent decrease in intravesical pressure of the bladder and an increase in bladder capacity . In patients with symptoms of OAB resulting from idiopathic detrusor muscle overactivity (IDO) or neurogenic detrusor overactivity (NDO), propiverine showed dose-dependent efficacy and tolerability . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Propiverine functions by: Propiverine demonstrates both anticholinergic and calcium-modulating properties. The efferent connection of the pelvic nerve is inhibited due to the anticholinergic action exerted by this drug, leading to relaxation of bladder smooth muscle. Propiverine blocks calcium ion influx and modulates the intracellular calcium in urinary bladder smooth muscle cells, resulting in the inhibition of muscle spasm . The bladder contains several muscarinic receptors. Acetylcholine is the main contractile neurotransmitter in the human bladder detrusor muscle, and antimuscarinics such as propiverine exert their effects by competitively inhibiting the binding of acetylcholine at muscarinic receptors on detrusor smooth muscle cells and other structures within the bladder wall . In one study, After oral treatment with propiverine, the bladder showed the highest concentration of M-2, indicating a targeted distribution of this metabolite into the bladder. Therefore, muscarinic receptor-2 may highly contribute to the relatively selective and long-lasting occupation of bladder muscarinic receptors after oral ingestion of propiverine . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Propiverine belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups, classified under the direct parent group Diphenylmethanes. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Diphenylmethanes subclass.

Categories:

Propiverine is categorized under the following therapeutic classes: Acids, Carbocyclic, Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Antagonists, Adrenergic Antagonists, Agents producing tachycardia, Agents that produce hypertension, Anticholinergic Agents, Autonomic Agents, Cholinergic Agents, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Diphenylacetic Acids, Drugs for Urinary Frequency and Incontinence, Drugs that are Mainly Renally Excreted, Genito Urinary System and Sex Hormones, Genitourinary Agents, Hydroxy Acids, Muscarinic Antagonists, Neurotransmitter Agents, Parasympatholytics, Peripheral Nervous System Agents, Phenylacetates, Urological Agents, Urologicals. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Propiverine include:

• Water Solubility: 5mg/mL
• Melting Point: 224-226
• Boiling Point: 484.2