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Tolterodine

Tolterodine is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below.

 

Tolterodine.jpg

 

 

 

1. Clinical pharmacology

 

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.

 

Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and 1 and 5 hours after a single 6.4-mg dose of tolterodine immediate release were determined in healthy volunteers. The main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.

 

 

2. Mode of action

 

Tolterodine belongs to a class of drugs called cholinergic (acetyl-choline) receptor blockers. It is used to treat disorders of the urinary bladder that affect urination.

The urinary bladder is a muscular "bag." Urine coming from the kidneys fills the bladder and causes it to stretch like a balloon. As it stretches, pressure in the bladder increases and, when the bladder reaches a certain level of stretch, a desire to urinate is felt. Nerves in the muscular wall of the bladder release acetyl- choline, a chemical that attaches to receptors on the muscle cells and causes the cells to contract (tighten). This contributes further to the increase in pressure within the bladder and the desire to urinate. At the appropriate time (e.g., when a toilet is available), there is conscious relaxation of the muscle at the outlet of the bladder, and the high bladder pressure forces urine out of the bladder.

 

Normally, urination is under conscious control; however, in some individuals normal control as well as normal sensation are lost. The desire to urinate may be felt when there is little urine in the bladder, and urination may occur without warning or control. By blocking the effect of acetyl-choline on the muscle cells, tolterodine slows the build-up of pressure in the bladder, reduces the sensation to urinate, and prevents uncontrolled urination. The FDA approved tolterodine in 1998. An extended release form of tolterodine, (Detrol LA) was approved by the FDA in 2001.

 

 

3. Pharmacokinetics

 

Absorption

In a study with 14C-tolterodine solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite ("active moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). Cmax and Cmin levels of tolterodine extended release are about 75% and 150% of tolterodine immediate release, respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after dose administration.

 

Distribution

Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 ± 26.7 L.

 

Metabolism

Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5- carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine, respectively.

 

Excretion

Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% ( < 2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% ( < 1% in poor metabolizers) was recovered as the active 5-hydroxymethyl metabolite.

 

 

4. Drug Interactions

 

Tolterodine follows a specific path through the liver in order to be eliminated from the body. Drugs that block this path may slow the elimination of tolterodine, raise tolterodine blood levels, and lead to side effects. No formal studies have been conducted showing such interactions, however.

The list of drugs that might possibly interfere with the elimination of tolterodine includes is erythromycin, clarithromycin (Biaxin), ketoconazole (Nizoral), itraconazole (Sporanox), and miconazole (Monistat, Micatin). The dose of tolterodine should be reduced to 1mg twice daily if taken with any of these drugs.

 

 

5. Adverse reactions

 

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using tolterodine and call your doctor at once if you have any of these serious side effects:

 

  chest pain, fast or uneven heart rate;

  confusion, hallucinations;

  urinating less than usual or not at all; or

  painful or difficult urination.

 

Less serious side effects may include:

 

  dry mouth, dry eyes;

  blurred vision;

  dizziness, drowsiness;

  constipation or diarrhea;

  stomach pain or upset;

  joint pain; or

  headache.







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