TAMTOL CAPSULES

Indications

• Urinary frequency
• Urgency
• Incontinence associated with overactive bladder
• Neurogenic bladder instability

Dosage

Children: The use of tolterodine in children is not well-established; refer to the BNF for Children for specific dosing information.

Adults: For immediate-release tablets, the usual starting dose is 2 mg taken twice daily, which may be increased to a maximum of 4 mg twice daily if necessary. For modified-release capsules, the recommended dose is 4 mg once daily, which may be increased to a maximum of 8 mg once daily depending on clinical response.

Mechanism of action

Tolterodine selectively antagonizes muscarinic receptors, primarily M2 and M3 subtypes, which are involved in the contraction of the detrusor muscle of the bladder. By inhibiting these receptors, tolterodine reduces involuntary bladder contractions and increases bladder storage capacity.

Pharmacodynamics

The pharmacodynamic effects of tolterodine include reduced urinary urgency and frequency. It improves bladder control and decreases the episodes of incontinence. The onset of action generally occurs within a few hours after administration, with a peak effect seen within 1-2 hours for immediate-release formulations.

Pharmacokinetics

Tolterodine is well-absorbed after oral administration, with peak plasma concentrations achieved within 1-2 hours. It undergoes hepatic metabolism via CYP2D6 and CYP3A4, with a resultant half-life of approximately 2-3 hours for immediate-release forms and up to 6-8 hours for extended-release forms. The drug is primarily excreted in urine as metabolites, with less than 10% excreted unchanged.

Contra-indications

• Hypersensitivity to tolterodine or any excipients in the formulation
• Severe hepatic impairment
• Urinary retention
• Uncontrolled narrow-angle glaucoma

Adverse effects

• Dry mouth
• Constipation
• Dizziness
• Fatigue
• Nausea
• Abdominal pain
• Headache
• Taste disturbances
• Anaphylactic reactions (rare)

Interactions

• Caution with other anticholinergic drugs
• May enhance the effects of drugs that prolong the QT interval
• Use with caution with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin)
• Antimuscarinic agents may have additive effects

Precautions

• Caution in patients with a history of urinary retention
• Caution in patients with bladder outflow obstruction
• Caution in elderly patients
• Monitor for signs of anticholinergic toxicity

Pregnancy

Manufacturer advises caution due to lack of human data; animal studies have shown adverse effects.

Breast-feeding

Manufacturer advises avoiding use; present in animal milk studies.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tolterodine tartrate 1 mg tablets
• Tolterodine tartrate 2 mg tablets
• Tolterodine tartrate 4 mg modified-release capsules
• Tolterodine tartrate oral solution 1 mg per 1 ml

Indications

• Benign prostatic hyperplasia
• Bladder outlet obstruction
• Urinary retention

Dosage

Children: Not established; refer to BNF for Children for any potential dosing information.

Adults: Initially 400 micrograms once daily, taken after a meal. Dosage may be adjusted based on clinical response and tolerability, typically not exceeding 800 micrograms daily.

Mechanism of action

Tamsulosin exerts its therapeutic effects through selective antagonism of the alpha-1A adrenergic receptors found predominantly in the smooth muscle of the prostate and bladder neck. This action results in relaxation of these muscles, leading to improved urinary flow and reduced bladder outlet obstruction.

Pharmacodynamics

The pharmacodynamics of Tamsulosin involve its ability to decrease urinary resistance and improve urinary flow rates. It exhibits a preferential binding affinity for the alpha-1A receptors compared to alpha-1B receptors, which minimizes cardiovascular side effects commonly associated with non-selective alpha blockers. The onset of action typically occurs within a few days of starting treatment, although maximum benefits may take several weeks.

Pharmacokinetics

Tamsulosin is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 6 hours post-administration. It has a bioavailability of about 90% due to extensive first-pass metabolism. The drug is primarily metabolized in the liver via CYP2D6 and CYP3A4 pathways, resulting in several active metabolites. Tamsulosin has a half-life of approximately 15 hours, allowing for once-daily dosing. It is excreted mainly in urine as metabolites, with less than 10% of the drug eliminated unchanged.

Contra-indications

• History of micturition syncope
• History of postural hypotension
• Congestive heart failure (due to mechanical obstruction such as aortic stenosis)

Adverse effects

• Asthenia
• Dizziness
• Constipation
• Fatigue
• Sweating

Interactions

• Caution with concomitant antihypertensives
• Potential for additive hypotensive effects when used with other antihypertensives

Precautions

• Caution in elderly patients due to risk of first dose hypotension
• Care during cataract surgery due to risk of intra-operative floppy iris syndrome
• Monitor for symptomatic orthostatic hypotension

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if clearly needed.

Breast-feeding

It is not known whether tamsulosin is excreted in human milk. Caution is advised when administering to breastfeeding mothers.

Storage

Store below 25 degrees Celsius. Keep the container tightly closed.

Formulations

• Tamsulosin hydrochloride 400 microgram capsules
• Tamsulosin hydrochloride 500 microgram tablets
• Tamsulosin hydrochloride modified-release capsules

Indications

• Benign Prostatic Hyperplasia (BPH)
• Lower urinary tract symptoms associated with BPH

Dosage

Children: null

Adults: The usual dose is 400 micrograms once daily, taken approximately 30 minutes after the same meal each day.

Mechanism of action

Tamsulosin selectively blocks alpha-1A and alpha-1D adrenoceptors, which are prevalent in the prostate and bladder respectively. This leads to relaxation of the smooth muscle in the prostate and the bladder neck, thereby enhancing urinary flow. The drug's specific action on alpha-1A receptors minimizes effects on vascular smooth muscle, resulting in a lower incidence of adverse cardiovascular effects.

Pharmacodynamics

Tamsulosin exhibits selective antagonism of alpha-1 adrenergic receptors, with a greater affinity for alpha-1A and alpha-1D subtypes compared to alpha-1B. This selectivity allows for effective relief of urinary symptoms associated with BPH while reducing the risk of orthostatic hypotension and other cardiovascular side effects. Its pharmacodynamic profile supports improved urinary flow rates without significant hemodynamic changes.

Pharmacokinetics

Tamsulosin is well absorbed after oral administration and reaches peak plasma concentrations within 4 to 6 hours. It has a high protein binding rate (approximately 99%) and is primarily metabolized by the liver via cytochrome P450 enzymes, notably CYP3A4. The elimination half-life is approximately 9 to 15 hours, allowing for once-daily dosing. The drug is excreted mainly in the urine, with both unchanged drug and metabolites found in the urine.

Adverse effects

• dizziness
• headache
• nasal congestion
• semen abnormality
• orthostatic hypotension

Interactions

• cobicistat+tamsulosin: Moderate (increases exposure)
• idelalisib+tamsulosin: Moderate (increases exposure)
• antifungals, azoles+tamsulosin: Unknown (increases exposure)
• crizotinib+tamsulosin: Unknown (increases exposure)
• imatinib+tamsulosin: Unknown (increases exposure)
• letermovir+tamsulosin: Unknown (increases exposure)
• nilotinib+tamsulosin: Unknown (increases exposure)
• dronedarone+tamsulosin: Unknown (increases exposure)
• erythromycin+tamsulosin: Unknown (increases exposure)

Pregnancy

Tamsulosin is not recommended during pregnancy due to limited data on its safety.

Breast-feeding

It is unknown whether tamsulosin is excreted in human milk; caution is advised.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Capsules 0.4 mg

Indications

• Overactive bladder
• Urinary incontinence
• Urgency and frequency of urination

Dosage

Children: Refer to the BNF for Children.

Adults: The usual starting dose is 2 mg twice daily, which may be increased to a maximum of 4 mg per day based on individual response.

Mechanism of action

Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, function as competitive antagonists at muscarinic receptors. This antagonism leads to inhibition of bladder contraction, a decrease in detrusor pressure, and incomplete bladder emptying.

Pharmacodynamics

As a competitive muscarinic receptor antagonist, tolterodine specifically inhibits cholinergic activity in the bladder, resulting in reduced urinary urgency and frequency. After oral administration, tolterodine is metabolized in the liver to form its active metabolite, which has similar antimuscarinic properties. This mechanism contributes to increased residual urine and decreased detrusor pressure.

Pharmacokinetics

Tolterodine is well absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. It undergoes extensive first-pass metabolism in the liver, predominantly via CYP2D6 and CYP3A4 enzymes, leading to the formation of its active metabolite. The elimination half-life is approximately 2-4 hours for tolterodine and longer for its metabolite. Excretion occurs mainly through urine.

Contra-indications

• Urinary retention
• Severe gastric retention
• Uncontrolled narrow-angle glaucoma
• Hypersensitivity to tolterodine or any of its components

Adverse effects

• Dry mouth
• Constipation
• Dizziness
• Somnolence
• Blurred vision
• Nausea
• Abdominal pain

Interactions

• dacomitinib+tolterodine: Severe (increases exposure)
• clarithromycin+tolterodine: Severe (increases exposure)
• eliglustat+tolterodine: Moderate (increases exposure)
• clozapine+tolterodine: Unknown (additive effect)
• cobicistat+tolterodine: Unknown (increases exposure)
• idelalisib+tolterodine: Unknown (increases exposure)
• antipsychotics, second generation+tolterodine: Unknown (additive effect)

Precautions

• Use with caution in patients with hepatic impairment
• Caution is advised in patients with a history of urinary retention
• Consider monitoring in elderly patients due to increased sensitivity to antimuscarinic effects

Pregnancy

Tolterodine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is limited data on its use in pregnant women.

Breast-feeding

Tolterodine is excreted in breast milk. Caution should be exercised when administering tolterodine to breastfeeding women.

Storage

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

Formulations

• Immediate-release tablets
• Extended-release capsules

Mechanism of action

Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. Tamsulosin hydrochloride is a sulfamoylphenethylamine-derivative alpha1-adrenergic blocking agent. The drug is pharmacologically related to doxazosin, prazosin, and terazosin; however, unlike these drugs, tamsulosin has higher affinity and selectivity for alpha1A-adrenergic receptors, which are mainly located in nonvascular smooth muscle (eg, prostate), than for alpha1B-adrenergic receptors located in vascular smooth muscle (eg, internal iliac artery). Results of in vitro studies indicate that tamsulosin has 7-38 times greater affinity for alpha1A-adrenoceptors than for alpha1B-adrenoceptors; the drug has about 12 times greater affinity for alpha1-adrenergic receptors in the prostate than for those in the aorta. Such selectivity of tamsulosin for alpha1A-receptors may result in a reduced incidence of adverse cardiovascular effects (eg, syncope, dizziness, hypotension). On a molar basis, the alpha1-adrenergic receptor affinity of tamsulosin is about 6 times that of prazosin when tested in human prostatic tissue. Because of the prevalence of alpha-receptors on the prostate capsule, prostate adenoma, and bladder trigone and the relative absence of these receptors on the bladder body, alpha-adrenergic blocking agents decrease urinary outflow resistance in men. The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resist

Pharmacodynamics

Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension.

Mechanism of action

Both tolterodine and its active metabolite, 5-hydroxymethyltolterodine, act as competitive antagonists at muscarinic receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder.

Pharmacodynamics

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. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract.