Xolamol

Indications

• Hypertension
• Angina
• Migraine prophylaxis
• Glaucoma
• Ocular hypertension

Dosage

Adults: Initially, 10 mg daily in 1-2 divided doses, then may be increased if necessary up to 60 mg daily, doses to be increased gradually. For glaucoma, the usual dose is 1 drop of 0.25% or 0.5% solution

Mechanism of action

Timolol maleate exerts its effects by blocking beta-adrenergic receptors (both beta-1 and beta-2). This blockade decreases heart rate and myocardial contractility, reduces renin secretion from the kidneys, and lowers aqueous humor production in the eye, thereby decreasing intraocular pressure in glaucoma. The inhibition of beta-2 receptors in bronchial tissues can lead to bronchoconstriction, which is important to consider in patients with respiratory conditions.

Pharmacodynamics

The pharmacodynamic effects of timolol maleate include its ability to lower heart rate and blood pressure through beta-adrenergic blockade. The onset of action for oral administration can be observed within 1 to 2 hours, with peak effects typically occurring within 2 to 4 hours. The duration of action allows for twice-daily dosing in many cases. In ocular formulations, timolol reduces intraocular pressure by approximately 20-30% in patients with glaucoma or ocular hypertension.

Pharmacokinetics

Timolol maleate is well-absorbed following oral administration, with a bioavailability of about 50-70%. It undergoes extensive hepatic metabolism, primarily through cytochrome P450 enzymes, and has an elimination half-life of approximately 4 to 6 hours. Renal excretion accounts for a significant portion of the drug's elimination. In patients with hepatic impairment, caution is advised due to altered metabolism.

Contra-indications

• Bradycardia
• Heart block
• Asthma or a history of bronchospasm
• Severe chronic obstructive pulmonary disease (COPD)
• Cardiogenic shock
• Uncontrolled heart failure
• Hypersensitivity to timolol or any of its components

Adverse effects

• Bradycardia
• Hypotension
• Dizziness
• Fatigue
• Depression
• Cold extremities
• Nausea
• Diarrhea
• Insomnia
• Shortness of breath
• Visual disturbances
• Ocular irritation (when used as eye drops)

Interactions

• Caution with other beta-blockers
• Caution with antihypertensives
• Caution with antiarrhythmics
• May enhance effects of oral hypoglycaemics
• May mask symptoms of hypoglycemia
• Caution with calcium channel blockers

Precautions

• Monitor heart rate and blood pressure regularly
• Use with caution in patients with hepatic impairment
• Use with caution in patients with renal impairment
• Consider potential for systemic absorption when used as eye drops
• Discontinue in case of severe allergic reactions

Pregnancy

Timolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Manufacturer advises avoidance during breastfeeding due to potential for serious adverse effects in the infant.

Storage

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

Formulations

• Timolol maleate 0.25% eye drops
• Timolol maleate 0.5% eye drops
• Timolol maleate oral tablets 5 mg
• Timolol maleate oral tablets 10 mg
• Timolol maleate oral solution

Indications

• Ocular hypertension
• Open-angle glaucoma

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing.

Adults: Apply 1 drop to the affected eye(s) three times daily.

Mechanism of action

Dorzolamide specifically inhibits carbonic anhydrase II, an enzyme crucial for the production of bicarbonate ions in the ciliary processes of the eye. This inhibition disrupts sodium and fluid transport, resulting in decreased secretion of aqueous humor and lower intraocular pressure. The drug exhibits a 4000-fold higher affinity for CA-II compared to CA-I, making it a potent inhibitor in the ocular context.

Pharmacodynamics

As a carbonic anhydrase inhibitor, dorzolamide effectively reduces elevated intraocular pressure in conditions like open-angle glaucoma and ocular hypertension. When used alongside topical beta-adrenergic antagonists, dorzolamide provides an additive effect in lowering intraocular pressure. The maximum reduction in intraocular pressure typically occurs approximately 2 hours after administration.

Pharmacokinetics

Dorzolamide is administered topically as eye drops, leading to systemic absorption that can cause sulfonamide-like side effects. The pharmacokinetic profile is characterized by rapid absorption and a relatively short half-life, necessitating multiple daily doses for sustained effect. It is advised to avoid use in patients with renal impairment due to the risk of metabolic acidosis.

Contra-indications

• History of sulfonamide hypersensitivity
• Severe renal impairment (creatinine clearance less than 30 mL/min)
• Hyperchloraemic acidosis

Adverse effects

• Decreased appetite
• Arthralgia
• Malaise
• Peripheral oedema
• Tremor
• Increased urinary frequency
• Dizziness
• Vertigo
• Bitter vision
• Disorders of vision
• Dry mouth
• Epistaxis
• Local reactions
• Paresthesia
• Severe cutaneous adverse reactions (SCARs)
• Angioedema
• Bronchospasm

Interactions

• Brimonidine
• Beta-blockers

Precautions

• Caution in patients with chronic corneal defects
• History of intraocular surgery
• History of renal calculi
• Low endothelial cell count
• Monitor blood count and plasma electrolyte concentrations with prolonged use

Pregnancy

Avoid-toxicity in animal studies, especially in the first trimester.

Breast-feeding

Use only if benefit outweighs risk; amount too small to be harmful.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Eye drops 2% (Dorzolamide hydrochloride 20 mg/ml)

Indications

• Hypertension
• Angina pectoris
• Heart attack (myocardial infarction) prevention
• Glaucoma
• Ocular hypertension

Dosage

Children: Refer to the BNF for Children for specific dosing information for pediatric patients.

Adults: For hypertension, the usual starting dose is 10 mg once daily, which may be increased to 20 mg after 1 to 2 weeks if necessary. In glaucoma, the recommended dose is one drop of the 0.25% solution in the affected eye(s) twice daily.

Mechanism of action

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, resulting in decreased heart rate, cardiac output, and blood pressure. It also decreases peripheral vascular resistance. The exact mechanism for reducing intraocular pressure is not fully understood but may involve decreased secretion of aqueous humor and reduced blood supply to the ciliary body.

Pharmacodynamics

Timolol, when administered ophthalmically, rapidly reduces intraocular pressure, typically within 20 minutes. When taken orally, it lowers blood pressure, heart rate, and cardiac output, with effects lasting up to 24 hours in specific formulations. It has minimal impact on accommodation and pupil size.

Pharmacokinetics

Timolol is absorbed systemically, with a peak effect observed within 1 to 2 hours after oral administration. The drug is extensively metabolized in the liver, and its elimination half-life is approximately 4 to 5 hours. When used topically in the eye, systemic absorption can occur, leading to potential systemic effects.

Contra-indications

• Asthma or a history of bronchospasm
• Severe chronic obstructive pulmonary disease (COPD)
• Bradycardia or heart block
• Cardiogenic shock
• Hypersensitivity to timolol or any of the excipients

Adverse effects

• Bradycardia
• Hypotension
• Dizziness
• Fatigue
• Depression
• Shortness of breath
• Ocular irritation
• Dry eyes
• Systemic absorption leading to bronchospasm

Interactions

• Propafenone: Unknown (increases exposure)
• Other antihypertensives may have additive effects
• Calcium channel blockers may increase the risk of heart failure

Precautions

• Caution in patients with diabetes (may mask hypoglycemia symptoms)
• Use with caution in patients with renal impairment
• Monitor for signs of heart failure
• Caution in patients with a history of severe allergic reactions

Pregnancy

Timolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Timolol is excreted in human milk, caution should be exercised when administering to nursing mothers.

Storage

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

Formulations

• Ophthalmic solution (0.25% and 0.5%)
• Oral tablets (various strengths)

Mechanism of action

Elevated intraocular pressure is a characteristic manifestation of ocular hypertension or open-angle glaucoma. The level of intraocular pressure (IOP) is governed by the balance between the production of aqueous humour (by ocular ciliary processes) and its outflow from the anterior segment of the eye via trabecular (conventional) or uveoscleral (unconventional) pathways. When there is an increase in the resistance to the trabecular outflow of aqueous humour, the intraocular pressure is elevated. Subsequently, optic nerve damage can occur from blood flow restrictions and mechanical distortion of ocular structures. Optic nerve damage can further result in optic disc cupping and progressive visual field loss (and blindness in some cases). Carbonic anhydrase (CA) is a ubiquitous enzyme that catalyzes the reversible hydration of carbon dioxide to bicarbonate ions and dehydration of carbonic acid. In the ocular ciliary processes, the local production of bicarbonate by CAs promotes sodium and fluid transport. CA-II is a key isoenzyme found primarily in red blood cells (RBCs) that regulates aqueous humour production. Dorzolamide is a highly specific CA-II inhibitor, where it displays a 4000-fold higher affinity for carbonic anhydrase II than carbonic anhydrase I. The inhibition of CA-II in the ciliary process disrupts the formation of bicarbonate ions and reduces sodium and fluid transport, which leads to decreased aqueous humour secretion and reduced intraocular pressure.

Pharmacodynamics

Dorzolamide is a carbonic anhydrase inhibitor that reduces elevated intraocular pressure in open-angle glaucoma or ocular hypertension. When used in combination with topic beta-adrenergic antagonists, dorzolamide has an additive effect of lowering intraocular pressure. The peak ocular hypotensive effect of dorzolamide is observed at about 2 hours following ophthalmic administration.

Mechanism of action

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. beta-Adrenergic blocker Following topical application to the eye, timolol maleate reduces both elevated and normal intraocular pressure in patients with or without open angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces intraocular pressure with little or no effect on accommodation or pupillary size. In patients with elevated intraocular pressure, timolol reduces mean intraocular pressure by about 25-33%. The drug appears to be equally effective in light and dark colored eyes. ... The exact mechanism by which beta-blockers, including timolol, reduce intraocular pressure has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. beta-Adrenergic blocking agents may block endogenous catecholamine stimulated increases in cyclic adenosine monophosphate concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility. ... In some studies, timolol maleate applied topically to one eye reduced intraocular pressure in both eyes; the mechanism of this effect has not been elucidated. ... A slight decrease in the intraocular hypotensive effect may occur during the first 3 wk of timolol therapy, and tolerance may develop with prolonged use; however, the intraocular pressure lowering effect has been maintained for at least 3 yr with continuous use of the drug in some patients. /Timolol maleate/ Timolol maleate has pharmacologic actions similar to those of other beta-adrenergic blocking agents. The principal physiologic action of timolol is to competitively block beta-adrenergic receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors). Unlike atenolol and metoprolol, timolol is not a beta1-selective adrenergic blocking agent; timolol is a nonselective beta-adrenergic blocking agent, inhibiting both beta1- and beta2-adrenergic receptors. Timolol also does not exhibit the intrinsic sympathomimetic activity seen with pindolol or the membrane stabilizing activity possessed by propranolol or pindolol. ... By inhibiting myocardial beta1-adrenergic receptors, timolol produces negative chronotropic and inotropic activity. The negative chronotropic action of timolol on the sinoatrial node results in a decrease in the rate of sinoatrial node discharge and an increase in recovery time, thereby decreasing resting and exercise stimulated heart rate and reflex orthostatic tachycardia by as much as 30%. High doses of the drug may produce sinus arrest, especially in patients with SA node disease (eg, sick sinus syndrome). Timolol also slows conduction in the atrioventricular node. Timolol usually produces a slight reduction in cardiac output, proba

Pharmacodynamics

Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses.