RIMOTIMO

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

• Seborrhoeic dermatitis
• Dandruff
• Scalp psoriasis
• Bacterial infections affecting the scalp

Dosage

Children: For children, apply 3 times a week for 1 week, then apply twice weekly as needed. Refer to BNF for Children for further details.

Adults: Apply to the affected area as directed, typically 1-3 times weekly depending on the condition being treated. Refer to specific product guidelines for detailed dosing.

Mechanism of action

Benzalkonium chloride exerts its antimicrobial effect by disrupting the cell membrane of microorganisms, leading to leakage of cellular contents and ultimately cell death. This is facilitated by its cationic nature, which allows it to bind to negatively charged bacterial surfaces.

Pharmacodynamics

Benzalkonium chloride demonstrates rapid bactericidal activity, with effectiveness observed against gram-positive and gram-negative bacteria, fungi, and some viruses. Its antiseptic properties may be enhanced in the presence of moisture and are typically influenced by the concentration of the solution used.

Pharmacokinetics

Benzalkonium chloride is poorly absorbed through the skin. After topical application, it remains primarily at the site of application, where it exerts localized effects. Systemic absorption is minimal, and it is primarily eliminated through the skin and urine. However, specific pharmacokinetic data may vary based on formulation and application site.

Pregnancy

Benzalkonium chloride should be used with caution during pregnancy. Refer to specific guidelines or consult a healthcare professional.

Breast-feeding

Benzalkonium chloride should be used with caution while breastfeeding. Refer to specific guidelines or consult a healthcare professional.

Storage

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

Formulations

• Shampoo
• Soap or detergent
• Topical solution

Indications

• Open-angle glaucoma
• Ocular hypertension

Dosage

Children: For paediatric dosing, consult the BNF for Children.

Adults: Apply one drop to the affected eye(s) once daily.

Mechanism of action

Brimonidine tartrate stimulates alpha-2 adrenergic receptors in the eye, which reduces the release of norepinephrine, leading to decreased production of aqueous humor and increased outflow. This action lowers intraocular pressure, making it effective for treating glaucoma and ocular hypertension.

Pharmacodynamics

Brimonidine exhibits a selective action on alpha-2 adrenergic receptors, leading to a decrease in presynaptic release of norepinephrine. This results in reduced aqueous humor production and enhanced outflow. The reduction in IOP is significant and can be sustained over time, although tolerance may develop with prolonged use.

Pharmacokinetics

Brimonidine is absorbed through the cornea after topical application. Peak plasma concentrations occur within 2 hours, and the drug undergoes extensive hepatic metabolism, primarily via glucuronidation. The elimination half-life is approximately 2 hours, and it is excreted primarily in the urine as metabolites.

Contra-indications

• Cerebrovascular disease
• Severe depression
• Heart failure
• History of angina
• Hypertension
• Parkinson's syndrome
• Raynaud's phenomenon
• Severe vasovagal attack

Adverse effects

• Eye disorders
• Ocular pruritus
• Conjunctival hemorrhage
• Dry eye
• Eye discomfort
• Eye inflammation
• Increased lacrimation
• Oedema of the eyelids and conjunctiva
• Bradycardia
• Diarrhea
• Gastrointestinal discomfort
• Irritability
• Decreased libido
• Nasal dryness
• Palpitations
• Postural hypotension
• Abnormal sensation
• Sleep disorders
• Syncope
• Vision disturbances
• Fatigue
• Dry mouth

Interactions

• Beta blockers
• Non-selective sympathomimetics

Precautions

• Use with caution in patients with chronic respiratory conditions
• Monitor intraocular pressure and visual fields regularly
• Monitor for excessive reduction in intraocular pressure following peri-operative use

Pregnancy

Manufacturer advises avoiding use due to lack of information on safety.

Breast-feeding

Manufacturer advises avoiding use due to lack of information on safety.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Eye drops containing Brimonidine tartrate 0.2% (2 mg/ml)

Indications

• Disinfection of surfaces
• Antiseptic for skin
• Preservative in pharmaceuticals
• Treatment of minor cuts and abrasions

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations in pediatric populations.

Adults: Refer to the BNF for specific formulations and concentrations as doses may vary based on the application and preparation.

Mechanism of action

The bactericidal action of benzalkonium chloride is believed to result from the disruption of intermolecular interactions, which leads to the dissociation of cellular membrane lipid bilayers in bacteria. This disruption compromises cellular permeability, causing leakage of vital cellular contents. Moreover, the agent can deactivate important molecular complexes such as enzymes that regulate various respiratory and metabolic activities within the cells. Cationic surfactants like benzalkonium chloride can thus effectively disrupt critical intermolecular interactions and tertiary structures in biochemical systems, impairing bacterial function.

Pharmacodynamics

Benzalkonium chloride is classified as a biocidal agent with a relatively long duration of action. It exhibits a spectrum of activity against various microorganisms, including bacteria, certain viruses, fungi, and protozoa; however, it is ineffective against bacterial spores. The agent tends to demonstrate greater efficacy against gram-positive bacteria compared to gram-negative ones. The mode of action can be bacteriostatic (preventing growth) or bactericidal (killing bacteria), depending on its concentration. The activity of benzalkonium chloride is generally stable across different pH levels but is enhanced at elevated temperatures and with extended exposure.

Pharmacokinetics

The pharmacokinetic properties of benzalkonium chloride, including absorption, distribution, metabolism, and excretion, are not fully characterized. Its topical application limits systemic exposure, and it primarily exerts localized effects at the site of application. The duration of action and efficacy may be influenced by the formulation and concentration used.

Pregnancy

Benzalkonium chloride is generally considered safe for use during pregnancy when applied topically, but systemic absorption should be minimized. Always consult a healthcare provider for use during pregnancy.

Breast-feeding

Benzalkonium chloride is considered safe for topical application during breastfeeding, but care should be taken to avoid exposure to the infant. Consultation with a healthcare provider is recommended.

Storage

Store at room temperature, away from moisture and heat. Keep in a tightly closed container, protected from light.

Formulations

• Topical solution
• Disinfectant wipes
• Liquid antiseptics

Indications

• Open-angle glaucoma
• Ocular hypertension

Dosage

Children: For paediatric patients aged 2 years and older, the usual dosage is one drop of brimonidine 0.1% in the affected eye(s) twice daily. For those aged 2 to less

Adults: The recommended dosage for adults is one drop of brimonidine 0.2% in the affected eye(s) twice daily.

Mechanism of action

In the eye, the activation of alpha-2 adrenoceptors by brimonidine leads to a reduction in aqueous humor production through inhibition of adenylyl cyclase and a decrease in cyclic AMP levels. This results in decreased norepinephrine release, which lowers IOP. Additionally, chronic dosing is proposed to increase uveoscleral outflow, further contributing to IOP reduction. The drug does not significantly affect episcleral venous pressure.

Pharmacodynamics

Brimonidine is highly selective for alpha-2 adrenergic receptors, being 1000-fold more selective than for alpha-1 receptors. This selectivity reduces the risk of systemic side effects, such as hypotension and sedation, and minimizes unwanted ocular effects typically mediated by alpha-1 receptors. The peak ocular hypotensive effect of brimonidine occurs approximately two hours after administration, with studies showing a consistent reduction in IOP over extended treatment periods.

Pharmacokinetics

Brimonidine is rapidly absorbed into the eye upon ophthalmic administration. Its onset of action occurs within a few hours, with a peak effect observed at around two hours post-dosing. The drug is metabolized in the liver, and its elimination half-life in plasma is approximately 2-4 hours. Due to its selective action, brimonidine exhibits a favorable pharmacokinetic profile with limited systemic exposure.

Contra-indications

• Hypersensitivity to brimonidine or any of its components
• Concurrent use with monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Ocular hyperemia
• Dry mouth
• Fatigue
• Dizziness
• Allergic conjunctivitis
• Blurred vision

Interactions

• Caution should be exercised when using with other CNS depressants
• Potential interaction with antihypertensive medications leading to additive effects

Precautions

• Use with caution in patients with severe cardiovascular disease
• Use with caution in patients with depression or other mood disorders
• Consider monitoring IOP regularly during therapy

Pregnancy

Brimonidine is classified as category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Brimonidine is excreted in human milk. Caution is advised when administered to nursing women.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Brimonidine 0.1% ophthalmic solution
• Brimonidine 0.2% ophthalmic solution

Dosage

Children: Refer to specific formulations and clinical guidelines for dosing information as this can vary widely based on the context of use.

Adults: Refer to specific formulations and clinical guidelines for dosing information as this can vary widely based on the context of use.

Mechanism of action

Dibasic compounds often act by providing a buffering effect in biological systems, which helps to maintain physiological pH levels. They may also interact with various biological targets depending on their specific structure, influencing metabolic pathways and cellular functions.

Pharmacodynamics

The pharmacodynamics of dibasic compounds is highly variable and depends on their specific chemical structure and the context of their use. Generally, these compounds may alter the absorption and distribution of other drugs, modulate enzyme activity, or affect cellular signaling pathways through their interactions with biological molecules.

Pharmacokinetics

The pharmacokinetics of dibasic compounds can vary widely. Factors such as solubility, stability, and route of administration influence their absorption, distribution, metabolism, and excretion. Typically, dibasic compounds may be absorbed in the gastrointestinal tract and may undergo various metabolic processes depending on their specific nature.

Pregnancy

Dibasic compounds should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult with a healthcare provider.

Breast-feeding

Caution is advised when administering dibasic compounds to breastfeeding mothers. Consult with a healthcare provider.

Storage

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

Dosage

Children: Refer to BNF for Children for specific dosing guidance, as heptachlor usage is largely restricted.

Adults: Refer to BNF for specific dosing information, as heptachlor is not commonly used in clinical settings due to safety concerns.

Mechanism of action

Heptachlor mimics the action of picrotoxin, inhibiting gamma-aminobutyric acid (GABA)-stimulated chloride uptake, which leads to nerve excitation in insects. It competes for binding sites in the brain, causing central nervous system stimulation and resulting in increased transmitter release. This mechanism can lead to increased excitability and potentially toxic effects in target organisms.

Pharmacodynamics

As a neurotoxic agent, heptachlor causes hyperactivity and central nervous system stimulation in insects. Its effects on GABA receptors disrupt normal inhibitory neurotransmission, resulting in uncontrolled neuronal firing. While primarily studied in insects, similar mechanisms may be inferred in higher organisms, including potential neurotoxic effects in humans.

Pharmacokinetics

Heptachlor is lipophilic, leading to significant bioaccumulation in organisms and environmental persistence. It is metabolized in the liver to heptachlor epoxide, which is the more toxic form. The elimination half-life varies but can be prolonged due to its fat solubility and tendency to accumulate in fatty tissues.

Pregnancy

Heptachlor is classified as a category B drug. Animal studies have not shown any harm to the fetus, but there are no adequate and well-controlled studies in pregnant women. Use only if clearly needed.

Breast-feeding

It is not known if heptachlor is excreted in human milk. Caution should be exercised when administering heptachlor to a nursing mother.

Storage

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

Dosage

Children: Refer to specific formulation guidelines for pediatric dosing, as heptahydrate is generally used in conjunction with other active ingredients.

Adults: Refer to specific formulation guidelines for dosing, as heptahydrate is typically a component rather than an active agent.

Mechanism of action

Heptahydrate itself does not have a specific pharmacological action as it is generally a structural component in formulations. However, the active ingredients in heptahydrate formulations may exert their effects through various mechanisms depending on their specific pharmacology.

Pharmacodynamics

Pharmacodynamics of heptahydrate salts is largely influenced by the active pharmaceutical ingredients they are combined with. The presence of water molecules can enhance solubility, thereby improving the absorption and overall efficacy of the drug when administered. The hydration state can also play a role in the release profile of the drug from solid dosage forms.

Pharmacokinetics

The pharmacokinetics of heptahydrate formulations depend on the specific active ingredient they harbor. The dissolution rate can be affected by the hydration state, leading to variations in absorption rates. Generally, the pharmacokinetic profile would include absorption, distribution, metabolism, and excretion characteristics of the active pharmaceutical ingredients rather than the heptahydrate component itself.

Indications

• pH regulation in biological systems
• buffering agents in pharmaceutical formulations
• stabilizers in chemical reactions

Dosage

Children: Refer to specific monobasic compound guidelines for pediatric dosing information, as this varies widely based on the specific application and formulation.

Adults: Refer to specific monobasic compound guidelines for dosing information, as this varies widely based on the specific application and formulation.

Mechanism of action

Monobasic compounds, depending on their chemical nature, often act by dissociating into their respective ions in solution. This dissociation can influence the pH and ionic strength of the solution, which in turn can affect various biochemical reactions and cellular functions.

Pharmacodynamics

The pharmacodynamic effects of monobasic compounds are largely dependent on their specific chemical structure and the physiological context. Generally, they can modulate pH levels, affect enzyme activity, and influence ion transport across cell membranes. These compounds may also play a role in maintaining homeostasis in biological systems.

Pharmacokinetics

The pharmacokinetics of monobasic compounds can vary widely based on their formulation and route of administration. Typically, they are rapidly dissociated in biological fluids, allowing for immediate effects on pH and ionic balance. They may be absorbed systemically or act locally, depending on their intended use.

Pregnancy

Safety in pregnancy has not been established; use only if clearly needed.

Breast-feeding

Caution is advised; consult a healthcare professional before use.

Storage

Store in a cool, dry place, away from light and moisture.

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

Although not entirely elucidated, the bactericidal action of benzalkonium chloride is believed to be due to the disruption of intermolecular interactions. Such disruption can cause the dissociation of cellular membrane lipid bilayers of bacteria, resulting in compromised cellular permeability control and the leakage of important cellular contents. Additionally, other important molecular complexes like enzymes which control the maintenance of a great range of respiratory and metabolic cellular activities, are also susceptible to such deactivation. Consequently, a variety of critical intermolecular interactions and tertiary structures in very highly specific biochemical systems that allow bacterial agents to function normally can be readily disrupted or deactivated by cationic surfactants like benzalkonium chloride..

Pharmacodynamics

Benzalkonium chloride solutions are generally categorized as biocidal agents with relative long durations of action. Their spectrum of activity has been demonstrated against bacteria, to some viruses, fungi, and protozoa, although bacterial spores are treated as being resistant to the agent. Additionally, the agent generally shows more activity against gram-positive than gram-negative bacteria. Finally, solutions of benzalkonium chloride are bacteriostatic or bactericidal based on their concentration. Bacteriostatic agents act to prevent further growth of bacterial organisms that are present while bactericidal agents function to kill bacteria that are present. In general, the activity of the agent is not largely affected by pH, but such activity does increase substantially at higher temperatures and prolonged exposure times.

Mechanism of action

In the eye, alpha-1 adrenoceptors play a role in vasoconstriction, mydriasis, eyelid retraction, and elevation of intraocular pressure (IOP) whereas alpha-2 adrenoceptors are responsible for IOP reduction via a complex Gi-coupled signaling cascade pathway. Activation of alpha-2 receptors leads to inhibition of adenylyl cyclase and reduction of cyclic AMP levels. As a result, there is a decrease in norpinephrine (NE) release at the synaptic junction, NE-induced stimulation of beta-2 adrenoceptors, and production of aqueous humor by the ciliary epithelium. An elevated IOP is the most significant risk factor for developing glaucomatous optic neuropathy, which is associated with progressive visual field loss and functional disability if left untreated. Regardless of the etiology of the disease, the aim of current therapies for glaucoma is to reduce IOP, as reduction of IOP significantly reduces the risk of progression of vision loss even when IOP is already within the normal range. When administered ophthalmically, brimonidine is rapidly absorbed into the eye, acts as an agonist at ocular alpha-2 adrenoceptors and lowers IOP via a dual mechanism of action. It is proposed that initial dosing of the drug causes a reduction in aqueous humour production and chronic dosing leads to an increase in uveoscleral outflow. Brimonidine does not affect episcleral venous pressure. By reducing IOP, brimonidine aims to reduce the likelihood of glaucomatous visual field loss in ocular hypertension, and slow the progression of visual field defect in established open-angle glaucoma. When applied topically on skin, brimonidine reduces erythema through direct vasocontriction of small arteries and veins. As brimonidine mediates a potent peripheral vasoconstrictive activity by selectively working on the alpha-2 adrenoceptors, the use of brimonidine is thought to be efficacious for the treatment of facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature of the face.

Pharmacodynamics

Brimonidine is a highly selective alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha1-adrenergic receptor. This characteristic gives the drug some therapeutic advantages, since it reduces the risk of systemic side effects, such as systemic hypotension, bradycardia, and sedation. In addition, there is a reduction in the risk for developing alpha-1 mediated ocular unwanted effects, such as conjunctival blanching, mydriasis, and eyelid retraction. However, despite high alpha-2 receptor specificity, brimonidine may still produce alpha-1 adrenoceptor-mediated ocular effects, such as conjunctival vasoconstriction. Brimonidine has a peak ocular hypotensive effect occurring at two hours post-dosing. In a randomized, double-blind clinical study, ocular administration of 0.2% brimonidine in healthy volunteers resulted in a 23% reduction of mean intraocular pressure from baseline at 3 hours following administration. In comparative studies consisting of patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive effect of brimonidine was maintained during treatment periods of up to 1 year. Brimonidine mediates vasoconstrictive effects and it was shown to exhibit anti-inflammatory properties in _ex vivo_ human skin model and _in vivo_ inflammation models. In a clinial trials consisting of adults with moderate to severe facial erythema of rosacea, brimonidine was shown to improve the extent of redness at 3 hours after application, compared to placebo. It was shown to be a potent vasoconstrictor of human subcutaneous vessels with a diameter of less than 200 µm. In _in vivo_ mouse inflammation models, brimonidine displayed anti-inflammatory properties by inhibiting edema. In a randomized, double-blind study, brimonidine reduced erythema for the 12 hours of the study in a dose-dependent manner. When adminsitered systemically, brimonidine was shown to cause cardiovascular effects by decreasing blood pressure, decreasing heart and respiratory rate, and prolonging the PR interval in the electrocardiogram. This is due to the targeting of adrenoceptors by the drug. Although the clinical significance has not been established, there is evidence that brimonidine exhibits neuroprotective activity in experimental models of cerebral ischemia and optic nerve injury. _In vitro_ studies show that brimonidine mediated protective effects on neuronal cells from kainate acid insult and on cultured retinal ganglion cells from glutamate-induced cytotoxicity, which is a possible mediator of secondary neuronal degeneration in human glaucoma. Neuroprotective actions of brimonidine were also demonstrated in rat models of acute retinal ischemia and chronic IOP elevation. It has been proposed that brimonidine may exert neuroprotective effects on the retina and optic nerve by enhancing intrinsic retinal ganglion cell survival mechanisms and/or induction of neuronal survival factors, such as bFGF. However, further investigations are needed to conclude on these possible therapeutic benefits of the drug.

Mechanism of action

EVIDENCE INDICATES THAT CYCLODIENE-TYPE-INSECTICIDES, EG, HEPTACHLOR EPOXIDE, MIMIC ACTION OF PICROTOXININ. THESE INSECTICIDES INHIBIT THE GAMMA-AMINOBUTYRIC ACID-STIMULATED CHLORIDE UPTAKE IN COXAL MUSCLE OF AMERICAN COCKROACH, & DIRECTLY COMPETE AGAINST LABELED DIHYDROPICROTOXININ FOR BINDING IN THE RAT BRAIN SYNAPTOSOMES. MOREOVER, SEVERAL CYCLODIENE RESISTANT INSECT STRAINS ARE RESISTANT TO PICROTOXININ. THIS CROSS-RESISTANCE IS SPECIFIC TO PICROTOXININ & DOES NOT EXTEND TO OTHER NEUROEXCITANTS. THESE INSECTICIDES, LIKE PICROTOXININ, CAUSE CENTRAL NERVOUS EXCITATION BY STIMULATING TRANSMITTER RELEASE. THESE RESULTS INDICATE THAT SOME OF THE NERVE EXCITATION SYMPTOMS THAT INSECTICIDES CAUSE ARE LIKELY DUE TO THEIR INTERACTION WITH PICROTOXININ RECEPTOR. HEPTACHLOR WAS EVALUATED FOR GENOTOXICITY & EPIGENETIC MEMBRANE EFFECTS. IT WAS NON-GENOTOXIC IN ARLHGPRT MUTAGENESIS ASSAY IN WHICH THE GENOTOXIC CARCINOGENS 7,12-DIMETHYLBENZ(A)ANTHRACENE & BENZO(A)PYRENE INDUCED SIGNIFICANT INCR IN MUTANT INCIDENCE. HEPTACHLOR INHIBITED INTERCELLULAR COMMUNICATION BETWEEN CULTURED LIVER CELLS, A PROPERTY DEMONSTRATED BY MANY TUMOR PROMOTING AGENTS, WHEREAS, BENZO(A)PYRENE DID NOT PRODUCE THIS EPIGENETIC EFFECT. The actions of the polychlorocycloalkane insecticide heptachlor, and its epoxide metabolite, were examined on GABA receptors in insects and vertebrates. Electrophysiological experiments on the cell body of the cockroach (Periplaneta americana) fast coxal depressor motor neuron (Df), and GABA-activated (36) Cl- uptake experiments on microsacs perpared from cockroach ventral nerve cords showed that both heptachlor and heptachlor epoxide blocked functional GABA receptors. The block appeared to be non-competitive and was voltage-independent over the membrane potential range -75 mV to -110 mV. There was no significant difference between the potencies of heptachlor and heptachlor epoxide in the functional assays for insect GABA receptors. Both compounds inhibited (35)S-t-butylbicyclophosphorothionate binding in insects and vertebrates. The findings provide further evidence for block of an insect GABA receptor/Cl- channel by the cyclodiene class of polychlorocycloalkanes, and reveal differences in the insecticide (35)S-t-butylbicyclophosphorothionate binding site interactions of insects and vertebrates. The effects of heptachlor on oxidative phosphorylation and electron transport in male Donryu rat liver mitochondria were investigated. The effects of 50 uM heptachlor on the respiratory activity of isolated liver mitochondria was tested in the presence of added succinate as a substrate. The effects of 100 uM heptachlor was tested in the presence of three kinds of substrates: succinate, beta-hydroxybutylate, and ascorbate plus N,N,N'N'-tetramethylphenylene-diamine. Heptachlor at 50 uM greatly inhibited the state 3 respiration, but inhibited the state 4 respiration hardly at all. The inhibition was released by 2,4-dinitrophenol. The higher dose suppressed state 3 and state 4 respiration almost completely with succinate as substrate. The findings suggest that the function of the electron transport system was also suppressed by the higher heptachlor dose even without oxidative phosphorylation.

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.