Tiagra

Indications

• Erectile dysfunction
• Pulmonary arterial hypertension

Dosage

Children: Not licensed for use in children; therefore, specific dosing is not provided.

Adults: For erectile dysfunction, the initial dose is 50 mg taken approximately 1 hour before sexual activity, with adjustments possible based on efficacy and tolerability (maximum of 100 mg). For pulmonary arterial hypertension, the recommended dose is 20 mg three times a day.

Mechanism of action

Sildenafil works by selectively inhibiting phosphodiesterase type 5 (PDE5), an enzyme that degrades cyclic guanosine monophosphate (cGMP) in the corpus cavernosum of the penis. During sexual stimulation, nitric oxide (NO) is released, which activates guanylate cyclase, leading to increased cGMP levels. This results in smooth muscle relaxation and increased blood flow, facilitating an erection. In pulmonary vasculature, sildenafil enhances cGMP levels, promoting vasodilation.

Pharmacodynamics

Sildenafil exhibits high selectivity for PDE5, being approximately 10-times more potent than for PDE6, which is involved in retinal function, and significantly more selective over other phosphodiesterases. This selectivity minimizes adverse effects related to vision. Clinical studies demonstrate that sildenafil improves erectile function significantly in response to sexual stimulation, with effects generally observed within 60 minutes post-administration, lasting for several hours.

Pharmacokinetics

Sildenafil is rapidly absorbed, with peak plasma concentrations occurring within 30 to 120 minutes after oral administration. Its bioavailability is approximately 40%, and it is extensively metabolized in the liver, primarily by CYP3A4 and CYP2C9 enzymes. The elimination half-life is about 4 hours, and it is excreted mainly in the urine as metabolites. Renal impairment may affect its clearance, necessitating dose adjustments in patients with significant renal dysfunction.

Contra-indications

• Hereditary degenerative retinal disorders
• History of non-arteritic anterior ischaemic optic neuropathy
• Recent history of myocardial infarction
• Recent history of stroke
• Systolic blood pressure below 90 mmHg
• Active peptic ulceration
• Anatomical deformation of the penis
• Severe cardiovascular disease
• Severe hepatic impairment
• Predisposition to priapism

Adverse effects

• Headaches
• Nasal complaints
• Asthenia
• Dizziness
• Drowsiness
• Dyspnoea
• Gastrointestinal discomfort
• Muscle complaints
• Nausea
• Palpitations
• Vision blurred
• Vomiting
• Angina pectoris
• Chest pain
• Diarrhoea
• Dry mouth
• Emotional disorder
• Genital pruritus
• Gout
• Haematuria
• Hypertension
• Increased risk of infection
• Influenza-like illness
• Insomnia
• Peripheral oedema
• Rash
• Seasonal allergy
• Tachycardia
• Urinary frequency
• Increased weight

Interactions

• Moderate interactions with antifungals (azoles) that increase exposure
• Moderate interactions with crizotinib, imatinib, letermovir, nilotinib that increase exposure
• Unknown interactions with cobicistat, idelalisib, ribociclib that may increase exposure
• Caution advised with concurrent use of moderate or potent inhibitors of CYP3A4

Precautions

• Careful monitoring in elderly patients and those with severe heart failure
• Caution in patients with anatomical deformation of the penis
• Consideration for active peptic ulceration and bleeding disorders
• Use of effective contraception required during administration
• Pregnancy tests advised for women of childbearing potential
• Caution in patients with cardiovascular disease

Pregnancy

Avoid; teratogenic in animal studies.

Breast-feeding

Manufacturer advises

Indications

• Dry eye conditions
• Tear deficiency
• Keratoconjunctivitis sicca

Dosage

Children: Apply as required, typically in the form of eye drops.

Adults: Apply as required, typically in the form of eye drops.

Mechanism of action

Hypromellose acts by forming a viscous gel upon contact with the ocular surface, which helps to retain moisture and protect against irritants. This gel-like property enhances the stability of the tear film and reduces evaporation, thereby alleviating symptoms associated with dry eye conditions.

Pharmacodynamics

The pharmacodynamic effects of hypromellose are primarily related to its ability to mimic natural tears, providing lubrication to the ocular surface. This lubrication reduces friction during blinking and maintains corneal hydration, which is critical for ocular comfort and health. Its high viscosity also contributes to prolonged retention time on the eye surface.

Pharmacokinetics

Hypromellose is administered topically as eye drops and is not significantly absorbed systemically. The retention time of hypromellose on the ocular surface is enhanced due to its viscosity, allowing for extended relief of dry eye symptoms. The elimination of hypromellose occurs primarily through drainage from the eye and dilution by the natural tear fluid.

Adverse effects

• Temporary visual disturbance
• Eye irritation

Precautions

• Should not be used during contact lens wear
• Use with caution in patients with known hypersensitivity to any component of the formulation

Pregnancy

Hypromellose is generally considered safe for use during pregnancy. However, it should be used only if clearly needed and after consulting a healthcare provider.

Breast-feeding

Hypromellose is unlikely to affect breastfed infants when used as directed, but consultation with a healthcare provider is advisable.

Storage

Store in a cool, dry place away from direct sunlight. Once opened, use within a specified period as indicated on the packaging.

Formulations

• {'name': 'Teardew', 'concentration': '0.3%', 'form': 'eye drops', 'volume': '10 ml'}
• {'name': 'Xailin Hydrate', 'concentration': '0.3%', 'form': 'eye drops', 'volume': '10 ml'}
• {'name': 'AacuLose', 'concentration': '0.3%', 'form': 'eye drops', 'volume': '10 ml'}
• {'name': 'Artelac', 'concentration': '0.32%', 'form': 'eye drops', 'volume': '10 ml'}
• {'name': 'Lacrilube', 'concentration': '2 mg/g', 'form': 'eye ointment', 'volume': '3.5 g'}
• {'name': 'Celluvisc', 'concentration': '1%', 'form': 'eye drops', 'volume': '0.4 ml unit dose'}

Indications

• Methemoglobinemia
• Urinary tract infections
• Surgical marking
• Treatment of certain types of cyanide poisoning

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing information.

Adults: Refer to the relevant clinical guidelines or the BNF for specific dosing recommendations.

Mechanism of action

Methylene blue acts as a reducing agent, converting methemoglobin back to its functional form, hemoglobin. This is primarily achieved through its action as an electron donor, facilitating the reduction of ferric iron (Fe3+) in hemoglobin to ferrous iron (Fe2+), thereby restoring its oxygen-carrying capacity. It also exhibits antimicrobial properties through its ability to generate reactive oxygen species when exposed to light, which can inhibit bacterial growth.

Pharmacodynamics

The pharmacodynamics of methylene blue involve its role in enhancing oxygen delivery in patients suffering from methemoglobinemia. By converting methemoglobin back to hemoglobin, it effectively increases the amount of hemoglobin available for oxygen transport. The drug also shows effects on the vascular system, where it can induce vasodilation and influence blood pressure.

Pharmacokinetics

Methylene blue is rapidly absorbed after intravenous administration, with peak plasma concentrations occurring within 1 to 3 hours. It is extensively distributed in body tissues and fluids, including the liver, kidneys, and lungs. The drug undergoes hepatic metabolism, primarily through the cytochrome P450 system, and is excreted mainly through urine. The half-life ranges from 5 to 24 hours, depending on the dosage and individual patient factors.

Pregnancy

Consult healthcare provider before use, as safety in pregnancy is not established.

Breast-feeding

Consult healthcare provider before use, as safety during breastfeeding is not established.

Storage

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

Indications

• Constipation
• Dietary fiber supplementation
• Irritable bowel syndrome
• Diverticular disease
• Weight management

Dosage

Children: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Adults: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Mechanism of action

Cellulose acts primarily as a bulk-forming laxative. It absorbs water in the intestines, which increases stool bulk and stimulates peristalsis, thus facilitating bowel movements. Additionally, cellulose is not digestible by human enzymes, leading to fermentation by gut bacteria, which may enhance gut health and alter gut microbiota composition.

Pharmacodynamics

Cellulose increases stool weight and frequency of bowel movements. It works by retaining water in the intestines, leading to softer stools and improved passage through the gastrointestinal tract. The bulking effect of cellulose can help alleviate constipation and promote overall digestive health. It may also play a role in cholesterol reduction and glycemic control through its effects on digestion and absorption of nutrients.

Pharmacokinetics

Cellulose is not absorbed into the bloodstream due to its indigestible nature. Instead, it passes through the gastrointestinal tract, where it adds bulk to the stool. Its fermentation by colonic bacteria produces short-chain fatty acids, which may have beneficial effects on colon health. The onset of action for cellulose as a laxative can vary but is generally within 24 to 72 hours after ingestion.

Adverse effects

• Bloating
• Flatulence
• Diarrhea
• Abdominal discomfort

Precautions

• Use with caution in patients with a history of gastrointestinal disorders.
• Monitor for potential allergic reactions in sensitive individuals.

Pregnancy

Cellulose is generally considered safe during pregnancy as it is a non-toxic, indigestible fiber.

Breast-feeding

Cellulose is also considered safe during breastfeeding; it is excreted in breast milk in negligible amounts.

Storage

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

Formulations

• Powder
• Capsules
• Tablets
• Granules

Indications

• Tablet formulation
• Capsule formulation
• Rapid release of active pharmaceutical ingredients

Dosage

Children: Refer to specific product guidelines for exact formulations. Typically used in concentrations of 1-5% in solid dosage forms.

Adults: Refer to specific product guidelines for exact formulations. Typically used in concentrations of 1-5% in solid dosage forms.

Mechanism of action

Crosscarmellose sodium works by swelling upon contact with water, leading to the rapid disintegration of the dosage form. This process increases the surface area of the active ingredient, promoting faster dissolution and absorption in the gastrointestinal tract. It does not possess any pharmacological activity of its own but acts as a functional excipient.

Pharmacodynamics

As a disintegrant, crosscarmellose sodium aids in the breakdown of solid dosage forms, allowing for quicker release and absorption of active ingredients. Its effectiveness is influenced by factors such as the formulation's composition, the presence of other excipients, and the conditions within the gastrointestinal environment.

Pharmacokinetics

Crosscarmellose sodium is not absorbed in the gastrointestinal tract and does not undergo metabolism. It functions primarily as a physical agent that enhances the disintegration of the dosage form. Its safety profile is well-established, and it is considered non-toxic and non-irritating.

Pregnancy

Crosscarmellose is considered safe for use during pregnancy as it is not systemically absorbed, but consult a healthcare provider for specific cases.

Breast-feeding

Crosscarmellose is not absorbed systemically and is generally considered safe during breastfeeding, but consult a healthcare provider for specific cases.

Storage

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

Formulations

• Tablets
• Capsules
• Powders

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.

Indications

• Monitoring respiratory function
• Assessment of metabolic status
• Management of respiratory acidosis
• Management of respiratory alkalosis

Dosage

Children: Dosing for interventions related to carbon dioxide levels in pediatric patients should be guided by clinical protocols and the BNF for Children.

Adults: Dosing for interventions related to carbon dioxide levels is typically based on clinical assessment and individual patient needs. Refer to clinical guidelines for specific scenarios.

Mechanism of action

Carbon dioxide acts primarily as a signaling molecule in the body, influencing respiratory drive and blood pH. It is produced during cellular respiration and is a critical component of the bicarbonate buffering system, which helps maintain acid-base homeostasis. Elevated levels of CO2 in the blood stimulate ventilation in the lungs, increasing the rate of gas exchange and facilitating the removal of excess CO2.

Pharmacodynamics

The pharmacodynamic effects of dioxides, particularly carbon dioxide, are closely related to its concentration in the blood. As CO2 levels increase, it leads to respiratory acidosis, which can stimulate the respiratory centers in the brain to increase ventilation. Conversely, low levels of CO2 can cause respiratory alkalosis, potentially leading to decreased respiratory drive. CO2 also plays a role in vasodilation and can affect blood flow and pressure through its influence on smooth muscle tone.

Pharmacokinetics

Carbon dioxide is produced endogenously during metabolic processes and is transported in the bloodstream primarily in three forms: dissolved in plasma, as bicarbonate ions (HCO3-), and bound to hemoglobin. The half-life of CO2 in the bloodstream is very short due to its rapid exchange with alveolar gas in the lungs. The elimination of CO2 occurs through exhalation, making it a dynamic component of respiratory physiology.

Pregnancy

Data on the effects of dioxide during pregnancy are limited. Caution is advised due to potential risks associated with exposure.

Breast-feeding

Limited data are available regarding the excretion of dioxide in human milk. Caution is recommended.

Storage

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

Indications

• Lactose intolerance
• As a filler or excipient in pharmaceutical formulations

Dosage

Children: Refer to the BNF for Children for specific dosing information based on age and clinical context.

Adults: Refer to the BNF for specific dosing information based on clinical context.

Mechanism of action

Lactose is metabolized in the intestine by the enzyme lactase into its constituent monosaccharides, glucose and galactose. In individuals with lactase deficiency, unabsorbed lactose passes into the colon, where it is fermented by bacteria, leading to gas production and osmotic effects that contribute to diarrhea.

Pharmacodynamics

The pharmacodynamics of lactose are primarily related to its effects on gastrointestinal function. In healthy individuals, lactose is effectively broken down into glucose and galactose, which are absorbed and utilized for energy. In individuals with lactose intolerance, the unabsorbed lactose can cause osmotic diarrhea and colonic fermentation, leading to discomfort and symptoms associated with lactose intolerance.

Pharmacokinetics

Lactose is not absorbed in the gastrointestinal tract until it is hydrolyzed into glucose and galactose by lactase. The absorption of glucose and galactose occurs in the small intestine. The half-life is not applicable as lactose is not typically administered as a medication but is rather ingested as a natural component of food. Its metabolism primarily occurs in the intestine.

Adverse effects

• Bloating
• Diarrhea
• Abdominal pain
• Flatulence

Precautions

• Use with caution in patients with lactose intolerance.
• Consider potential for gastrointestinal upset in sensitive individuals.

Pregnancy

Lactose is generally considered safe for use during pregnancy. However, consult a healthcare professional for individual advice.

Breast-feeding

Lactose is safe to use while breastfeeding, as it is a natural sugar present in breast milk.

Storage

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

Formulations

• Powder
• Granules
• Tablets
• Syrup

Indications

• Used as an excipient in tablet formulations
• Used as a bulking agent in capsule formulations
• Used in food products as a thickener or stabilizer

Dosage

Children: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Adults: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Mechanism of action

Microcrystalline cellulose acts as a non-digestible filler that enhances the flow properties of powders during the manufacturing of tablets and capsules. It does not have a direct pharmacological action on the body but ensures that the active ingredients are effectively delivered to the patient.

Pharmacodynamics

As a non-active ingredient, microcrystalline cellulose does not exert pharmacodynamic effects typical of active pharmaceutical ingredients. Its primary role is to provide a stable and consistent matrix for the drug, facilitating the release of the active compound once ingested.

Pharmacokinetics

Microcrystalline cellulose is not absorbed in the gastrointestinal tract; it passes through the digestive system largely unchanged. It adds bulk to the stool, which may aid in promoting regular bowel movements. The substance is excreted in feces, where it contributes to dietary fiber intake.

Pregnancy

Data regarding the use of microcrystalline cellulose during pregnancy is limited. It is advisable to consult with healthcare professionals before use.

Breast-feeding

Microcrystalline cellulose is considered safe during breastfeeding, as it is not absorbed systemically.

Storage

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

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Dosage

Children: Refer to specific product formulations for guidelines, as dosing can vary based on the formulation and therapeutic context.

Adults: Refer to specific product formulations for guidelines, as dosing can vary based on the formulation and therapeutic context.

Mechanism of action

Stearates, such as magnesium stearate, function primarily by reducing friction during tablet manufacturing and enhancing the flow properties of powders. They do not exert a therapeutic pharmacological action in the body but facilitate the delivery of other active substances.

Pharmacodynamics

Given that stearates are primarily excipients, they do not exhibit traditional pharmacodynamic properties as active drugs do. Their role is to optimize the formulation of drugs, enhancing physical characteristics such as texture and consistency, which indirectly affect the performance of the active ingredients.

Pharmacokinetics

Stearates are poorly absorbed in the gastrointestinal tract due to their lipid nature. When ingested, they may pass through the digestive system with minimal systemic absorption. Their primary action occurs at the site of formulation, where they assist in the dispersion and release of active ingredients rather than being metabolized or exerting effects in the body.

Pregnancy

The safety of sterate during pregnancy has not been established. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether sterate 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.

Indications

• Used as an excipient in drug formulations
• Pleurodesis for the management of recurrent pleural effusions

Dosage

Children: Refer to specific guidelines for paediatric use, as dosing may differ based on age and clinical condition.

Adults: Refer to specific guidelines for the appropriate dosage in pleurodesis and other applications, as it may vary based on clinical context.

Mechanism of action

Talc exhibits very good absorptive properties, allowing it to absorb moisture and other substances effectively. This characteristic is particularly useful in pharmaceutical formulations, where it may enhance the stability and texture of the drug product.

Pharmacodynamics

Talc's primary pharmacodynamic effect is its ability to act as an inert filler and bulking agent in pharmaceutical preparations. It does not have any intrinsic pharmacological activity but serves to improve the physical properties of formulations, such as flowability and compressibility.

Pharmacokinetics

Talc is not absorbed systemically when used as an excipient or in medical procedures. Its effects are local, and it remains in the site of application, where it functions primarily as a mechanical agent. The pharmacokinetics of talc in the context of its use in pleurodesis involves its ability to promote adhesion of the pleural surfaces, thereby preventing fluid accumulation.

Pregnancy

Talc is classified as a substance with minimal systemic absorption, but safety during pregnancy has not been well established. Consult relevant guidelines.

Breast-feeding

Talc is not expected to be absorbed in significant amounts; however, caution is advised and consult guidelines.

Storage

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

Indications

• Orthopedic implants
• Dental implants
• Prosthetic devices
• Surgical instruments

Mechanism of action

Titanium does not have a specific mechanism of action as it is not a drug in the traditional sense. Instead, its biocompatibility allows it to integrate with biological tissues without eliciting significant immune responses, making it suitable for use in implants and prosthetic devices. The presence of titanium ions can influence biological processes, including cell proliferation and differentiation.

Pharmacodynamics

Titanium itself does not exhibit pharmacodynamics as it is not administered as a drug. Its interactions within biological systems are primarily mechanical and structural, providing support and stability in orthopedic and dental applications. The biocompatibility of titanium allows for favorable tissue integration and reduced rejection rates compared to other materials.

Pharmacokinetics

As titanium is not a pharmacological agent, traditional pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion do not apply. Titanium is typically utilized in solid forms, such as implants, where it remains localized and does not undergo metabolism or systemic circulation.

Pregnancy

There is limited data on the use of titanium during pregnancy. Consult a healthcare professional before use.

Breast-feeding

There is limited data on the excretion of titanium in breast milk. Consult a healthcare professional before use.

Storage

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

Mechanism of action

Triacetin functions primarily as a plasticizer, improving the flexibility and workability of polymers. In pharmaceutical formulations, it may enhance the solubility and stability of active ingredients, allowing for better drug delivery.

Pharmacodynamics

The pharmacodynamic properties of triacetin are associated with its role as a plasticizer, impacting the physical characteristics of polymeric materials. In a pharmaceutical context, it can improve the release profile of drugs from solid dosage forms, potentially enhancing bioavailability.

Pharmacokinetics

Triacetin is absorbed through the gastrointestinal tract and metabolized into glycerol and acetic acid. The elimination half-life and specific metabolic pathways in humans are not extensively characterized. It is known to undergo hydrolysis, resulting in the formation of glycerol and acetic acid, which are further utilized in metabolic processes.

Pregnancy

There is no specific information available regarding the use of triacetin during pregnancy. Caution is advised.

Breast-feeding

There is no specific information available regarding the use of triacetin during breastfeeding. Caution is advised.

Storage

Store in a well-closed container, at room temperature, away from direct sunlight and moisture.

Formulations

• {'formulation': 'Liquid', 'strength': 'Not specified'}

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. By diminishing the effect of PDE5, sildenafil facilitates the effect of nitric oxide during sexual stimulation; cGMP levels increase, smooth muscle relaxes, and blood flows into the corpus cavernosum, producing an erection. Without sexual stimulation, sildenafil has no effect on erections. It has been extensively demonstrated that hydrogen sulfide (H2S) is implicated is several physiological and pathological conditions. In particular, it has been shown that H2S causes relaxation in human penile tissues and inhibits phosphodiesterase (PDE) activity in vessels. Beside sildenafil increases H2S generation in human bladder and tadalafil in myocardial tissues. Therefore, /the/ aim /of the study/ was to demonstrate the link between H2S and PDE-5 in mice corpus cavernosum tissues. ... The effects of sildenafil (10 uM, 0.5 hr); PDE-5 inhibitor, on H2S production as well as the H2S -induced relaxations in mice penile tissues /was investigated/. Penile tissues from CD1 mouse corpus cavernosum (MCC) were used. Functional studies were performed by myograph in Krebs solution. Western blot analysis was performed in order to evaluate CBS and CSE expression and methylene blue assay for measurement of H2S levels. In order to investigate functional significance of H2S on sildenafil-induced augmentation of endothelial relaxation in MCC the sildenafil effect was evaluated on acetylcholine (ACh), L-cysteine and NaHS-induced relaxations in presence or not of CSE enzyme inhibitor PPG (10 uM, 0.5 hr). In order to achieve this issue the H2S production in MCC tissues was also evaluated by incubating the penile tissue with sildenafil in presence or absence of the CSE inhibitor PPG (10 uM, 0.5 hr) Both CBS and CSE were expressed in MCC and the enzymes efficiently converted L-cysteine into H2S. Further /it was shown/ that sildenafil caused a significant increase in H2S production and this augmentation was reversed by CSE inhibition. /It was/ found that sildenafil induced an increase in both ACh and L-cysteine-induced relaxations and these augmentations reversed by CSE inhibitor PPG in MCC pre-contracted with phenylephrine (3.10-5M). Beside sildenafil did not sign

Pharmacodynamics

In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg) . At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test).

Mechanism of action

It has very good absorptive properties.