OLFEN 75MG INJECTION

Indications

• Pain and inflammation in musculoskeletal disorders
• Rheumatic disease
• Osteoarthritis of the knee
• Postoperative pain
• Control of anterior segment inflammation following ophthalmic surgery

Dosage

Children: For paediatric dosing, please refer to the BNF for Children as specific dosages are not provided in this text.

Adults: For topical application, apply 3–4 times a day to the affected area. For injection, 75 mg may be administered intravenously, then 75 mg after 4–6 hours if required, up to a maximum of 150 mg per day for no more than 2 days.

Mechanism of action

Diclofenac sodium primarily acts as a selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). By blocking these enzymes, diclofenac decreases the production of prostaglandins, which are mediators of inflammation and pain. This mechanism leads to reduced inflammatory responses and alleviation of pain.

Pharmacodynamics

The pharmacological effects of diclofenac include anti-inflammatory, analgesic, and antipyretic properties. The onset of action is typically within a few hours following administration, with peak effects seen within 1 to 2 hours. The duration of analgesia can vary depending on the formulation and dosage used.

Pharmacokinetics

Diclofenac is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is extensively metabolized in the liver to active metabolites and has a half-life of approximately 1 to 2 hours. The drug is primarily excreted in the urine, with both unchanged drug and metabolites being eliminated. Food can affect the absorption, so it is often recommended to take it on an empty stomach.

Contra-indications

• History of hypersensitivity to diclofenac or other NSAIDs
• Active gastrointestinal ulceration
• History of recurrent gastrointestinal bleeding
• History of cerebrovascular bleeding
• Severe renal impairment
• Severe hepatic impairment
• Dehydration
• Hypovolaemia
• History of asthma precipitated by NSAIDs
• History of gastro-intestinal perforation related to previous NSAID therapy
• History of confirmed or suspected hemorrhagic diathesis

Adverse effects

• Gastrointestinal discomfort
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Headache
• Dizziness
• Rash
• Tinnitus
• Elevated liver enzymes
• Renal impairment
• Fluid retention
• Increased blood pressure

Interactions

• Increased risk of gastrointestinal bleeding when used with other NSAIDs or anticoagulants
• Caution with diuretics due to potential for renal impairment
• May enhance the effects of anticoagulants like warfarin
• Caution with antihypertensive medications due to potential for reduced efficacy

Precautions

• Use with caution in patients with a history of cardiovascular disease
• Monitor renal function in patients with pre-existing renal impairment
• Long-term use may affect female fertility, reversible upon discontinuation
• Use with caution during pregnancy, especially in the third trimester

Pregnancy

Avoid unless the potential benefit outweighs the risk. Avoid during the third trimester due to risks of fetal ductus arteriosus closure and pulmonary hypertension of the newborn.

Breast-feeding

Use with caution; amount in milk is generally too small to be harmful.

Storage

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

Formulations

• Diclofenac sodium 1% gel
• Diclofenac sodium 75 mg injection
• Diclofenac sodium eye drops 0.1% (Voltarol Ophtha)

Indications

• Ventricular arrhythmias, especially after myocardial infarction
• Local anesthesia for minor surgical procedures
• Pain relief in conditions such as oral ulceration and inflammation

Dosage

Children: Refer to the BNF for Children

Adults: For ventricular arrhythmias, an initial intravenous bolus of 100 mg is given over a few minutes, followed by a continuous infusion of 4 mg/minute for 30 minutes, then reduced to 2 mg/minute for 2 hours, and finally to 1 mg/minute. The total dose should not exceed 3 mg/kg.

Mechanism of action

Lidocaine hydrochloride exerts its effects by blocking voltage-gated sodium channels in neurons, which inhibits the influx of sodium ions during depolarization. This action prevents the generation and conduction of nerve impulses, resulting in local anesthesia. The drug also stabilizes neuronal membranes and decreases the excitability of both peripheral and central nerves.

Pharmacodynamics

The onset of action for lidocaine is rapid, typically occurring within minutes of administration, with a duration of action that can vary based on the route of administration and the presence of additives such as epinephrine. Lidocaine can be used to manage ventricular arrhythmias by decreasing myocardial excitability and conduction velocity, thus stabilizing the cardiac rhythm.

Pharmacokinetics

Lidocaine is well-absorbed when administered intravenously, with peak plasma concentrations occurring shortly after infusion. It is extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP1A2 and CYP3A4, producing active metabolites. The elimination half-life of lidocaine ranges from 1.5 to 2 hours, and it is excreted mainly in urine. Caution is advised in cases of hepatic impairment, as the metabolism of lidocaine may be significantly reduced, leading to increased plasma levels.

Contra-indications

• All grades of atrioventricular block
• Severe myocardial depression
• Sino-atrial disorders

Adverse effects

• Anxiety
• Arrhythmias
• Cardiac arrest
• Circulatory collapse
• Confusion
• Dizziness
• Drowsiness
• Euphoric mood
• Headache
• Hypotension (may lead to cardiac arrest)
• Loss of consciousness
• Methaemoglobinaemia
• Muscle twitching
• Nausea
• Neurological disorders
• Tinnitus
• Tremor
• Blurred vision
• Vomiting

Interactions

• Antiarrhythmics

Precautions

• Acute porphyrias (consider infusion of glucose for its anti-porphyrinogenic effects)
• Congestive cardiac failure (consider lower dose)
• Post cardiac surgery (consider lower dose)
• Monitor serum potassium
• Caution in hepatic impairment (risk of increased exposure)
• Caution in renal impairment (possible accumulation of lidocaine and active metabolites)

Pregnancy

Crosses the placenta but not known to be harmful in animal studies-use if benefit outweighs risk.

Breast-feeding

Present in milk but amount too small to be harmful.

Storage

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

Formulations

• Lidocaine hydrochloride 5 mg per 1 ml solution for injection
• Lidocaine hydrochloride 10 mg per 1 ml solution for injection
• Lidocaine hydrochloride 10% solution for oral use

Indications

• Pain and inflammation in musculoskeletal disorders
• Rheumatic diseases
• Acute gout
• Postoperative pain

Dosage

Children: For children aged 9–13 years (body weight 35 kg and above), up to 2 mg/kg daily in 3 divided doses; maximum 100 mg per day. For children aged 14–17 years, 75–100 mg daily in 2–3 divided doses.

Adults: 75–150 mg daily in 2–3 divided doses.

Mechanism of action

Diclofenac potassium works primarily by inhibiting the cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2. This inhibition decreases the synthesis of prostaglandins, which are mediators involved in inflammation, pain, and fever. This action results in reduced inflammation and pain sensation in affected tissues.

Pharmacodynamics

The analgesic effects of diclofenac potassium are evident within a few hours after administration. It shows a dose-dependent response in reducing pain and inflammation, making it effective for managing acute pain and inflammatory conditions. The drug can also have a beneficial effect on reducing fever.

Pharmacokinetics

Diclofenac potassium is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1-2 hours after oral administration. It has a half-life of approximately 1-2 hours, but its anti-inflammatory effects can last longer due to its active metabolites. The drug is extensively metabolized in the liver, and its metabolites are excreted primarily in the urine.

Contra-indications

• Active gastrointestinal bleeding
• Active gastrointestinal ulceration
• History of recurrent gastrointestinal haemorrhage
• Cerebrovascular disorders
• History of hypersensitivity to aspirin or any other NSAID
• Severe cardiac impairment
• Severe hepatic impairment
• Severe renal impairment
• History of allergic disorders

Adverse effects

• Diarrhoea
• Gastrointestinal disturbances
• Headache
• Insomnia
• Malaise
• Acute gout pain
• Palpitations
• Skin reactions
• Vertigo
• Angioedema
• Decreased appetite
• Dyspepsia
• Hypertension
• Nephritis
• Neutropenia
• Photosensitivity
• Severe cutaneous adverse reactions
• Syncope
• Tachycardia
• Thrombocytopenia
• Tinnitus
• Blurred vision

Interactions

• Increased risk of gastrointestinal bleeding with other NSAIDs
• Caution with anticoagulants due to potential increased bleeding risk
• Caution with antihypertensives as NSAIDs may reduce their efficacy
• Caution with diuretics due to potential renal impairment

Precautions

• Caution in patients with dehydration
• Caution in elderly patients due to increased risk of serious side effects
• Caution in patients with a history of cardiovascular disease
• Use with caution in patients with renal impairment
• Monitor for signs of gastrointestinal bleeding

Pregnancy

Avoid unless the potential benefit outweighs the risk. Avoid during the third trimester due to risk of fetal ductus arteriosus closure and possible persistent pulmonary hypertension in the newborn.

Breast-feeding

Use with caution during breastfeeding; no specific information available.

Storage

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

Formulations

• Oral tablets
• Oral suspension

Indications

• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Acute pain
• Dysmenorrhea
• Postoperative pain
• Inflammatory conditions

Dosage

Children: For children, the dosage must be determined based on weight and the specific indication. It is essential to refer

Adults: The usual oral dose for adults is 50 mg taken two to three times daily, with a maximum daily dose of 150 mg. In specific cases, doses may vary based on the condition being treated and the patient's response.

Mechanism of action

Diclofenac inhibits cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes responsible for the conversion of arachidonic acid to prostaglandins. This inhibition reduces the levels of prostaglandins G2, leading to decreased inflammation, pain, and fever. Prostaglandin E2 (PGE2), a primary mediator of nociception, is suppressed, which lowers pain sensitivity and peripheral sensitization via G-protein coupled receptors.

Pharmacodynamics

Diclofenac reduces inflammation and nociceptive pain while also exhibiting antipyretic effects. Its action can increase the risk of gastrointestinal ulceration due to the inhibition of protective mucus secretion in the stomach, which is a common side effect of NSAIDs.

Pharmacokinetics

Diclofenac is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a high volume of distribution and is extensively metabolized in the liver, primarily by cytochrome P450 enzymes. The elimination half-life is approximately 1 to 2 hours, with metabolites excreted in urine. Its pharmacokinetics can be influenced by factors such as age, liver function, and concurrent medications.

Contra-indications

• Untreated local infection

Adverse effects

• Gastrointestinal ulceration
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Rash

Interactions

• Ciclosporin: Unknown (increases concentration)
• Iron chelators: Unknown (increases exposure)
• Deferiprone: Unknown (increases exposure)

Precautions

• Use with caution in patients with a history of gastrointestinal disease
• Monitor renal function in long-term use
• Consider cardiovascular risks in patients with pre-existing conditions

Pregnancy

Manufacturer advises to avoid unless essential.

Breast-feeding

Manufacturer advises to avoid unless essential.

Storage

Store below 25°C. Protect from light and moisture.

Formulations

• Diclofenac 50 mg oral tablet
• Diclofenac 100 mg extended-release oral tablet
• Diclofenac 75 mg injection
• Diclofenac 1% gel

Indications

• Local anesthesia for surgical and diagnostic procedures
• Management of certain types of arrhythmias
• Topical anesthesia for mucosal surfaces

Dosage

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

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Lidocaine acts by diffusing through neural sheaths into the axoplasm, where it is ionized and binds reversibly to sodium ion channels on nerve cell membranes. This binding keeps the channels in an open state, preventing nerve depolarization and thus blocking action potential transmission. This mechanism facilitates its anesthetic effects by aborting pain signal generation and preventing their transmission to the brain.

Pharmacodynamics

Excessive blood levels of lidocaine may lead to changes in cardiac output, total peripheral resistance, and mean arterial pressure. The block of autonomic fibers and the direct depressant effect on the cardiovascular system can cause hypotension when recommended dosages are exceeded. Lidocaine's action on sodium channels affects cardiac myocytes, potentially leading to hypotension, bradycardia, myocardial depression, arrhythmias, or even cardiac arrest.

Pharmacokinetics

Lidocaine is absorbed rapidly and widely distributed throughout the body. It undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, leading to various metabolites. Its elimination half-life is approximately 1.5 to 2 hours, but this can vary based on factors such as hepatic blood flow and enzyme activity.

Contra-indications

• Hypersensitivity to lidocaine or any amide local anesthetics
• Severe degree of heart block
• A history of malignant hyperthermia

Adverse effects

• Hypotension
• Bradycardia
• Myocardial depression
• Cardiac arrhythmias
• CNS stimulation followed by depression
• Dizziness
• Nausea
• Vomiting
• Tinnitus

Interactions

• cimetidine+lidocaine: Moderate (increases exposure)
• cobicistat+lidocaine: Unknown (increases concentration)
• lidocaine+suxamethonium: Unknown (increases effects)
• ciprofloxacin+lidocaine: Unknown (increases exposure)

Precautions

• Use with caution in patients with hepatic impairment
• Use with caution in patients with cardiac conditions
• Monitor for signs of systemic toxicity, especially after high doses or rapid administration

Pregnancy

Lidocaine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is categorized as FDA pregnancy category B.

Breast-feeding

Lidocaine is excreted in breast milk, but at therapeutic doses, it is not expected to cause adverse effects in nursing infants. Monitor infants for any signs of sedation.

Storage

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

Formulations

• Lidocaine injection solution
• Lidocaine cream
• Lidocaine gel
• Lidocaine patch

Mechanism of action

Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G₂ which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac. PGE₂ is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE₂ activates the G_q-coupled EP₁ receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE₂ also activates the EP₄ receptor, coupled to G_s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE₂ act via EP₃ to increase sensitivity to bradykinin and via EP₂ to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP₂ receptor which couples to G_s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI₂ is known to play a role via its G_s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain. PGI₂ and PGE₂ contribute to acute inflammation via their IP and EP₂ receptors. Similarly to β adrenergic receptors these are G_s-coupled and mediate vasodilation through the AC/PKA pathway. PGE₂ also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD₂ plays a role in the activation of endothelial cell release of cytokines through its DP₁ receptor. PGI₂ and PGE₂ modulate T-helper cell activation and differentiation through IP, EP₂, and EP₄ receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation. PGE₂ can cross the blood-brain barrier and act on excitatory G_q EP₃ receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE₂ thereby reducing the activity of these neurons. Diclofenac has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been c

Pharmacodynamics

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever. It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.

Mechanism of action

Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction. Abnormal, repetitive impulse firing arising from incomplete inactivation of Na+ channels may be involved in several diseases of muscle and nerve, including familial myotonias and neuropathic pain syndromes. Systemic local anesthetics have been shown to have clinical efficacy against myotonias and some forms of neuropathic pain, so we sought to develop an in vitro model to examine the cellular basis for these drugs' effects. In frog sciatic nerves, studied in vitro by the sucrose-gap method, peptide alpha-toxins from sea anemone (ATXII) or scorpion (LQIIa) venom, which inhibit Na+ channel inactivation, induced repetitively firing compound action potentials (CAPs) superimposed on a plateau depolarization lasting several seconds. The initial spike of the CAP was unaffected, but the plateau and repetitive firing were strongly suppressed by 5-30 uM lidocaine. Lidocaine caused a rapid, concentration-dependent decay of the plateau, quantitatively consistent with blockade of open Na(+) channels. Early and late repetitive firing were equally suppressed by lidocaine with IC50 = 10 uM. After washout of lidocaine and LQIIa, the plateau and repetitive firing remained for > 1 hr, showing that lidocaine had not caused dissociation of channel-bound alpha-toxin. These findings indicate that therapeutic concentrations of lidocaine can reverse the "abnormal" features of action potentials caused by non-inactivating Na+ channels without affecting the normal spike component. Lidocaine controls ventricular arrhythmias by suppressing automaticity in the His-Purkinje system and by suppressing spontaneous depolarization of the ventricles during diastole. These effects occur at lidocaine concentrations that do not suppress automaticity of the sinoatrial (SA) node. At therapeutic plasma concentrations, lidocaine has little effect on atrioventricular (AV) node conduction and His-Purkinje conduction in the normal heart. Specialized conducting tissues of the atria are less sensitive to the effects of lidocaine than are those of ventricular tissues. Lidocaine has a variable effect on the effective refractory period (ERP) of the AV node; the drug shortens the ERP and the action potential duration of the His-Purkinje system. Lidocaine does not appear to affect excitability of normal cardiac tissue. Prilocaine and lidocaine are classified as amide-type local anesthetics for which serious adverse effects include methemoglobinemia. Although the hydroly

Pharmacodynamics

Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels.