GLOACE-TZ

Indications

• Pain and inflammation in rheumatoid arthritis
• Pain and inflammation in osteoarthritis
• Pain and inflammation in ankylosing spondylitis

Dosage

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

Adults: The recommended dose for adults is 100 mg twice daily.

Mechanism of action

Aceclofenac acts by inhibiting the cyclooxygenase (COX) enzymes, specifically COX-2, leading to a decrease in the synthesis of prostaglandins. This results in an anti-inflammatory effect, pain relief, and reduction in swelling. The pathway involves the blockade of the arachidonic acid pathway, which is vital for the production of pro-inflammatory mediators.

Pharmacodynamics

Aceclofenac exhibits anti-inflammatory, analgesic, and antipyretic properties. By inhibiting COX-2, it reduces inflammation and pain while sparing COX-1, which helps maintain gastric mucosal integrity, thereby potentially lowering the risk of gastrointestinal side effects compared to other NSAIDs. However, it still poses risks such as gastrointestinal bleeding, renal impairment, and cardiovascular events.

Pharmacokinetics

Aceclofenac is well-absorbed after oral administration, with peak plasma concentrations occurring approximately 1-2 hours post-dose. It is extensively metabolized in the liver, primarily via glucuronidation, with its metabolites being excreted through urine. The half-life of aceclofenac is about 4 hours, necessitating twice-daily dosing for effective pain management. The drug's clearance may be reduced in patients with hepatic impairment.

Contra-indications

• Active bleeding
• Active gastrointestinal bleeding
• History of hypersensitivity to aspirin or any other NSAID
• Severe renal impairment
• Severe hepatic impairment

Adverse effects

• Constipation
• Vomiting
• Anaemia
• Angioedema
• Depression
• Drowsiness
• Dyspnoea
• Fatigue
• Haemolytic anaemia
• Headache
• Heart failure
• Hepatic disorders
• Hyperkalaemia
• Hypertension
• Inflammatory bowel disease
• Leg cramps
• Nephrotic syndrome
• Neutropenia
• Oedema
• Palpitations
• Pancreatitis
• Paraesthesia
• Respiratory disorders
• Severe cutaneous adverse reactions (SCARs)
• Sleep disorders
• Taste altered
• Thrombocytopenia
• Tinnitus
• Tremor
• Vasculitis
• Vertigo
• Visual impairment
• Weight increased

Interactions

• Increased risk of gastrointestinal side effects when combined with low-dose aspirin
• Alcohol increases risk of gastrointestinal hemorrhage
• NSAIDs may exacerbate symptoms in asthma patients

Precautions

• Use with caution in elderly patients and those at risk of gastrointestinal ulceration
• Patients with serious rheumatic diseases may become dependent on NSAIDs
• Consider gastroprotective treatment for at-risk patients

Pregnancy

Most manufacturers advise avoiding the use of NSAIDs during pregnancy unless the potential benefit outweighs the risk, particularly during the third trimester due to risks associated with fetal ductus arteriosus closure.

Breast-feeding

Use with caution during breastfeeding.

Storage

Store in a cool, dry place away from light.

Formulations

• Oral tablets

Indications

• Spasticity associated with multiple sclerosis
• Spasticity due to spinal cord injury or disease

Dosage

Children: Refer to the BNF for Children for specific dosing guidance.

Adults: Initially 2 mg daily, increased in steps of 2 mg at intervals of 1 to 4 days, with a maximum of 36 mg per day in divided doses.

Mechanism of action

Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons through agonist actions at Alpha-2 adrenergic receptor sites. This central action decreases the release of excitatory amino acids like glutamate and aspartate, which are involved in muscle spasm. The primary effect occurs on spinal polysynaptic pathways, and it may also exhibit anti-nociceptive and anticonvulsant effects through its action on Alpha-2 receptors.

Pharmacodynamics

Tizanidine is effective in reducing muscle spasticity, characterized by increased muscle tone and involuntary contractions, which can significantly impair mobility and quality of life. By acting as an agonist at Alpha-2 adrenergic receptors, Tizanidine allows for the relief of muscle tightness and spasms, enabling individuals to engage more comfortably in daily activities. It does not exert direct effects on skeletal muscle fibers or the neuromuscular junction and shows minimal impact on monosynaptic spinal reflexes.

Pharmacokinetics

Tizanidine is rapidly absorbed after oral administration, with peak plasma concentrations typically occurring within 1 to 2 hours. It has a relatively short half-life, necessitating multiple daily doses for effective management of spasticity. The drug is extensively metabolized in the liver, primarily by the cytochrome P450 system, and caution is advised in patients with hepatic impairment due to the potential for altered drug levels. Renal impairment may also influence its pharmacokinetics.

Contra-indications

• Brain damage
• Coma
• Epilepsy
• Myasthenia gravis
• Pre-coma

Adverse effects

• Angioedema
• Anxiety
• Bradycardia
• Confusion
• Conjunctivitis
• Dizziness
• Drowsiness
• Dyspepsia
• Fever
• Flushing
• Headache
• Hepatic disorders
• Hypotension
• Insomnia
• Leukopenia
• Memory loss
• Nasal congestion
• Nausea
• Seizures
• Skin reactions
• Syncope
• Taste disturbance
• Metallic taste
• Vertigo
• Vision disorders
• Vomiting

Interactions

• Combined hormonal contraceptives: Severe (increases exposure)
• Mexiletine: Severe (increases exposure)
• Osilodrostat: Severe (increases exposure)
• Ciprofloxacin: Severe (increases exposure)
• Rucaparib: Severe (increases exposure)
• Fluvoxamine: Severe (increases exposure)
• Vemurafenib: Severe (increases exposure)
• Givosiran: Moderate (increases exposure)
• Axitinib: Unknown (increases exposure)
• Ritonavir: Unknown (decreases exposure)

Precautions

• Caution in hepatic impairment (risk of increased half-life)
• Caution in renal impairment
• Drowsiness may affect performance of skilled tasks (e.g., driving); effects may be enhanced by alcohol

Pregnancy

Avoid in the first trimester; thereafter, sufficient use only if potential benefit outweighs risk (no information available).

Breast-feeding

Avoid-no information available.

Storage

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

Formulations

• Tablets: 2 mg, 3 mg, 4 mg
• Oral suspension: 36 mg per day

Mechanism of action

Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes.

Pharmacodynamics

Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF). It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects.

Mechanism of action

Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system.

Pharmacodynamics

**A note on spasticity** Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. **General effects** Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. **Effects on blood pressure and heart rate** This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued.