ZULU SPAS TABLETS (Each tablet contains Aceclofenac 100mg/ Drotaverine HCL 80mg)

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

• Abdominal pain
• Dysmenorrhea
• Visceral spasms
• Cervical dilation during labor

Dosage

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

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Drotaverine is an inhibitor of phosphodiesterase 4 (PDE4), an enzyme that degrades cyclic adenosine monophosphate (cAMP). By inhibiting PDE4, drotaverine increases cAMP levels, leading to relaxation of smooth muscles. Additionally, it may exhibit minor allosteric calcium channel blocking effects, acting similarly to voltage-dependent L-type calcium channel blockers.

Pharmacodynamics

Drotaverine is classified as a spasmolytic agent, exerting a relaxing effect on smooth muscles. It effectively relieves visceral spasms and enhances cervical dilation. In vitro studies have shown that drotaverine can induce cytostatic effects on various human tumor cell lines, indicating potential anticancer properties. However, its primary clinical use remains in the management of smooth muscle spasms.

Pharmacokinetics

The pharmacokinetics of drotaverine, including absorption, distribution, metabolism, and excretion, are not detailed in the provided information. General pharmacological knowledge suggests that spasmolytics are typically well-absorbed and distributed widely throughout body tissues, with metabolism primarily occurring in the liver and excretion through urine. For specific pharmacokinetic parameters, further studies or data would be required.

Contra-indications

• Hypersensitivity to drotaverine or any of its excipients
• Severe liver or kidney impairment

Adverse effects

• Nausea
• Vomiting
• Constipation
• Dizziness
• Headache
• Dry mouth
• Allergic reactions

Interactions

• May enhance the effects of other antispasmodics
• Caution when used with other medications that affect smooth muscle tone

Precautions

• Use with caution in patients with hypotension
• Monitor for signs of allergic reactions

Pregnancy

Drotaverine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult with a healthcare professional before use.

Breast-feeding

It is not known whether drotaverine is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

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

Formulations

• Tablets
• Injectable solution

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

Drotaverine is an inhibitor of phosphodiesterase 4 (PDE4), which is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to elevated levels of cAMP, leading to smooth muscle relaxation. Recent research showed that low levels of cAMP have been associated with brain tumorigenesis, leading to the investigation of PDE4 inhibitors as potential anticancer agents.

Pharmacodynamics

Drotaverine is an e spasmolytic agent with a relaxing effect on smooth muscles. It works to relieve visceral spasms and improve cervical dilation. _In vitro_, drotaverine mediated cytostatic effects on several human tumor cell lines and nonmalignant mouse fibroblasts. Drotaverine may have minor allosteric calcium channel blocking properties: _in vitro_, drotaverine behaves like voltage-dependent L-type calcium channel blockers.