Download to read offline
Paracetamol and buprenorphine transdermal patch
- 1. 1 /38 1 Paracetamol and Buprenorphine transdermalpatch Dr. Yakshetha Moderator: Dr. Balavenkat sir 09.05.2024
- 2. 2 /38 2 Synopsis • Physiochemicalproperties • Pharmacokinetics • Mechanism of action • Dosage • Uses (General and anaesthesia-related) • Drug interactions • Adverse effects • Paracetamol toxicity • Buprenorphine transdermal patch
- 3. 3 /38 3 Physiochemical properties Structure –Activity – Relationship: (a) Para-aminophenol moiety: •The intact para-aminophenol group (with an amine group attached to the benzene ring at the para position) is crucial for activity. •Modification or removal of the amine group significantly reduces analgesic and antipyretic effects.
- 4. 4 /38 4 Structure – Activity- Relationship (b) Acetamide functional group: •The acetamide group (acetyl group linked to the amine) contributes to the water solubility and improved bioavailability of paracetamol compared to phenacetin (a similar molecule lacking the acetamide group). •However, some studies suggest the acetamide group might play a role in paracetamol's MoA, potentially through N-acetylation processes.
- 5. 5 /38 5 Structure – Activity- Relationship (c) Hydroxyl Group: • The phenolic hydroxyl group (OH group on the benzene ring) is essential for activity. • It's believed to be involved in hydrogen bonding with essential biomolecules, potentially influencing paracetamol's interaction with its targets.
- 6. 6 /38 6 Other physiochemicalproperties • pH: approximately 6 • Storage: Store in a cool, dry place away from direct sunlight and heat. High temperatures can degrade the medication. • Stability: Dry, pure paracetamol exhibits good stability at temperatures up to 45°C. However, contamination with traces of para-aminophenol or exposure to humid conditions can lead to hydrolysis and degradation, resulting in discoloration. • Isomerism and its properties: 1. Para-aminophenol (amino group in 4th position) Paracetamol derived from this 2. Ortho-aminophenol no medical use
- 7. 7 /38 7 Pharmacokinetics Distribution: •Plasma halflife = 1.5-2.5 hours •Onset of action around 40 mins (oral), 8 mins (IV) •Protein binding – negligible (15- 20% in case of overdose) •Large volume of distribution (50 L) •Widely distributed throughout the body tissues, with high penetration into the central nervous system (CNS) •Log P (Octanol-Water Partition Coefficient): Around 0.5. This value suggests moderate lipophilicity, allowing for passive diffusion across cell membranes, Absorption: •Route: Oral or IV or IM or rectal •Rapid from small intestine, usually high (but variable) bioavailability •Dose-dependent Bioavailability 63% (500 mg) to 89% (1000 mg) •pKa: Approximately 9.4. This value indicates minimal pH- dependent solubility within the physiological range (pH 7.3-7.4).
- 8. 8 /38 8 Pharmacokinetics -Metabolism Metabolism: in liver; Excretion: of metabolized product (95%) or direct excretion (5%) renally
- 9. 9 /38 9 Pharmacokinetics -Metabolism
- 10. 10 /38 10 Mechanism ofaction - Endocannabinoid enhancement increasing cannabinoid receptor activation on the post-synaptic membrane Fatty acid amide hydrolase (found predominantly in CNS) N-arachidonoylphenolamine (AM404) in synaptic clefts activate transient receptor potential vanilloid type 1 (TRPV1) inhibition of prostaglandin production in the brain (apart from COX3) inhibit COX, NO and TNF-a ANALGESIC EFFECT ANTIPYRETIC EFFECT
- 11. 11 /38 11 Mechanism ofaction: POX and COX inhibition (This enzyme has two active sites (POX – Peroxidase, and COX) In brain, a splice variant of COX-1 (termed as COX-3) was present, which was inhibited by paracetamol Paracetamol acts as reducing substrate for POX (decreases its regeneration) (this is peroxide-level dependent reaction: In periphery due to inflammation peroxides are usually present; compared to periphery, peroxide levels are low in the brain since they cannot cross BBB)
- 12. 12 /38 12 Mechanism ofaction - Serotoninergic pathway activation PARACETAMOL activation of descending serotonergic pathways (originating in the brainstem nuclei, hypothalamus, and cortex, and interact with pain afferents in the dorsal horn) ANALGESIC EFFECT
- 13. 13 /38 13 Dosage Adults: 1gram/ dose, 4 gram/ day In hepatic failure – avoid or use with caution, upto 2 g/day No dose adjustment in renal failure; In severe renal failure (GFR <10 ml/hr), frequency can be reduced to 8 hourly dosage In alcoholics – maximum dose is 2.5 g/day
- 14. 14 /38 14 In pregnancy •No dose adjustment is required • Oral/ rectal – category B; IV – category C
- 15. 15 /38 15 Uses • Fever •Headache • Musculoskeletal pain like Osteoarthritis • Dental pain • Back ache • Dysmenorrhoea
- 16. 16 /38 16 Uses inAnaesthesia 1. Multimodal Analgesia – with opioids and NSAID’s 2. Premedication with paracetamol (oral or IV) before anesthesia induction can: • Minimize propofol injection pain, a common complaint during induction. • Improve surgical tolerance by reducing intraoperative awareness. 3. Post operative shivering - IV paracetamol has central thermoregulatory effects, helping to prevent and treat postoperative shivering. 4. Post operative Nausea and Vomiting (PONV) (inconsistent evidence)
- 17. 17 /38 17 Novel uses– IV Regional anaesthesia augmentation • During IV regional anaesthesia, adding paracetamol to the injected lidocaine improve the overall quality of the block. • In view of the overall consensus that paracetamol’s actions are centrally mediated, an analgesic benefit conferred from its addition to a peripherally sequestered pool of drug is a surprising finding. • Onset of motor block was sooner • Tourniquet pain was reduced • Recovery of motor and sensory block was delayed • resulting in lower intraoperative pain scores and • Decreased total systemic analgesic requirements.
- 18.
- 19. 19 /38 19 Adverse events •Paracetamol can be associated with non-specific gastrointestinal symptoms, such as nausea and vomiting, dyspepsia, abdominal pain, and bloating. (long term users irritation of mucosa)
- 20. 20 /38 20 Paracetamol toxicity •Toxic dose: >150 mg/kg (or) >10 gram in adult • Fatality is common with >250 mg/kg • In certain individuals, doses in less than usual toxic dose can cause toxicity, secondary to deficiencies in glutathione because of: a) inadequate nutrition b) CYP2E1 enzyme induction by chronic alcohol excess, or concomitant use of other drugs. • Paracetamol toxicity can cause acute liver failure. This can be associated with acute renal failure • Acute poisoning has 4 stages
- 21.
- 22.
- 23.
- 24. 24 /38 24 Paracetamol toxicity- treatment N-Acetyl Cysteine: • MOA: It replenishes glutathione stores of liver and prevents binding of toxic metabolites to other cellular constituents • 140 mg/kg • Followed by • 70 mg/kg every 4 hours (repeated 17 times) • Oral or IV route Since Over the Counter drug intake of paracetamol had increased, DGCI had recommended to use 325 mg tablet instead of 500 or 650 mg tablets, to prevent potential paracetamol toxicity
- 25.
- 26. 26 /38 26 Transdermal patch •The transdermal route for drug delivery avoids first pass metabolism and large variations in plasma drug concentrations. • Drugs suitable for transdermal administration have a low molecular weight and high lipid solubility. • There are two types of patches available: reservoir and matrix systems.
- 27. 27 /38 27 Skin andTDDS 1.Skin structure and permeability: The stratum corneum, the outermost layer of the epidermis, is the primary barrier to drug absorption. This highly lipophilic membrane, with low water content (20%), impedes penetration of foreign molecules. 2.Drug absorption pathway: Drugs must traverse the lipophilic and hydrophilic domains of the stratum corneum to reach the dermis, where a dense capillary network facilitates rapid systemic absorption.
- 28. 28 /38 28 Skin andTDDS 3.Alternative pathways: Hydrophilic drugs can utilize pathways like hair follicles, sweat glands, and blood vessels for dermal delivery. However, these routes have minimal contribution to steady- state drug flux in the systemic circulation. 4.Factors influencing absorption: Individual variations in stratum corneum thickness, skin hydration, underlying skin conditions, ethnicity, and body temperature can affect the rate of percutaneous drug absorption.
- 29. 29 /38 29 Pharmacokinetics ofTDDS Drug release and absorption: • The TDDS acts as a drug depot, storing the drug in a reservoir or within its matrix. • Upon application, a concentration gradient drives drug movement from the patch towards the dermis. • A secondary reservoir is established within the stratum corneum. • The drug is then absorbed into the local capillaries and enters systemic circulation. • This process leads to a delay (variable by drug) in achieving the desired minimum effective concentration (MEC) in plasma, with undetectable levels initially.
- 30. 30 /38 30 Pharmacokinetics ofTDDS Steady-state and duration of action: • Reaching steady-state plasma concentration can take time, potentially requiring multiple patch applications (2-3). Once achieved, this concentration is maintained for the duration of patch use. • TDDS offers the benefit of continuous drug delivery, improving patient compliance. Drug depletion after removal: • Following patch removal, drug concentrations decline gradually. • The rate of decline depends on the drug's context-sensitive half-life and the presence of a residual skin reservoir.
- 31. 31 /38 31 Effect ofdrug characteristics All of the drugs currently available in patch formulation share three features : 1. molecular mass, <500 Da; 2. high lipophilicity; and 3. low required daily dose (<2 mg).
- 32.
- 33. 33 /38 33 Transdermal patch Cross-section througha reservoir patch Cross-section through a matrix patch There are two designs of transdermal patch currently available: the reservoir, or membrane- controlled system, and the matrix system
- 34. 34 /38 34 Reservoir patchvs Matrix patch Reservoir patch Matrix patch holds the drug in a gel or solution incorporates the drug into an adhesive polymer matrix. Delivery dose is determined by a rate- controlling membrane between the drug reservoir and the skin slow rate of drug release (less interpatient variability) Delivered dose depends on the amount of drug held, and area of the patch applied. formulation of the drug/polymer matrix slow rate of drug release Reservoir patches give tighter control of delivery rates but can have an initial burst of drug release. The active ingredient is distributed evenly throughout the patch. One-half of a patch will have half the original surface area and deliver half the original dose per hour. Accidental overdose if the membrane is damaged which causes risk of sudden Less risk of accidental overdose and offers less potential for abuse
- 35. 35 /38 35 Improving transdermalpatch delivery Iontophoresis: • This physical method utilizes an electric field to drive charged drug molecules across the skin. • The charged drug resides in an electrolyte solution near an electrode with matching polarity, placed on the skin. A counter electrode placed elsewhere completes the circuit. • Upon applying an electromotive force, the drug gets repelled from the electrode, traversing the stratum corneum towards the opposite electrode.
- 36. 36 /38 36 Improving transdermalpatch delivery Iontophoresis: • This movement also generates convective flow within the solvent, dragging neutral drug molecules along (electro- osmosis).Additionally, electric current might transiently enhance skin permeability. • This technique allows for delivering bolus doses of drugs and has been utilized in the development of fentanyl patient-controlled analgesia (PCA) patches. Chemical enhancement Examples include adding solvents like ethanol or propylene glycol to increase drug solubility and facilitate permeation via stratum corneum
- 37. 37 /38 37 Buprenorphine TDDS(matrix) • Buprenorphine is a partial agonist at μ-receptors; it is 60 times more potent than morphine. • A ceiling effect is reached at doses of >16 mg/ day. This does not happen in clinical practice as the patches are designed to deliver 35, 52.5, or 70 μg/hr and the maximum dose is 3.36 mg/day (two 70 μg/hr patches). • Effective plasma concentrations are reached within 12 –24 h. • Metabolism is by the CYP 3A4 system but offset after patch removal is slower due to the high affinity of buprenorphine for opioid receptors. • A recent development is the release of a 7 days buprenorphine patch. This buprenorphine patch is a matrix system, available in three sizes, delivering 5, 10, or 20 μg/hr over 7 days, and used for the treatment of moderate to severe post-operative pain.
- 38.
Editor's Notes
- #6 This near-neutral pH makes it suitable for various pharmaceutical formulations and minimizes potential interactions with other drugs based on pH.
- #7 IV paracetamol: Offers faster onset (within 5 minutes) and predictable plasma concentrations compared to oral and rectal routes, crucial in the perioperative period. Oral Tablet, Syrup, Powder, Effervescent granules, Capsule Rectal suppositories Intravenous Intramuscular
- #10 . This would explain the experiences of relaxation, tranquility, and euphoria reported by many paracetamol users, apparently independent of analgesia.
- #11 The exact MoA of paracetamol remains somewhat elusive, with both central and peripheral effects proposed.
- #12 Serotonin receptors are present throughout the central nervous system, involved in a number of functions, including consciousness, mood, memory, and nausea and vomiting, the latter of which are mediated via the 5-HT3-receptor subtype. It has become widely accepted that the plays a key role in the action of paracetamol, and it has been demonstrated that the antinociceptive effects of paracetamol can be partially inhibited by co-administration of 5-HT3-receptor antagonists, interestingly using anti-emetic drugs which are indeed frequently given together with paracetamol in the perioperative period.
- #16 Postoperative shivering is a common complication that can increase oxygen demand and discomfort.
- #27 Epidermis thickness varies across the body (0.06-0.8 mm), impacting permeability.
- #39 In general, paracetamol is thought to have only minor effects on renal function, of no clinical relevance in the vast majority of patients. that said, acute tubular necrosis has been observed as an isolated finding in rare cases.
- #40 In adult patients, the hypotension was associated with increased skin blood flow, consistent with its antipyretic action; these effects were not demonstrated in healthy afebrile volunteers, or in elective surgical patients when given paracetamol perioperatively. Conversely, regular use of oral paracetamol has been linked with a raised blood pressure (studies: heart rate and blood pressure may show statistically, though perhaps not clinically, significant rises) The limited evidence on the subject would suggest that adults and neonates in a critical care setting, who are either febrile or have pre-existing low blood pressure, may have increased susceptibility to a period of hypotension after either enteral or i.v. paracetamol. Whilst often only modest and brief, a proportion of these hypotensive episodes did require supportive intervention, although no long-term sequelae were reported. Whilst much of these data come from retrospective observational studies, results from two small randomized, placebo-controlled crossover trials conducted in patients with known coronary artery disease or treated hypertension suggest that after as little as 2 weeks of paracetamol at submaximal doses of 1 g three times a day,
- #41 In adult patients, the hypotension was associated with increased skin blood flow, consistent with its antipyretic action; these effects were not demonstrated in healthy afebrile volunteers, or in elective surgical patients when given paracetamol perioperatively. Conversely, regular use of oral paracetamol has been linked with a raised blood pressure (studies: heart rate and blood pressure may show statistically, though perhaps not clinically, significant rises) The limited evidence on the subject would suggest that adults and neonates in a critical care setting, who are either febrile or have pre-existing low blood pressure, may have increased susceptibility to a period of hypotension after either enteral or i.v. paracetamol. Whilst often only modest and brief, a proportion of these hypotensive episodes did require supportive intervention, although no long-term sequelae were reported. Whilst much of these data come from retrospective observational studies, results from two small randomized, placebo-controlled crossover trials conducted in patients with known coronary artery disease or treated hypertension suggest that after as little as 2 weeks of paracetamol at submaximal doses of 1 g three times a day,
- #43 In adult patients, the hypotension was associated with increased skin blood flow, consistent with its antipyretic action; these effects were not demonstrated in healthy afebrile volunteers, or in elective surgical patients when given paracetamol perioperatively. Conversely, regular use of oral paracetamol has been linked with a raised blood pressure (studies: heart rate and blood pressure may show statistically, though perhaps not clinically, significant rises) The limited evidence on the subject would suggest that adults and neonates in a critical care setting, who are either febrile or have pre-existing low blood pressure, may have increased susceptibility to a period of hypotension after either enteral or i.v. paracetamol. Whilst often only modest and brief, a proportion of these hypotensive episodes did require supportive intervention, although no long-term sequelae were reported. Whilst much of these data come from retrospective observational studies, results from two small randomized, placebo-controlled crossover trials conducted in patients with known coronary artery disease or treated hypertension suggest that after as little as 2 weeks of paracetamol at submaximal doses of 1 g three times a day,