VIVA: Pharmacology - Analgesics and anti-inflammatories Flashcards
Describe the pharmacokinetics of ibuprofen
2 needed to pass:
- NSAIDs well-absorbed, food does not substantially change their bioavailability
- Highly protein bound
- Highly metabolised by liver (cytochrome p450)
Describe the pharmacodynamics of ibuprofen
Inhibition of prostaglandin synthesis*
Additional possible mechanisms of action, including inhibition of chemotaxis, downregulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events
NSAIDs are reversible inhibitors of COX*
Anti-inflammatory, antipyretic and analgesic*
- needed to pass
What are the side effects of NSAIDs?
CNS: headaches, tinnitus, dizziness
CVS: fluid retention, HTN, oedema, rarely MI, CCF
GIT *: abdominal pain, dyspepsia, nausea, vomiting, ulcers or bleeding
Renal *: renal insufficiency, renal failure, hyperkalaemia, proteinuria
Haematologic: rarely thrombocytopaenia, neutropenia, aplastic anaemia
Hepatic: abnormal LFTs, rarely liver failure
Pulmonary: asthma
Skin: rashes (all types), pruritis
*4 side effects needed to pass (must include GIT and renal)
Describe the mechanism of action of fentanyl
Synthetic opioid that acts on the mu receptor*
*needed to pass
Describe the pharmacokinetics of fentanyl
- High first-pass metabolism *, low oral bioavailability
- Highly lipid soluble
- Duration of action 1-2hr *
- Half-life 5mins
- Metabolised by P450 CYP 3A4 with no active metabolites
- Transdermal, mucosal and IM absorption are good
- Fentanyl may be given IV, IM, IN, SC, SL/buccal (with lozenge), transdermal patch, epidural
*needed to pass + two routes
Describe the potency of fentanyl relative to morphine
100x more potent (0.1mg of fentanyl = 10mg morphine)
List the adverse effects of fentanyl
4 needed to pass:
- Respiratory depression
- Nausea and vomiting
- Dysphoria
- Cough
- Sedation
- Constipation
- Urinary retention
- Itch
- Urticaria
- Chest wall and laryngeal rigidity
Describe the pharmacokinetics of oxycodone
Absorption:
- Commonly given orally *, also available subcut, IV and IM as well as PR and epidural
- Good oral absorption *
- Low first pass metabolism (cf morphine)
Distribution:
- High volume of distribution
Metabolism:
- Duration of action 3-4hrs, longer if controlled release formulation *
- Hepatic metabolism by P450
Elimination:
- Metabolites excreted by kidneys
Dosing:
- Relative potency: 10mg morphine = 4.5mg oxycodone
*needed to pass + one characteristic
What strategies may be used when prescribing oxycodone to reduce the development of dependence?
3/5 to pass:
- Establish goals at start of Rx
- Smaller doses at longer intervals
- Limit doses
- Use of controlled release preparations
- Combine with non-opioid analgesics
- Frequent evaluation of ongoing requirements
What is the mechanism of action of morphine?
- Acts on receptors: mu */delta/kappa
- Reduce presynaptic neurotransmission (especially glutamate) *
- Inhibit postsynaptic neurons *
- Central (thalamic action)
*Mu receptors + one other mechanism to pass
Why do opiates cause respiratory depression?
Inhibition of brainstem respiratory controls *, allowing less response to hypercapnoea
*needed to pass
How is morphine metabolised?
Conjugated in liver* (morphine-3-glucuronide = most)
Small amount (10%; morphine-6-glucuronide = increased analgesic potency)
Renal excretion
*needed to pass
How does oxycodone produce its analgesic effects?
Opioid agonist that acts mainly on mu receptors* in brain and spinal cord, but also outside CNS
*needed to pass
Outline the mechanisms of action for aspirin
Irreversible non-selective cyclooxygenase inhibition* (COX-1 and COX-2) resulting in:
- In platelets: irreversible inhibition of COX-1 results in reduction in thromboxane A2 and inhibition of platelet aggregation* for the life of the platelet (10 days)
- In tissues: inhibits prostaglandin synthesis* (COX-2), results in anti-inflammatory action as well as analgesic and antipyretic effects
*needed to pass: also need to mention platelet effect (COX-1) AND tissue (COX-2) anti-inflammatory or analgesic effect
Describe the pharmacokinetics of aspirin
Absorption:
- pKa 3.5, rapidly absorbed from stomach and intestine* as acetylsalicylic acid
- Peak plasma levels within 1-2hrs
- ASA rapidly hydrolysed to salicylic acid by esterases in plasma and blood with half-life of 15mins
Distribution:
- Salicylate bound to albumin
- Small Vd
Metabolism:
- Saturable metabolism with increasing doses (switches from first to zero order metabolism)*
Elimination:
- Urinary alkalinisation increases excretion of salicylate and its conjugates*
*needed to pass
What are the adverse effects of therapeutic doses of aspirin?
CNS: headache, tinnitus, dizziness
CVS: fluid retention, HTN, oedema
GIT: abdo pain, nausea and vomiting, ulcers, bleeding*
Haem: thrombocytopaenia, neutropaenia, aplastic anaemia
Hepatic: abnormal LFTs, liver failure
Pulmonary: asthma*
Skin: all types of rashes, pruritis
Renal: impairment and failure, hyperkalaemia, proteinuria
Allergy*
- needed to pass
Describe what happens to aspirin in the gut following oral administration
Highly soluble in acid environment of the stomach as it is a weak acid (rapidly absorbed)
Becomes much less soluble (100x less) in the alkali environment of the upper small bowel
Most of the administered dose is absorbed in the small bowel (due to the vastly increased surface area)
Possibility of formation of concretions/bezoars
What are the toxic effects of aspirin in overdose?
Salicylism (5 needed to pass):
- Vomiting, tinnitus, vertigo, loss of hearing
- Tachypnoea (leading to respiratory alkalosis)
- Fever
- Dehydration
- Metabolic acidosis
- Hyperglycaemia
- Clotting disturbance
- CVS collapse
- Renal and respiratory failure
- Coma
What are the therapeutic indications of asthma?
TIA
ACS
Pre-thrombolysis
Anti-inflammatory
Analgesia
Anti-pyretic
Describe the mechanism of action of colchicine
Anti-inflammatory effect* (binds to tubulin, inhibits WBC migration and phagocytosis)
Inhibits formation of leukotriene B4
No effect on uric acid metabolism*
- needed to pass
What are the indications and dosage of colchicine?
Treatment of acute episodes of gout (0.6-1.2mg PO 12hrly until pain reduces or diarrhoea results; 8mg is a fatal dose)*
Gout prophylaxis (0.6mg PO TDS)*
Prevention of Mediterranean fever
Treatment of sarcoid arthritis
- need either of these to pass
Describe the mechanism of action of the COX-2 selective inhibitors
Inhibits prostacyclin synthesis by selectively binding to and blocking the active site of the COX-2 isoenzyme
What adverse effects can be associated with the use of COX-2 selective inhibitors?
2/3 needed to pass:
- Renal toxicity
- GIT (fewer than non-selective NSAIDs)
Possible increased CVS thrombotic events
What other drugs are inhibitors of the cyclooxygenase enzyme system?
Arthritis
Non-steroidals
What is drug potency?
Dose or concentration to achieve 50% maximal effect (EC50 or ED50)
Draw and explain dose-response curves comparing morphine with fentanyl
What is bioavailability?
Fraction of unchanged drug reaching the systemic circulation* following administration by any route
- needed to pass
What factors affect bioavailability?
- Extent of absorption*
- Too hydrophilic or too lipophilic = decreased absorption
- Reverse transporter associated with p-glycoprotein pumps drug back to gut lumen = decreased absorption
- Gut wall metabolism = decreased absorption - First pass metabolism*
- Metabolism by liver before it reaches systemic circulation
- Small additional effect if drug has biliary excretion - Rate of absorption
- Determined by site of administration and drug formulation
- needed to pass (with reasonable explanation of each)
What is the bioavailability of ibuprofen?
High:
- Weak organic acid
- Well-absorbed rapidly
- Minimal first pass metabolism*
- needed to pass
Describe the central nervous effects of morphine
Analgesia*
Sedation*
Respiratory depression* (dose-related): inhibits brainstem respiratory mechanisms, limited response to hypercarbia
Euphoria
Cough suppression
Miosis
Truncal rigidity
Nausea and vomiting
Temperature
- should be able to describe in detail
Describe the peripheral effects of morphine
Cardiovascular: peripheral arterial and venous dilation via histamine release and central depression of vasomotor stabilising mechanisms
GI: constipation
Biliary: smooth muscle constriction may cause biliary colic
Renal: decreased renal function due to decreased renal plasma flow; antidiuretic effect of mu opioids
Uterus: may prolong labour
Genitourinary: increased ureteral and bladder tone may lead to urinary retention
Neuroendocrine: stimulates ADH, prolactin and GH release, inhibits LH
Pruritis: CNS effect and peripheral histamine release
Immune: effects on lymphocyte proliferation, antibody production and chemotaxis
- should be able to describe in detail
Describe the effects of morphine on the different opioid receptors
Full agonist at the mu receptor*:
- Analgesia, sedation, respiratory depression, decreased GI transit, modulation of hormone and neurotransmitter release
Minor activity at delta receptor:
- Analgesia, modulation of hormone and neurotransmitter release
Minor activity at kappa receptor:
- Analgesia, psychomimetic effects, decreased GI transit
- needed to pass + one other receptor
What is the mechanism of action of morphine at the cellular level?
By binding to specific G-protein-coupled receptors in brain and spinal cord:
- Closes voltage-gated Ca2+ channels: decreased Ca2+ influx on presynaptic nerve terminals and decreased transmitter release
- Hyperpolarises postsynaptic neurons by increasing K+ conductance, producing an inhibitory postsynaptic potential
How does aspirin differ from other NSAIDs in its action on COX?
Cyclooxygenase is the key catalyst for arachidonic acid conversion to prostaglandins
NSAIDs inhibit COX, thus inhibiting conversion
Aspirin (original NSAID) irreversibly inhibits COX, whilst the newer NSAIDs (ibuprofen, diclofenac) reversibly inhibit COX*
Two types of COX exist:
- COX-1 is expressed in most cells
- COX-2 is inducible and its expression varies depending on stimulus
Selective COX-2 inhibitors (celecoxib) do not affect platelet function at usual doses, whilst the other NSAIDs do inhibit platelet aggregation
- needed to pass
Name some drugs that are used in the treatment of opiate addiction
Methadone*
N-acetylmethadol
Buprenorphine
Clonidine
Lofexidine
Naltrexone
Naloxone
- needed to pass + one other
Outline the principles of how drugs used to treat opioid addiction work
Overall agents must be orally active and long-acting*
Methadone*:
- Long-acting opioid antagonist
- Orally active
- Patient can be stabilised and gradually withdrawn
- Also addictive
N-acetylmethadol:
- Even longer-acting methadone analogue
Buprenorphine:
- Partial opioid agonist that can be given once daily
- Low doses for detoxification, higher doses for maintenance
Clonidine:
- Centrally-acting sympatholytic agent that mitigates signs of withdrawal (sympathetic overactivity)
Lofexidine:
- Clonidine analogue with less hypotensive effects
Naltrexone:
- Long-acting orally active pure opioid antagonist
- Patients must be detoxified first
Naloxone:
- Rapid onset pure antagonist
- Short half-life
- Precipitates withdrawal
- needed to pass + pharmacodynamics of one other agent
Describe the clinically important pharmacological differences between morphine and fentanyl
Morphine is naturally occurring, fentanyl is synthetic
2/3 needed to pass:
- Receptor effects: both are strong agonists (all receptors), potency of fentanyl exceeds morphine
- Absorption: both morphine and fentanyl have low oral:parenteral potency ratios
- Elimination: elimination half-life of morphine exceeds fentanyl
How does methadone differ from morphine and fentanyl?
Pharmacodynamic differences:
- Methadone also blocks NMDA receptors and monoamine reuptake (may explain its ability to relieve difficult-to-treat pain)
Pharmacokinetic differences:
- Methadone has a high oral:parenteral potency ratio*
- Elimination half-life of methadone»_space; morphine > fentanyl*
- Methadone has highly variable pharmacokinetics between individuals
- needed to pass
What advantages and disadvantages might a drug like buprenorphine have in the treatment of heroin addiction, as compared to methadone?
- Buprenorphine is a partial agonist at the mu receptor, and has a long duration of action due to slow dissociation from the receptor; said to be as effective as methadone in the detoxification and maintenance treatment of heroin addiction
- Lower risk of overdose fatalities compared to methadone due to its partial agonist action
- Slower receptor dissociation renders its effect resistant to naloxone reversal and prevents action of other narcotic analgesics (if needed)
- must describe what buprenorphine does and that it is relatively safe to pass
What adverse effects of oxycodone might you anticipate?
3 needed to pass:
- Sedation
- Respiratory depression
- Nausea and vomiting
- Hypotension
- Dysphoria
- Biliary colic
- Pruritis
- Use with caution in renal failure (accumulation of active metabolites)
Describe the pharmacokinetics of paracetamol
3 needed to pass:
- Rapid absorption
- Oral bioavailability 70-90%
- Peak concentration after 30-60mins
- Half-life 2-3hrs
- Slightly protein bound, Vd 1L/kg (approximates body weight)
- Hepatic metabolism: 95% undergoes glucuronidation and sulfation, 5% undergoes metabolism via CYP 450 enzymes (phase 1 hydroxylation reaction) to form toxic NAPQI, which is usually detoxified by glutathione*
- Renal excretion (<5% unchanged)
- First order kinetics
Describe the mechanism by which paracetamol causes toxicity
Zero order kinetics*
Paracetamol is conjugated with glucuronide and sulphate (by transferase enzymes): this pathway becomes saturated in overdose, allowing increasing paracetamol to be metabolised by the smaller CYP 2E1 pathway to NAPQI (N-acetyl-p-benzoquinone imine)
NAPQI is detoxified by glutathione which becomes depleted resulting in high levels of toxic metabolite (NAPQI)*
- needed to pass
How does N-acetylcysteine work in the treatment of paracetamol overdose?
Sulfhydryl group donor - restores hepatic reduced glutathione levels
Or acts as alternative substrate for conjugation with the toxic metabolite
- need concept to pass
What is the toxic dose of paracetamol?
150-200mg/kg or >7g in an adult
(>4g/day can cause LFT derangement; >150mg/L 4hrs post ingestion indicates risk of liver injury)
What is the mechanism of action of paracetamol?
Weak COX-1 and COX-2 inhibitor in peripheral tissues (preferentially inhibits COX-2*)
- needed to pass
What are the clinical manifestations of paracetamol toxicity?
4 needed to pass:
- Nausea and vomiting
- Abdominal pain
- Liver failure
- Renal failure (tubular necrosis)
- HAGMA
- Coma with massive doses
Describe the enhanced elimination strategies employed in managing a patient with salicylate overdose
pH manipulation/urinary alkalinisation
Forced diuresis
Dialysis (peritoneal, haemodialysis, haemofiltration, haemoperfusion)
