Clinical%20Pharmacology

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• Clinical Pharmacology

• of Analgesic Medications
• Non-Phramacologcial Treatments

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Contents of this Lecture

• (1) Clinical Pharmacology of
• Paracetamol (Acetaminophen)
• Non-steroidal anti-inflammatory drugs (NSAIDS) /
  COX-2 specific inhibitors
• Opioids
• Ketamine
• Drugs used for neuropathic pain
• Local Anaesthetic agents
• Others - Steroids
• (2) Non-drug treatments

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Clinical Pharmacology includes

• Mechanism of Action
• Absorption / Elimination of the drug
• Indication for use / dosage
• Adverse / side effects
• Any special precautions that should be taken

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Paracetamol

• Paracetamol has been in use for more than a
  century
• It has both analgesic and antipyretic action
• However, the exact mechanism of its action is
  unclear
• Absorption / Elimination from the body
• It is well tolerated when taken orally.
• On oral administration it is absorbed from the
  intestine (70), stomach and colon (30)
• The rate of absorption is rapid and depends on
  the dose

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Absorption / Elimination

• The time taken to reach maximum plasma
  concentration (Tmax) is 15 - 30 minutes depends
  on the preparation
• It is available as tablets (adults), suspension
  or syrup for children and suppositories
• Tmax is 2 - 3 hours with suppositories
• Bioavailability ranges from 60-90
• Elimination
• Paracetamol is metabolized in the liver and only
  2 - 5 is excreted unchanged

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Indications and dosages

• It is used as an analgesic drug for mild to
  moderate pain
• E.g. Tooth ache / teething pain in children,
  backpain, joint and muscle pain, headache,
  dysmenorrhoea
• Relief of fever in adults and children
• Dosage
• Adults Up to 1g oral / rectal, every 6 hours (
  4g should not be exceeded / day
• Children Oral / rectal 20 mg / kg every 6
  hours

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Side effects

• Paracetamol is well tolerated and has no side
  effects at therapeutic doses
• It has good haematological tolerability and does
  not alter haemostasis

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Caution

• Since it is metabolized in the liver it must be
  used with caution / or omitted in the presence of
  liver impairment
• In patients with renal impairment, the dose of
  paracetamol should be reduced
• Do not exceed 4g/day in adults and 125 mg/ kg in
  children

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Adverse effects

• Hepatotoxicity with an overdose of paracetamol
• This can occur when a patient does not get
  adequate relief with paracetamol and decides to
  take more than the prescribed dose of a maximum
  of 4g/day (8 - 10 g / day)
• Intentional overdose (Paracetamol overdose /
  poisoning is the leading cause of acute liver
  failure in the US, UK and Australia)
• Overdose causes acute liver failure, as the
  elimination pathways are saturated resulting in
  elevated levels of toxic metabolites

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Adverse Effects

• N-acetylcysteine (NAC) is the antidote for
  paracetamol poisoning and it is most effective
  when administered within 8 - 10 hours after
  ingestion
• Renal toxicity Overdose can cause severe
  kidney necrosis
• Allergic reactions are rare

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NSAIDs

• Non Steroidal Anti-inflammatory Drugs

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History of Aspirin

• Salicylate from the bark of the willow tree and
  was used to treat fever and rheumatism for
  centuries
• In the late 19th century, salicylic acid and
  later acetylsalicylic acid was synthesized and
  called aspirin.
• Aspirin was widely used to treat fever and pain
  till the availability of other drugs with similar
  mechanisms of action. It continues to be used in
  many parts of the world

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Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

• They are diverse group of compounds which were
  later synthesized, with actions similar to that
  of aspirin and became known as NSAIDs
• The mechanism of action of aspirin / NSAIDs was
  discovered in the 1960s by Prof Vane, who was
  awarded a Nobel prize in Medicine in 1982

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Non-steroidal Anti-inflammatory Drugs -NSAIDs

• NSAIDs are widely used to treat pain and
  inflammation
• They act through inhibition of the two isoforms
  of the enzyme cyclooxygenase (COX) i.e. COX-1
  and COX-2
• NSAIDs that act on both the enzymes are known as
  non-selective NSAIDs (ns-NSAIDs)
• NSAIDs which act predominantly on the COX-2
  enzyme are known as specific COX-2 inhibitors
  (also referred to as Coxibs)

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The Two Isoforms of COX

• COX-1 is a normal constituent in the body for
  homeostasis, such as in
• Gastric mucosa gastric cytoprotection
• Kidney Sodium and water balance / renal
  perfusion
• Platelets for aggregation
• COX-2 is induced in the presence of injury and
  inflammation
• COX-2 is also a normal constituent in the many
  organs such as Kidney, brain, endothelium, ovary
  and uterus

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What happens when there is tissue injury?
Cell wall injury
Releases
Membrane phospholipids
Phospholipase A2
Arachidonic Acid
COX-1 COX-2 that is induced with injury and
inflammation, cancer
PGH2
(Prostaglandin H2)
PGD2
TXA2
PGE2
PGI2
PGF2
Prostaglandins- PGE2 as the most significant
Thromboxane
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Arachidonic Acid Cascade
Phospholipid from cell membrane
Arachidonic Acid
Lipoxygenase
Cyclo-oxygenase
PGH2
5-HPETE
Leukotrienes
Prostaglandins
Thromboxane
These inflammatory mediators activate the
nociceptors on the Ad and c fibres and result in
pain and sensitization
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Arachidonic Acid Cascade
Phospholipid from cell membrane
Arachidonic Acid
NSAIDs / COX-2 inhibitors
Lipoxygenase
Cyclo-oxygenase
PGH2
5-HPETE
Leukotrienes
Prostaglandins
Thromboxane
Reduce Prostaglandins and Thromboxane, resulting
in reduced pain
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ns-NSAIDs
COX-2 specific inhibitors ( Coxibs)

• Acetylsalicylic acid (aspirin)
• Tablet, suppository
• Ibuprofen
• Tablet, suspension for children
• Indomethacin
• Tablet
• Diclofenac
• Oral tablet, suppositories, parenteral form
  available
• Mefenamic acid
• Oral tablets

• Celecoxib
• Oral capsules
• Etoricoxib
• Oral tablets
• Parecoxib
• parenteral

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Anti-Pyretics / NSAIDs on the WHO essential drug
list

• Acetylsalicylic acid (Aspirin)
• Tablet 100 mg to 500 mg
• Suppository 50 mg to 150 mg
• Ibuprofen gt 3 months in age
• Tablet 200 mg 400 mg
• Oral liquid 200 mg / 5 ml
• Paracetamol
• Tablet 100 mg to 500 mg
• Suppository 100mg, 250 mg
• Oral Liquid 125 mg / 5 ml

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Absorption and Elimination

• When administered orally, aspirin, ns-NSAIDs and
  Coxibs are well absorbed and reach therapeutic
  levels within 30 to 60 minutes.

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Indications

• Both the ns-NSAIDs and Coxibs have the same
  efficacy in postoperative analgesia
• Sole analgesia for day surgery
• Along with opioids for major surgery
• Musculo-skeletal pain e.g. back pain, joints,
  muscle sprains etc.
• Osteoarthritis
• Rheumatoid arthritis
• Not indicated for neuropathic pain

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Side effects / Adverse effects

• Gastrointestinal effects
• The risk of erosions, ulcers and bleeding is
  higher with ns-NSAIDs compared to Coxibs.
• This risk with ns-NSAIDs is also variable with
  some being less than others.
• Risk is greater
• In elderly patients
• Those who are also taking aspirin
• Risk can be reduced by adding a proton-pump
  inhibitor (e.g. omeprazole) to ns-NSAIDs.
• H2 receptor blockers are not very effective.

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Renal effects

• Both COX-1 2 are constituent enzymes in the
  kidney
• Maintain renal perfusion and sodium/water balance
• Both ns-NSAIDs and Coxibs can cause
• Hypertension, odema
• Decrease in creatinine clearance that may be
  significant in patients with impaired renal
  function or transient hypotension / hypovolaemia
  in the postoperative period

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Cardiovascular effects

• Some studies have shown that there was a higher
  risk of thrombotic cardiovascular events
  (stroke, heart attack) when on Coxibs when
  compared to ns-NSAIDs such as naproxen
• Other studies have shown that the cardiovascular
  events are similar
• Nevertheless, current recommendations are that
  Coxibs should not be used in patients with active
  cardiovascular disease and a known thrombotic
  condition

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Effect on platelets

• ns-NSAIDs are able to prevent platelet
  aggregation as platelets do not have COX-2. There
  is therefore a potential for bleeding with
  ns-NSAIDs
• Coxibs do not prevent platelet aggregation
• ns-NSAIDs should be used with caution in patients
  who are already on aspirin

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Others

• Some ns-NSAIDs can precipitate asthma is aspirin
  sensitive asthmatic patients.
• Coxibs are well tolerated by patients who have
  aspirin sensitive asthma

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Summary (cont.)

• NS-NSAIDs / Coxibs

• Both drugs are effective in providing pain relief
  for moderate pain
• The mechanism of action of both groups of drugs
  is by inhibiting the COX-2 enzyme that is induced
  with injury, inflammation and cancer
• Gastrointestinal side effects are less with
  coxibs

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Summary

• NS-NSAIDs / Coxibs

• Coxibs have no effect on platelet aggregation
• Both drugs should be used with caution in
  patients with renal impairment and in the elderly
• Coxibs should not be used in patients with active
  cardiovascular disease or known thrombotic
  effects
• Coxibs can be given to patients with aspirin
  sensitive asthma
• Both drugs should be used for the shortest period
  of time at the lowest dosage

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Opioids
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Opioids

• Opium alkaloids derived from the opium poppy has
  been used for pain relief for centuries
• Morphine was isolated by Sertuner in 1813
• The glass syringe was introduced in 1844
• Since then morphine has been the mainstay in the
  management of severe pain
• The term opioid is referred to any drug, either
  natural, semi-synthetic or fully synthetic, which
  has actions similar to morphine

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Available Opioids

• Natural
• Morphine
• Codeine

• Semi-Synthetic
• Hydromorphone
• Oxycodone
• Diacetylmorphine(heroin)
• Naloxone (antagonist)

• Fully Synthetic
• Pethidine (meperidine)
• Tramadol
• Nalbuphine
• Methadone
• Pentazocine
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil

• Opioids on the WHO essential drug list
• Morphine
• Codeine
• Tramadol

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Opioids can be classified as

• Strong opioids used for severe pain
• Morphine, Oxycodone, Pethidine, Fentanyl
• Weak Opioids used for moderate pain
• Codeine, Tramadol

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The analgesic ladder for acute pain management
Strong opioids
Weak opioids
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Mechanism of Action

• Opioids act by binding to opioid receptors
  (complex proteins embedded within the cell
  membrane of neurons)

There are three different opioid receptors - µ,
d, ? µ - most relevant as all clinically used
opioids exert their action via the µ -opioid
receptor
Opioid receptors are found in the brain and in
the dorsal horn of the spinal cord
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Mechanism of Action

• Opioids bind to opioid receptors
• Activate intracellular signaling events
• Leading to reduction in excitability of neurons
  and inhibition of pain signals
• Resulting in reduction of pain perception

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Opioids can be administered via several routes

• Opioids produce potent analgesia when
  administered
• Systemically oral, Intravenous, intramuscular,
  subcutaneous, transcutaneous, per rectal
• Spinally epidural, intrathecal,
  intraventricular
• Time to peak action and duration of action
  depends on the route and dose of the drug

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Morphine

• Is the most widely used opioid for the control
  of severe pain
• It can be given by all the routes that was
  described in the previous slide.
• It is well absorbed when given orally and has a
  bio-availability of around 30-35.
• Bio-availability means the amount of drug that is
  available in the systemic circulation after an
  oral dose is given.

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Oral morphine

• Immediate release morphine
• Aqueous / liquid morphine (usually prepared as
  1-2 mg / ml)
• Tablet morphine (10 mg)
• Need to be given every four hours for continuous
  relief of severe pain
• Sustained Release (SR) Morphine Tablets
• Morphine is released slowly over 12 hours
• 10 mg, 30 mg, 60 mg
• These tablets are given twice a day

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Parenteral morphine (10 mg / I ml ampoule)

• Intramuscular / subcutaneous morphine
• Onset of Analgesia 15 - 20 min
• Peak action 45 - 90 min
• Duration of action 4 hours
• Intravenous route is chosen when rapid control of
  severe pain is desired.

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Metabolism

• The principle pathway of metabolism is
  conjugation with glucuronic acid in hepatic and
  extra-hepatic (kidney) sites
• Morphine -3 and morphine -6 glucuronides that are
  excreted mainly by the kidneys
• Morphine should be used with caution in patients
  with hepatic and renal impairment

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Codeine phosphate Weak opioid

• Oral tablet 15mg 30 mg
• Is well absorbed and there is no first pass
  metabolism in the liver
• Codeine is metabolized to morphine which
  accounts for its analgesic effect
• 60 mg of codeine has an equi-analgesic effect of
  650 mg aspirin
• Has an anti-tussive effect and is often used in
  cough mixtures
• Is available in combination with paracetamol
• Cause minimal sedation, nausea, vomiting and
  constipation

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Tramadol Weak opioid

• This is also known as an atypical opioid
• It has a dual mechanism of action
• weak opioid receptor binding properties
• Inhibits the reuptake of serotonin and
  noradrenaline at the descending inhibitory
  pathway
• It is available
• Oral capsule (50 mg)
• Injection 50 mg / ml in 2 ml ampoules
• Due to its weak opioid activity it is not placed
  in the same schedule as the strong opioids such
  as morphine

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Tramadol

• It is well absorbed when given orally
• Time to effect is around 30 minutes and can last
  5 - 6 hours
• Sedation is minimal
• Can cause nausea, vomiting, dizziness
• Abuse potential is minimal
• Is used as a weak opioid, however as it has a
  dual mechanism of action its analgesic efficacy
  is superior to codeine Maximum daily dose is
  400 mg

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Metabolism

• Tramadol is metabolized by the liver and excreted
  by the kidneys
• Tramadol has an active metabolite
  (O-desmethyltramadol) that is also excreted
  by the kidney
• The daily dose should be reduced in the presence
  of chronic renal failure

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Opioid related side effects

• Gastrointestinal
• Nausea and vomiting
• Constipation
• Sedation
• Respiratory depression in overdose
• Pruritus
• Cough suppression (anti-tussive)

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Opioid related side effects

• On initiation of opioid therapy, patients
  frequently report acute side effects of sedation,
  dizziness, nausea and vomiting
• After a few days these symptoms subside except
  for constipation
• This is noted in patients with cancer pain

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Opioids and Tolerance

• Patients can develop tolerance when opioids are
  used for an extended period
• E.g. cancer pain intensive care units
• Tolerance is defined as reduction of the
  pharmacological effect of an opioid
• When the same dose produces a lesser effect
• Increasing doses of drug is required to produce
  the same effect
• The mechanisms of the development of tolerance
  are complex

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Physical Dependence and Addiction

• Physical dependence is a state of adaptation by
  the body with extended use of an opioid
• It is manifested by withdrawal symptoms with
  abrupt cessation of the opioid, rapid dose
  reduction or administration of an opioid
  antagonist
• Addiction to opioids is drug seeking behaviour
  where the person is looking for opioids for its
  euphoric action rather than pain relief alone

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Ketamine is on the WHO essential drug list

• It is a phencyclidine derivative
• It has been used to provide anaesthesia for many
  years
• The side effect of hallucinations has limited its
  use as an anaesthetic agent
• Ketamine causes an increase in blood pressure and
  heart rate, hence it is used as an induction
  agent when a patient is in shock
• It has multiple mechanisms of action
• The main mechanism of action is that of a
  non-competitive antagonist at the NMDA receptors

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Ketamine

• Routes of administration
• Intravenous
• Intramuscular / Subcutaneous (onset 10 - 15
  min)
• Oral (bioavailability 20) / sublingual (30) /
  rectal (30)
• Metabolized by the liver
• Metabolites are about 1/5th as potent as ketamine

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Ketamine has potent analgesic properties

• Analgesia
• Low dose ketamine 0.1 - 0.5 mg / kg / hr can
  provide excellent analgesia
• It can reduce opioid requirements in the
  postoperative period
• It can be used for the management of neuropathic
  pain such as in patients with complex regional
  pain syndrome
• As an adjunct for the relief of cancer pain,
  particularly for the neuropathic component

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Ketamine

• 5mg / kg IM can be used for painful dressing
  change in children
• An anti-sialagogue should be added as it causes
  salivary secretions that can cause coughing /
  laryngospasm

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Side effects of ketamine

• Dizziness
• Hallucinations
• Emergence delirium when larger doses are used
• Benzodiazepines can reduce these side effects
• Salivary secretions
• Anti-sialagogues should be used with ketamine

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Ketamine and drug abuse

• In recent years, ketamine has been known to be
  abused for its euphoric effects
• Long term use can lead to cognitive impairment
  and memory loss

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Drugs for Neuropathic Pain
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Neuropathic pain

• Is defined as pain that arises as a result of
  injury or disease of the somatosensory system
• Neuropathic pain is not responsive to ns-NSAIDs.
• Poorly responsive to Opioids

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Drugs used for treating neuropathic pain

• Amitriptyline
• Carbamazepine
• Sodium valproate
• Gabapentinoids (not on the WHO essential drug
  list)

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Amitriptyline

• Is a tri-cyclic anti-depressant drug
• Used more for the management of neuropathic pain
  than for symptoms of depression
• Low dose amitryptyline is a first line drug for
  neuropathic pain
• Mechanism of action
• Inhibits the reuptake of noradrenaline and
  serotonin (thus increasing these two
  neurotransmitters) at the descending inhibitory
  pathway
• The descending inhibitory tract influences the
  output of the neurons in the dorsal horn of the
  spinal cord

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Absorption / Elimination

• Amitriptyline is well absorbed on oral
  administration
• Bioavailability 30 - 60
• Effects last 2 - 12 hours
• Metabolized in the liver (de-methylation) and
  excreted in the urine

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Adverse effects

• Common ones
• Dry mouth, disturbances of visual accommodation
• Constipation and urinary retention
• Light-headedness, drowsiness
• Less common effects
• Cardiac Arrhythmias
• It should be used cautiously in the elderly and
  in those with a history of cardiovascular disease

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Carbamazepine

• Is an antiepileptic drug
• It is currently the drug of choice for the
  management of pain in patients with trigeminal
  neuralgia
• Mechanism of action
• It blocks the frequency and use of the
  voltage-gated neuronal sodium channels
• Limits repetitive firing action of action
  potentials
• There is a proliferation of sodium channels when
  there is nerve injury thus the efficacy of
  carbamazepine in patients with neuropathic pain

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Side effects

• The most common side effects are neurotoxic and
  dose-related. They include
• Drowsiness, diplopia, headache, ataxia, nausea
• Vomiting, dizziness
• These side effects tend to occur within a week of
  initiation or dosage increase.
• In chronic therapy, they typically are noticeable
  3 - 4 hours after a dose (associated with peak
  serum concentrations)
• Systemic effects
• Abdominal pain, diarrhea, hyponatraemia in the
  elderly

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Serious side effects

• Agranulocytosis and aplastic anaemia
• Skin eruptions and life threatening
  Steven-Johnsons syndrome
• Blood tests should be done early in the course of
  therapy and patients should be asked to report
  easy bruising.

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Interaction with other drugs

• Carbamazepine is an inducer of CYP450 in the
  liver
• Efficacy of other drugs are reduced notably e.g.
• Warfarin
• Phenytoin
• Valproic acid
• Some drugs reduce the metabolism of carbamazepine
  and therefore increase its plasma level
• Erythromycin
• Cimetidine
• Calcium channel blockers

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Local Anaesthetics (LA)

• Lignocaine (short acting) 0.5, 1.0, 2.0
  solutions
• Bupivacaine (long acting) 0.5
• Both belong to the amide group of LA drugs
• Mechanism of action
• LA drugs act by producing a reversible block to
  the transmission of peripheral nerve impulses
• i.e. they block membrane depolarization of all
  excitable tissue, in particular the nerves
• This action is on the sodium channels of the
  peripheral nerves.

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LA drugs

• Can provide both surgical anaesthesia and
  analgesia
• Depends on the site of administration
• Concentration of the drug used
• Common routes of administration
• Local infiltration
• Individual nerve block
• Plexus block
• Epidural administration

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Absorption / Elimination

• LA drugs are absorbed into the systemic
  circulation from the site of administration
• Rate of absorption depends on the site
• Addition of adrenaline can delay absorption
• After absorption, they are distributed rapidly
  and taken up by organs
• Metabolized in the liver and excreted by the
  kidney
• LA cross the placenta, but their effects are of
  minimal significance

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Systemic toxicity

• If significant amounts of LA drugs are absorbed
  they can cause toxicity
• Nervous system
• Numbness and tingling over the circumoral area
• Anxiety, Light-headedness, tinnitus
• Loss of consciousness and convulsions
• Heart
• Direct myocardial depression and hypotension
• Vasodilatation
• Cardiac arrest

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Systemic toxicity can occur due to

• Inadvertent intravenous administration of LA
  drugs
• Overdose if the following limits are exceeded
• Lignocaine plain 4 mg / kg
• Lignocaine with adrenaline 7 mg / kg
• Bupivacaine 2 mg / kg

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Other Drugs (Miscellaneous category)

• Steroids
• Dexamethasone , Prednisone

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Dexamethasone

• Is a potent synthetic member of the
  glucocorticoid class of steroid drugs
• It acts as anti-inflammatory
• Immunosuppresant
• Can be taken orally and is more potent than the
  naturally occurring hormone cortisol
• Used to reduce pain and inflammation in
• Rheumatoid arthritis

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Non-pharmacological treatments

• Both physical and psychological factors affect
  our perception of pain. Treatments include
• Physical
• Rest, Ice (cold), Compression, Elevation of
  injuries
• Surgery (e.g. draining an abscess / fixing
  fractures)
• Acupuncture, massage, physiotherapy
• Ultrasound therapy
• Transcutaneous electrical nerve stimulation
  (TENS)

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Psychological treatments

• Adequate explanation
• Reassurance that their pain will be addressed
• Counseling
• Individual
• Family
• This is particularly important when dealing with
  patients with cancer pain
• Cognitive Behavioural Therapy (CBT) for chronic
  non-cancer pain

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Conclusion Adequate control of pain requires

• An understanding the mechanisms of pain
• Nociceptive or neuropathic pain
• An understanding of the drugs that help to
  control it
• Mechanism of action
• Pharmacokinetics (Absorption and time to onset
  and peak action and elimination)
• Side effect profile

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This talk was originally prepared by

• Ramani Vijayan, M.D.
• Kuala Lumpur, Malaysia

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International Pain School
Talks in the International Pain School include
the following
Physiology and pathophysiology of pain Nilesh Patel, PhD, Kenya
Assessment of pain taking a pain history Yohannes Woubished, M.D, Addis Ababa, Ethiopia
Clinical pharmacology of analgesics and non-pharmacological treatments Ramani Vijayan, M.D. Kuala Lumpur, Malaysia
Postoperative low technology treatment methods Dominique Fletcher, M.D, Garches Xavier Lassalle, RN, MSF, Paris, France
Postoperative high treatment technology methods Narinder Rawal, M.D. PhD, FRCA(Hon), Orebro, Sweden
Cancer pain low technology treatment methods Barbara Kleinmann, MD, Freiburg, Germany
Cancer pain high technology treatment methods Jamie Laubisch MD, Justin Baker MD, Doralina Anghelescu MD, Memphis, USA
Palliative Care Jamie Laubisch MD, Justin Baker MD, Memphis, USA
Neuropathic pain - low technology treatment methods Maija Haanpää, MD, Helsinki Aki Hietaharju, Tampere, Finland
Neuropathic pain high technology treatment methods Maija Haanpää, M.D., Helsinki Aki Hietaharju, M.D., Tampere, Finland
Psychological aspects of managing pain Etleva Gjoni, Germany
Special Management Challenges Debra Gordon, RN, DNP, FAAN, Seattle, USA
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International Pain School
The project is supported by these organizations