Title: Clinical%20Pharmacology
1(No Transcript)
2- of Analgesic Medications
- Non-Phramacologcial Treatments
type in the name of your institution
3Contents 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
4Clinical Pharmacology includes
- Mechanism of Action
- Absorption / Elimination of the drug
- Indication for use / dosage
- Adverse / side effects
- Any special precautions that should be taken
5Paracetamol
- 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
6Absorption / 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
7Indications 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
8Side effects
- Paracetamol is well tolerated and has no side
effects at therapeutic doses - It has good haematological tolerability and does
not alter haemostasis
9Caution
- 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
10Adverse 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
11Adverse 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
12NSAIDs
- Non Steroidal Anti-inflammatory Drugs
13History 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
14Non-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
15Non-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)
16The 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
17What 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
18Arachidonic 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
19Arachidonic 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
20ns-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
21Anti-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
22Absorption and Elimination
- When administered orally, aspirin, ns-NSAIDs and
Coxibs are well absorbed and reach therapeutic
levels within 30 to 60 minutes.
23Indications
- 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
24Side 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.
25Renal 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
26Cardiovascular 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
27Effect 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
28Others
- Some ns-NSAIDs can precipitate asthma is aspirin
sensitive asthmatic patients. - Coxibs are well tolerated by patients who have
aspirin sensitive asthma
29Summary (cont.)
- 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
30Summary
- 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
31Opioids
32Opioids
- 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
33Available Opioids
- 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
34Opioids can be classified as
- Strong opioids used for severe pain
- Morphine, Oxycodone, Pethidine, Fentanyl
- Weak Opioids used for moderate pain
- Codeine, Tramadol
35The analgesic ladder for acute pain management
Strong opioids
Weak opioids
36Mechanism 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
37Mechanism 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
38Opioids 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
39Morphine
- 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.
40Oral 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
41Parenteral 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.
42Metabolism
- 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
43Codeine 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
44Tramadol 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
45Tramadol
- 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
46Metabolism
- 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
47Opioid related side effects
- Gastrointestinal
- Nausea and vomiting
- Constipation
- Sedation
- Respiratory depression in overdose
- Pruritus
- Cough suppression (anti-tussive)
48Opioid 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
49Opioids 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
50Physical 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
51Ketamine 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
52Ketamine
- 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
53Ketamine 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
54Ketamine
- 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
55Side 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
56Ketamine 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
57Drugs for Neuropathic Pain
58Neuropathic 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
59Drugs used for treating neuropathic pain
- Amitriptyline
- Carbamazepine
- Sodium valproate
- Gabapentinoids (not on the WHO essential drug
list)
60Amitriptyline
- 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
61Absorption / 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
62Adverse 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
63Carbamazepine
- 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
64Side 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
65Serious 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.
66Interaction 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
67Local 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.
68LA 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
69Absorption / 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
70Systemic 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
71Systemic 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
72Other Drugs (Miscellaneous category)
- Steroids
- Dexamethasone , Prednisone
73Dexamethasone
- 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
74Non-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)
75Psychological 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
76Conclusion 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
77This talk was originally prepared by
- Ramani Vijayan, M.D.
- Kuala Lumpur, Malaysia
78International 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
79International Pain School
The project is supported by these organizations