Analgesics & Muscle Relaxant

Analgesics
Jarir At Thobari, MD, DPharm, PhD
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Aspirin consumption worldwide
12
15x10 tablets per year or 45,000 tons per year

bmj.com 2004;328:434
CYCLOOXYGENASE PATHWAY

Burden of pain
15% moderate to severe

at least 50% of time
Seriously ill
Hospitalized patients
15% dissatisfied with
pain treatment
50% incidence
of pain

Pain Treatment Methods
Physical Methods
Psychological Method
Removed the cause of pain
Regional Anesthesia
Medication

WHO Pain Ladder

ANALGESICS
I. Opioid (narcotic) analgesics

1. Agonists of opioid receptors – morphine hydrochloride, promedol,
omnopon, fentanyl, codeine;
2. Agonists – antagonists and partial agonists of opioid receptors –
pentazocin, buprenorphine.
II. Non-opioid analgesics and non steroidal anti-
inflammatory drugs - NSAIDs
acetylsalicylic acid, paracetamol, antalgin, indomehtacin, butadion,
ibuprofen, piroxicam, diclofenac-sodium, ketorolac, ketoprofen.
III. Substances with mixed mechanism of action
(opioid and non-opioid components : tramadole)

NSAIDs
• Efficacy is similar amongst NSAIDs

• Differences in potency, time of onset, &
duration of action
• Side effects:
– GI bleeding
– renal dysfunction
– platelet dysfunction

Pharmacokinetic & Pharmacodynamic profile

For what conditions are NSAIDs
used?
• Rheumatoid Arthritis • Dysmenorhea

• Osteoarthritis • Headache, migraine
• Inflammatory arthritis, • Postoperative pain
psoriatic arthritis, • Pyrexia (fever)
Reiter’s syndrome • Ileus
• Acute gout • Renal colic
• Metastatic bone pain

Mechanism of Action of NSAIDs
CO2
H
Arachidonic acid
COX-1 Non-specific NSAIDs COX-2
“Constitutive” “Inducible”
COX-2 NSAIDs
GI Mucosa Platelet
Prostaglandins
Prostaglandins Thromboxane
Mediate pain,
GI mucosal
Hemostasis inflammation, and fever
Protection

Classification NSAID
Acetic acid derivatives Enolic acid derivatives

• Arthrotec • Meloxicam
(diclofenac/misoprostol)
• Piroxicam
• Diclofenac
• Tenoxicam
• Ketorolac
• Tolmetin
Napthylkanone derivatives
• Etodolac
• Nabumetone
• Indomethacin
• Sulindac

Classification NSAID
Propionic acid derivatives Carboxylic acid derivatives
• Flurbiprofen • Diflunisal
• Ketoprofen • Salsalate
• Oxaprozin
• Ibuprofen
COX-2 inhibitor
• Naproxen • Celecoxib
• Rofecoxib
• Valdecoxib

NSAIDs: COX-2 vs COX-1 Selectivity
6-MNA
100.00 Naproxen
Acetaminophen
COX-2 IC50 (µM) Ibuprofen
10.00
Meloxicam
1.00 Indomethacin Nimesulide
Celecoxib Rofecoxib
0.10
Diclofenac
0.01
0.01 0.10 1.00 10.00 100.00
COX-1 IC50 (µM)
6-MNA = 6-methoxy-2-naphthylacetic acid;

IC50 = drug concentration at which the enzymatic activity is inhibited by 50%.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.

CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib 6
p = 0.02
= NSAIDs (ibuprofen + diclofenac) 5
4 49 / 1384
p = 0.09
3
30 / 1441
All Patients 20 / 1384
Annualized Incidence %
2
1
11 / 1441
0
6
5 p = 0.02
4
p = 0.04 32 / 1101
Patients Not Taking Aspirin 3
2
14 / 1101 16 / 1143
1
5 / 1143
0
p = 0.49
6 17 / 283
5 14/ 298
4 p = 0.92
Patients Taking Aspirin 3
2
6 / 298 6 / 283
1
Silverstein et al. JAMA 2000; 284:1247-1255 0
Ulcer Complications Symptomatic Ulcers and
Ulcer Complications
Risk factors for upper GI bleeding
associated with NSAID use
Lanas A Rheumatology 2010;49:ii3-ii10

Gastro protection:
Misoprostol (MUCOSA trial)
% of patients with serious upper GI complications at 6 months
1,0 p=0.049
0,9
40% reduction in GI
0,8 complications
0,6
0,6
0,4
0,2
0,0 Silverstein et al.

Placebo + NSAID Misoprostol + NSAID Ann Intern Med
1995;123:241–249
(n=4439) (n=4404)

Gastro protection:
Proton Pump Inhibitors
% of patients with recurrent upper GI bleeding at 6 months
p=0.005
20 18,8
15 76% reduction in upper

GI bleeding
10
4,4
5
0
Chan et al. N Engl J
H. pylori eradication Omeprazole + NSAID Med 2001;344:967–
+ NSAID (n=75) 973
(n=75)
Results of Case-Control and Cohort Studies Reporting
on Cardiovascular Risks With Nonselective NSAIDs.
McGettigan, P. et al. JAMA 2006;296:1633-1644

Case-Control and Cohort Studies Reporting
on Cardiovascular Risks With Cyclooxygenase 2 Inhibitors.
McGettigan, P. et al. JAMA 2006;296:1633-1644

NSAIDs & Renal Effect
Arachidonic acid
Coxibs NSAIDs
COX-1
COX-2
PGE2 PGI2
Sodium retention Hyperkalemia Acute renal

Peripheral edema failure
 Blood pressure
CHF (rarely)
Others : Nephrotic syndrome
Brater. Am J Med. 1999;107:65S. interstitial nephritis

During pregnancy
• NSAIDs are not recommended during pregnancy,

particularly during the third trimester.
• While NSAIDs as a class are not direct teratogens, they
may cause premature closure of the fetal ductus arteriosus
and renal ADRs in the fetus. Additionally, they are linked
with premature birth.
• In contrast, paracetamol (acetaminophen) is regarded as
being safe and well-tolerated during pregnancy.
• Doses should be taken as prescribed, due to risk of
hepatotoxicity with overdoses

Acetaminophen (APAP)
• Mechanism of action unclear

• No anti-inflammatory effects
• Causes liver toxicity at high doses
– Max dose: 4 gm/day, if no liver disease
– Newest recommendation 2.6 gm/day
• Decreases opioid requirements

The effect of acetaminophen (paracetamol) on the rectal
temperature of unanesthetized rats.
Botting R M Clin Infect Dis.

2000;31:S202-S210

Paracetamol and Cox3 and Cox4
Paracetamol very likely produces analgesia and

hypothermia in mice by inhibiting COX-3 in the central
nervous system and lowering PGE2 levels.
Inhibition of an inducible COX, perhaps COX-4, may also

mediate some of the actions of paracetamol but this
putative enzyme has so far only been characterised in
isolated cells.
Botting R, et al. Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 85–87

Aspirin (Acetyl salicylate)
Actions
• Analgesic - central and peripheral action
• Antipyretic - act in hypothalamus to lower the set
point of temperature control elevated by fever, also
causes sweating
• anti-inflammatory - inhibition of peripheral
prostaglandin synthesis
• respiratory stimulation - direct action on respiratory
centre, indirectly by ↑ CO2 production

• Uricosuric effects
reduces renal tubular reabsorption of urate but treatment of
gout requires 5-8g/d, < 2g/d may cause retention of urate.
antagonises the uricosuric action of other drugs
• Reduced platelet adhesion- irreversible inhibition of COX by
acetylation, prolongs bleeding time, useful in arterial
disease
Note: low doses are adequate for this purpose since the
platelet has no biosynthetic capacity and can not
regenerate the enzyme
• Hypothrombinaemia : occurs with large doses ie >5g/day

OVERDOSAGE
• Ingestion of > 10 g can cause moderate/severe
poisoning in an adult
• Clinical features - ‘salicylism’
tremor, tinnitus, hyperventilation, nausea,
vomiting, sweating
• Management- mainly supportive

Daily Aspirin Dose and
Admission for Ulcer Bleeding
Aspirin Dose Odds Ratio (95% Cl)

75 mg (n=27) 2.3 (1.2-4.4)
150 mg (n=22) 3.2 (1.7-6.5)
300 mg (n=62) 3.9 (2.5-6.3)
Weil J et al. BMJ. 1995;310:827-830.

Risk of UGI bleeding with Different Formulations of
Low-Dose Aspirin (< 325mg)
Relative Risk Plain ASA

4
3.6
3.2 Coated ASA
2.6 2.6 2.6 Buffered ASA

2.4
550 cases of UGIB

admitted to hospital
with melena or
confirmed
hematemesis
0
Gastric bleeding Duodenal bleeding
Kelley et al, Lancet 1996; 348; 1413

Efikasi berbagai AINS berdasarkan
nilai NNT (Number Needed to Treat)
Diklofenak 50 mg
Naproksen 440 mg
Ketorolak 10 mg
Ibuprofen 400 mg
Morfin 10 mg IM
Parasetamol 650 mg + kodein 60 mg
Aspirin 650 mg
Parasetamol 1000 mg
Parasetamol 650 mg
Tramadol 75mg
0 1 2 3 4 5 6
Number Needed to Treat (NNT)

Opioids
• Originally derived from
poppies
• Body possesses
endogenous opioids
– enkephalins
– endorphins
• Opiate Receptors
– mu ()
– delta ()
Papaver somniferum
– kappa ()
– sigma ()

Pharmacology of Opioids
• 1: inhibit transmission of pain

• 2: respiratory depression, euphoria,
constipation, physical dependence
• : inhibit transmission of pain
• : inhibit transmission of pain

Pharmacology of Opioids
Image borrowed from Wyeth library

The mechanism of action of heroin at the delta (δ)
and kappa (κ) opiate receptors

Opioids Analgesics
Codeine
Low Dihydrocodeine
efficacy Dextropropoxyphene
(withdrawn)
Medium Buprenorphine
efficacy Meptazinol
Morphine
High
Diamorphine
efficacy Pethidine
Pharmacokinetic Opioid

Opioid Therapy in Pain Related to
Medical Illness
Opioid therapy is the mainstay approach for

• Acute pain
• Cancer pain
• AIDS pain
• Pain in advanced illnesses
But under treatment is a major problem

Common Side Effects of Opioids
Constipation
Nausea/Vomiting
Urticaria
Sedation
Delirium
Respiratory depression
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM R

Opioid Therapy: Drug Selection
• Immediate-release preparations
– Used mainly
• For acute pain
• For dose finding during initial treatment of chronic
pain
• For “rescue” dosing
– Can be used for long-term management in
select patients

Opioid Therapy: Drug Selection
• Extended-release preparations
– Preferred because of improved treatment
adherence and the likelihood of reduced risk in
those with addictive disease
– Morphine, oxycodone, fentanyl,
hydromorphone, codeine, tramadol,
buprenorphine
– Adjust dose every 2–3 days

Opioid Therapy and Chemical Dependency
• Physical dependence
• Tolerance
• Addiction
• Pseudoaddiction

Opioid Therapy: Monitoring Outcomes
• Critical outcomes
– Pain relief
– Side effects
– Function—physical and psychosocial
– Drug-related behaviors

Adjuvant Pain Medications
“drugs that are used

primarily for treating
conditions other than
pain, but may be
analgesic in selected
circumstances”
-AMA

Common Adjuvant Medications
• Antidepressants
• Anticonvulsants
• Corticosteroids
• Topical Anesthetics
• Calcitonin
• Bisphosphonates

Muscle Relaxant Drug
Jarir At Thobari, MD, DPharm, PhD

Mucsle relaxant
• Muscle relaxant is a term usually used to

refer to skeletal muscle relaxants (drugs),
which act on the central nervous system
(CNS) to relax muscles. These drugs are
often prescribed to reduce pain and
soreness associated with sprains, strains,
or other types of muscle injury.

Muscle Relaxants
• What are they used for?

–Facilitate intubation of the trachea
–Facilitate mechanical ventilation
–Optimized surgical working
conditions

Muscle Relaxants
• How do they work?
– Neuromuscular junction
• Nerve terminal
• Motor endplate of a muscle
• Synaptic cleft
– Nerve stimulation
– Release of Acetylcholine (Ach)
– Postsynaptic events

Clasification Skeletal Muscle Relaxants
– Peripherally acting:
• Pre-synaptic Neuromuscular blockers
– Inhibit Ach synthesis
– Inhibit Ach release
• Post-synaptic Neuromuscular blockers
– Non-depolarizing blockers (competitive)
– Depolarizing blockers
– Centrally acting
– Direct acting

Binding of Ach to receptors on muscle end-plate

Curare

Muscle Relaxants
• Non-Depolarizing muscle relaxants
– Short acting
– Intermediate acting
– Long acting
• Depolarizing muscle relaxant
– Succinylcholine

Non Depolarizing Muscle relaxant

Non-depolarizing Muscle Relaxants
• What is the mechanism of action?
– Compete with Ach at the binding sites
– Do not depolarize the motor endplate
– Act as competitive antagonist
– Excessive concentration causing channel
blockade
– Act at pre-synaptic sites, prevent movement of
Ach to release sites

Nondepolarizing Muscle Relaxants
• Long acting
– Pancuronium
• Intermediate acting
– Atracurium
– Vecuronium
– Rocuronium
– Cisatracurium
• Short acting
– Mivacurium

Depolarizing Muscle Relaxant
• Succinylcholine
– Physically resemble Ach
– Act as acetylcholine receptor agonist
– Not metabolized locally at neuromuscular junction
– Metabolized by pseudo cholinesterase in plasma
– Depolarizing action persists > Ach
– Continuous end-plate depolarization causes muscle
relaxation
• Succinylcholine
• What is the clinical use of succinylcholine?
– Most often used to facilitate intubation
• What is intubating dose of succinylcholine?

– 1-1.5 mg/kg
– Onset 30-60 seconds, duration 5-10 minutes

• Succinylcholine
– Does it has side effects?
• Prolong respiratory paralysis and apnea
• Bradycardia
• Muscle pain (due to fasciculation)
• Increase intraocular pressure (contraction
intraocular muscle during phase 1 block)
• Increase gastric pressure (vomiting)
• Increase intracranial pressure
• Hyperkalemia (due to muscle damage)
• Malignant hyperthermia (idiosyncratic)

Antagonism of Neuromuscular Blockade
Effectiveness of anti cholinesterase depends on
the degree of recovery present when they are
administered
• Anti cholinesterase
– Neostigmine
• Onset 3-5 minutes, elimination halflife 77 minutes
• Dose 0.04-0.07 mg/kg
– Pyridostigmine
– Edrophonium

– Inhibiting activity of acetylcholine esterase
– More Ach available at NMJ, compete for sites
on nicotinic cholinergic receptors
– Action at muscarinic cholinergic receptor
• Bradycardia
• Hypersecretion
• Increased intestinal tone

• Muscarinic side effects are minimized by
anticholinergic agents
– Atropine
• Dose 0.01-0.02 mg/kg
– Scopolamine
– glycopyrrolate

Reversal of Neuromuscular Blockade
• Goal : re-establishment of spontaneous

respiration and the ability to protect
airway from aspiration

Analgesics &amp; Muscle Relaxant

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Analgesics

Jarir At Thobari, MD, DPharm, PhD

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

15% moderate to severe

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Removed the cause of pain

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

I. Opioid (narcotic) analgesics

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Efficacy is similar amongst NSAIDs

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Rheumatoid Arthritis • Dysmenorhea

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Acetic acid derivatives Enolic acid derivatives

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Propionic acid derivatives Carboxylic acid derivatives

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

6-MNA = 6-methoxy-2-naphthylacetic acid;

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Lanas A Rheumatology 2010;49:ii3-ii10

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

0,0 Silverstein et al.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

15 76% reduction in upper

McGettigan, P. et al. JAMA 2006;296:1633-1644

McGettigan, P. et al. JAMA 2006;296:1633-1644

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Sodium retention Hyperkalemia Acute renal

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• NSAIDs are not recommended during pregnancy,

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Mechanism of action unclear

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Botting R M Clin Infect Dis.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Paracetamol very likely produces analgesia and

Inhibition of an inducible COX, perhaps COX-4, may also

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Aspirin Dose Odds Ratio (95% Cl)

Weil J et al. BMJ. 1995;310:827-830.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Relative Risk Plain ASA

2.6 2.6 2.6 Buffered ASA

550 cases of UGIB

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• 1: inhibit transmission of pain

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Image borrowed from Wyeth library

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Opioid therapy is the mainstay approach for

But under treatment is a major problem

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Analgesics & Muscle Relaxant

Analgesics & Muscle Relaxant