Download Analgesic Drugs

Analgesic Drugs
Dr. Chameli Deb
Ibn Sina Hospital,
Kuwait.
Pain Production
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Pain is produced by
mechanical or thermal damage to tissues
ischemia of somatic or visceral structures
spasm of smooth or striated muscles
dilatation of blood vessels of at the base of
the brain.
Substances which produce pain
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H+, K+, phosphate ions
Acetyl choline, histamine, 5HT, CCK, bradykinin
certain prostaglandin and leukotrienes
sensory neuropeptides (substance P), neurokinin A
(sub K), CGRP
• NK enhance hyper excitability of sensory neurons
which may induce Painful sensation by light touch
or pressure by A fibre.
Classification of analgesics
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1. Primary, general or non-specific
a. Opioid analgesics - Morphine
b. simple analgesics - Aspirin, Ibuprofen
2. Secondary or specific analgesics vasodilators - NTG for ischemia
• Carbamazepime for Trigeminal neuralgia
• antacids - acid peptic disease
Opioid Analgesics
• Opiate is specific term to describe drugs derived from
Opium poppy (papaver somniferum).
• Opioid describes naturally occurring semi-synthetic
and synthetic compounds that produce analgesia by
combining with Opioid receptor.
• Characteristics of Opioids
• stereo specific- activity is associated with levo rotatory
isomer
• Action is antagonised by Naloxone.
• Development of highly potent opiod analgesic indicate
that receptor mediated mechanism is involved.
Location
• Spinal Cord - Substantia gelatinosa - arrest of
noceptive input.
• Brain stem- area postrema, CTZ, tractus solitariusrespiratory control, cough reflex, nausea & vomiting
and some autonomic effects
• Hypothalamus - temperature & neuro-endocrine
function
• Medial thalamus- poorly localised deep pain
• Limbic system- influence mood & emotional aspect of
pain
• others - peri-aqueductal grey matter, cerebral cortex &
some peripheral site (GIT)
Endogenous Opiod peptides
» Receptor
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Enkephalin - delta
Endorphin - mu
Dynorphine - kappa
Nociceptin - ORL 1(orphan FQ)
• Endomorphine 1&2
precursor
-pro Enkaphalin
-pro opiomelanocortin
-pro dynorphine
Endogenous peptides are found in spinal cord
hypothalamus, pituitary gland, limbic system,
sympathetic ganglia, skin, GIT. They mediate a variety
of physiological & autonomic functions.
Structural classification of Opioid drugs
• Naturally occurring -Morphine & codeine
• Semi-synthetic Morphine analouge - Diamorphine,
Hydrocodeine, Naloxone
• synthetic - Meptazinal
Pheny piperidine - Pethidine
Anilinopiperidine - Fentanyl, Alfentanil, Sufentanil,
Remifentanil
Diphenylheptanes - Methadone, Dextropropoxyphene
Benzomorphan derivatives - Pentazocine, Levorphanol
Thebaine derivatives - Buprenorphine
Functional classification of Opioid drugs
Receptor Agonist
Partial agonist
mu
Buphrenorphine
Butorphanol
Naloxone
Naltrexone
Naloxonazine
B- Funaltrexamine
Nalorphine
Pentazocine
Nalbuphine
Naloxone
Naltrexone
B-Endorphin
Endomorphine
Morphine
Pethidine
Methadone
Fentanyl
kappa
Dynorphin
Morphine
Pentazocine
delta
Leu-enkephalin
Meta-enkephalin
Antagonist
Naloxone
Naltrindole
Mechanism of Action
• Opioids bind to mu, delta or kappa receptor and acts
via inhibitory G protein.
• On pre synaptic terminal of primary nociceptive
afferent, inhibition of calcium influx prevents
excitatory neuro transmitter release
• On post synaptic terminal increased potassium efflux
cause hyper polarisation making it less excitable.
• Inhibition of Adenyl Cyclase, decrease cAMP and
decrease alteration of ion channels.
• Activation of descending inhibition by stimulating the
cells in PAG which relay to the Raphi Neucli of medulla
thence to dorsal horn, reduces nociceptive input.
Morphine
• Natural alkloid
• Phenanthrene derivative
• Piperidine skeleton
• Amphoteric molecule
Action
• Analgesia
• Sedation - drowsiness, sleep, euphoria
- dysphoria in absence of pain
EEG
- delta rhythm - increase voltage low frequency wave
- suppress REM sleep,
• Respiratory depression - decrease rate and depth, ventilatory
response to Pco2 and the curve shift to the right & slope decrease.
Suppression of protective reflexes.
• Anti-tussive
Cardiovascular System
• Bradycardia
• Hypotension
• Vasodilatation
due to
decreased sympathetic drive
vagal effect, no myocardial depression
histamine release
Histamine release - causes vasodilatation, hypotension,
bronchospam, itching (nasal), pruiritis.
Atropine partially antagonises these effects.
Ocular
miosis is caused by stimulation of Edinger Westphal nucleus,
depression of supra nuclear pathway or central symphathetic
activity. Pinpoint pupil are characterstic of morphine poisoning
GIT
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Opioids cause:
delayed gastric emptying
constipation
decreased secretions
increased biliary tone
Hormonal
• increased ADH secretion
• decreased release of ACTH, Prolactin and Gonadotrophic
hormones
Muscle rigidity
may involve inhibition of Dopamine release & GABA pathway.
True convulsions rarely occurs.
Others - constipation, spasm of ureter, bladder & uterus
Pharmacokinetics- Morphine
• Morphine is a weak bases- highly ionised in stomach.
• Bio-availability 15-50%.
• Extensively metabolised by liver to Morphine 6 glucuronide
& Morphine 3 glucuronide. Undergo entero-hepatic
circulation.
• CNS level lags behind behind the plasma level.
Pharmacokinetics of opioids
• Weak bases pK - 6.5 - 9.3
• Considerable first pass
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/ lipid solubility
Distribution depends on --------- degree of ionisation
\ plasma protein binding
predominantly inactivated in the liver by conjugation
to active or inactive metabolites & are excreted in the urine or bile
Most Opiods have a volume of distribution several times greater
than total body water.
Total clearance similar to hepatic blood flow. Entero- hepatic
circulation is present for Morphine metabolites. May accumulate
& cause respiratory depression.
Accumulation of Norpethidine with half life 5 times that of
Pethidine. May cause agitation & convulsions.
Tolerance and Dependence
Tolerance occurs for all opioid effects except constipation & miosis.
Mechanism- decreased production of endogenous opiods
down regulation of receptors
Glutamate mediated transmission via NMDA
Dependence - physical & psychological
withdrawal symptoms - nausea, vomiting, diarrhoea
- restlessness, insomnia
- pupillary dilation
- fever, sweating , lacremation
- severe muscle cramps
symptoms are maximum at 2 days and lasts for 8-10 days,
but some residual symptoms lasts for several weeks.
Pharmacokinetics
Drug
Lipid solu. Vol. Of dist Clearance t1/2
pKa % ionised prot. Binding
----------------------------------------------------------------------------------------------------------------------------- -Morphine
1
3.5
15
3
7.9
76
25-35
Pethidine
30
4
12
4
8.7
95
40-50
Diamorphine
200
0.6-0.8
31
2-3.5
7.8
----
----------
Fentanyl
580
4
13
3.5
8.4
91
80
Alfentanil
90
0.8
6
1.6
6.5
11
90
Sufentanil
1285
2.9
0.75
2.5
8
----
92
Remifentanil
50
0.4
50
0.06
7.1
35
70
Tramadol
1
3.1
6
5
4.5
0.1
Naloxone
----
2
25
1
---
-------
--------45
Diamorphine - Diacetyl Morphine (Heroin)
• Pro-drug
• MAM
• 1.5 - 2 times more potent
Codeine (3 - Methyl Morphine)
• pro drug
• higher bio-availablity.
• less effective against pain. 10% metabolised to parent drug by
CYP 2 D6.
• Used in head injury, combined with NSAID’s, anti-diarrhoeal
prepartion & as an anti-tussive.
Papaveretum - semi-synthatic hydrochloride mixture of
natural alkloids. Morphine + Codeine + Papaverine + Noscapine.
Phenylpiperidine derivatives
• Pethidine, Fentanyl, Alfentanil, Sufentanil, Remifentanil &
Tramadol
• Except Pethidine others have similar pharmacokinetic properties.
• They are pure mu agonist & highly lipophylic.
• Highly potent intravenously and have faster onset of action.
• Shorter duration of action ( context sensitive half life is prolonged
except Remifentanil).
• Minimal CVS side effects except some bradycardia. Effectively
attenuates the response to larngoscopy.
• All cause chest wall rigidity & respiratory depression.
• Metabolised mainly in liver except Remifentanil. Clearance is
largely unaffected by renal disease, but prolonged in cirrhosis.
• Concomitant use with MAOI is contraindicated.
Pethidine
• Pethidine has anti cholinergic property - tachycardia
and less miosis.
• orally absorbed
• less potent
• elimination half life of metabolites increase with renal
dysfunction.
Pure Opioid antagonist
Naloxone
• N-allyl derivative of Oxymorphone
• pure Opioid antagonist. Has high affinity for mu receptor.
• No intrinsic activity
• Naloxone reverses the respiratory depression & analgesia of
Opioids and precipitate withdrawal in addicts.
• Naloxone reversal usually lasts for 30-45 min. So repeat dosage
may be needed to sustain the effect for reversal of respiratory
depression. Also alleviate pruritis & urinary retention symptoms.
Naltrexene
• longer acting. Orally effective due to low first pass. T1/2 -8 hrs.
• It is used as maintenance therapy in detoxified addicts.
Spinal Epidural Opiods
Advantages
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low dosage
prolonged analgesia
no hpotension
no motor block
Disadvantages
• respiratory depression
• pruritis
• urinary retention
NSAID s’
• Heterogeneous class of drugs with common anti inflammatory,
analgesic & antipyretic properties.
• Mechanism of action - by inhibition of enzyme Cyclo Oxygenase
which reduces PG synthesis.
• PGs’ are part of a large family of unsaturated fatty acids present
in all organs. They are involved in modulation of pain at the
periphery & central sites.
• PGs’ sensitise primary nerve ending to analgesic action of agents.
• Cyclo Oxgenase is thought to exist as two iso enzymes.
• Cox -1 (constitutive) is important to physiological homeostasis
• Cox -2 (induced) when tissues are exposed to inflammatory
reaction.
Synthesis of Prostaglandins
Membrane Phospholipids
| PLA2
Inactive metabolite ------Archidonic Acid --------------Leukotrienes
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|PG synthetase
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(COX)
LTC4 & LTD4
Cyclic Endoperoxidase
Platelet
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Throboxane /
synthetase
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Tx A2
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Tx B2
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Mast cell
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PG2 & PgF2 alpha
\Vs. Endothelium
\ Prostacyclin synthetase
\
\
Prostacyclin
PG I2
Classification of NSAIDs
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Salicylic acid derivatives. e.g. aspirin
para-Aminophenol derivatives, e.g. paracetamol
Arylpropionic acids, e.g. ibuprofen
indole and indene acetic acids, e.g. indomethacin
Heteroaryl acetic acids, e.g. diclofenac, ketorolac
Anthranilic acids (fenamates), e.g. mefenamic acid
Enolic acids, e.g. piroxicam, phenylbutazone
Alkanones, e.g. nabumentone
Pharmakokinetics of NSAIDs
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weak organic acids (pKa 3-5)
rapidly absorbed orally
low first pass & high oral bioavailablity
highly protein bound & have the potential to displace other drugs
from plasma proteins. So potentiating the effects of these drugs,
e.g. oral anticoagulant, anticonvulsant, Lithium, oral
hypoglycaemic agents.
• low volume of distribution.
• In general NSAIDs are eliminated by hepatic bio-transformation,
followed by renal excretion
Clinical effects of NSAIDs
• The ubiquitous nature of PGs in the maintenance of normal
homeostasis explains their diverse range of effects.
CNS: NSAIDs are thought to be primarily peripherally acting
drugs due to their protein binding, low lipophilicity & polar
nature .
• provide analgesia for moderate to severe pain
• various degree of opiod sparing effect of upto 60%
• adverse effects include dizziness, depression, depression,
confusion & seizures
Respiratory System:
• Bronchospasm in susceptible individuals.
• Various hypersensitivity reaction, urticaria, rashes & angiooedema have been reported
Clinical effects of NSAIDs
GIT
• causes dyspepsia, gastroduodenal erosions, ulcerations,
perforation & diarrhoea.
• GI damage is common in - women, age > 60 yrs, pr. h/o of peptic
ulcer, smoker & alcohol ingestion.
• co-administration of PG E2 analogue, Misoprostol may be
effective in preventing ulcerations.
Renal
• NSAIDs impair renal function & may cause acute renal ischaemia
>> ATN >> Renal failure.
• Risk factors - elderly, dehydration, hypovolaemia, hypotension,
cardiac failure, cirrhosis & co administration of ACE inhibitors &
diuretics.
• Analgesic Nephropathy is a severe & often irreversible form of
NSAID induced renal toxicity mostly due to long term
consumption leading to ch. Nephritis & Renal papillary necrosis.
Clinical effects of NSAIDs
Haematologcal
• NSAIDS interfere with platelet aggregation.
• Coagulation time is not affected & bleeding time remains
within normal range.
• Bone marrow dyscrasias can occur.
Antipyretic effect is a consequence of central prostaglandin
inhibition in hypothalamus. Reset the thermostat at higher level.
Anti inflammatory
Other effects: some NSAIDs delay the closure of Ductus Arteriosus
in neonate if used in pregnancy in some CDH to buy time before
surgical correction.
Aspirin
• Rapidly absorbed from the stomach
• 50% potent & toxic than Sodium salicylate.
• On absorption rapidly hydrolysed to salicylate ions by esterase
enzymes.
• Mainly metabolised in liver to Salicylic acid & Glucuronic acid.
• 60-90% is found in urine as free form when urine is alkaline.
• 70% 0f patients on Aspirin lose 5-10 ml of blood per day.
• Aspirin induced asthma affects 10-20% of adults with asthma &
can be fatal.
• Aspirin interferes with platelet aggregation & adhesion by
irreversible inhibition of Cox & the effect last for the life time of
platelets (7-10 days).
• As low as 75 mg/day has been shown to reduce TIA, secondary MI
& has been used following CABG, angioplasty.
Aspirin
• Salicylism: This is a syndrome of Tinnitus, dizziness, deafness,
sweating, hyperventilation, nausea & vomiting due to chronic
ingestion at large doses. When blood level is 300 ug/ml or more.
• Aspirin is contraindicated in children <12 years (except for
Juvenile Arthritis) due to malignant rise in ICP following acute
viral illness. Mortality 20-40%.
• Overdose of Aspirin cause complex acid base imbalance.
Respiratory alkalosis by direct stimulation of respiratory centre.
Respiratory acidosis
Metabolic acidosis
• In children hyperventilation is rare & usually present with
respiratory depression( metabolic & respiratory acidosis).
• Treatment - includes gastric lavage, forced alkaline diuresis,
haemodialysis & charcoal haemoperfusion.
Selectivity of action
Drug
Aspirin
< 3 gm/day
> 3 gm/day
Paracetamol
Phenylbutazone
Indomethacin
Ibuprofen
Diclofenac
Ketorolac
Analgesic
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+
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Antipyretic
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Anti inflammatory
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-+++
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+
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+
Metabolism of Paracetamol
1-5%
PCM ---------------------------->Toxic metabolite
/ \
(N-acetyl-paramino-benzoquinonine)
/
\
/\
60% /
\ 35%
/ \
Glutathione
/
\
/
\
/
/
\
/
\__SH group
/
\
/
\
\
Gluoronide
Sulphate
/
\ N-actely cysteine
conjugate
conjugate /
\
/
\
Hepatocellular
conjugated & excreted
damage
Treatment - Paracetamol toxicity
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N-acetyl cysteine (12-15 hours)
Methionine
Cysteamine
Gastric lavage < 4 hrs.
Vit. K & other clotting factors
Symptomatic care
Specific Analgesics
• Migraine --------------------> 5HT agonist, Ergot alkaloids,
NSAIDs’
• Trigeminal neuralgia ----> Carbamazepine
• Paget’s disease -------------> Calcitonin
• UMN lesion torticollis ----> Baclofen
Benodeanpin
• Vasospasm,ischemia ----->
Vasodialator