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AnalgesicsAnalgesics

..

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Analgesic

The major classes

1. Paracetamol and NSAIDs

2. COX-2 inhibitors

3. Opiates and morphinomimetics

4. Specific agents

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Analgesicsanalgesics (also known as a painkillers) area group of drugs used to relieve pain (achieveanalgesia). Analgesic drugs act in various ways

on the peripheral and central nervous systems;they include paracetamol (acetaminophen), thenon-steroidal anti-inflammatory drugs (NSAIDs),narcotic drugs such as morphine, synthetic

drugs with narcotic properties such astramadol, and various others.

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Mode of action

Most NSAIDs act as non-selective inhibitors ofthe enzyme cyclooxygenase, inhibiting boththe cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2) isoenzymes.Cyclooxygenase catalyzes the formation ofprostaglandins and thromboxane from

arachidonic acid (itself derived from the cellularphospholipid bilayer by phospholipase A2).

Prostaglandins act as messenger molecules inthe process of inflammation.

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PGsof lipid compounds that are derivedenzymatically from fatty acids and haveimportant functions in the body.

Prostaglandins are found in most tissues andorgans. They are produced by all nucleatedcells except lymphocytes.

They are lipid mediators that act upon platelets,endothelium, uterine and mast cells.

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Biosynthesis of PGs

phospholipid (in cell wall lipid) -------(phospholipase A

2)

arachidonic acidPGsynthasecox1 &2 Prostaglandins

leukotrines

prostacyclin thromboxane

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Classes of NSAIDs SalicylatesSalicylates Acetylsalicylic acid (Aspirin)

Methyl salicylate

Magnesium salicylate

Arylalkanoic acidsArylalkanoic acids Diclofenac Bromfenac

Indomethacin

Sulindac

Tolmetin Arylpropionic acidsArylpropionic acids

(profens)(profens) Ibuprofen

Fenoprofen

Ketoprofen

Arylanthranilic acids (Arylanthranilic acids (fenamic acidsfenamic acids))

Mefenamic acid

Meclofenamic acid

Pyrazolidine derivativesPyrazolidine derivatives Phenylbutazone

Phenazone

Sulfinpyrazone

OxicamsOxicams

Piroxicam Meloxicam

COX-2 inhibitorsCOX-2 inhibitors Celecoxib

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Pharmacokinetics

Most NSAIDs are weak acids, They areabsorbed well from the stomach and intestinalmucosa. They are highly protein-bound in

plasma (typically >95%), usually to albumin.Most NSAIDs are metabolized in the liver toinactive metabolites which are typicallyexcreted in the urine .

Ibuprofen and diclofenac have short half-lives(2-3 hours). Some NSAIDs (typically oxicams)have very long half-lives (e.g. 20-60 hours).

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Adverse effects of

NSAIDsThe two main adverse drug reactionsassociated with NSAIDs relate togastrointestinal (GI) effects and renal effects of

the agents.These effects are dose-dependent, and in

many cases severe enough to pose the risk ofulcer perforation, upper gastrointestinal

bleeding, and death, limiting the use of NSAIDtherapy.

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Adverse effects CONT

1. Dyspepsia, nausea and vomiting. Gastric damagemay occur in chronic users, with risk of haemorrhage.

The cause is suppression of gastroprotectiveprostaglandins in the gastric mucosa.

2. Skin reactions.3. Reversible renal insufficiency. Seen mainly in

individuals with compromised renal function when thecompensatory prostaglandin E2-mediatedvasodilatation is inhibited.

4. Analgesic-associated nephropathy . This canoccur following long-continued high doses of NSAIDsand is often irreversible.

5. Liver disorders, bone marrow depression.Relatively uncommon.

6. Bronchospasm. Seen in 'aspirin-sensitive'

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opioid analgesicAn opioidis a morphine - acting analgesic, usedfor pain relief. These agents work by binding toopioid receptors, which are found principally in

the CNS and the GIT. The receptors in thesetwo organ systems mediate both the beneficialeffects, and the undesirable side effects.

There are three principal classes of opioid

receptors , , , (mu, kappa, and delta).

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classes of opioidsThere are a number of broad classes of opioids:2. natural opiates, including morphine, & codeine

3. semi-synthetic opiates, created from the

natural opioids, such as hydromorphone,desomorphine, diacetylmorphine (Heroin ).

4. fully synthetic opioids, such as fentanyl,pethidine, methadone, tramadol .

NOTE: endogenous opioid peptides, producednaturally in the body, such as endorphins,enkephalins, dynorphins, and endomorphins.

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indications for opioidsThe sole clinical indications for opioids in the UnitedStates, are:

2. Analgesia i.e. to combat pain of various types and

induction and the continuance of anesthesia as wellas allaying patient apprehension right before theprocedure. Fentanyl, oxymorphone, hydromorphone,and morphine are most commonly used for thispurpose, in conjunction with other drugs such asscopolamine, short and intermediate-actingbarbiturates, and benzodiazepines, especiallymidazolam which has a rapid onset of action andlasts shorter than diazepam or similar drugs.

3. Cough (codeine, dihydrocodeine )

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Indications for

opioids.cont.

3.Diarrhea (generally loperamide,diphenoxylate) but , morphine may beused in some cases of severe diarrhealdiseases)

Diarrhea of Irritable Bowel Syndrome(Codeine, diphenoxylate, loperamide)

4.Anxiety due to shortness of breath(oxymorphone and dihydrocodeine only)

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Adverse effects

nausea and vomiting, drowsiness, itching, drymouth, miosis, and constipation. Fortunately,

most of these are not a problem . Infrequent adverse reactions in patient

taking opioids for pain relief: Theseinclude:

dose-related respiratory depression (see below),

confusion, hallucinations, hypothermia,bradycardia/tachycardia, orthostatic hypotension,dizziness, headache, urinary retention, ureteric orbiliary spasm, muscle rigidity, myoclonus (withhi h doses), and flushin .

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Adverse effectsCONT. Opioid-induced hyperalgesia has been

observed in some patients, wherebyindividuals using opioids to relieve pain may

paradoxically experience more pain as aresult of their medication. This phenomenon,although uncommon, is seen in somepatients,when dose is escalated rapidly.

Both therapeutic and chronic use of opioidscan compromise the function of the immunesystem. Opioids decrease the proliferation ofmacrophages and lymphocytes, and affect

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Tolerance is the process wherebyneuroadaptation occurs (through receptordesensitization) resulting in reduced drug

effects. Tolerance is more pronounced for someeffects than for others - tolerance occursquickly to the effects on mood, itching, urinaryretention, and respiratory depression, but

occurs more slowly to the analgesia and otherphysical side effects.

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Tolerance..CONT.Tolerance to opioids is attenuated by a number

of substances, including :

calcium channel blockers.

intrathecal magnesium and zinc .

NMDA* antagonists such as ketamine.

All can be used to reduce tolerance to opioid

drugs.

*NMDA receptor antagonists are a class of anesthetics that work toantagonize, or inhibit the action of, the N-methyl d-aspartatereceptor (NMDAR).

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Dependence

Dependence is characterised by extremelyunpleasant withdrawal symptoms that occur if

opioid use is abruptly discontinued aftertolerance has developed.

Addiction is the process whereby physicaland/or psychological dependence develops to adrug - including opioids. The withdrawalsymptoms can reinforce the addiction, drivingthe user to continue taking the drug.

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Treating opioid adverse

Nausea& Vomiting: haloperidol,ondansetronare very effective

Drowsiness: oxycodone

Itching: fexofenadine

Constipation :stool-softeners

Respiratory depression: respiratory stimulant

currently approved for this purpose isdoxapram. tolerance to respiratory depressionoccurs rapidly, so that it is not a clinicalproblem

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Contraindications for

Some opioids are relatively contraindicated inrenal failure because of the accumulation ofthe parent drug or their active metabolites

(e.g. morphine and oxycodone). Age (young orold) is not a contraindication to strong opioids.Some synthetic opioids such as pethidine havemetabolites which are actually neurotoxic and

should therefore be used only in acutesituations.