Dr. Jannatul FerdoushAssistant ProfessorDepartment of Pharmacology

Pain

Unpleasant sensory & emotional experience

associated with actual or potential tissue damage.

Component of pain:

Perception of pain- drugs act on this by

increasing threshold for pain

Emotional response

Component of regulationPeripheral factor: Tissue damage ↓ Release of certain factor bradykinin, PG

Brady kinin- pain producing subs.PG- for inflammation PGE1 & PGI2 is responsible.Bradikinin sensitize PG to produce pain.

For pain relief:Antagonist of BK ( not available)PG synthesis Blocker –NSAID-act by inhibiting Cyclooxygenase or

PG synthase.

Central regulation of painPain R are distributed in pain pathway,

hypothalamus, limbic system, spinal cord.

Brain

Nociceptive pathway(spinal, supraspinal- thalamus, cortex)

Spinal cordglutamate,Subs P, neurokinin, NO

BK, 5HTPG

Afferent nerve

(-) NSAID

Periphery

Opioids stimulates

DescendingInhibitoryPathway(Enchephalin,5HT, NE)

Dorsal horn

Pain pathway

Tissue injury

We can block nociceptive pathway Peripheral R Ascendind pain pathway

Pain transmitted by Pain inhibited by NO Opiates Glutamate Enkaphalin Subs P 5HT,

GABA,NE

Classification of AnalgesicBased on – Peripherally acting -Centrally acting

Peripheally acting : NSAID or non narcotic analgesic (Block

nociceptive impulse) e.g. Paracetamol, Diclofenac, Ibuprofen

Centrally acting: Narcotic analgesic ( act on opioid R act mainly on neuronal

pathway - Spinal, Supraspinal)

Choice of analgesicDepends on: Origin – visceral / somaticSeverity of pain (mild,moderate, severe)

Mild pain: Headache, Myalgia Non narcotic analgesic: 1)Paraceatamol, if not response – 2)antiinflammatory drug- ketoprofen, ibuprofen3)Then diclofenac

If visceral pain : opioid analgesicMild to moderate pain with an antiinflammatory

componant, generally chronic pain E.g. RAUse: NSAID + low efficacy opioid

• Severe Pain:If visceral (acute pain) MI , biliary colic etc.Use: opioid analgesic- morphine ,pathedrinePurely visceral with an antiinflammatory componant:Gout, bone metastesis, post operative pain

Intolarable Pain: High efficacy opioid analgesic + anxiolytic , sometimes

adjuvant drug.

Neuropathic painNeurological damage to the nervous system Drug use which inhibit pain pathway.

e.g. 5HT agonist.

Narcotic:

Depress CNSProduce sedation & drowsinessAct by central mechanismThey also cause euphoria, physical

dependence & tolerance.

Non-narcotic: Act chiefly peripherallyRelief somatic pain (muscle,joint, skin)Do not produce physical dependence &

tolerance

Adjuvant Medication

Usually not used for pain but rather for other management.

They are not themselves analgesic, though they may modify the perception or the concomitants of pain that make it worse (anxiety, fear, depression), e.g. psychotropic drugs, steroid, antidepressant.

They may modify underlying cases, e.g. spasm of smooth or of voluntary muscle eg. Local anasthetics,alpha 2 agonist

Mechanism of pain

Noxious stimuli(temp, mechanical , chemical) ↓Stimulate sensory R (periphery)(1st order neuron) ↓Transmitted to lateral spinothalamic tract or

spinal cord (2nd order neuron)

↓ Thalamus (interation) ↓ Sensory area of cortex( interpretetion)( area no 1,2,3 Post cetral gyrus)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Chemical classification –

Para-amino phenol derivatives : Paracetamol (acetaminophen)

Salicylic acids :Aspirin, Diflunisal, Benorilate

Acetic acids : Indomethacin, Sulindac, Diclofenac sodium, Etodolac, Ketorolac

Fenamic acid :Mefenamic acid, Meclofenamic acid

Propionic acids :Ibuprofen, Ketoprofen, Fenoprofen,

Naproxen, Flurbiprofen, Oxaprozin

Enolic acids :Piroxicam, Meloxicam, Nabumetone

NSAIDs may be categorized according to their COX specificity as:

COX-2 selective compounds-

CelecoxibEtorocoxib

NON-selective – all other NSAIDs.These drugs inhibit COX-1 as much, or even more than, COX-2.

According to potency of anti-inflammatory effect:

Strong anti-inflammatory drug: IndomethacinPiroxicamAspirinDiclofenacTenoxicum

Moderate anti-inflammatory drug: NaproxenKetoprofen Ibuprofen

Weak anti-inflammatory drug: Paracetamol is not a NSAID.

Most of the NSAIDs have three major types of effect:

Anti-inflammatory effects:

In acute inflammation

PGE2 & PGI2 generated by local tissue & PGD2 released by mast cell

↓These are powerful vasodilator and potentiate other

inflammatory Vessodilatator ( Histamine and bradykinin) ↓ the combined dilator action on precapillary arterioles cause

redness & ↑ blood flow in the areas of inflammation. ↓Blocks PG synthesis and thereby suppress pain, swelling, ↑

blood flow associated with inflammation

NSAIDs have some general properties in common:

All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone pro-drug that is metabolized to the acidic active drug.

Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms & others by direct glucoronidation (phase II) alone

Metabolism proceeds, in large part, by way of P450 enzymes in the liver

Pharmacokinetics of NSAIDs

Renal excretion is the most important route for final elimination

Nearly all undergo varying degrees of biliary excretion & reabsorption (enterohepatic circulation)

Most of the NSAIDs are highly protein bound (98%), usually to albumin

All NSAIDs can be found in synovial fluid after repeated dosing

Analgesic actionTrauma

↓Pain↓

Tissue damage ↓

Liberation of chemical sustance bradykinin & prosglandin.

↓Bradykinin sensitize pain R to PG.

↓NSAID blocks PG synthesis

↓Relieve of pain

Antipyretic effect

Normal body temperature regulates a center of hypothalamus .

Inflammatory reaction bacterial endotoxin

release of a pyrogen-IL-1 from macrophage stimulate the generation of PGE2 in hypothalamus Disturbance of this hypothalamic ‘thermostate’ leads to the set point of body temperature being raised causes the elevation of the set-point for temperature fever

So, NSAID inhibit PGE2 production & release in the hypothalamus antipyretic effect

Anti-platelet action Low dose Aspirin

Primary dysmennorhea:

Mefenamic acid is used to reduce the production of PGs

by the uterus which cause uterine hypercontractility &

pain.

Patency of the ductus arteriosus:

As PGs maintain the patency, indomethacin given to a

new-born child with a patent ductus arteriosus can

result in closure, avoiding the alternative of surgical

ligation

Unwanted effects of NSAIDs

Unwanted effects of NSAIDs

Renal effect: Prolong high dose of NSAID

↓ ↓PGI2

↓ No renal Vessodilatation

↓ Renal ischemia

↓↓GFR

↓ Na & water retention

↓ HTN, HF aggravates.

NSAID induce gastric ulcer:

Aspirin which is acidic drug remains unionized in gastric acidic environment.

So, drug enters into cell by simple diffusion

In cell pH is high, the drug become ionized & trapped & cannot diffuse back. So an ion trapping occur and this may cause gastric erosion, ulceration.

Drug interactions of NSAIDs

NSAID + Warfarin: the risk of hemorrhage.

NSAID + Antidiabetics: Azapropazone & phenylbutazone inhibit the metabolism of sulfonylurea hypoglycemics, their toxicity

Aspirin + phenytoin, valproic acid: the plasma conc. of phenytoin, valproic acid

Antihypertensives: Their effect is lessened due to sodium retention by inhibition of renal PG formation

Diuretics: NSAIDs causes Na+ retention & reduce diuretic & antihypertensive efficacy

Lithium: NSAIDs delay the excretion of lithium by the kidney & may cause lithium toxicity

ACEI & angiotensin II antagonists: there is a risk of renal impairment & hyperkalemia

Caution & contraindications

In the elderly, allergic disorders, during pregnancy & breast feeding, & coagulative defects.

In patients with renal, hepatic or cardiac disease.

• In patient with bronchial asthma –

• NSAIDs or aspirin block the COX-1enzyme →↓ TXA2 & PGE2→ overproduction of leukotrienes & produces the severe asthma and allergy-like effects.

Over expression of both the LT R & the LTC4 synthase enzyme in respiratory tissue from patients with aspirin-induced asthma, cause ↑ response to LT & ↑ production of LT.

Paracetamol

Acetaminophen inhibits PG synthesis in the CNS.

This explains its antipyretic & analgesic properties.

Acetaminophen has less effect on COX in peripheral tissues,

which accounts for its weak anti-inflammatory

Inactivated in the liver principally by conjugation as glucoronide & sulphate.

Minor metabolites of paracetamol are also formed N-acetyl-p-benzoquinoneimine (NABQI), is highly reactive chemically.

This substance is normally rendered harmless by conjugation with glutathione.

• At normal doses of paracetamol, the NABQI reacts with the sulfhydryl group of glutathione, forming a nontoxic substance.

• But the supply of hepatic glutathione is limited & In overdose,

• NABQI formed is greater than the glutathione available,

then the toxic metabolite accumulates & reacts with nucleophilic constituents in the cell.

• The excess metabolite oxidises thiol (SH-) groups of key enzymes, which causes cell death.

• Cause hepatic & renal tubular necrosis.

Paracetamol poisoningTreatment –

Gastric lavage followed by oral activated charcoal if ingested within 1 hour

liver damage can be prevented by giving agents that increase glutathione formation in the liver (acetylcysteine intravenously, or methionine orally)

If more than 12 hours of ingestion of a large dose, the antidotes, which themselves can cause adverse effects (nausea, allergic reactions), are less likely to be useful

Aspirin (acetylsalicylic acid) is the prototype of traditional NSAIDs

The bark of the willow tree (Salix) contains salicin from which salicylic acid is derived; it was used for fevers in the 18th century as a cheap substitute for imported cinchona (quinine) bark

Rarely used as an anti-inflammatory medication; it has been replaced by ibuprofen & naproxen

Effective, available as OTC & safe .

Aspirin

Aspirin is a weak organic acid

Irreversibly acetylates (& thus inactivates) COX, so preventing the formation of products including thromboxane, prostacyclin & other PGs

The other NSAIDs, including salicylate, are all reversible inhibitors of COX.

Aspirin is rapidly deacetylated (hydrolysed) by esterases in the plasma, producing salicylate

Has anti-inflammatory, anti-pyretic & analgesic effects but additionally exerts important effects on respiration, intermediary metabolism & acid-base balance

Mode of action of aspirin

Actions of aspirin:Aspirin has 3 major therapeutic actions –

They reduce - Inflammation (anti-inflammation) Pain (analgesia)Fever (antipyrexia)

Anti-inflammatory action: Nonselective inhibitor of both COX isomers. irreversibly inhibits COX activity the formation of PGs &, thus, modulates those aspects

of inflammation in which PGs act as mediators.

Antiplatelet action: Low doses (75mg daily) of aspirin can irreversibly inhibit

TXA2 production in platelets without markedly affecting PGI2 production in the endothelial cells of the blood vessel.

As a result of the in TXA2, platelet aggregation (the 1st step in thrombus formation) is reduced, producing an anticoagulant effect with a prolonged bleeding time.

• The acetylation of COX is irreversible. Because platelets lack nuclei, they cannot synthesize new enzyme, & the lack of TXA2 persists for the lifetime of the platelet (3-7 days). This contrasts with the endothelial cells, which have nuclei &, therefore, can produce new COX.

Respiratory action: At therapeutic doses, aspirin alveolar ventilation. Salicylates uncouple oxidative phosphorylation elevated

CO2 respiration. Higher doses work directly on the respiratory center in the

medulla, resulting in hyperventilation & respiratory alkalosis that is usually compensated by the kidney ( bicarbonate excretion).

At toxic levels, central respiratory paralysis occurs, & respiratory acidosis ensures due to continued production of CO2

GIT effects: PGI2 inhibits gastric acid secretion.

PGE2 & PGF2α stimulate synthesis of protective mucus in both the stomach & small intestine.

Aspirin (-) PG synthesis → gastric acid secretion & mucus protection

Actions on the kidney: COX inhibitors prevent the synthesis of PGE2 & PGI2 –

PGs maintain renal blood flow, particularly in the presence of circulating vasoconstrictors.

synthesis of PGs can result in retention of sodium & water & may cause edema & hyperkalemia in some patients.

Aspirin in high dose reduces renal tubular reabsorption of urate

Low dose (< 2g/d) inhibit urate secretion, causing urate retention

Dosage of aspirin:

75-300 mg/d are used routinely to prevent thromboembolic vascular occlusion;

Low doses (75mg or 100mg) are to be prescribed following bypass surgery & post MI

300 mg as immediately after the diagnosis of IHD. Aspirin decrease the mortality after MI;

300-900 mg every 4-6 hourly when necessary for analgesia

Salicylates, especially methyl salicylates, are absorbed through intact skin.

Aspirin has a PKa of 3.5. After oral administration, in the stomach aspirin is un-ionised & thus lipid-soluble & diffusible.

In gastric epithelial cells (PH 7.4) it will ionise, become less

diffusible & so harms, the gastric mucosa.

In the body aspirin is metabolised to salicylic acid (Pka 3.0), which at PH 7.4 is highly ionised & thus remain in the ECF.

salicylic acid in the plasma are filtered by the glomeruli & pass into the tubular fluid, which is generally more acidic than plasma & causes a proportion of salicylic acid to become un-ionised & lipid-soluble so diffuses back into the tubular cells.

P/K of aspirin

At normal low dosages (650 mg/d), aspirin (half-life 15 minutes) is hydrolysed to salicylate & acetic acid by esterases in tissues & blood.

Salicylate is converted by the liver to water-soluble conjugates (glycine conjugation) that are rapidly cleared by the kidney, resulting in elimination with first-order kinetics & a serum half-life of 3.5 hours.

At anti-inflammatory dosages (> 4g/d), the hepatic metabolic pathway becomes saturated, & zero-order kinetics are observed, with the drug having a half-life of 15 hours or more

Salicylate is an organic anion & in addition to undergoing glomerular filtration, is secreted by the proximal renal tubule

Alkalinising the urine with sodium bicarbonate causes more salicylic acid to become ionised & lipid-insoluble so that it remains in the tubular fluid, & is eliminated in the urine

Most absorption of aspirin, however, occurs in the ileum because of the extensive surface area of the microvilli

Rectal absorption of salicylates is slow & unreliable, but it is a useful route for administration to children with vomiting. Salicylates (except diflunisal) cross both BBB & the placenta.

GIT: Epigastric distress, nausea, vomiting

Blood: prolonged bleeding time due to (-) platelet aggregation. Should not be taken for at least one week prior to surgery.

Allergy: severe rhinitis, urticaria, angioedema, asthma or shock. Those who already suffer from urticaria, nasal polyps or asthma are more susceptible

Adverse effects of aspirin

Salicylism: occurs with repeated ingestion of large doses of

salicylate. It is a syndrome consisting of tinnitus (a high-pitched

buzzing noise in the ears), vertigo, hearing, dizziness, headache & confusion.

Sometimes also nausea & vomiting

Reye’s syndrome: Rare disorder in children. It is a combination of liver disorder & encephalopathy

(CNS disturbances) that can follow an acute viral illness & has a 20-40% mortality.

Should not be given to children under 12 years unless specially indicated, e.g. for juvenile arthritis, should be avoided in those up to & including 15 years (paracetamol is preferred)

Respiratory alkalosis develops: Salicylates uncouple oxidative phosphorylation (mainly

in the skeletal muscle) → O2 consumption & production of CO2. This stimulates respiration, which is also stimulated by a direct action on the respiratory center.

The resulting hyperventilation causes a respiratory alkalosis that is normally compensated by renal mechanisms involving HCO3

- excretion

The blood pH thus rises, & renal loss of HCO3- is

accompanied by Na+ & K+ as well as water; dehydration & hypokalemia result

Salicylate poisoning

Metabolic acidosis : Accumulation of lactic & pyruvic acids due to

interference with TCA cycle enzymes stimulation of lipid metabolism causing

production of ketone bodies. Late toxic respiratory depression may also cause

CO2 retentionSalicylate poisoning -More serious in children than in adults. -The acid-base disturbance seen in children is

usually a metabolic acidosis whereas that in adults is a respiratory alkalosis

Treatment:Activated charcoal: adsorbs salicylate & prevents

its absorption from the alimentary tract; gastric lavage or the use of an emetic is no longer recommended

Correction of dehydration: alkalosis or mixed alkalosis/acidosis need no specific treatment.

Metabolic acidosis is treated with sodium bicarbonate, which alkalinises the urine & accelerates the removal of Salicylate in the urine

Hemodialysis: may be necessary, either if renal failure develops or the plasma salicylate concentration exceeds 900 mg/l

COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit PG synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active “house-keeping” COX-1 isoenzyme found in the GIT, kidneys, & platelet

COX-2 selective NSAIDs

COX-2 inhibitors have analgesic, antipyretic, & anti-inflammatory effects similar to those of nonselective NSAIDs but with an approximate halving of GI adverse effects

These selective agents also have no significant effects on platelets

The COX-2 inhibitors (like the traditional NSAIDs) may cause renal insufficiency .

Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib & valdecoxib, resulting in their withdrawal from the market

Celecoxib is useful for long term use in chronic arthritis. It has minimal side effects

Etorocoxib is indicated for symptomatic relief of osteoarthritis & acute gout

Nimesulide, a relatively selective COX-2 inhibitor is useful in mild to moderate arthritis, somatic pain & fever

Aceclofenac has a chondroprotective property, which may be useful for long term management of osteoarthritis. It is also effective in rheumatoid arthritis & alkylosing spondylitis. It is well tolerated, thus suitable for the elderly

COX I & COX II

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