Pain Relievers 1

Peripheral

Prostaglandinds produce pain, How?

_________: PGs sensitize the nerve endings to bradykinin and histamine

Central

Prostaglandinds produce pain, How?

_________: PGs lower the threshold for central pain circuits

NSAIDS

block peripherally and centrally to reduce pain intensity.

Noxious stimulus → C-fibre activity → Excitation of transmission neuron → Pain

Four main stage of the Nociceptive Pathway (pain)

_____ → ______ → _____ → ______

Bradykinin (BK), Serotonin (5-HT), Prostaglandins (PG)

Primary peripheral mediators released during inflammation

Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP)

Specific neuropeptides released to excite the transmission neuron

Nerve Growth Factor (NGF)

Produced during inflammation and exerts positive feedback on C-fibre activity

NO formation

Gas mediator formed downstream of transmission neuron excitation

GABA and Enkephalins

2 Neurotransmitters released by local interneurons to inhibit pain

Serotonin and Noradrenaline

Mediators of the descending inhibitory pathways

NSAIDs

It inhibits the release of inflammatory mediators, specifically prostaglandins

Hypothalamus

Contains thermoregulatory center

Thermoregulatory center (Hypothalamus)

Maintains balance between heat production and heat loss; heat dissipating mechanisms

Fever

a temporary rise in body temperature, typically defined as an oral reading of 100°F (37.8°C) or higher, or a rectal or ear measurement of 100.4°F (38°C) or more

Sweating and Vasodilation

Hypothalamus activates heat losing mechanism like ______ and ______.

Interleukin - 1 (IL-1)

Neutrophil releases ______

heat production and heat losing mechanism

PGE2 has two mechanisms:

• Increases ____

• Shuts down _____

NSAIDS

inhibits PGE2 synthesis and reduces fever

Inflammation

NSAIDS reduces fever due to _____ but not due to:

• heatstroke

• exercise-induced/physiological diurnal variation in temperature

Sweating and Vasodilation

What mechanism does the hypothalamus activates to lower body temperature during a fever?

Neutrophils

The release of this triggers the release of Interleukin-1

PGE2 and Fever

Role of NSAIDS in fever:

• Inhibits ____ synthesis

• Reduces _____

Release of arachidonic acid

Immediate biochemical event following trauma or inflammation in the peripheral pathway

COX-2

Specific enzyme that processes arachidonic acid in both peripheral and central pain pathways

Prostaglandins E2

Primary mediator increased downstream of COX-2 in the peripheral pathway

Peripheral sensitization

Outcome of sustained inflammatory pain signaling in the peripheral nervous system

IL-6 and IL-1B

Cytokines that bridge peripheral trauma to the central pain pathway

IL-6 and IL-1B → COX 2 → Increase prostaglandins → Pain

The sequence of mediators in the central pain pathway

Central sensitization

Term for the increased responsiveness of central neurons to peripheral input

Peripheral: Prostaglandins E2

Central: Prostaglandins

Difference of COX-2 products between two pathway

Peripheral: _____
Central: ____

Peripherally

PGs sensitize the nerve endings to bradykinin and histamine

Centrally

PGs lower the threshold for central pain circuits

Pain

Central PG effect + Peripheral PG effect =

Increase permeability

Effect of prostaglandins (PGs) on capillary walls during inflammation

Infiltration of leucocytes

Prostaglandin-mediated (PGs) movement of immune cells into the tissue

Vasodilation of some vascular beds

Specific vascular change prostaglandins (PGs) cause in certain vascular beds

Vasoconstriction in capillaries

Specific vascular change prostaglandins (PGs) cause within capillaries

Activation of kininogens

Prostaglandin-mediated (PGs) effect on plasma proteins the leads to inflammatory peptide production

Cyclooxygenase and Prostaglandin

Anti-inflammatory mechanism of action of NSAIDS:

“Inhibits the ________ enzyme and reduces _______ biosynthesis

Thrombus

Antiplatelet action:

Platelets aggregate lead to _______ formation

PGI2

Platelet aggregation is prevented by:

TXA2

Platelet aggregation is promoted by:

Aspirin

It inhibits TXA2 at lower dose (75-150mg) to reduce platelet aggregation

Acetaminophen

Aka paracetamol

Acetaminophen

Has anti-pyretic (fever) and analgesic (pain) effect

Anti-pyretic

Drug that reduces fever

Analgesic

A pain reliever drug.

Paracetamol/Acetaminophen

Proposed as COX-3 inhibitor involved in pain perception and fever but NOT in inflammation

NAPQI

The reactive metabolite produced by the minor CYP-dependent pathway

Glutathione

The substance responsible for inactivating the reactive metabolite NAPQI

Hepatocytes

Target of NAPQI-mediatedd damage during paracetamol toxicity

CYP2E1

Specific enzyme induced by alcohol that enhances paracetamol toxicity

326-650 mg

Usual therapeutic dosage range for paracetamol in mg TID-QID

2.6 g/day

Maximum daily dose for paracetamol

More than 7.5 grams

Threshold for acute ingestion of paracetamol likely to result in severe liver damage.

Nausea, vomiting, dizziness, abdominal pain, elevated plasma transaminases

S&S of Paracetamol toxicity in 12-24 hours

2-4 days

Timeline where serious signs of hepatic damage appear

Renal tubular necrosis

Specific renal complication associated with acute paracetamol toxicity

Hepatic encephalopathy/Worsening of coagulopathy

Poor prognostic indicators occurring after the initial toxicity phase

> 300 microgm/ml

Plasma paracetamol concentration at 4 hours indicating risk of severe liver damage.

> 45 microgm/ml

Plasma concentration at 15 hours indicating risk of severe liver damage

Within 4 hours; reduces paracetamol absorption by 50-90%

Optimal timeframe and efficacy for activated charcoal administration

N-acetylcysteine (NAC)

Antidote for paracetamol toxicity

Antioxidant and Anti-inflammatory

Secondary pharmacological properties of N-acetylcysteine (NAC)

Salicylates

• aspirin

• sodium salicylate

• diflunisal

Propionic acid derivatives

Ibuprofen, ketoprofen, naproxen

Aryl Acetic Acid derivatives

Diclofenac and ketorolac

Indole derivatives

Indomethacin and ketorolac

Alkanones

Nebumetone

Oxicams

Piroxicam and tenoxicam

Anthranilic acid derivatives

• fenamates

• mefenamic acid

• flufenamic acid

Pyrazolone derivatives

• phenylbutazone

• oxyphenbutazone

• azapropazone

• dipyrone

Aniline derivatives

Paracetamol

Stomach and Upper small intestine

Primary sites of aspirin absorption

Aspirin

• It is well absorbed from the stomach, more from upper small intestines.

• Distributed 50-80% bound to plasma protein

50-80%

% of aspirin binded to plasma proteins

Acetic Acid and Salicylates

Major matabolites of Acetyl and Salicylic acid

Glucuronic acid and glycine

Substance conjugated to salicylate during metabolism by the kidneys

Kidney

Primary organ responsible for salycylate excretion

Alkalinization of urine

Urinary modification that increases the rate of salicylate excretionA

Prostaglandins and thromboxane A2

Biochemical mediators whose synthesis is blocked by aspirin

irreversible

The nature of aspirin’s inhibition of cyclo-oxygenase is ______

COX enzyme

Specific enzyme targeted by aspirin

Analgesic, antipyretic, and anti-inflammatory

Three primary therapeutic effects of aspirin in standard dose

Analgesia

Inhibition of PG 300-600mg, 6-8 hourly

hypothalamic thermostat

Antipyretic Action: Inhibition of PG which rests the _______

Antiplatelet

Most important use of aspirin

headache, tinnitus, dizziness, blurred, vision, irritability, hyperventilation

CNS aspirin adverse effects

fluid retention, HT, edema, CHF (rarely)

CVS aspirin adverse effect

abdominal pain, nausea, vomiting, peptic ulcer, and bleeding

GIT Upset from aspirin

Bronchial asthma, angioedema and rashes, thrombocytopenia, hypoprothrombinemia and bleeding tendency as aspirin competes with vitamin K, so decreasing prothrombin synthesis

Hypersensitivity from aspirin

Renal insufficiency, renal failure, hyperkalemia, proteinuria; analgesic nephropathy on chronic use.

Adverse renal effects of aspirin

Liver function abnormality, rarely liver failure

Adverse hepatic effects of aspirin

Reye's syndrome

Serious condition associated with aspirin use in children with viral infection

• aspirin and derivatives may be a trigger

• highly lethal

• hepato ecephalopathy

Tinnitus, dizziness, and hearing loss.

Early signs of salicylism (chronic aspirin toxicity)

Respiratory alkalosis

aspirin overdose: 400-500 microgm/ml

Metabolic acidosis

Aspirin overdose: 0.5-1 ml/ml

Acute aspirin poisoning

S/S: restlessness, tremors, convulsion, vomiting, dehydration, hypotension, hyperventilation, hyper reflexia, hyperpyrexia and coma.

Treatment to acute aspirin poisoning:

• activated ___

• alkalinize ____

anticoagulant and hypoglycemics

Aspirin displaces oral _______ and oral _______ from their plasma protein binding sites, so increasing their activities ad may lead to toxicity