ANALGESICS: USES, TREATMENT, RISKS- STUDSAVER

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ANALGESICS

 1. Non-steroidal anti-inflammatory drugs (NSAIDs) 

(i) Non-selective e.g. ibuprofen, diclofenac , naproxen, salicylates (aspirin) etc

(ii) Selective COX-2 inhibitors e.g. celecoxib, aceclofenac


2. Narcotic analgesics/opiates /opioids e.g. morphine, pethidine, tramadol, codeine, oxycodone  etc


3. Miscellaneous e.g. acetaminophen (paracetamol)



COX-enzymes

•COX-1 is present in all tissues and cell types. It is involved in blood clot and protects the stomach lining.

•COX-2 is produced at the sites of trauma or injury (inducible) . It is associated with pain and other signs of inflammation.

•COX-3 is present in the CNS and it is associated with pain and fever.
NSAIDs

Therapeutic effects of NSAIDS

•Suppression of inflammation: Initial drug of choice for rheumatoid arthritis.

•Analgesia: Drug of choice for mild to moderate pain e.g. headache, toothache etc.

•Reduction of fever: Reduces fever by inhibiting pyrogen-induced prostaglandin synthesis.

•Dysmenorrhoea: Inhibit prostaglandin synthesis in the uterine smooth muscle.

•Suppression of platelet aggregation – synthesis of thromboxane A2 in the body




Analgesics-Studsaver


Adverse effects of NSAIDS

•Gastric ulceration – Inhibit prostaglandin (PG12)which protects gastric mucosa.


•Bleeding- Inhibit thromboxane A2 synthesis and thus prevent platelet aggregation.


•Acute renal failure – Inhibit renal prostaglandin which causes vasodilation. The resultant effect is vasoconstriction leading to decreased renal blood flow.

 

Caution/contraindication of NSAIDS usage

•Asthma – aspirin causes bronchospasm.

•Children under 12yrs – Aspirin causes Reye’s syndrome.

•Haemophilia

•Peptic ulcer

•Gout – Aspirin is contraindicated in gout.


Acetaminophen (paracetamol) 

Therapeutic effect of ACETAMINOPHEN

•Reduces pain and fever by inhibiting COX-3 enzyme in the CNS.


 It cannot suppress inflammation hence it is not an NSAID.


•It is limited to the CNS and therefore has limited effect on prostaglandin synthesis in the peripheral sites. This may explain the absence of anti-inflammatory effect.


Metabolism of ACETAMINOPHEN

•Acetaminophen is metabolized via two (2) pathways i.e. major and minor pathways.


•Major pathway – Acetaminophen undergoes conjugation with glucuronic acid to form non-toxic metabolites.


•Minor pathway – Acetaminophen is oxidized by cytochrome P450 enzyme into highly reactive and toxic compound (N-acetyl-p-benzo-quinone-imine).


Acetaminophen

Therapeutic dose of ACETAMINOPHEN

•At therapeutic dose, large amount is converted to non-toxic compounds (glucuronide and sulfate moeity) via the major pathway. Only a small fraction is converted to toxic metabolite (N-acetyl-p-benzo-quinone-imine) via the minor pathway. The toxic metabolite undergoes rapid conversion to a non-toxic form (cysteine and mercapturic acid conjugates) by glutathione.


Overdose of  ACETAMINOPHEN

•When an overdose of acetaminophen is taken, a larger than normal amount is processed via the minor pathway; hence a large quantity of toxic metabolite is produced. As the liver attempts to detoxify the metabolite, glutathione is rapidly depleted and further detoxification stops. As a result, the toxic metabolite accumulates, causing damage to the liver.



Effects of Alcohol on Acetaminophen 

•Alcohol induces cytochrome P450  enzyme thereby increasing the production of acetaminophen’s toxic metabolite (N-acetyl-p-benzo-quinone-imine) via the minor pathway. The liver uses glutathione to detoxify this toxic metabolite to the non-toxic form. As a result, stores of glutathione is depleted in chronic alcoholics  and when this happen, the liver is unable to convert the toxic metabolite to the non-toxic form. The toxic metabolite then causes damage to the liver.



Mechanism of Action of Narcotic analgesics/opiates/opioids 

•Opiates stimulate opioid receptors in the CNS. 


•Opioid receptors are found in the CNS because of naturally occurring compounds such as endorphins, enkaphalins and dynophins that suppress pain messages in the CNS. These naturally occurring compounds are called endogenous opioids. These endogenous opioids explain why people in road accidents can be fully conscious but unaware of the damage to their bodies.


•The opioid receptors are delta, kappa and mu receptors. Stimulation of delta receptors lead to behavioral changes and hallucination whereas stimulation of kappa receptors lead to sedation.


   

Therapeutic uses of  Narcotic analgesics/opiates/opioids                               

•Severe /chronic pain e.g. morphine, pethidine, oxycodone

•Cough suppression e.g. codeine 

•Management of diarrhoea e.g. codeine                                              



Side effects of  Narcotic analgesics/opiates/opioids 

GIT - Vomiting , constipation 

CNS - Drowsiness, euphoria, hallucination

Respiratory system - respiratory depression 

Urinary system -Urine retention


Contraindication of Narcotic analgesics/opiates/opioids                                          

Bronchial asthma

Bowel obstruction                                            

Heart failure



 

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