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1997 Clinical pharmacology By Duy Thai

Definition • Drugs which are used to decrease pain • There are 3 main classes of analgesics: 1. NSAIDs 2. Paracetamol 3. Opiods NSAIDs • Mechanism of action is via inhibition of cyclo oxygenase • This prevents the production of prostaglandins from arachidonic acid • Since there is no prostaglandin synthesis, the unused arachidonic acid gets converted to leukotrienes via lipoxygenase. • Have analgesic, antipyretic and anti inflammatory actions (Aspirin is often used as an antithrombotic agent because the levels required are low, so there are no other effects which occur at higher doses) • The analgesic action results from 2 mechanisms: 1. Peripheral mechanisms: • Inhibition of prostaglandins (particularly PGE2 at peripheral pain receptors. • PGE2 is a hyperalgesic. This means that it does not cause pain directly, instead, it enhances the pain receptor’s sensitivity to algesic (pain producing) substances such as bradykinin and substance P 2. Central mechanisms • Prostaglandins act in the spinal cord and higher centers to promote the transmission of pain signals to the brain. • Level of analgesia produced by NSAIDs: • Effective for mild to moderate pain associated with inflammation • NSAIDs reduce the cause of the pain (inflammatory mediators) as well as the sensation of pain • Effective for headache • Headaches may be caused by cerebral vasodilation due to prostaglandins. Therefore, inhibition of prostaglandins can relieve the vascular pain • Surgical and cancer pain (if combined with opioids) Paracetamol • Analgesic and antipyretic, but it is NOT anti inflammatory • Its mechanism of action is similar to that of NSAIDs • It inhibits COX, but it only works in the CNS • It does not inhibit peripheral COX. Why? • There are various peroxides produced in inflammatory states. The presence of these peroxides inhibits the action of paracetamol. However, peroxides are not produced in the CNS and so paracetamol only works centrally to relieve pain and fever • Therapeutic uses of paracetamol: 1. Analgesic • Does not act on the peripheral nociceptors like NSAIDs do • It inhibits spinal or supraspinal pain pathways • It can be used to treat mild to moderate pain, but not pain due to inflammation (e.g. arthritic pain). It does not attack the cause, only the symptoms. 2. Anti pyretic • Inhibits PGE2 synthesis in the hypothalamus Inflammation PMN activated Produce IL1 Activate production of PGE2 Increase cAMP Increase set point (temp) •

Paracetamol is recommended for use in children with fever. Aspirin should never be used when a young child has fever: ASPIRIN + FEVER = REYES SYNDROME
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1997 Clinical pharmacology By Duy Thai • • Reyes syndrome manifests as liver damage and encephalopathy, leading to coma Beneficial and adverse effects of paracetamol • No gastric irritation (gentle on the stomach) • Gastric irritation is due to the inhibition of prostaglandins in the mucosal lining. The prostaglandins are necessary to promote blood flow to the mucosa, facilitating protective mucous production. • Since paracetamol is not active in the periphery, it cannot cause gastric irritation like NSAIDs do • Only minor allergic reactions to paracetamol • In toxic doses (2 - 3 times the normal daily max) – Hepatotoxicity OPIOID ANALGESICS • • Have a different mechanism of actions to NSAIDs or paracetamol (It does not inhibit COX) The term opioids, encompasses: 1. Natural analgesic substances • Obtained from the opium poppy - morphine, codeine • These are called opiates 2. Synthetic analgesic substances • Pethidine • Fentanyl 3. Endogenous analgesic substances • Encephalins • Endorphins

Mechanism of action (taking morphine as the phenotype) • Produces analgesia • No effect on prostaglandins • Works by acting on specific receptors which are located presynaptically (involved in presynaptic inhibition). • Activation of the receptors leads to inhibition of pain transmission. • Here’s how it works - pretty confusing I admit but I’ll try my best. • Normal pain mechanisms: • When you step on a pin. nocireceptors fire away, sending the pain signals to the brain • The brain can do one of 2 things: A. It can cause you to ignore the pain (like a tough guy.. . or girl) • Not feeling the pain is possible because there are descending inhibitory fibres which turn off the pain signal which is going towards the brain B. It can may you scream, and jump up and down etc.. . • To feel the pain, the descending inhibitory fibres need to be inactivated. • This is achieved by interneurons in the brain which are activated by the incoming pain signals. Once activated, they then turn off the descending inhibitory fibres.

Ascending afferent fibre sending pain signals to brain

Iinterneuron which turns off decending inhibitory fibres

Decending inhibitory fibre

Ouch!!! Primary afferent fibre


* Denotes where opioids act to
presynaptically inhibit the fibre

Opioids act by: 1. Inhibiting the transmission of pain signals by preventing the primary afferent fibre from releasing neurotransmitter (presynaptic inhibition) 2. Preventing the interneuron from firing (via presynaptic inhibition), thus allowing descending inhibitory fibres to work again
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1997 Clinical pharmacology By Duy Thai What are the effects of opioids? • Opioids have actions in the CNS and at the periphery • Central effects of opioids 1. Analgesia 2. Reduce nociception 3. Also reduce the affective component of pain (the distressing psychological response to pain) • You can still feel the pain, but you are no longer distressed by it. 4. Euphroia • Elevated mood, relief of the anxiety associated with pain • This is also what attracts recreational use 5. In a few instances, dysphoria rather than euphoria can occur 6. At therapeutic levels, respiratory depression occurs • This will be fatal if the person overdoses on the drug • The respiratory depression occurs due to dulling of the respiratory reflex. There is a reduction in the normal response to an elevation of PaCO2 7. Antitussive effect • Suppression of the cough reflex by depression of the area in the brain which controls the cough reflex 8. Nausea and vomiting • Via direct stimulation of the vomiting reflex 9. Constriction of the pupil • This sign is a useful indicator of opioid overdose. When a person is unconscious. lift up the eyelids: • If pupil dilated - normal • If pupil constricted - morphine overdose • Peripheral effects of opioids 1. Decrease in propulsive motility of the GIT, increase in sphincter tone • Results in slowed transit time allowing increased absorption of water and hence constipation • This is a real problem because it occurs at therapeutic levels. Hence morphine is usually given in combination with laxative. 2. Urinary retention • Due to increased tone of the bladder sphincter 3. Histamine release (Anaphylactoid reaction) • This is a feature only of morphine • Morphine acts on mast cells causing them to degranulate, causing redness, itchiness and oedema at the site of injection • Asthmatics who are using morphine are signing a death wish: • The possibility of histamine release added with the complication of respiratory depression is not good. Opioid receptors • There are 4 receptor types: µ, δ, κ, σ • µ and δ are functionally identical • They cause hyperpolarisation of a nerve terminal by opening K+ channels • µ receptors are highly concentrated in brain areas involved in nociception and it is the receptor which morphine predominantly interacts with • The κ receptor inhibits membrane Ca2+ channels • The σ receptor is no longer considered to be a true opioid receptor because it is not blocked by naloxone, which is an antagonist at all other opioid receptors. Pharmacological effect Analgesia µ and δ Supraspinal (higher centers) and spinal ++ Constriction Reduced ++ Euphoria ++ Sedation ++ ++
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κ Spinal

σ -

Respiratory depression Pupil GI motility Smooth muscle spasm (affects sphincter tone) Behaviour/affect Physical dependence

+ Dysphoria + Sedation + +

Dilation Dysphoria + Psychotomimetic -

1997 Clinical pharmacology By Duy Thai Pharmacokinetics (using morphine as the example) • Well absorbed from the GIT • Undergoes significant first pass hepatic metabolism (hence a low bioavailability, 20 - 30%) • As a consequence, there is a greater level of activity if the morphine is given intravenously • The disadvantages of IV use are: 1. Increased risk of tolerance to develop • Increased doses are required for an equivalent effect • The level of tolerance depends on a number of factors: A. The potency of the drug • The more potent the opioid, the more likely it will cause problems B. Route of administration • IV causes increased tolerance C. Frequency and concentration of administration • The more often the receptors are occupied, the more likely they are to develop tolerance • If an oral dose is given, there is slow absorption and a lower concentration, hence there is no peak concentrations like we see in an IV administration. • The person becomes tolerant to: A. Analgesia B. Euphoria C. Sedation D. Nausea E. Respiratory depression • This is important because it means that the tolerant person will be able to withstand concentration that would normally cause fatal respiratory distress in a naive user. • Tolerance to one opioid will also convey tolerance to others (there is cross tolerance). • Since there is cross tolerance, it means that the tolerance has got nothing to do with altered pharamacokinetics (e.g. the drug is not being metabolised at a faster rate) • The mechanism of tolerance is: • Uncoupling of the receptor and 2nd messengers • There is a smaller rise in the number of 2nd messengers which the receptor is activated. Hence, there is a lower response • Reduction in the number of receptors 2. Dependence • Accompanying the tolerance is physical dependence • The more tolerant you are, the more dependent you are • Physical dependence is characterised by an abstinence/withdrawal syndrome • In order to maintain normal physiological functioning, the body now requires the presence of the drug • The intensity of the withdrawal syndrome is proportional to the degree of tolerance • The withdrawal syndrome for morphine (the time course differs for other drugs): • 8-12hrs Anxiety, craving, cough, sneeze, shivering, sweating • 20-30 hrs Vomiting and cramps • 36-72hrs Tremor, rigidity, convulsions, piloerection Extent of tolerance developed to some of the effects of opioids High degree of tolerance Moderate degree of Minimal or no tolerance tolerance Analgesia Bradycardia Miosis (pupil constriction) Euphoria. dysphoria Constipation Mental clouding Convulsions Antagonist actions Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression

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