Clinical Pharmacology PDF

2. Codeine Similar to morphine with the following differences:  Has greater oral bioavailability (60%) due to less first-pass effect.  The analgesic potency is 20% of morphine, but more potent cough suppressant  It has little euphoric effect....

2. Codeine Similar to morphine with the following differences:  Has greater oral bioavailability (60%) due to less first-pass effect.  The analgesic potency is 20% of morphine, but more potent cough suppressant  It has little euphoric effect.  Most of the systemic effects of codeine are due to conversion in the liver into morphine by demethylation (codeine is methylmorphine). Therapeutic uses – Analgesic for mild to moderate pain (usually combined with paracetamol). – As central antitussive (see chapter 7). Adverse effects: (less than morphine) – Constipation – RC depression and addiction liability but it is fewer than morphine. Morphine Codeine Oral bioavailability: 25% 60% Analgesic effects: Strong Weak (20%). Antitussive effect: Weak Strong Uses: Mention its 4 uses Analgesic and antitussive █ SYNTHETIC AND SEMISYNTHETIC OPIOID AGONISTS 1. Heroin and hydromorphone  They are semisynthetic opioids (heroin is diacetylmorphine).  They are more potent than morphine but with rapid onset and shorter duration.  They are not used clinically because they are highly addictive. 2. Meperidine (Pethidine) Synthetic opioid similar to morphine with the following differences:  Better absorbed orally and has greater bioavailability than morphine.  The analgesic potency is 10% of morphine.  It is used as analgesic alternative to morphine in the following cases: – Inferior MI because in this case the patient usually has bradycardia. – It is preferred than morphine during labor because it has short duration and doesn't prolong labor (little or no spasmogenic action). 334 Adverse effects – It causes RC depression and addiction liability but weaker than morphine. – It causes histamine release and bronchoconstriction – It has weak atropine-like actions → dry mouth, tachycardia, etc. – It has No GIT, No antitussive, and No vagal stimulant effects. Morphine Meperidine Chemistry Natural opioid Synthetic opioid Bioavailability 25% Greater (50%) Analgesic effect Strong Weak (10% of morphine) Spasmogenic effects Present Absent Autonomic effects Vagal stimulation Atropine-like action Uses Mention its 4 uses Analgesic only 3. Fentanyl and alfentanil  They are synthetic derivatives of meperidine. They are the most potent and the shortest duration opioid agonists.  They are used as analgesic in severe pain (as long-acting transdermal skin patch). A transdermal fentanyl 12 microgram patch equates to approximately 30 mg oral morphine daily. 4. Methadone Synthetic opioid similar to morphine with the following differences:  The analgesic effect is equal to morphine.  Has longer duration of action than morphine (t1/2 is 24h). Uses:  As analgesic.  Treatment of chronic opiate addiction and heroin users: – It can satisfy the craving needs of the patient with less addictive features. – Methadone withdrawal symptoms are less severe than other opioids. 5. Tramadol  It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin and NA.  Uses: as analgesic for moderate to severe pain, especially musculoskeletal pain  Adverse effects: It has relatively fewer side-effects than most opioids (but addiction can occur). It may induce seizures in epileptic patients. 335  6. Diphenoxylate and loperamide (see chapter 8) █ SEMISYNTHETIC MIXED AGONISTS-ANTAGONISTS (partial agonists) Nalorphine – Nalbuphine – Pentazocin – Butorphanol  All these drugs have agonist activity on  receptors and antagonist or partial agonist activity on  receptors.  They are used as analgesics alternative to morphine but their analgesic activity and respiratory depression are less marked than morphine.  All these drugs (except nalbuphine) increase systemic and pulmonary vascular resistance N.B. leading to ↑ cardiac load, so they are, thus, For opioid analgesics, contraindicated to relieve pain of acute MI. potency of the analgesic  They can lead to withdrawal symptoms if should be considered more given to opioid addict patients. important than efficacy because respiratory depression is dose- █ SYNTHETIC FULL ANTAGONISTS dependent. Naloxone and naltrexone  They are competitive blockers of all opioid receptors.  Naloxone is given i.v. and has short t½ (~1h) but naltrexone could be administered orally and has longer t½ (~48 h).  They can precipitate severe withdrawal syndrome if administered to opioid- addict patient. Therapeutic uses of naloxone  Acute opioid toxicity: given i.v., the adverse respiratory and CVS effects of opioids are reversed within 1-2 min and lasts for 1-2 hrs.  It is given during labor to mothers who received opioids to prevent neonatal respiratory depression, or it can be given to the neonate via the umbilical vein. 336