Pharmacology: Analgesics (PDF)

Part 2 2: Ana algesics Definittion: drugss that reliev ve or decre ease pain sensation. s ▌Class sification of o analges...

Part 2 2: Ana algesics Definittion: drugss that reliev ve or decre ease pain sensation. s ▌Class sification of o analges sics: Opiioid (narco otic) analg gesics NSA AIDs (see chapter 4). Ana ntipyretics: e.g. para algesic an acetamol, Dipyron D & Nefopam. N Dru f speciffic painfull conditions e.g. ca ugs used for arbamazep pine for trig geminal neu uralgia, ergotamine fo or migraine e. █ OPIOID ANAL LGESICS  Theey are dru ugs that decrease p pain sensa ation withhout loss of o conscio ousness annd can ind duce phyysical depe endence.  Opiiates: are drugs derived from m opium plant p (Pappaver som miniferum).. They in nclude ma ainly morrphine, cod deine and papaverin e.  Opiioids: are drugs d with h morphinee-like activity.  Opiiopeptins:: are endo ogenous p peptides with w opiooid-like acttivity e.g. en ndorphins & enkepha alins  Narrcotics: arre drugs th hat producce narcosiss i.e. drowsiness or o stupor, with ana lgesia (stu upor mea ans marke ed impairm ment, but not comp plete losss of consciousness). These dru ugs are usu ually adddictive. It is a legal, not a mediccal, term. Classiffication off opioid drrugs 329  Mechanism of action  Opioids such as morphine are believed to interact with three major receptors (μ, δ, κ). Each opioid receptor has distinct subtypes (e.g., μ1, μ2). All three major receptors are present in high concentrations in the dorsal horn of the spinal cord.  Interaction with μ-receptors contributes to supraspinal and spinal analgesia, respiratory depression, sedation, euphoria, decreased GI peristalsis, and physical dependence (addiction).  The significance of interaction with κ-receptors is unclear, but it may contribute to analgesia (through inhibition of release of substance P at dorsal horn). █ NATURAL OPIOID AGONISTS 1. Morphine Pharmacokinetics  Oral absorption: good (bioavailability is 25% due to significant first-pass effect). However, the analgesic effect is greater when the drug is administered parentrally  t½ : 4-5 hrs.  Metabolism: in the liver by conjugation leading to inactive metabolites.  Excretion: renal (90%) – bile (10% as conjugated morphine). Pharmacological effects  Analgesia  Dose-dependent analgesia (sensory & emotional): consciousness is not lost and the patient can still locate the source of pain. Analgesia may be associated with euphoria and decreased anxiety.  Analgesia results from direct activation of μ and δ receptors in the spinal cord and possibly higher centers (thalamaus) leading to: – Activation of descending inhibitory pathways. – ↓ release of substance-P in pain transmission neurons in the spinal cord.  The psychic effect results from ↓ NA release in some CNS areas leading to decrease anxiety and reaction of the patient to pain.  Morphine and other exogenously administered opioids may also have some action on peripheral inflamed tissue. N.B.Morphine can treat all types of pain except itching. Why? a) Because morphine stimulates histamine release → ↑ itching. b) Itching is different from pain sensation and has different receptors and centers. 330  Euphoria (large doses produce dysphoria).  Miosis: due to central stimulation of Edinger-Wistphal nucleus. Severe miosis is indicative of toxic doses.  Respiratory center depression. This RC depression leads to CO2 retention and cerebral VD → ↑↑ intracranial tension.  Cough suppression.  Vagal stimulation.  Nausea & vomiting: due to stimulation of chemoreceptor trigger zone (CTZ). CVS effects:  Orthostatic hypotension: due to (a) Histamine release; (b) vagal stimulation.  Bradycardia: due to vagal stimulation. Smooth ms (Spasmogenic effects):  Bronchoconstriction: due to: (a) Vagal stimulation. (b) Histamine release.  Constipation: due to (a) spasmodic non-propulsive contractions of intestinal smoothms& decreased peristalsis; (b) ↑ intestinal water absorption.  Spasm of the sphincter of Oddi → ↑ biliary pressure.  Feeling of urgency with difficult micturition due to ↑ detrusor muscle tone with spasm of the internal urethral sphincter.  Uterus: prolongation of labor by unclear mechanism. Therapeutic uses  Analgesia: for severe pain e.g. acute MI, cancer, surgery, etc.  Acute pulmonary edema (cardiac asthma).Why? – ↓ stress & anxiety of the patient. – Venodilatation → ↓ VR & preload → ↓ pulmonary congestion. – Decrease tachypnea caused by the CNS response to hypoxic drive (due to its depressant effect on RC).  In anesthesia: – As adjuvant to anesthetic agents (preanesthetic medication). – Regional anesthesia (epidural) to achieve long lasting analgesia by its effect on the spinal cord.  In severe colic: (morphine combined with atropine). Why? – Because morphine is spasmogenic and atropine is spasmolytic. – To counteract muscarinic effects caused by excessive vagal stimulation (e.g. bronchoconstriction and bradycardia). 331