Opioid Analgesics (Part 1) PDF

I-Drugs Affecting the Central Nervous System 1-Analgesics (Opioid and Non-opioid) 2- Sedative–Hypnotic and Anxiolytic Drugs 3- Antidepressant Drugs 4-Neurodegenerative Disorders...

I-Drugs Affecting the Central Nervous System 1-Analgesics (Opioid and Non-opioid) 2- Sedative–Hypnotic and Anxiolytic Drugs 3- Antidepressant Drugs 4-Neurodegenerative Disorders 5- Antiepileptic Drugs 6-Antipsychotic Drugs 7-Anesthetics- 8-CNS stimulants II- Drug therapy of Bronchial Asthma III- Drug therapy of gout IV-GIT: peptic ulcer, Diarrhea, Constipation Prof. Dr. Gehan Hussein Heeba 1  Analgesics (Opioid and Non-opioid) Or both Analgesic: A drug that relieves pain by acting in the CNS or on peripheral pain mechanisms, without altering consciousness. A- Opioid analgesics ► Opioids: drugs with morphine-like activity. The term opioid refers to all compounds related to opium. ► Opiates are drugs derived from opium, and they include the natural products morphine, codeine, and thebaine, and many semisynthetic derivatives. ► Narcotics : drugs that produce narcosis ;The term narcotic was derived from the Greek word for "stupor." referred to any drug that induced sleep, but then it became associated with opioids. ► Endogenous Opioids endorphins – enkephalins – dynorphins 2 Prof. Dr. Gehan Hussein Heeba Juice of the opium poppy Papaver somniferum 3 Prof. Dr. Gehan Hussein Heeba Classification of opioid Prof. Dr. Gehan Hussein Heeba 4  Classification of opioid 1- Strong agonists: - Morphine - Hydromorphone - Oxymorphone - Heroin (diacetylmorphine) - Methadone - Mepridine - Fentanyl - Sufentanil, - Alfentanil 2- Mild-Moderate/ low agonists: -Codeine - Dihydrocodeine - Oxycodone - Hydrocodone - Propoxyphene - Diphenoxylate - Loperamide 3- Mixed agonist/antagonist and partial agonist: Butorphanol - Nalbuphine - Pentazocine 4- Antagonists: - Naloxone - Naltrexone Prof. Dr. Gehan Hussein Heeba 5 Occupied receptor without any activity Opioid Receptors - Opioid receptors are of multiple subtypes, all G-protein linked, µ (mu), δ (delta), and κ (kappa). - Opioid receptors are distributed throughout the brain and spinal cord. -Opioid receptors are members of the large superfamily of G protein–coupled receptors. Subtypes of the opioid receptors: ►µ Receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are µ-receptor agonists. µ1-receptors mediate the analgesic and euphoric effects of the opioids and physical dependence on them. µ2-receptors mediate the bradycardia and respiratory depressant effects. ► δ Receptor activation results in analgesia but also can be proconvulsant ► κ Receptors: Three κ - receptors mediate spinal analgesia, miosis, sedation, and hallucinations. Prof. Dr. Gehan Hussein Heeba 6 Cellular Mechanisms of Action ♦ These drugs act in part via receptors for endogenous opiopeptides. ♦ Effects of specific opioid drugs depend on the receptor subtype with which they interact as full agonists, partial agonists, or antagonists. ♦ Some drugs (mixed agonist-antagonists) may activate one receptor subtype and act as antagonists at another subtype. ► Activation of presynaptic opioid receptors causes inhibition of Ca2+ influx through voltage-gated Ca2+ channels so inhibits neurotransmitter release. Neurotransmitters ♦ The net result of the cellular decrease in calcium is a decrease in the release of glutamate and nociceptive peptides, such as substance P, resulting in blockage of nociceptive transmission. ► Activation of postsynaptic opioid receptors results in K+ efflux and membrane hyperpolarization then inhibition. Prof. Dr. Gehan Hussein Heeba 7 Mechanism of action of μ opioid receptor agonists 8 Prof. Dr. Gehan Hussein Heeba Morphine is the principal alkaloid in opium and is widely used till today. Therefore, it is described as prototype. Pharmacokinetics ► Opioids are usually administered orally, but some like morphine can also be administered rectally or parenterally. ► ► The first-pass effect on drugs like morphine is glucuronidation by the Liver which decreases the oral bioavailability of the drug. Very short duration of action ► The drugs distribute rapidly to all tissues, although the distribution is limited by their lipophilicity. Fentanyl (highly lipophilic) distributes to the brain rapidly. Partial agonist ► Heroin passes readily into the brain. Codeine passes into the brain more readily than morphine, which is slow in crossing the blood-brain barrier. ► The drugs cross readily into fetal tissues across the placenta and therefore shouldn't be used during pregnancy. glucuronidation by the fetus is slow, increasing their half-life in the fetus and also increase liability to addiction. ►Metabolism ►Excretion 90% kideny 10%liver 9 Prof. Dr. Gehan Hussein Heeba Pharmacological Effects: 1- Analgesia, euphoria, sedation ► analgesia: Analgesia may be associated with euphoria and decreased anxiety. Analgesia results from direct activation of μ and δ receptors in the spinal cord and higher centers leading to: 1-Activation of descending inhibitory pathways. 2-Inhibits release of substance-P in pain transmission neurons in the spinal cord. 3-The psychic effect results from ↓ NA release in some CNS areas leading to decrease anxiety and reaction of the patient to pain. ► Morphine can treat all types of pain except itching. Why? 2- CVS Parasympathetic ► They produce bradycardia due to vagal stimulation and histamine release ► In large doses, they decrease BP (Orthostatic hypotension) due to inhibition of VMC and peripheral VD due to histamine release. 10 Prof. Dr. Gehan Hussein Heeba 3- Medullary Effects ► Antitussive effects: The opioids block cough by inhibiting the cough center. ► Opioids reduce respiration, an effect that is fatal in the case of overdose. Opioids inhibit respiratory center (at high dose) via the µ-receptor in the medulla and so depress respiration and decreases its sensitivity to CO2. ► They stimulate chemoreceptor trigger zone (CTZ) Vomiting 4- Miosis Miosis, Severe miosis is indicative of toxic doses. the pinpoint pupil (PPP) response to the opioids, is diagnostic of the use and abuse of the opioids Prof. Dr. Gehan Hussein Heeba 11 5- GIT Effects ► Morphine and most other opioids produce some degree of constipation by increasing sphincter tone and decreasing gastric motility. ► The decrease in gastric motility increases gastric emptying time and reduce absorption of other drugs. ◊ Constriction of the urinary bladder wall can lead to felling of urgency. and constriction of the urinary sphincter can lead to painful urine retention. ◊ Constriction of the gall bladder wall and sphincter 6- Immune Function and Histamine ► Opioids induce the release of histamine, which leads to the itching sensation associated with use and abuse of opioids. ► Opioids are also immunosuppressive, having effects on the T-helper and T- suppressor cells. 7- Uterus ► Therapeutic doses will prolong or delay labour, morphine will pass the placental membrane barriers 8- Bronchoconstriction: due to: (a) Vagal stimulation. (b) Histamine release Prof. Dr. Gehan Hussein Heeba 12 Clinical Uses of Opioid Analgesics Analgesia - Acute Pulmonary Edema – Cough -Diarrhea- in Anesthesia ►Analgesic: for moderate to severe and chronic deep pain. e.g. acute MI, bone fractures, cancer, surgery, etc. (with atropine in renal colics) Morphine is the drug of choice for the treatment of myocardial infarction because of its bradycardiac and vasodilatory effects. ► In severe colic: (morphine combined with atropine). Why? ► Acute pulmonary edema (cardiac asthma).Why? ► In anesthesia: – As adjuvant to anesthetic agents (preoperatively) for sedation, anxiolytic effects, and to reduce the dose of anesthetics. – Regional anesthesia (epidural) to achieve long lasting analgesia by its effect on the spinal cord 13 Prof. Dr. Gehan Hussein Heeba ► Commonly used opioids: Morphine, Mepridine, Oxycodone, Propoxyphene……………analgesic Codeine…………………………..analgesic + antitussive Methadone………….treatment of narcotic dependence Lopramide, diphenoxylate, opium tincture…….antidiarrheal Heroin…….abused, the most abused opioid, this agent is used by about 80% of narcotic abusers. ► Preparations and doses Subcutaneous -Morphine sulphate: 10 mg s.c. or i.m. In acute MI it is given 5 mg i.v. -Sustained release preparations &transdermal patches are available. -Intrathecal (epidural) injection: produce long lasting analgesia which is useful for critically ill patients at risk of RC depression. Prof. Dr. Gehan Hussein Heeba 14 Specialized administration ♦ Patient controlled analgesia: By infusion ♦ Regional analgesia: Epidural route is favored because it produces fewer adverse effects. May also be administered into subarachnoid space. There may be delayed respiratory depression, nausea, and vomiting that can be reversed with naloxone. ♦ Transdermal fentanyl patch: Used for chronic pain Prof. Dr. Gehan Hussein Heeba 15 ►Adverse effects: CNS - Tolerance & physical dependence (addiction) with prolonged use: – Physical dependence can occur within 24 h if given /4 h. – Tolerance may occur to analgesia and euphoria but not to respiratory depression. - ↑↑ intracranial tension. - RC depression: the most important effect and is dose-dependent. Resp - Bronchoconstriction. CVS - Postural hypotension GIT - Nausea, vomiting, and constipation. Increased biliary tract pressure and biliary colic. Genito-Urinary - Urine retention especially in patients with enlarged prostate. - Prolongation of labor. Eye - Miosis is a consistent finding in morphine addiction. Prof. Dr. Gehan Hussein Heeba 16 Contraindications to opioids: 1 ► Morphine and other opioids are contraindicated in patients with hypersensitivity reactions to the opioids. 2 ► Morphine should not be used in patients with bronchial asthma and shouldn't be given as the drug of first choice in patients with pulmonary disease, Why? 3 ► When used via the epidural route, the site for injection must be free of infection. In addition, the use of corticosteroids by the patient should be stopped for at least 2 weeks prior to the insertion of the catheter to prevent infection, Why? 4 ► Opioids are contraindicated in head trauma (???) 17 Prof. Dr. Gehan Hussein Heeba 5 ► Morphine, like all opioids, passes through the placenta rapidly 6 ► Morphine and other opioids exhibit intense sedative effects and increased respiratory depression when combined with other sedatives, such as alcohol or barbiturates. 7 ► Senile enlarged prostate: Morphine ↑ detrusor muscle tone with spasm of the internal urethral sphincter → feeling of urinary urgency with difficult micturition. 8 ► Use in patients with impaired hepatic or renal function—Why? 9 ► Morphine Biliary colic & gallstones: ?? Prof. Dr. Gehan Hussein Heeba 18 10 ► Use in patients with endocrine disease—►adrenal insufficiency (Addison’s disease) and hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids. 11 ►Undiagnosed acute abdominal pain: Morphine masks the pain (which may be dangerous e.g. appendicitis) and interferes with the correct diagnosis. 12 ►Hypotension and hypovolemia: morphine causes postural hypotension Tolerance It occurs after 10-14 days to the analgesia, euphoria effects, but not to the other effects like constipation, miosis (ppp). -chronic administration of opioids ↓↓ endogenous production of endorphins and NA. Following sudden withdrawal, there is an immediate deficiency of endogenous opioids with rebound ↑ of NA release. Prof. Dr. Gehan Hussein Heeba 19 Toxicity Acute toxicity Supportive treatment - In large dose, morphine overdose characterized by: miosis (ppp), hypotension, respiratory depression, coma and death. Antiagonist I.v - While the IV administration of naloxone reverses the toxic effects of morphine, naloxone has a short duration of action and must be administered repeatedly at 30- to 45 minute intervals until morphine is cleared from the body. - Artificial respiration and stomach wash with KMnO4 Chronic toxicity (addiction) - characterized by: miosis (ppp), constipation, psychosis - If sudden stoppage of morphine►withdrawal symptoms (abstinence syndrome) which characterized by: lacrymation, rhinorrhea, anxiety, anorexia, tremors, vomiting, diarrhea, hypertension, hyperpyrexia, aggressive behavior and muscle cramps. - Once the patient takes morphine again all these symptoms will disappear. Treatment of addiction: - By gradual withdrawal of morphine till reaching a stabilizing dose (just sufficient to prevent the withdrawal symptoms), - Replacement with less addictive narcotic like methadone - Then gradual withdrawal of methadone. - Sedatives 20 Prof. Dr. Gehan Hussein Heeba