1. Dr. Laila M. Matalqah Ph.D. Pharmacology PHARMACOLOGY OF CNS part 2 General Pharmacology M212

2. Opioids analgesics

3. Opioid receptors All opioids act by binding to specific opioid receptors Location: CNS, periphery, GIT and other organs Receptor families: μ (mu), κ (kappa) and δ (delta) Endogenous peptide neurotransmitters (endogenous opioids): endorphins, enkephalins and dynorphins

4. Opioid receptors FunctionsReceptor subtype Analgesia Sedation Inhibition of respiration Slowed gastrointestinal transit Modulation of hormone and neurotransmitter release μ (mu) Analgesia Modulation of hormone and neurotransmitter release δ (delta) Analgesia Psychotomimetic effect Slowed gastrointestinal transit Κ (kappa)

5. Opioid analgesics A. STRONG AGONISTS  Morphine:  Main receptor: μ (mu) agonist Side effects: 1. Euphoria: General feel of well being ?? 2. Respiratory depression: Due to ↓ sensitivity of respiratory centre neurons to CO 2 level 3. Miosis: Pinpoint pupil 4. Emesis: CTZ 5. Constipation: Decrease GIT motility 6. Depression of cough reflex 7. Histamine release --- bronchospasm, hypotension 8. Increase ADH- less urine output 9. Tolerance and dependence

6. Morphine Ph/K: 1. Oral, IV, S.C, and IM 2. Duration of action is 4 – 6 hours for morphine naïve patients Metabolism: glucoronidation in the liver to Morphine-6-glucoronide (very potent analgesic) Morphine-3-glucuronide (no analgesic activity – believed to cause neuroexcitatory @ high doses) Avoid in neonates  no enough glucoronidation Opioid analgesics

7. 1. Morphine Therapeutic uses: 1. Analgesics: Analgesia: loss of pain without loss of consciousness 2. Treatment of diarrhea 3. Relief of cough Pulmonary edema associated with left ventricular failure, possibly by its vasodilatory effect. Antidote: (Opioids anatgonists) 1. Naloxones 2. Naltrexones Opioid analgesics

8. 2. Heroin  Same action like morphine  Heroin is converted to morphine in the body  threefold more potency than morphine  More euphoria and marked dependence and tolerance 3. Methadone MOA: μ receptors agonist and antagonist of the N-methyl- D-aspartate (NMDA) receptor Orally Action similar to morphine (equianalgesic) less Euophoria than morphine Less withdrawal syndrome Use in treatment of morphine and heroin dependence, neuropathic pain Opioid analgesics

9. 2. Opioids analgesics B. Moderate Agonists: 1. Codeine Is a much less potent analgesic than morphine. Codeine’s analgesic potency is approximately 30 percent that of morphine. Good antitussive activity at doses that do not cause analgesia. Has a lower potential for abuse than morphine. Codeine is often used in combination with aspirin or acetaminophen

10. 2. Opioids analgesics C. Mixed agonist-antagonists and partial Agonists : 1. Pentazocine acts as an agonist on κ receptors and weak antagonist at μ and δ receptors. used to relieve moderate pain. orally or parenterally Tolerance and dependence

11. 3. Other analgesics 4. μ-Opioid receptor weak agonist Tramadol is a centrally acting analgesic that binds to the μ -opioid receptor. It is used to manage moderate to moderately severe pain. Its respiratory-depressant activity is less than that of morphine.

12. Meperidine / Pethidine Synthetic opioid - lower potency – structurally not related to morphine κ agonist with some μ agonist The active metabolite is normeperidine is very neurotoxic  Analgesic for acute pain only (short term less than 48 hours) Shorter duration of action than morphine (2 – 4 hours) Oral, but parenteral is more often used

13. Opioid antagonists Drugs that bind to opioid receptors  block  the full agonist at μ-receptor won’t be able to exert it’s effect, they reverse its effect and precipitate symptoms of opioids withdrawal. Alone  no effect, no activation receptor-mediated response Uses: opioid toxicity antidote, and aid for opioid dependence withdrawal They antagonise I.V opioids and not oral Naloxone and naltrexone

14. 4. Anticonvulsant (Drugs for Epilepsy) Epilepsy is a sudden, excessive, and synchronous discharge of cerebral neurons. This abnormal electrical activity may result in a variety of events:  loss of consciousness,  abnormal movements,  atypical behavior,  abnormal movements  distorted perceptions

15. 4. Anticonvulsant (Drugs for Epilepsy)  Classification of seizures

16. 4. Anticonvulsant (Drugs for Epilepsy) Mechanism of action of antiepileptic drugs 1. Blocking voltage-gated channels (Na+ or Ca2+), 2. Enhancing inhibitory γ -aminobutyric acid (GABA)-ergic impulses, 3. Inhibit the excitatory glutamate transmission.

17. 4. Anticonvulsant (Drugs for Epilepsy) 1. Benzodiazepines: MOA: bind to GABA inhibitory receptors Diazepam and lorazepam for: Status epilepticus Prolonged generalised tonic-clonic seizures 2. Carbamazepine: reduces the propagation of abnormal impulses in the brain by blocking sodium channels

18. 4. Anticonvulsant (Drugs for Epilepsy) 3. Ethosuximide: MOA: inhibiting calcium channels Only for absence generalised seizures 4. Felbamate: broad spectrum 1) blocking sodium channels, 2) competing with glutamate receptor, 3) blocking calcium channels, and 4) potentiating the action of GABA. 5. Gabapentin: is an analog of GABA, Well tolerated by elderly patients 6. Lamotrigine: blocks sodium channels as well as high voltage– dependent calcium channels For broad variety of seizures

19. 4. Anticonvulsant (Drugs for Epilepsy) 7. Phenobarbital: enhancing the inhibitory effects of GABA- mediated neurons For status epilepticus when other agents fail 8. Phenytoin and fosphenytoin: blocks voltage-gated sodium channels 9. Pregabalin: Binds to Ca +2 voltage-gated channels in CNS 10. Topiramate: blocks voltage-dependent sodium channels, 11. Valproic acid (Divalproex): sodium channel blockade and calcium channels, blockade of GABA transaminase 12. Primidone: Prodrug  Phenobarbital Longer t1/2 than phenobarbital Only for refractory epilepsy

20. 4. Anticonvulsant (Drugs for Epilepsy) Drugs of choice: 1. Partial epilepsy: lamotrigine and Topiramate 2. Primary generalized a) Absense : Ethosuximide b) Tonic clonic / Myoclonic : Benzodiazepines, Carbamazipines, Lamotrigine and valproic acid c) Status epilipticus: Phenobarbital, Phenytoin, Benzodiazepines, and Barbiturate Epilepsy in pregnancy: Divalproex and barbiturates should be avoided. Elderly: Gabapentin and lamotrigine epilepsy

21. Phenytoin blocks voltage-gated sodium channels can also block voltage- dependent calcium channels Phenytoin is effective for treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus The drug is 90 percent bound to plasma albumin. Phenytoin induces drugs metabolized by the CYP2C and CYP3A families

22. Phenytoin Phenytoin exhibits saturable enzyme metabolism at a low serum concentration (zero-order kinetics) Small increases in a daily dose can produce large increases in the plasma concentration, resulting in drug-induced toxicity Side effect / toxicity: Depression of the CNS Ataxia and Nystagmus Gingival hyperplasia peripheral neuropathies and osteoporosis Orally, can not be given I.M?? Tissue necrosis and damage

23. Fosphenytoin Prodrug of phenytoin Converted to phenytoin Given : I.M and I.V Rapid onset of action

24. Valproic acid and divalproex Divalproex Na = Na valproate + valproic acid Sodium valproate was developed to improve gastrointestinal tolerance of valproic acid MOA sodium channel blockade blockade of GABA transaminase action at the calcium channels broad spectrum of activity against seizures. It is effective for the treatment of focal and primary generalized epilepsies Drug-drug interactions : 1. Valproate is b ound to albumin (greater than 90 percent), which can cause significant interactions with other highly protein-bound drugs 2. inhibits metabolism of the CYP2C9 Teratogenic

25. Carbamazepine Carbamazepine is effective for treatment of partial seizures and, secondarily, generalized tonic-clonic seizures. C/I: absence seizures It induces its own drug metabolism and has an active metabolite. Carbamazepine is an inducer of the isozyme families CYP1A2, CYP2C, and CYP3A S/E: Hyponatremia (Elderly) Rash