g DR. Killua Zoldyck CNS Module - 2nd year Clinical Pharmachology Opioid Narcotics SubClass MAO ■ Morphine ++ opiate receptors μ, κ, δ in C.N.S & periphery: 1. ++ of these receptors ➩)--) adenyl cyclase ➩ ↓ cAMP. 2. Presynaptically: block Ca++ channels ➩↓ excitatory transmitters e.g. glutamate,substance P & PG. 3. Postsynaptically: open K+ channels ➩ hyperpolarization→inhibitory post synaptic potential. 1. Morphine ■Strong Natural opioid ■Phenanthrene Derivative CNS Action 1. Depressant actons: مهم A. Analgesia B. Narcosis. C. Depresses R.C, cough center D. (--) Heat regulatng center )κ receptors) E. ACTH, FSH & LH. F. (--) of withdrawal refex 2. Stimulant effects: a. Euphoria. b. Miosis (PPP). c. Bradycardia→ )++) )CIC) d. vomiting→ )++) )CTZ). e. Oliguria→ ↑ ADH release. f. ↑ Monosynaptic reflex: stretch reflex g. ↑ ICP. 2. Codeine Natural pure Agonist 3.Meperidine Synthetic pure Agonist 4. Naloxone Pure Opioid Antagonist Uses Adverse Effects CI 1- Pain: 1. CNS: ■ )--) RC → Resp depression ■ )--) VMC → Hypotension. ■ ++ CTZ → vomiting. ■ ↑ )ICP). 2. Respiratory system: BC. 3. GIT: Constipation. 4. Urinary: urine retention. 5. Allergy. 6. Dependence (Addiction). 7. Tolerance: No tolerance For Miosis P.P.P, Constipation & Excitation. ttt of Acute toxicity: 1. Extremities of age. 2. Head injuries Why?: 3. Increased intra-cranial pressure & epilepsy. 4. Impaired pulmonary functions: BA,COPD & Emphysema. 5. Liver & Kidney Dz. 6. Alone in biliary or renal colic. 7. Acute abdomen 8. During pregnancy & lactation. 9. During labor. 10. Myxedema )↓ BMR). 11. Addison. Cardiac pain (MI),Cancer pain, Colic, Post-operative, Fracture: but not in head. 2- Preanesthetic drug. But has disadvantages: Outlines the Disadvantages of Morphine in Preanathetic Medication? Q سؤال نظري سنين سابقة a- Delay awakening from anesthesia b- Depresses R.C &VMC. c- Post operative urine retention & constipation d- Bronchospasm. e- Miosis (PPP). f- Vomiting. 3- Pulmonary edema (acute left ventricular failure): ↓ after load, ↓ preload, ↓Anxiety, ↓ over stimulated R.C & cough center. 4- 1ry neurogenic shock: 5- Anesthesia. 1. Anti-tussive: dry cough. 2. Analgesic: moderate pain. 1- Pain: MI & colic 2- Preanesthetic 3- Labor: obstetric analgesia 1. tt of acute morphine poisoning. 2. Neonatal asphyxia. 3. Diagnosis of opiate Addiction. 1. Artificial respiration.. 2. Stomach wash. 3. Naloxone or Nalmefene. ttt of Chronic toxicity (Addiction) 1- Hospitalization & psychotherapy. 2- Gradual withdrawal of Morphine 3- Replacement morphine with Methadone or Buprenorphine 4- Give reason: Use of methadone in morphine addiction?Written Q As it has longer duration. Less withdrwal symptoms. 5- Clonidine: After Methadone . 6- Oral Naltrexone )μ antagonist): prevents recurrence. Maintenance: prevent desire for morphine.[craving] Q: Compare ( ) Morphine & Meperidine. Chemistery Bioavilability Analgesic effect Antitussive effect Addiction Effect on R.C Anaethesia Pupil Size Morphine Natural Opioid 30% More More More More R.c Depression Genral Miosis Meperidine Synthetic opioid agonist 50% Less )1/10 of Morphine) No antitussive effect Less less Local Mydriasis g DR. Killua Zoldyck CNS Module - 2nd year Clinical Pharmachology Hypnotics SubClass MAO Uses Adverse Effects 1. Barbiturates 1. Binds to & ++ specific binding site on GABA receptor ➩↑binding of GABA to its site➩opening of Clchannels with Cl- influx ➩postsynaptic hyperpolarization & inhibition. 1- Anticonvulsants & Antiepileptics:Phenobarbitone. 2- Anesthesia & preanesthetic: ■ IV thiopentone. ■ Hexobarbital rectally → basal anesthesia. 3- Hyperbilirubinaemia & kernicterus In neonates MCQ. ■ Hepatic microsomal enzyme inducer➩↑ bilirubin metabolism. 1- Idiosyncrasy: excitation in elderly. 2- Idiosyncrasy: precipitate porphyria. 3- ↑ hepatic microsomal enzyme: ↑drugs metabolism ☟to: Tolerance, cross tolerance, ↑ metabolism 4- Interactions with other drugs: a) Phenobarbitone P450 inducer b) Potentiate CNS depressants 5- Allergy: skin rash. 6- Amnesia & Automatism, 7- Abnormal sleep : ↓ REM→ hang over & rebound paradoxical sleep. 8- Extravasation of thiopental: gangrene. 9- Acute Barbiturates toxicity. 10- Addiction = dependence 1. Daytime sedation. 2. Dependence ➩ addiction. 3. Mental, psycho-motor & sexual effects. 4. Amnesia esp. short acting triazolam. 5. Elders: mental confusion & hypotension. 6. With Alcohol ➩ severe C.N.S inhibition. 7. Ataxia. 8. Allergy. 9. Amenorrhea,↓ ovulation, ↓ejaculation & teratogenic. 10. ↑ Appetite → ↑ body weight. 11. Acute toxicity: rare. Phenobarbital Amobarbital Phenobarbitone Secobarbital Thiopental Methohexital 2. (--) release of excitatory neurotransmitters 2.Benzodiazepines (BZd) Alprazolam Chlordiazepoxide Clorazepate Clonazepam Diazepam Flurazepam Lorazepam Midazolam Triazolam Flumazenil 5-HT agonist Buspirone 1. Bzd binds to specific Actions = Uses 1. Anxiolytic = antianxiety = minor tranquilizer 2. Hypnotic action. 3. Antiepileptics. 4. Antispasticity = sk ms relaxant: ■used in multiple sclerosis & cerebral palsy. 5. Induction of anesthesia: ■ Selective & competitive Bzd receptor blocker MCQ ■The specific antidote of Bnz ■ Partial agonist on presynaptic )5-HT1A) in brain. ■ Anxioselective 1. Acute Bzd toxicity. 2. Awake patients from anesthesia. 3. In hepatic coma. Advantages of (anxioselective) 1. No anticonvulsant 2.No ms relaxation. 3. No hypnosis 4.No rebound anxiety. 5. No tolerance or cross dependence. 6. Little dependence & least additive to alcohol. binding site on GABA receptors➩☟ ■Facilitate binding of GABA to its binding site. ■Open of Cl- channels➩↑ Clinflux➩ hyperpolarization & post synaptic inhibition. 2. Bzd & newer hypnotic (zolpidem) bind to α & γ subunits of the GABA receptor ➩ ↑ opening of Cl- channels. ■ Tachycardia, palpitation & nervousness. ■ If taken with MAOI → hypertension. CI 1. Allergy to barbiturates 2. Idiosyncrasy (porphyria). 3. Head injury. 4. Hypotension )shock). 5. Liver & kidney 6. Depressed RC. 7. Respiratory: emphysema, BA. g DR. Killua Zoldyck SubClass 1. Levodopa Madopar [levodopa + benserazide] Sinemet [levodopa + carbidopa] 2. Bromocriptine, pergolide MAO CNS Module - 2nd year Drugs used in ttt Of Parkinsonism Adverse Effects 1. Dopamine itself does not cross BBBMCQ. 2. Its immediate precursor )levodopa) can cross BBB where it is decarboxylated to dopamine which replenishes stores. 3. It ↓↓ all clinical features of Parkinsonism esp. bradykinesia. Specific D2 receptors agonist USES OF Bromocriptine: 1- Parkinsonism. 2- Inhibit lactation. 3- ttt of amenorrhea-galactorrhea➩ )induce ovulation)➩Blocks prolactin secretion. 4- Pituitary tumors + hyperprolactinemia. 3. Selegiline (Deprenyl) 4. Antimuscurinic Agents Benztropine Trihexyphenidyl Biperiden 5. Amantadine Clinical Pharmachology Selective MAO-B inhibitor MCQ. ↑ Dopamine levels in the brain. 1. Block cholinergic transmission➩restore balance ) ) dopaminergic /cholinergic systems. 2. Improve tremors & rigidity. 3. A little effect on bradykinesia. 4. Effective in drug-induced parkinsonism 1. ↑ release of dopamine, )--) its uptake. 2. Slight anticholinergic effect. 3. ↓ bradykinesia & muscle rigidity. 4. Antiviral drug against influenza A2 1. Anorxia, nausea, vomiting )reduced by domperidone). 2. Postural hypotension & cardiac arrhythmias. 3. Brownish discoloration of urine. 4. Mydriasis. 5. Visual & auditory hallucinations & involuntary movements )dyskinesia). 6. Mood changes & depression. 7. Fluctuation of the response: ■ Wearing off effect: progressive ↓ in duration of benefit. ■ On-off effect: Swings from relative mobility to hypotonia & bradykinesia. Management: a. ↑ frequency of intake of L-dopa. b. Use of slow release preparations. c. Add long-acting direct dopamine agonists➩bromocryptine. d. Drug holiday for 3- 21 days. 1. Dyskinesia, mental disturbances. 2. Arrhythmia, digital vasospasm. 3. Erythromyalgia: swollen, red, hot & tender feet. 4. Anorexia, nausea, vomiting, dyspepsia, constipation, PU. 5. Postural hypotension:1st dose phenomenon )sudden collapse). Advantages of bromocryptine over L-dopa: written Q 1. Does Not need synthesizing enzymes. 2. More specific on D2 receptors. 3. No active transport system. 4. No competition with amino acid. 5. Longer t1/2 so ➩ less fluctuation in response. Related to ↑ levels of Dopamine. Blurred vision-. Dry mouth Constipation Urine retention 1. CNS: insomnia, hallucinations, rarely fits. 2. Skin: livedo-reticularis 3. Ankle edema. 4. Postural hypotension. 5.Dry mouth and urine retention. 6. Used with caution in patients with seizures & CHF. CI 1. Closed angle glaucoma. 2. Coronary artery disease. 3. Severe psychosis 4. Melanoma 1. Psychiateric illness. 2.Peripheral vascular disease. 3. Peptic ulcer. 4. MI. g DR. Killua Zoldyck SubClass 1. (SSRIs): Fluxetine Citalopram Fluvoxamine Paroxetin Sertraline. CNS Module - 2nd year Antidepressant drugs Uses MAO 1. Specific inhibitor of 5-HT reuptake . 2. Have little ability to block dopamine transporter. 3. SSRIs have little blocking activity at muscurinic, alpha & histamine receptors. 1. Depression. 2. Obsessive compulsive disorder (fluvoxamine) 3. Panic disorder. 4. Generalized anxiety 2. (TCAs) 1. TCA block both NE & 5-HT reuptake into the neurons➩↑ level of monoamines in the synaptic cleft. 2. They also block M, H and α receptors. 3. (MAOIs) 1. Irreversible inactivation of MAO➩ ↑ stores of NE, 5-HT & DA within the neurons. 2. Mild Amphetamine like stimulant effect. 1- Depression. 2- Phobias. 4.Atypical antidepressants 1. Mirtazepine: Blocks 5-HT2 & α2 receptors 2. Nefozodone &Trazodone: blocks 5-HT1 1. Bupropion: ↓ craving for nicotine in tobacco abusers. Imipramine Amitriptyline Clomipramine Doxepin Desipramine nortriptyline Phenelzine Tranylcypromine Bupropion Mirtazepine Nefozodone Trazodone presynaptic, inhibits 5-HT reuptake. Enumerate Drugs used in tt of Huntington’s 1. Reserpine. 2. Dopamine receptor antagonists: Haloperidol , chloropromazine. 3. GABA agonist: Baclofen. Clinical Pharmachology Adverse Effects 1. 2. 3. Sleep disturbances. Sexual dysfunction. Nausea, vomiting & diarrhea. 1- Blurred vision, dry mouth, retention of urine, constipation. 2- Orthostatic hypotension. 3- Sedation. 4- Sexual dysfunction. 5- ↑ catecholamines➩cardiac overstimulation. Drugs used in tt Alzheimer’s 1. Glucoma 2. Senile prostatic enlargement. 3. Myocardial infarction. 4. With MAOI. 1- ↑↑ CNS stimulation: tremors, irritability, hyperthermia. 2- Postural hypotension. 3- Constipation, dry mouth. 4- Weight gain. Drugs used in [ لو جت تيجيenumerate] A. Acetylcholinestrase Inhibitors Donepezil, Galantamine, Rivastigmine & Tacrine B. NMDA Antagonist: Memantine CI Drug therapy of acute migraine I- Triptans e.g, Somatriptan. II- Ergotamine III- Analgesics e.g NSAIDs Drug Prophylaxis of Migraine 1. Beta Blockers: propranolol & nadolol. 2. Methysergide:MCQ 3. Pizotifen 4. Flunarizine: Calcium channel blocker. 5. Clonidine. g DR. Killua Zoldyck CNS Module - 2nd year Clinical Pharmachology Antiepileptic drugs SubClass 1. Phenytoin MAO 1. Blocks Na+ channels. 2. At higher concentrations➩ blocks Ca++ channels & interferes with release of neurotransmitters + 2. Carbamazepine ■ Blocks Na channels ➩ ↓propagation of abnormal impulses in the brain. Uses 1. Antiepileptic: ■ 1st choice in grand mal & focal seizures. ■ Status epilepticus. 2. Ventricular arrhythmia. 1. Grand mal and focal seizures. 2. Trigeminal neuralgia 3. Cerebral or nephrogenic D.I. 4. Mood stabilizer 3. Barbiturates & related drugs Selective anticonvulsant activity Potentiate the inhibitory pathway )GABA). ■ Partial & grand mal epilepsy & febrile convulsion 4. Valproic acid 1. ↑ GABA in synaptic regions by: ■ Inhibition of GABA transaminase ■ Inhibition of GABA reuptake. 2. Blocks Na+ channels & T-Ca++ channels. 1. Broad spectrum aniepileptic: ■ effective in grand mal epilepsy & partial seizures. ■ But it is not the drug of choice )sedation & hepatotoxicity). 2. Petit mal epilepsy. 3. Febrile convulsion. 4. Myoclonus. 5. Prophylaxis of migraine. Phenobarbitone Primidone Adverse Effects 1. C.N.S: nystagmus, ataxia, diplopia & vertigo. 2. Gingival hyperplasia MCQ 3. G.I.T disturbances. 3.Chronic use )it interferes with vit D hydroxylation & ↓ GIT Ca+2 absorption) 5. Megaloplastic anemia. 6. Hypersensetivity reactions. 7. Hirsutism & acne due to ↑androgen 8. TeratogenicityMCQ : cleft palate and hare lip )fetal hydantoin syndrome)➩1st Trimester. Hypoprothrombinemia of the baby ➩if taken before labor. 1. C.N.S: diplopia, ataxia & drowsiness. 2. G.I.T: nausea & vomiting. 3. Allergy: rash & photosensitivity. 4. Hyponatremia, water toxicity. 5. Aplastic anemia, Agranulocytosis. 6. Liver dysfunction. 1. Sedation, nystagmus, ataxia. 2. Megaloblastic anemia. 3. Osteomalacia. 4. Addiction. 1. G.I.T: anorexia, nausea & vomiting. 2. Hair loss. 3. Hepatotoxicity. 4. Teratogenic: Spina Bifida CI / Precautions Precautions 1. Serum level monitoring. 2. Oral hygiene. 3. Vit D and folate supplements. Treatment of status epilepticus 1. 2. 3. Written Q. Diazepam: slow intravenous (1st choice). IV phenytoin. General anesthesia in highly resistant cases)thiopental IV, intubation, muscle relaxant & artificial respiration). h SubClass I. Typical Antipsychotic drugs antischizophrenic= neuroleptics =major tranquilizers Uses Adverse Effects MAO 1. Typical drugs ☞block D2 receptors in +ve symptoms mainly the mesolimbic system. Chloropromazine 2. Atypical drugs☞inhibition of 5-HT receptors, block presynaptic D1 receptors. Haloperidol 3. Blocking dopamine receptors in: Droperidol Nigrostriatal pathway➩ Flupentixol extrapyramidal adverse effects. II. Atypical Tubero-infandibular pathway➩ -ve symptoms mainly ↑prolactin secretion. C.T.Z. ➩antiemetic action. Clozapine Medullary periventricular pathway ➩ Olanzepine change eating behavior. 4. Block cholinergic, adrenergic & histaminergic receptors. MAO of General Anaethetic Drugs 1. GABAA-receptor Cl- channels: ↑ GABA- mediated ↑ in Cl- ➩hyperpolerization & )-) of neuronal membrane activity. 2. Lignad-gated K+ channels➩↑ K+ conductance➩hyperpolarization & )--) neuronal membrane activity. 3. NMDA receptors: Anesthetics )e.g., NO & ketamine)➩ )--) excitatory glutamate. 1- Schizophrenia, organic psychosis, manic phase. 2- Antiemetic. 3- Persistant pruritis. 4- Hiccough. 5- Neuroleptanalgesia )droperidol + fentanyl): for minor procedure as endoscopy 6- Tics )haloperidol is used). 7- Hypothermic anesthetic medication )lytic cocktail). 1- Extrapyramidal manifestations. 2- Anticholinergic side effects. 3- Orthostatic hypotension. 4- Cholestatic jaundice➩ chloropromazine. 5- Phenothiazines ➩urticaria, dermatitis & photosensitivity. 6- Galactorrhoea, gynecomastia, amenorrhoea. 7- ↑ appetite, weight gain. 8- Clozapine➩agranulocytosis. Anesthesia Enumerate Inhaled Anesthetic Enumerate 2 IV Anaethetics I- Nitrous oxide [gas] II- Halogenated Volatile anesthetics: A. Halothane➩arrhythmias ,Hepatotoxic B. Sevoflurane➩Nephrotoxic, bronchodilator C. Enflurane➩nephrotoxic, CNS stimulant in high conc. D. Isoflurane➩preserves cardiac output. E. Desflurane➩irritating to the airway. 1. Propofol 2. Fospropofol [prodrug] 3. Thiopental )Barbiturates) 4. Midazolam (Benzodiazepines): 5. Fentanyl, Sufentanil, Remifentanil (opioid) 6. Ketamine 7. Etomidate 1- Epilepsy as antipsychotics lower seizure threshold. 2- Agranulocytosis (avoid clozapine). 3- Infertility. 4-Liver impairment (chlorpromazine). MAO of Local Anaethetic Drugs 1. Block Na+ channels. 2. ↓ influx of Na+ ions. 3. Block the initiation & propagation of action potentials CI Enumerate 2 local Anaethetics Amides: Lidocaine, Bupivacaine, Mepivacaine, Prilocaine, Ropivacaine. Esters : Procaine, Tetracaine, Benzocaine, Cocain. Morphine not used in head injuries. On Pharmachological Basis Give Reason: مهم 1. ↑ ICP. 2. Miosis → Mask sign of lateralization. 1. As it has longer duration. 2. Less withdrwal symptoms. Use of Naltrexone in Morphine addiction? Combining Levodopa with Benserazide or carbidopa? 1. Prevents recurrence. 2. Prevent desire for morphine.[craving] a. As They potentiate its action. b. ↓daily levodopa req. by 75%. c. ↓ side effects such as nausea, vomiting, risk of cardiac arrhythmias & postural hypotension. As they lower seizure threshold. Adding Bromocryptine or Selegiline to L-dopa in tt of parkinsonism? 1. ↓ required dose of levodopa. 2. improves on-off phenomena & wearing off. Combining Fentanyl with Droperidol? As Droperidol blocks the emetic effect of fentanyl. Epinepherine is often added to local anesthetics ? Anxioselective so effective in generalized anxiety syndrome not in acute panic attacks? As Its anxiolytic effect appears after 12 weeks. TCAs shouldn’t be used with MAOIs ? 1. Localize the anesthetic to the site of injection. 2. Slow its absorption and prolong its effect. 3. Minimizing the systemic toxicity. As it can lead to hypertension crisis. Use of methadone in morphine addiction? Use of Morphine in Acute left vwntricular failure (Pulmonary Edema)? Antipsychotics are contraindicated in Epilepsy? a-↓ anxiety → ↓ after load. b- Venodilatation →↓ preload. c-↓ over stimulated R.C & cough center Advantages of Bzd over barbiturates as hypnotics written Q Barbiturates Benzodiazepines Sleep Patttern Hepatic Microsomal Enzs Therapeutic Index Antidote Marked )--) of REM: a. Hang over b. Rebound sleep Induction: a. Tolerance. b. cross tolerance c. Dependence d. Drug interactions ↓ inhibition of REM: a. ↓ hang over b. ↓ rebound sleep No Induction: a. ↓ Tolerance. b. ↓ cross tolerance c. ↓ Dependence d. ↓ interactions Low )depress R.C) ➩ narrow safety margin No Higher )safe R.C) ➩ wide safety margin Flumazenil