Pharmacology Psychotropic Drugs PDF

Made with Xodo PDF Reader and Editor PHARMACOLOGY Psychotropic Dugs Psychotropic Drugs are drugs affect behavior and psychology of individuals. Classification of Psychotropic Drugs: A) Tranquilizers (Psycoleptics): 1- Minor Tranquillizers...

Made with Xodo PDF Reader and Editor PHARMACOLOGY Psychotropic Dugs Psychotropic Drugs are drugs affect behavior and psychology of individuals. Classification of Psychotropic Drugs: A) Tranquilizers (Psycoleptics): 1- Minor Tranquillizers (Anti-anxiety, Anxiolytics): e.g. Diazepam. (Discussed before P 151) 2- Major Tranquillizers (Anti-psychotic, Neuroleptics): e.g: Chlorpromazine. B) Anti-Depressants (psycoanaleptics) and Lithium: 1- Anti-Depressants (Mood Elevating): e.g. Tricyclic antidepressants. 2- Lithium Carbonate (Mood Stabilizing & Anti-Manic). C) Psychotomimetics (Psychedelics, Hallucinogens): e.g. LSD. D) Psychomotor Stimulants (psychostimulants) e.g. Amphetamine. Major Tranquillizers (Anti-Psychotic, Neuroleptics, Anti-Schizophrenic) Useful in major psychiatric illness e.g. Schizophrenia and Mania. Classification of Anti-Psychotic Drugs: I- Typical Antipsychotics: 1) Phenothiazines: Chlorpromazine, Thioridazine, Trifluoperazine, Fluphenazine 2) Thioxanthenes: Thiothixene 3) Butyrophenones: Haloperidol & Droperidol II- Atypical Antipsychotic Drugs: (more effective, less side effects) a- Pimozide b-Sulpiride c- Clozapine d- Risperidone e-Olanzapine NB) Most of neuroleptics act via blocking central D2-receptors in hypothalamus and limbic system N.B.) Dopamine receptors: 1- D1-Family (D1 + D5) Gs Adenylate Cyclase cAMP Most of peripheral actions e.g. Renal VD. 2- D2-Family (D2 + D3 + D4) Gi Adenylate Cyclase cAMP, K+ & Ca2+ Most of Central actions e.g. Psychotic & Anti-Parkinsonian actions. Site Dopamine Dopamine Antagonists 1- Limbic system, 1- Euphoria then Psychosis 1- Anti-Psychotic. Frontal cortex 2- Basal Ganglia. 2- Anti-Parkinsonian. 2- Parkinsonism. 3- Hypothalamus. 3- Temperature 3- Temperature Hypothermia Appetite Appetite Prolactin Prolactin 4- C. T.Z. 4- Nausea & Vomiting 4- Anti-emetic EXCEPT in motion sickness 10  Made with Xodo PDF Reader and Editor PHARMACOLOGY I- Typical Antipsychotics 1- Phenothiazines Chlorpromazine Pharmacodynamics: 1- C.N.S. a- Antipsychotic Blocks Dopamine (D2-receptor) in limbic system, Neocortex & Hypothalamus. b- Basal Ganglia Large doses Block D2-receptors Worsen Parkinsonism. c- Hypothalamus: - Hypothermia Heat loss by cutaneous VD ( HRC, VMC & -Blocker) Heat production by Shivering. - Appetite & Weight gain. - Prolactin. d- C.T.Z.: Antiemetic in ALL vomiting EXCEPT in motion sickness. e- Potentiates other CNS depressants e.g. Barbiturates & Morphine. f- Lowers seizure threshold. 2- Endocrine a. b. FSH & LH gonadotrophins Infertility & Amenorrhea in females. c. Prolactin Gynecomastia & Galactorrhea (Non-puerperal lactation). 3- Receptors a. Potent Anti-Dopamine. b. Potent a-blocker. c. Weak Anti-Muscarinic (Atropine-like d. Weak ganglion blocker. e. Potent Anti-Serotonin. f. Weak H1-blocker (Anti-Histamine) 4- Skeletal Muscle Muscle relaxation. 5- Local Anesthetic 11  Made with Xodo PDF Reader and Editor PHARMACOLOGY 6- C.V.S. a. Hypotension & Postural Hypotension VMC + Ganglion Block + - Block + Direct VD + Direct myocardial depressant. b. Tachycardia Atropine like + Reflex from BL.Pr. c. Increases coronary flow. Therapeutic Uses: 1- Psychosis e.g. Schizophrenia (200-1000 mg/Day). Treats mainly the positive signs such as hallucinations, illusions & delusions. 2- Preanesthetic medication. 3- Hypothermic agent Tissue metabolism during cardio-pulmonary surgery. 4- Hiccough. 5- Anti-emetic (25 mg) EXCEPT motion sickness & pregnancy (Teratogenic). Adverse Effects of Chlorpromazine 1- C.N.S.: a. SEDATION. b. Extrapyramidal Manifestations: 1- Acute dystonia (muscle spasm). 2- Akathisia (motor restlessness). 3- Parkinsonism: Treat by dose of neuroleptic & use Anti-cholinergic Anti- Parkinsonian drug. c. Neurolept-malignant syndrome (NMS). Idiosyncratic reaction, similar to Malignant Hyperthermia. Treat by IV Dantrolene. d. Tardive dyskinesia (abnormal movements) occurs after long use of neuroleptics, due to upregulation of D-receptors. NO treatment. Can be prevented by lithium. 2- Increased body weight. 3- Opacities of cornea and lens. 4- Dry mouth 5- Allergy: Dermatitis, photosensitivity & Agranulocytosis. 6- Tachycardia. 7- Endocrine disturbances e.g. Gynecomastia & galactorrhea. 8- Allergic obstructive cholestatic jaundice. 9- Teratogenic, so not used in vomiting of pregnancy. 10- Postural hypotension. 12  Made with Xodo PDF Reader and Editor PHARMACOLOGY Drug Interactions of Chlorpromazine 1- Chlorpromazine Potentiates a- Sedatives e.g. Alcohol. b- Hypotensive e.g. V.D. c- Anti-cholinergic e.g. Atropine d- Muscle relaxants e.g. Curare 2- It Neuronal uptake1 of Guanethidine Antagonize its hypotensive effect. 3- Chlorpromazine -blocker Reverses pressor effect of Adrenaline. Other Phenothiazines - Thioridazine: - Phenothiazine, similar to chlorpromazine, BUT: a- NOT Anti-emetic. b- RARE Extra-pyramidal manifestations. - Uses: Schizophrenia - Side Effects: Similar to Chlorpromazine + Cardiotoxic & Retinopathy. - Trifluperazine: Phenothiazine, similar to chlorpromazine, BUT: More D2-Block More POWERFUL Anti-psychotic & More Extrapyramidal manifestations. 2- Thioxanthenes 1- Examples: Thiothixene 2- Similar in actions to the Phenothiazines but less toxic 3- Butyrophenones 1- Examples: Haloperidol & Droperidol 2- Similar to Chlorpromazine BUT STRONGER Anti-Dopamine effects. 3- STRONGER Antipsychotic, Anti-Emetic & Extrapyramidal manifestations. 4- Uses: a- Anti-psychotic in Schizophrenia. b- Droperidol + Fentanyl (Opioid Analgesic) I.V. Neurolept Analgesia for minor operations. The emetic effect of Fentanyl is Antagonized by the Antiemetic effect of Droperidol. II- Atypical Anti-Psychotic Drugs - More effective in ttt of schizophrenia with Less side effects. Examples: o Sulpiride: Selective D2-blocker specific on Limbic system, not approved in USA, Canada and Australia. o Clozapine: It blocks D4 & 5-HT2 receptors. has high incidence (1-2%) of Agranulocytosis. o Risperidone: It blocks D2 & D4 = 5-HT2 receptors. o Olanzapine: It blocks 5-HT2 > D2 receptors. o Quetiapine: A 5-HT1A partial agonist. 13  Made with Xodo PDF Reader and Editor PHARMACOLOGY Treatment of Affective (Mood) Disorders Affective (mood) disorders include: - Psychic Depression is caused by functional deficit of the monoamines transmitters (Noradrenaline & Serotonin) in certain parts in the brain. - Mania is caused by functional excess of monoamines. Types of Depression % Features Management 1- Reactive "Secondary" 60% - Adverse life events, - Spontaneous recovery. Depression. death, diseases & drugs. - Ministration. 2- Major "Endogenous" 25% - Spontaneous. - Antidepressants. Depression. - Genetically determined. - Electro-Convulsive - Biochemical causes. Therapy (ECT). 3- Bipolar Affective 15% - Spontaneous. - Lithium. Manic-Depressive - Genetically determined. ± Antidepressant. Disorder - Biochemical error. ± Neuroleptic. Anti-Depressant Drugs Psycho-analeptics, Thymoleptics, Psychic Energizers Classification of Anti-Depressants 1- Selective serotonin re-uptake inhibitors (SSRI) e.g. fluoxetine 2- Tricyclic anti-depressants (TCA): the oldest group, considered as first generation: they decrease the reuptake of both noradrenaline and 5-HT 3- Atypical anti-depressants (second & third generation) e.g. bupropion, amoxapine 4- Monoamine oxidase inhibitors (MAOI) e.g. tranylcypromine 1- Selective Serotonin Reuptake Inhibitors (SSRI) Most commonly prescribed antidepressants 14  Made with Xodo PDF Reader and Editor PHARMACOLOGY Fluoxetine Pharmacodynamics Antidepressant Effect: Elevate mood in depressed patients by selective block of serotonin uptake by nerve endings The Antidepressant Effect appears after 2-3 WEEKS and lasts for 2-3 WEEKS after stop of SSRI 2-3 Weeks 2-3 Weeks Therapeutic Uses Psychic depression panic disorders Obsessive compulsive disorders (better than the TCA clomipramine). Eating disorders e.g. Bulimia nervosa. Advantages of Fluoxetine over TCA a- Less Adverse Effects: NO Atropine like effects (Allowed in Glaucoma patients), NO CVS side effects, NO weight gain. b- Low acute toxicity: NO Cardiotoxicity or Hepatotoxicity c- Little interactions & NO Interaction with food. Adverse Effects of Fluoxetine a- Anorexia, nausea & diarrhea. b- Anxiety, insomnia & mania. c- Increases aggression, violence & suicide. d- Fluoxetine + MAOI Serotonin syndrome. May be FATAL. NB) Other SSRI Similar to Fluoxetine 2- Citalopram 3- Escitalopram 4- Sertraline 5- Fluvoxamine 6- Paroxetine II- Tricyclic Antidepressants (TCA) * Members: 1- Imipramine 2- Desipramine 3- Clomipramine 4- Amitriptylin 5- Nortriptyline 15  Made with Xodo PDF Reader and Editor PHARMACOLOGY Pharmacokinetics of TCA 1- Absorbed orally extensive hepatic first pass metabolism. 2- Highly bound to plasma & tissue proteins. 3- Highly lipid soluble. Pass easily BBB & Placental barriers. 4- Hepatic Metabolism: a- Change of Tertiary amines Active Secondary amines: - Imipramine (Active) Active Desipramine. - Amitriptyline (Active) Active Nortriptyline. b- Glucuronic acid conjugation + Inactive metabolites. 5- Excretion in urine mainly in conjugated form Pharmacodynamics Mechanism of Action of TCA: Inhibit Neuronal Uptake1 of Noradrenaline & Serotonin NA, 5-HT Inter-Synaptic. Actions of Tricyclic Antidepressants 1- Antidepressant Effect: 2-3 Weeks 2-3 Weeks The antidepressant effect appears after 2-3 WEEKS and lasts for 2-3 WEEKS after stop of TCA. 2- SEDATION: Especially at beginning of treatment & in Normal individuals. Amitriptyline Imipramine Desipramine. 3- Lower Seizure Threshold. 4- Anti-Cholinergic (Anti-Muscarinic = Atropine-Like). Amitriptyline Imipramine Desipramine. 5- Anti-Histaminic (H1-Block) & H2-Block. 6- Anti-Serotonin. 7- Alpha blocking effect. Therapeutic Uses of TCA 1- Psychic depression (Main Use). 2- Panic & Phobic states. 3- Obsessive Compulsive disorders (Clomipramine or Better SSRI as Fluoxetine). 4- Chronic pain 5- Nocturnal enuresis in children (Imipramine). But ADH is better alternative. 16  Made with Xodo PDF Reader and Editor PHARMACOLOGY Adverse Effects & Toxicity OF TCA 1- Delayed onset of action (2-3 weeks). 2- C.N.S.: SEDATION, Seizures, Tremors, Confusion & Delirium. 3- C.V.S.: a. Postural hypotension (an-block). b. Tachycardia (Atropine-like). c. CARDIOTOXICITY FATAL ARRHYTHMIAS. 4- ATROPINE-like effects Blurring of vision, dry mouth, tachycardia, constipation & urinary retention. Paradoxical sweating may occur. Contraindicated in: Glaucoma & Enlarged Prostate. 5- Weight gain. 6- Allergic Obstructive jaundice & Agranulocytosis. 7- Acute Toxicity: Common & FATAL. a- Manifestations: Excitement, Seizures, Arrhythmia & Atropine Like. b- Treatment: - ICU - Stomach wash + Charcoal. + Diazepam Treats excitement & Seizures. + Phenytoin Treats Seizures & Ventricular arrhythmias. + Physostigmine treats Atropine-like effects. Drug Interactions of TCA 1- Potentiate: a- Sedatives e.g. Alcohol. b- Anticholinergics e.g. Major tranquillizers & Anti-Parkinsonians. c- Direct Catecholamines e.g. Adrenaline by #their Neuronal Uptake1. 2- Antagonize: Antihypertensive effect of Clonidine & a-Methyl-Dopa due to Down-regulation of Presynaptic 2-receptors. 3- TCA + MAO-I Severe Atropine- III- Other (Non-Tricyclic) - NA/5-HT Reuptake Inhibitors 1- Venlafaxine (Efexor) a- Selective serotonin and norepinephrine reuptake inhibitor (SNRI) b- Claimed to act more rapidly and effective in resistant cases. 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake 2- Desvenlafaxine (Pristiq) Synthetic form of the isolated major active metabolite of venlafaxine (similar in Action - less side effects) 3- Duloxetine (Cymbalta) a- Selective serotonin and norepinephrine reuptake inhibitor (SNRI) b- Also useful in urinary incontinence, anxiety disorders, pain disorder 4- Milnacipran (Savella) Help manage fibromyalgia 17  Made with Xodo PDF Reader and Editor PHARMACOLOGY IV- Selective NA Reuptake inhibitor 1- Bupropion (Wellbutrin)) a- Atypical antidepressant- norepinephrine-dopamine reuptake inhibitor(NDRI) and a nicotinic receptor antagonist b- Slow release formulations used to help cessation of smoking (nicotine dependence). c- Other uses: ADHD - help to alleviate sexual dysfunction used for treating obesity - mood stabilizer 2- Maprotiline: Has NO advantage over TCA. NB) ATOMOXETINE & REBOXETINE 1- It is a selective NA reuptake inhibitor. 2- Recently introduced for the treatment of attention deficit hyperkinetic disorder in children. V-Herbal Antidepressants St. John's Wort for Treating Depression Hypericum perforatum - St. John's wort plant has flowering plant - Used as an Alternative Medicine for treatment of depression - anxiety and Menopause- related symptoms - Premenstrual syndrome (PMS) Seasonal affective disorder - Smoking cessation - 300 mg three times per day as a standardized extract VI- Monoamine Receptor Antagonists 1- Mirtazapine (Remeron): a- Blocks -2, 5-HT2C and 5-HT3 receptors Release of NA & 5-HT. b- Claimed to have faster onset of action. 2- Trazodone (Trittico): a- Blocks 5-HT2A, 5-HT2C Release of 5-HT, and H-1 receptors. b- Weak 5-HT reuptake inhibitor. VII- Mono-Amine Oxidase Inhibitors (MAOI) Types of MAO Enzymes M. A. O. -A M. A. O. -B 1- Location: 1- Placenta, Gut mucosa, Liver & Brain. 1- Platelets, Liver & Brain. 2- Substrate: 2- NA & 5-HT. 2- Dopamine. 3- Selective Inhibitors 3- Clorgyline & Moclobemide 3- Selegiline Noradrenaline MAO-A Vanyl Mandelic Acid (VMA) Urine. Serotonin MAO-A 5-Hydroxy-Indol Acetic Acid (5-HIAA) Urine Classification of MAO-Inhibitors Non selective MAO inhibitors: Antidepressants e.g. Phenelzine, Tranylcypromine Selective MAO-A inhibitors: Moclobemide- Clorgyline Selective MAO-B inhibitors: Anti-Parkinsonian.e.g. Selegiline 18  Made with Xodo PDF Reader and Editor PHARMACOLOGY Pharmacodynamics of MAO- Inhibitors Antidepressant effect: elevate mood in depressed patients by: - Inhibition of MAO enzyme: accumulation of Intra-cytoplasmic Noradrenaline & serotonin. - MAOI monoamines in CNS & body BUT VMA & HIAA in urine. - The Antidepressant effect of MAOI appears after 2-3 weeks & Lasts for 2-3 weeks after stop of MAO.I. 2-3 Weeks 2-3 Weeks Advers Effects & Toxicity of MAO- Inhibitors 1- C.N.S.: Excitation Insomnia, hyperhidrosis, hallucination & Seizures. 2- C. V. S.: Hypotension & Postural hypotension. 3- Some has Atropine-like effect. 4- Weight gain. 5- HEPATOTOXIC. Drug Interactions of MAO- Inhibitors 1- Cheese Reaction (NOT with Moclobemide or Selegiline): Eating or drinking foods that contain TYRAMINE or DOPA such as Aged cheese, Broad beans or Yogurt Severe Hypertension (Pheochromocytoma-like reaction). Treatment by IV Phentolamine or Nitroprusside ± -Blocker. 2- I-DOPA (Anti-Parkinsonian) Agitation & Hypertension. 3- Potentiates Indirectly Acting Sympathomimetics e.g. Amphetamine. 4- SSRI (Fluoxetine), Melatonin & Meperidine Serotonin Syndrome Excitation, Hyperthermia, Cardiac arrhythmia, Hypotension, Tremors & Coma. May be FATAL. 5- MAOI + TCA Toxicity. 6- MAO-I Enzyme inhibitors Potentiate other drugs e.g. Alcohol. Mood Stabilizing Drugs (Antimanic Drugs) 1- Lithium carbonate 2- Carbamazepine 3- Valproate 4- Lamotrigine Used for treatment of mania. Carbamazepine, valproate & lamotrigine were discussed previously with antiepileptic drugs. 19  Made with Xodo PDF Reader and Editor PHARMACOLOGY LITHIUM CARBONATE (PRIANIL) 1- Antimanic & Mood Stabilizing agent. 2- Used mainly as mood stabilizing in manic depressive disorder. 3- Slow onset in acute mania add antipsychotic. Pharmacokinetics 1- Well absorbed orally. 2- Distributed in total body fluid. NOT bound to plasma proteins. 3- NO Hepatic Metabolism. 4- Excreted unchanged in urine. a- Urinary excretion of lithiuri is INCREASED by: - Na+ load e.g. NaCl. - Alkalinizer of urine e.g. NaHCO3. - Osmotic diuretics e.g. Mannitol. - Acetazolamide & Triamterene. b- Urinary excretion of lithium is DECREASED by: - Hyponatremia (Low salt intake, vomiting & diarrhea). - Most of Diuretics e.g. Thiazides, Frusemide & Spironolactone. - Most of NSAID. Mechanism of Action Frequency & severity of mania by release of noradrenaline, serotonin & dopamine. Therapeutic Uses: mood stabilizer for: 1- Prophylaxis of Manic-Depressive disorder. 2- Prophylaxis of recurrent endogenous depression. 3- Acute mania but slow onset. So, add antipsychotic drug as haloperidol 4- Management of aggressive & violent behavior in prisoners. Adverse Effects & Toxicity 1- C. N. S.: Tremors, dyskinesia & Confusion. 2- Thyroid: Hypothyroidism, Smooth benign enlargement of thyroid gland (Goiter). 3- C. V. S.: Depresses sinus node. 4- Renal: a- Initial polydipsia and polyuria. May be through antagonizing the effect of ADH on adenylate cyclase enzyme of the distal convoluted tubules i.e. nephrogenic diabetes insipidus. b- Nephrotoxic. Frequent urine analysis is required. 5- Edema: Na+ and water retention, may be via increased release of aldosterone 6- Weight gain, partially by edema formation. 7- During Pregnancy & Lactation: a- Teratogenic b- Lithium is secreted in milk and affects suckling baby leading to lethargy. 8- Skin: Acniform eruptions and folliculitis. 20  Made with Xodo PDF Reader and Editor PHARMACOLOGY 9- Leukocytosis 10- Diminished sexual functions. Psychotomimetics [Hallucinogens, Psychedelics] Produce symptoms like psychosis as hallucinations, elation, delusions. 1- Cannabis (Hashish, Bango, Kif, Marijuana) 1- Active principle is Tetra-hydro-cannabinol Specific cannabinoid receptors. 2- Cannabinoid receptors are present mainly in CNS & in lymphoid system. 3- Anandamide is an endogenous ligand for the cannabinoid receptors in CNS 4- The person loses the sense of time & space. 5- Euphoria & attacks of uncontrolled laughter. 6- Congestion of conjunctiva, I.O.P. & Tachycardia. 7- Derivatives are used clinically as analgesics & Antiemetics e.g. The antiemetic Dronabinol 2- Lysergic Acid Di-Ethylamide (LSD, Acid) Related to Ergot alkaloids. Central 5-HT Agonist (Auto-receptors) BUT peripheral 5-HT antagonist. 3- Mescaline Obtained from Mexican cactus. Cross tolerance with LSD. 4- Khat ( ) Amphetamine-like 5- Phencyclidine (PCP, Angle Dust) a- Related chemically to Meperidine (Opioid) & Ketamine (IV Anesthesia). b- It Stimulates o-opioid receptor & blocks NMDA-glutamate receptor. c- Produces Dissociative Anesthesia = Analgesia, stupor & Amnesia. Patient is conscious hut detached from the environment Aim of treatment is to restore the balance between Dopamine (D2) and A.Ch (M). Anti-Parkinsonian Drugs A) Dopaminergic Drugs: [ Dopamine]: 1- Levodopa (L-DOPA) + Peripheral Dopa Decarboxylase Inhibitors e.g. Carbidopa. 2- COMT-Inhibitors: Tolcapone & Entacapone. 3- MAO-B Inhibitors: Selegiline. 4- Direct Dopamine Agonists: a- Ergolines: Bromocriptine, Pergolide. b- Non-Ergot. Pramipexole, Ropinirole & Rotigotine. 5- Amantadine. B) Anti-Cholinergic Drugs: [ acetylcholine effect] Synthetic Atropine Substitutes - Benztropine. - Benzhexol Biperiden 21  Made with Xodo PDF Reader and Editor PHARMACOLOGY Pharmacologic strategies for dopaminergic therapy of Parkinson's disease. A- Dopaminergic Drugs 1- Levodopa (L-DOPA) Pharmacokinetics of L-DOPA 1- L-DOPA orally is well absorbed from intestine. Food specially proteins its Absorption 2- L-DOPA is a prodrug (inactive drug) activated by decarboxylase enzyme into dopamine (active): 3- > 95% of ingested DOPA (90% in gut mucosa & 5% in blood & peripheral tissues) are metabolized by Peripheral Dopa-Decarboxylase enzyme (PDD)into Dopamine that cannot pass the BBB. 4- Part of L-Dopa COMT 3-0-Methyl-Dopa (30MD) uptake of L-Dopa into CNS. 5- Only < 5% of ingested L-DOPA can escape metabolism and passes the BBB by active process. 6- In CNS L-Dopa Central Dopa Decarboxylase dopamine. 7- Fate of Dopamine: a- Dopamine MAO-B Di-Hydroxy-Phenyl-Acetic Acid (DOPAC) inactive metabolite) Urine b- Dopamine MAO & COMT Homovanilic acid (HVA) inactive metabolite Urine. Dynamics of L-DOPA: Anti-Parkinsonian Effect: 1- L-DOPA (Prodrug) by Central Dopa Decarboxylase (CDD) Dopamine D2-receptors. 2- Best results are obtained in the first few (3-4) years. 3- Treats all manifestations of Parkinsonism, especially Bradykinesia > Tremors by stimulating D2 receptors in basal ganglia. Uses: PARKINSONISM - Used combined with a peripheral decarboxylase inhibitor as carbidopa to t central L-Dopa. - Start with small frequent doses to be increased gradually. 22  Made with Xodo PDF Reader and Editor PHARMACOLOGY Adverse Effects of L-DOPA: 1- Fluctuation in Response: a- At first there is increased sensitivity to L-DOPA Good response then response b- Wearing-off - Formation of DOPAC + H2O2+ Free radicals c- End-of-dose Akinesia. Destroy Dopamine storage vesicles d- On-off phenomena. Rapid then rapid of Dopamine level in CNS. Management: a- Increase the frequency of intake of L-DOPA. b- Use of slow release preparations (Sinemet CR). c- Add long acting direct dopamine agonists e.g. Bromocriptine & Pergolide. d- Drug-holiday for 3-21 days. 2- C.N.S.: a. Dyskinesia e.g. chorea and athetosis. Reduce dose of L-Dopa. b. Psychological disturbances e.g. delusions, hallucinations & aberrant sexual activity. Either reduce the dose of L-DOPA or use the atypical antipsychotic Clozapine. 3- Eye: Mydriasis & may IOP. 4- C.V.S.: Tachycardia, arrhythmias, postural hypotension or Hypertension (especially with the use of Large dose or concurrent use of MAO-I). 5- G.I.T.: Nausea and vomiting that can be treated by Domperidone. Constipation and sometimes bleeding peptic ulcer. 6- Contraindications of L-Dopa 1- Psychological disturbances. 2- Closed angle glaucoma. 3- Cardiac diseases. 4- Peptic ulcer 5- Unfavorable drug interactions. Drug Interactions of L-Dopa: I) Desirable = Favorable:t L-DOPA effect 1- Peripheral Dopa Decarboxylase Inhibitor (Can NOT pass BBB) Dose of L-DOPA Peripheral Adverse effects But Central Adverse effects. Examples: a- Carbidopa (10 & 25 mg) + L-DOPA (100 & 250 mg) 1:10 = Sinemet b- Benserazide (25 mg) + L-DOPA (100 mg) 1:4 = Madopar. 2- MAO-B inhibitor e.g. Selegiline 3- COMT-Inhibitors e.g. Tolcapone & Entacapone. 4- Anti-Muscarinic drugs e.g. Benztropine. II) Undesirable = Unfavorable: A- L-DOPA effect 1- Dopamine (D2) receptor blockers: a- Neuroleptics e.g. Phenothiazines & Butyrophenones. 23  Made with Xodo PDF Reader and Editor PHARMACOLOGY b- Anti-emetics e.g. Metoclopramide. 2- Pyridoxine (Vit B6) PDD Accelerates peripheral decarboxylation Dopamine. B- With Non-selective MAO-I Severe hypertension. 2- COMT Inhibitors [Tolcapone, Entacapone] - Decrease peripheral metabolism of Levodopa L-DOPA COMT 3-O - Methyl-Dopa (3OMD) uptake of L-Dopa into CNS. a- Tolcapone Hepatotoxic. b- Entacapone Less Toxic AS NO HEPATOTOXICITY. Use: Parkinsonism 3- MAO-B INHIBITORS [Selegiline] 1- Selective MAO-B inhibitor degradation of central dopamine. 2- Potentiates effect of L-DOPA. Use: Parkinsonism. 4- Direct Dopamine Agonists A) Ergolines = Ergot Alkaloids derivatives [bromocriptine, pergolide]: B) Non-Ergot Direct D-Agonists+Pramipexole, Ropinirole & Rotigotine. Stimulate dopamine receptors [D2] in basal ganglia Bromocriptine - Direct Dopamine D2-Agonist & D1-Partial agonist. - Absorbed orally. Longer plasma t ½ = 7 Hs. Advantages over I-DOPA: a- Does not need synthesizing enzymes & More specific on D2 receptors. b- No active transport system. No competition with aminoacids. c- No toxic oxidative metabolites. d- Longer t ½ + Less fluctuations in response. Used in: a- Parkinsonism Monotherapy or as Add-on to Sinemet. b- Prolactin Treat Hyperprolactinemia e.g. Galactorrhea-amenorrhea syndrome. c- Suppress lactation. Safer than Estrogen. d- d- Acromegaly. Adverse effects & Contraindications of Bromocriptine: a- CNS: Dyskinesia and mental disturbances. b- CVS: Arrhythmia, hypotension (first dose) & digital vasospasm. c- Erythromyalgia (swollen, red, hot & tender feet). d- GIT: Anorexia, nausea, vomiting, dyspepsia, constipation & bleeding peptic ulcer. 24  Made with Xodo PDF Reader and Editor PHARMACOLOGY 5- Amantadine 1- Antiviral agent in prophylaxis of influenza A. 2- Acts mainly by Release & Uptake of Dopamine. 3- Less efficacious than Sinemet. Its effect wears off within few weeks. 4- Side effects: a- CNS disturbances up to acute toxic psychosis. b- CVS: Hypotension, CHF and peripheral edemas c- GIT disturbances. B- Anticholinergic drugs (Anti-muscarinic Drugs) Synthetic Antiparkinsonian Atropine Substitutes: If one fails try another - Benztropine - Benzhexol [Trihexyphenidyl] - Biperiden block muscarinic receptors in basal ganglia effect of acetyl choline - Treat mainly tremors, rigidity & Salivation. But no effect on Bradykinesia. Uses: Parkinsonism a- Add-on to L-DOPA. b- Used mainly to treat latrogenic Parkinsonism induced by neuroleptic drugs. Adverse effects & Contraindications: similar to atropine NB) latrogenic Parkinsonism = Drugs Contra-indicated in Parkinsonism 1- Blockers of Central D2-receptors: a- Neuroleptic drugs: Phenothiazines & Butyrophenones. b- Antiemetics: Metoclopramide. 2- Reserpine Depletion of Dopamine stores 3- Alpha-methyl Dopa Inhibition of Dopamine synthesis 4- Destruction of Dopamine neurons: MPTP. 5- Parasympathomimetic drugs that pass BBB: Physostigmine & Pilocarpine. 25  Made with Xodo PDF Reader and Editor PHARMACOLOGY f- Coffee & Tea are NOT Contraindicated: They are Methyl-Xanthines Methyl-uric acid Soluble. Self-Assessment 1- Enumerate drugs used in treatment of acute attack of gout 2- Colchicine, mechanism of action and adverse effect 3- Allopurinol, mechanism of action and adverse effect 4- List advantage of Febuxostat over allopurinol. Central Nervous System Stimulants Central nervous system stimulants (CNS stimulants) are medicines that stimulate the brain, speeding up both mental and physical processes. They increase energy, improve attention and alertness, and elevate blood pressure, heart rate and respiratory rate. They decrease the need for sleep, reduce appetite, improve confidence and concentration, and lessen inhibitions. Possible mechanism of action is increasing levels of one or more neurotransmitters in the brain, such as dopamine, norepinephrine, or serotonin. CNS stimulants are common in clinical practice, and have a high potential for abuse. The CNS stimulants can be classified as: 1. Analeptic stimulants: Doxapram activates peripheral chemoreceptors and respiratory center in a dosedependent manner. 2. Psychomotor stimulants: e.g. cocaine, Ephedrine and amphetamines Psychomotor stimulants increase sympathetic nervous system activity may result in hemodynamic instability, cardiac dysrhythmias, and myocardial ischemia. Methylphenidate: Similar to Amphetamine BUT Weaker & Less toxic used in attention- deficit/hyperactivity disorder (ADHD) Other drugs: Phendimetrazine, phentermine, Pemoline are used in ADHD, cause life-threatening hepatic failure. Atomoxetine: Selectively inhibits the reuptake of norepinephrine with little to no activity at the other neuronal reuptake pumps or receptor sites. Used in treatment of attention- deficit/hyperactivity disorder (ADHD) 3. Methylxanthines: e.g. Caffeine used mainly to stimulate respiratory center. 4. Psychotomimetic stimulants (hallucinogenic drugs). e.g. cannabis, lysergic acid diethylamine (LSD), THC (tetrahydrocannabinol). The CNS stimulants can be classified according to their site of action into: 1- Cerebral Cortex Stimulants: a- Methyl-xanthines e.g. Caffeine. b- Cocaine (see Local Anesthetics). 27  Made with Xodo PDF Reader and Editor PHARMACOLOGY c- Autonomic drugs e.g., Amphetamine, Methylphenidate & Atropine 2- Brain stem stimulants as bemegride, doxapram stimulate vital centers in brain stem especially RC 3- Spinal cord stimulant as strychnine; a competitive antagonist of the inhibitory neurotransmitter glycine (Toxic) Uses of CNS Stimulant Label uses: 1. Narcolepsy: to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy. 2. Obstructive sleep apnea: To improve wakefulness in adult patients with obstructive sleep apnea (OSA). 3. Shift work sleep disorder: To improve wakefulness in adult patients with shift work sleep disorder (SWSD). 4. Attention-deficit/hyperactivity disorder (ADHD). Off Label Uses 1. Fatigue (cancer-related). 2. Major depressive disorder (antidepressant augmentation). 3. Multiple sclerosis-related fatigue. Methyl-Xanthines 1- Include Caffeine, Theophylline & Theobromine. 2- Source: Natural Alkaloids of plant origin (coffee, tea, cocoa, cola). 3- They are present naturally in caffeinated beverages: a- Tea: Caffeine (30-50 mg) + Theophylline. b- Coffee: Caffeine (100 150 mg). c- Cola: Caffeine (30 50mg). d- Cocoa: Caffeine (5 8 mg) + Theobromine Pharmacokinetics: 1- Absorbed orally, rectally (suppository) & parenterally. 2- Distributed all over the body. They pass B.B.B. & placental barriers. 3- Metabolism in liver Methyluric acid Soluble NOT contraindicated in gout. Pharmacodynamics: A) Mechanism of Action of methylxanthines Sympathomimetics B-Agonists Methylxanthines ++ -- A.T.P. Adenylate cyclase Active 3' 5' CAMP Phosphodiesterase Inactive AMP - Inhibit Phosphodiesterase enzyme IV (PDE-4) increase cAMP - Block adenosine receptors in C.N.S. & periphery. 28  Made with Xodo PDF Reader and Editor PHARMACOLOGY B) Pharmacological Actions: - Caffeine is Stronger on CNS, Skeletal muscles &Gastric acidity - Theophylline is Stronger on CVS, smooth muscles& kidney 1- C.N.S. Stimulation in a descending manner (Specially Caffeine): a- Stimulate Cortex Mental activity, Alertness, Acuity of sensations & anti-fatigue. Large dose Insomnia, anxiety & tremors specially in children. b- Stimulate Medulla: R.C. (Analeptic), V.M.C., Vagal center (C.I.C.). c- Stimulate Spinal cord in large dose. 2- C.V.S.: (Especially Theophylline) Direct ( cAMP) Heart H.R., Contractility, Work & Automaticity a- Heart C.N.S. C.I.C. H.R. b- B.V Direct ( CAMP) V.D. Bl.Pr. CNS VMC V.C. Bl.Pr. c- Aminophylline Small Dose & Slow I.V. Minimal change in H.R. & BL.Pr. While large dose or rapid I.V. Direct effect Tachycardia + Hypotension d- V.C. of Cerebral arteries 3- Respiration: a- Direct ( cAMP) Bronchodilatation specially Theophylline. b- C.N.S. R.C. specially Caffeine. 4- G.I.T.: a- Caffeine Gastric acidity b- Theophylline Spasmolytic & Irritant Nausea & Vomiting. 5- Renal: a- Theophylline Spasmolytic action on ureter & bladder. b- Diuretic action: (Theophylline > Theobromine (Longer) > Caffeine) - Extra-Renal C.O.P. + Renal V.D. R.B.F. G.F.R. - Renal Na & H2O reabsorption from the renal tubules. 6- Smooth Muscles Spasmolytic specially Theophylline. 7- Skeletal Muscles Stimulation & Anti-fatigue specially Caffeine. Preparations: - Aminophylline (Theophylline ethylene diamine) ampoules, suppositories - Theophylline SR tablets, capsules Therapeutic Uses of Methyl-Xanthines: a) Aminophylline 1- Bronchial Asthma: Mechanism of action: - Inhibits PDE-4 increase CAMP & Block adenosine receptors Bronchodilatation. - Stabilization of Mast cells. 29  Made with Xodo PDF Reader and Editor PHARMACOLOGY - Improve contraction of respiratory muscles e.g. Diaphragm. Indications: - Acute attacks: Aminophylline250-500 mg Slow I.V.But better selective B2-Agonists inhalation. - Status Asthmaticus: Aminophylline I.V. infusion + Corticosteroids + Salbutamol inhalation. - Prophylaxis: Theophylline S.R. 200 mg / 12 hours. 2- Chronic Obstructive Pulmonary Diseases (COPD) e.g. Emphysema. 3- Cardiac Asthma = Left Ventricular failure = Pulmonary edema: Aminophylline slowly I.V.: a- +ve Inotropic BUT short duration = 30 min (Add Digoxin). b- Diuretic c- Bronchodilator b) Caffeine 1- With Ergotamine Cafergot in acute attack of Migraine headache. With Aspirin or paracetamol in simple headache. 2- Fatigue (Physical or mental). 3- With Neostigmine in Myasthenia Gravis. 4- Poisoning by C.N.S. depressants e.g. Hypnotics. c) Pentoxifylline: methylxanthine derivative used in treatment of: - Chronic occlusive arterial diseases e.g. intermittent claudication: a- Improves RBCs flexibility & Plasma fibrinogen Blood viscosity b- Platelet aggregation. Adverse Effects of Xanthines: A) Caffeine: (Wide safety margin) 1- C.N.S. Insomnia, anxiety & tremors. 2- G.I.T. Hyperacidity. B) Theophylline: 1- Narrow safety margin of therapeutic plasma concentration 10 - 20 ug/ml. 2- Irritant: a- I.M. or S.C. Painful. b- Orally Gastritis (use after meals) c- Rectally (suppository) Proctitis especially in children. 3- Rapid I.V. injection Velocity reaction a- Heart: - Theophylline Tachycardia & Arrhythmia - Ethylene diamine Cardiac arrest. May be FATAL b- BL.Pr. Severe hypotension & syncope. 4- C.N.S.: Insomnia, anxiety, tremors & seizures especially in children. 5- C.V.S.: Tachycardia, palpitation, angina, arrhythmia & hypotension. 6- G.I.T.: Anorexia, nausea, vomiting & ulceration. 30  Made with Xodo PDF Reader and Editor PHARMACOLOGY C) Long Use: 1- Tolerance & Cross tolerance between the xanthines. 2- Psychic dependence for caffeine = Habituation. Contraindications of Xanthines 1- Angina (t cardiac work), Arrhythmia (t Automaticity) & Hypertension (Caffeine) 2- Peptic ulcer 3- Cardiac arrhythmias N.B.: Tea Tannic acid Precipitates: a- GIT surface proteins = Astringent Constipation. b- Iron Hypochromic microcytic anemia. Drug Interactions of Theophylline A) Drugs Metabolism of Theophylline its plasma level Toxicity: a- Cimetidine. b- Antimicrobials: Erythromycin & Quinolones. c- Heart & Hepatic Diseases, and Hypothyroidism. B) Drugs Metabolism of Theophylline Its Plasma level Effect: a- Rifampicin b- Anti-Epileptics: Phenobarbitone c- Hyperthyroidism d- Tobacco (Heavy smokers) & Alcohol 31