PSYCHOPHARMACOLOGY UNDERGRADUATE COURSE ABDULLAH ALSUBAIE MBBS FRCP C

PSYCHOPHARMACOLOGY UNDERGRADUATE COURSE ABDULLAH AL-SUBAIE, MBBS, FRCP (C) PROFESSOR OF PSYCHIATRY Psychopharma/ Prof. Subaie 1

DRUGS IN PSYCHIATRY PSYCHOACTIVE DRUGS n n n ANTIPSYCHTIC DRUGS ANTIDEPRESSANT DRUGS MOOD STABILIZING DRUGS ANTIANXIETY DRUGS ELECTROCONVULSIVE THERAPY (ECT) Psychopharma/ Prof. Subaie 2

ANTIPSYCHOTIC DRUGS NEUROLEPTICS / MAJOR TRANQUILIZERS n n n Treat all psychoses & psychotic symptoms e. g. in autism, organic brain syndrome. . . Block D 2 receptors in the mesolimbic system Not addictive Psychopharma/ Prof. Subaie 3

g) m 0 0 5 -1 Buterophenones ( ole d i r pe o l Ha Olanz e Rispe pine (10 -3 ri 0 mg) Cloze done. Atypical ( 4 1 2 pine (100 - mg) 800 m g) ) 0 mg mg) 0 8 0 020 Others -80 ( 0 0 e (2 rid Sulp ulpride s Ami g g) Antipsychotics -100 m Dibenzoxazipines 5 2 ( ne i Loxap Mol indo n e (5 0 -2 Dihydroindolones 5 0 mg ) m 500 1 0 ) (30 00 mg e azin 300 -8 m o rpr zine ( o l Ch orida. g. Phenothiazines hi e T c i. t ha e. g Alip ridine i Pip razine e Pip Alipathic e. g. Chlor prothexin Piperazine e (75 -600 e. g. Thiot mg) hexine (5 6 0 mg) Fluanoxol Thioxanthines (3 -10 mg ) Diphenylbutyl mg) 2 1 2 zide ( Pimo. Pipiridines Psychopharma/ Prof. Subaie 4

ANTIPSYCHOTIC DRUGS NEUROLEPTICS / MAJOR TRANQUILIZERS Mechanism of action n In typical antipsychotics n Blockage of D 2 – receptors in: n n Nigro-strial (psychiatric tract) Substantia Nigra (Neurological tract) Tubero-infundibular tract (Endocrine tract) In atypical antipsychotics: n Blockage of 5 HT 2 A/D 2 receptors Psychopharma/ Prof. Subaie 5

ANTIPSYCHOTIC DRUGS NEUROLEPTICS / MAJOR TRANQUILIZERS Meso-limbic (Psychiaitrc tract) Nigro-strial (Neurologic tract) Meso-cortical (Psychiatric tract) Tubero-infundibular (Endocrine tract) Psychopharma/ Prof. Subaie 6

ANTIPSYCHOTIC DRUGS Side effects (hint) n n High Potency typical antipsychotics: Neurological side effects Low Potency typical antipsychotics: other side effects Psychopharma/ Prof. Subaie 7

ANTIPSYCHOTIC DRUGS Neurologic Side effects n Due to D 2 blockade n How to manage? Parkinsonian syndrome Position & gait Apathy Drooling Fine tremor Staring eyes Psychopharma/ Prof. Subaie 8

ANTIPSYCHOTIC DRUGS Neurologic Side effects n Due to D 2 blockade n n Parkinsonian syndrome Akathesia (Motor restlessness) D. Dx How to manage? Subjective feelings of restlessness Objective signs of restlessness Feelings of anxiety, inability to relax, jitteriness, pacing, rocking motions while sitting, rapid alterations of position. More in middle aged women Psychopharma/ Prof. Subaie 9

ANTIPSYCHOTIC DRUGS Neurologic Side effects n How to manage? Due to D 2 blockade n n Parkinsonian syndrome Akathesia (Motor restlessness) n Acute dystonia Brief or prolonged muscle contraction leading to abnormal movements or postures e. g. Occulogyric crises, tongue protrusion, torticollis, laryngeal pharyngeal dystonias and dystonic Postures Early onset, more in young men and high doses of typical neurosleptics Psychopharma/ Prof. Subaie 10

ANTIPSYCHOTIC DRUGS Neurologic Side effects n Due to D 2 blockade n n Parkinsonian syndrome Akathesia (Motor restlessness) n n Acute dystonia Tardive Dykinesia Why? How to manage? Involuntary choreiform, athetoid or rhythmic movements of the tongue, jaw, trunk or extremities More with long term typical neuroleptic treatment, old age, female sex, mood disorder, cognitive disorders. Psychopharma/ Prof. Subaie 11

ANTIPSYCHOTIC DRUGS Neurologic Side effects n Due to D 2 blockade n n Parkinsonian syndrome Akathesia (Motor restlessness) How to manage? n n n Acute dystonia Tardive Dyskinesia Neuroleptic malignant syndrome Muscular rigidity, akinesia, mutism, obtundation & agitation, hyperthermia, swaeting, tachycardia, Hypertension. Increased w. BC, incraesed CPK, liver enzymes, and plasma myoglobulin. Myoglobulinuria, may occur and may lead to renal failure. Symptoms evolve in 1 -3 days & may last 10 -14 days. May occur at any time More common in young men Mortality: 20% - 30%( higher with depot) Psychopharma/ Prof. Subaie 12

ANTIPSYCHOTIC DRUGS Other Side effects n Muscarenic (anti-cholenergic): n n dry mouth Constipation Blurred vision, urinary retention Precipitation of narow angle glucoma n Alpha– 1–adrenergic blockade: n n n Orthostatic hypotension Impotence Impaired ejaculation Psychopharma/ Prof. Subaie 13

ANTIPSYCHOTIC DRUGS Other Side effects CNS Side effects: n n n Sedation Cardiac side effects: n n Metabolic / Endocrine Side effects: n n n weight gain Increased BS & lipids Galactorrhea Amenorrhea Allergic Side effects n n n Cholestatic jaundice Agranulostasis n Occular Side effects: n n n EKG changes Arrythmias Corneal Opacities Retinitis pigmentoza Dermatological Side effects: n n n Photosensitivities Metallic discoloration Contact dermatitis Psychopharma/ Prof. Subaie 14

ANTIDEPRESSANTS n n n Treat: Major depression, dysthymic disorder, nocturnal enuresis, chronic pain, panic disorder, OCD, ADHD, school phobia, other phobias, generalized anxiety disorder, insomnia… Work through: Serotonin, Norepinephrine, Dopamine Not addictive Psychopharma/ Prof. Subaie 15

ANTIDEPRESSANTS Imipr amin 0 0 – 6 00 3 ( Reversible Inhibitors ide of Mono-amines m be(RIMA) o l c Mo ) mg e, Am itript Heterocyclic yline Antidepressants Chlo)m (, HCAs i pram ine (1 50– 3 00 mg g) ) m -80 20 ( Serotonin Specific m Reuptake a r p alo. Inhibitors t i (SSRIs) e, c Antidepressants tin e x ro g) a m 60 30 e pin , P ine xet u Flo ze rta Me , Mono-amine oxidaze Serotonin/Norepinephrine g) m Inhibitors Reuptake Inhibitors Phenelzine (15 -60 mg), Tranycypramine (10 -30 mg) 00 3 NSRIs (MAOI) ( ) 75 ( ine x a laf n Ve Psychopharma/ Prof. Subaie 16

ANTIDEPRESSANTS Mechanism of action Inhibition of reuptake Inhibition of mono-amaine oxidaze enzyme Inhibition of auto-receptors Down regulation of beta-adrenergic postsynaptic receptors Psychopharma/ Prof. Subaie 17

ANTIDEPRESSANT DRUGS Side effects n HETEROCYCLICS: n Muscarenic (anti-cholenergic): n n dry mouth Constipation Blurred vision, urinary retention Precipitation of narow angle glucoma n Alpha– 1–adrenergic blockade: n n n Orthostatic hypotension Impotence Impaired ejaculation Psychopharma/ Prof. Subaie 18

ANTIDEPRESSANT DRUGS Side effects Central anti-cholenergic syndrome: n n n Delirium Coma seizures Agitation Hallucinations Severe hypotension Supra-ventricular tachycardia Flushing Mydriasis Dry skin Hyperthermia Decreased bowel sounds. n n Management Stop HCA immediately Physostigmine (anticholinesterase inhibitor) 1 -2 mg IV or IM every 20 – 60 minutes, until improvement occurs n Cardiac monitoring and life support (physostigmine may lead to severe BP drop and bronchial constriction) n Benzodiazepines may be used. Psychopharma/ Prof. Subaie 19

ANTIDEPRESSANTS Side effects n n HETEROCYCLICS: SSRI: n have a much better side effect profile: n n Agitation Sexual problems Stomach upset Hypersomnia/insomnia Psychopharma/ Prof. Subaie 20

ANTIDEPRESSANTS Side effects n n n HETEROCYCLICS: SSRIs MAOI: n Hypertensive crisis (tyramine reaction) Nifedipine (guard, against rapid BP drop) (patient bites the capsule and swallows its contents in water) Phentolamine (alpha-adrenergic antagonist) Chlorpromazine (alpha-adrenergic Antagonist) Psychopharma/ Prof. Subaie 21

ANTIDEPRESSANTS Side effects n n n HETEROCYCLICS: SSRI: MAOI: n n Cardiovascular (orthostatic hypotension, tyramine hypertensive crisis) Sexual (Impotence & delayed ejaculation) Neurologic (insomnia, seizure& euphoria) Hepatic: (Cholestatic reaction). Psychopharma/ Prof. Subaie 22

ANTIDEPRESSANTS Side effects n n n HETEROCYCLICS: SSRI: MAOI: n n Interaction: Diet: Aged cheese Pickled herriag Raisin Alcohol Chicken liver Beans Figs Yeast products Chocolate Amphetamines Decongestants & nasal sprays (Ephedrine…. ) Epinephrine (local anesthesia) Aldomet Psychopharma/ Prof. Subaie 23

TREATING DEPRESSION n n n Confirm diagnosis Rule out contraindications Make use of side effects Start with a small dose and build it up Side effects start sooner but therapeutic effects start only 2 -3 weeks later When patient improves, maintain treatment for 9 months, then cut down gradually watching for re-emergence of symptoms Psychopharma/ Prof. Subaie 24

TREATING DEPRESSION Vegetative symptoms Motor symptoms SUICIDE Psychological symptoms Psychopharma/ Prof. Subaie 25

MOOD STABLIZERS n n n Lithium Carbonate Sodium Valproate Carbamazepine Lamotrigine Topiramate Clozapine Psychopharma/ Prof. Subaie 26

MOOD STABLIZERS Indications n n Acute mania Prophylaxis against both mania and depression Schizoaffective disorder. Impulse control disorder Psychopharma/ Prof. Subaie 27

LITHIUM CARBONATE n PHARMACOLOGY n n n n Rapidly absorbed Peaks in 30 -60 minutes Completely absored in 8 hours Water soluble, not protein bound Steady state is reached in 7 days. Excreted though the kidneys, not metabolized. MECHANISM OF ACTION n n Unknown exactly ? stabilizes cell membranes Psychopharma/ Prof. Subaie 28

LITHIUM CARBONATE Administration n Assess the kidney functions, thyroid functions, cardiac and CNS condition. After starting treatment, periodically assess drug level and kidney & thyroid functions. Aim at a blood level of of: 0. 8 – 1. 2 m. Eq/l (acute mania), 0. 6 – 0. 8 m. Eq/l (prophylaxis) (12 hours after the last dose) Psychopharma/ Prof. Subaie 29

LITHIUM CARBONATE Side effects n n n n Neurological: Tremor (50%), weakness, cog-wheeling Renal: Occur in 10 -50 % e. g. polyuria, polydipsia, nephrogenic D. I. , nephrotic syndrome, (tubular changes with chronic use and high levels) Cardiac: Similar to those of hypokalimia e. g. U-wave and T-wave depression Endocrine: Goiter, hypothyroidism, abnormal thyroid functions (30 -40%) Dermatological: Acne, exacerbation of psoriasis ), hair loss. Pregnancy and lactation: Teratogenicity (level in milk=30 -100% of maternal blood level) Toxicity: (seizures, delirium, cerebellar signs, coma) occurs in blood level= 1. 2 – 2 m. Eq/l. Lethal levels above that. Psychopharma/ Prof. Subaie 30

CARBAMAZPINE PHARMACOLOGY n n Absorbed slowly from the G. I. tract Peaks in plasma in 2 -8 hours and steady state level is reached in 2 -4 days Induces liver enzymes MECHANIZM OF ACTION n n UNCLEAR: increase of hippocampal GABA receptor density Psychopharma/ Prof. Subaie 31

CARBAMAZEPINE Administration n n Assess blood count and liver functions Start with a small dose and use clinical condition & drug level as a guide Assess liver functions, blood level and blood count periodically. Aim at a blood level of 6 -12 mg/l after 10 -12 hours of last dose (12 hours after the last dose) Psychopharma/ Prof. Subaie 32

CARBAMAZEPINE Side effects n n CNS: drowsiness and in diplopia, dizziness, nausea, vomiting and ataxia(toxic doses) Dermatological: skin rash, Steven– Johnson Syndrome, photosensitivity. Hepatic: cholestatic jaundice. Hematological: Leuckopenia, thrombocytopenic purpura, and bone marrow suppression. Psychopharma/ Prof. Subaie 33

CARBMAZEPINE Contra-indications n n n A-V heart block Liver disease Leuckopenia Cerebellar lesions Co-administration with Clozapine Psychopharma/ Prof. Subaie 34

SODIUM VALPROATE PHARMACOLOGY n n Completely absorbed from the stomach Peaks in plasma in 1 -2 hours n Metabolized by liver n MECHANIZM OF ACTION n n UNCLEAR: increase of hippocampal GABA receptor density Psychopharma/ Prof. Subaie 35

SODIUM VALPROATE Administration n n Assess liver functions Start with a small dose and use clinical condition & drug level as a guide. Assess liver functions and blood level periodically. Aim at a blood level of 50 -120 mg/l after 10 -12 hours of last dose (12 hours after the last dose) Psychopharma/ Prof. Subaie 36

SODIUM VALPROATE Side effects n n n n Nausea & vomiting. Impairment of liver enzymes Liver toxicity (in toxic doses) Hair loss Weight gain Sedation, ataxia and dyarthria Ovarian cysts in young females ? Psychopharma/ Prof. Subaie 37

SODIUM VALPROATE Contra-indications n n n Liver disease. Co-administration with hepatotoxic drugs such as pemoline. Thrombocytopenia and platelet dysfunction Psychopharma/ Prof. Subaie 38

ANTI-ANXIETY DRUGS n n n Barbiturates Benzodiazepines Non-benzodiazepines, nonbarbiturates: e. g. TCAs and antihistamine Buspirone SSRIs Antipsychotics Psychopharma/ Prof. Subaie 39

BENZODIAZEPINES n CLASSIFICATION: n n PHARMACOLOGY: n n n Very short acting e. g. Triazolam Short acting: e. g. Oxazepam, Lorazepam, Alprazolam Long acting : e. g. Diazepam, Chlordiazepoxide Completely absorbed from the G. I. tract Rapid action due to high lipid solubility Peaks in plasma in 1 -3 hours. Metabolized in the liver MECHANIZM OF ACTION: n n Through its own receptors Through increased affinity for GABA receptors Psychopharma/ Prof. Subaie 40

BENZODIAZEPINES Side-effects n n n Sedation Dizziness and ataxia CNS depression when used with sedative substances or alcohol Disinhibition and aggression Tolerance and withdrawal (dependence) Psychopharma/ Prof. Subaie 41

BENZODIAZEPINES Indications n n n n Insomnia Anxiety Symptoms Panic Disorder Social phobia and other phobias Mania Akathesia Alcohol Withdrawal Psychopharma/ Prof. Subaie 42

BENZODIAZEPINES Contra-indications n n Potential abuse Compromised cardiovascular system functions Caution in elderly Driving & operating heavy machines Psychopharma/ Prof. Subaie 43

BUSPIRONE PHARMACOLOGY: n n Well absorbed from the G. I. tract Metabolized by the liver Peaks in plasma in 1 -1. 5 hours MECHANISM OF ACTION: n n n Unlike benzodiazepines it has no effect on GABA neurotransmitter It is an agonist of 5 HT-1 -A, reduces firing of the serotonegic neurones in the median raphe nuclei Psychopharma/ Prof. Subaie 44

BUSPIRONE Administration n Well tolerated & safe n Takes long time to work n Does not lead to dependence Psychopharma/ Prof. Subaie 45

Electroconvulsive Therapy Mechanism of action n not fully known Induction of a bilateral generalized seizure is required for both the beneficial and adverse effects Nearly every neurotransmitter system is affected Psychopharma/ Prof. Subaie 46

Electroconvulsive Therapy Indications n Major Depression n Bipolar Mood Disorder n Schizophrenia n Other psychoses Psychopharma/ Prof. Subaie 47

Electroconvulsive Therapy In Depression n Severe, dysfunctional n Psychotic, catatonic n Suicidal n Free of contra-indications Psychopharma/ Prof. Subaie 48

Electroconvulsive Therapy In Bipolar Mood Disorder n Severe, treatment resistant n Rapid-cycling or mixed mania n Psychotic n Free of contra-indications Psychopharma/ Prof. Subaie 49

Electroconvulsive Therapy In Schizophrenia n Acute, Severe n In combination with antipsychotics n Treatment resistant n Free of contra-indications Psychopharma/ Prof. Subaie 50

Electroconvulsive Therapy Contra-indications n No absolute contra-indication n Relative contra-indication include: n n Pregnancy Increase intra-cranial pressure Open chest infection Recent Myocardial infarction Psychopharma/ Prof. Subaie 51

Electroconvulsive Therapy Preparation n Medical evaluation n Discontinue sedatives n Informed consent n NPO after midnight n Remove dentures Psychopharma/ Prof. Subaie 52

Electroconvulsive Therapy Procedure n Pulse oximeter n ECG n EEG n A blood pressure cuff is placed on the patient's arm Psychopharma/ Prof. Subaie 53

Electroconvulsive Therapy Procedure n Anesthesia n Muscle relaxant n Bite block n Electrical stimulation to induce a fit for 30 sec Psychopharma/ Prof. Subaie 54

Electroconvulsive Therapy Placement Psychopharma/ Prof. Subaie 55

Electroconvulsive Therapy Mortality/Morbidity n n Cardiovascular and pulmonary complications Mortality rate for ECT is about 1 per 10, 000 patients or 1 per 80, 000 treatments (about the same as that associated with minor surgery) n Pains & headach n Cognitive impairment Psychopharma/ Prof. Subaie 56