Psychopharmacology PDF

Psychopharmacology By Dr Ali Bahathig “Make sure to check out the cases at the end” Objectives: ◄ Discuss classification of main psychotropic medications ◄ Know Mechanism of action of psychotropic medications ◄ Know common & dangerous adverse effects ◄ Choose a psychotropic medication ratio...

Psychopharmacology By Dr Ali Bahathig “Make sure to check out the cases at the end” Objectives: ◄ Discuss classification of main psychotropic medications ◄ Know Mechanism of action of psychotropic medications ◄ Know common & dangerous adverse effects ◄ Choose a psychotropic medication rationally ◄ Manage failure of response to a therapeutic trial Color index: Old notes (439/438) Important New notes (441) Golden Extra Textbook  Introduction 1 Why medications? Dopaminergic theory of Schizophrenia Monoaminergic theory of Mood Disorders Neurotransmitters Go through 7 steps “No Qs here” 1. Synthesis. 2. Storage. 3. Enzymatic destruction if not stored. 4. Exocytosis. 5. Termination of release via binding with autorecptors. 6. Binding to receptors. 7. Inactivated either by reuptake or degradation. Drugs are developed that address these actions as an AGONIST (mimic the NT) or ANTAGONIST (block the NT). Psychopharmacologic Drugs work over A Spectrum Antipsychotics Mood stabilizers Antidepressants Anxiolytics / sedative Stimulants Psychotropics are one of the most prescribed drugs but this chart is outdated  Antipsychotics 2 Antipsychotics “They work on Dopamine” Attention Motivation & Reward Prolaction inhibition Functions of Dopamine involuntary movements Energy Nausea Psychosis (it's not a function but high dopamine cause it) Antipsychotics and dopamine system “No Qs here but understand it” → Mesocortical pathway functions: Motivation, Attention, cognitive. → Mesolimbic pathway is the reward area, high dopamine in this area will cause psychosis so we want to close it. → Nigrostriatal pathway functions: involuntary movement. → Tuberoinfundibular pathway functions: Prolaction inhibition (posterior pituitary). Schizophrenia Schizoaffective disorder Bipolar disorder- for mood stabilization and/or when psychotic features are present Indications for use Delirium (small doses) “Psychotic Symptoms” Psychotic depression Augmenting agent in treatment resistant depression or anxiety disorder Dementia (psychotic symptoms or aggressive behavior) Trichotillomania Typical Atypical 1st generation (conventional) 2nd generation Treat psychotic symptoms, regardless of the illness, remember Psychosis is a Sx not a diagnosis. Requires about one month for significant antipsychotic effect. Dopamine (D2) receptor antagonists Serotonin-dopamine antagonists Effective against: Effective against both Positive symptoms > Negative symptoms (makes negative Positive and Negative symptoms symptoms worse but treats positive symptoms) Chlorpromazine perphenazine aripiprazole fluphenazine pimozide Clozapine Haloperidol prochlorperazine Olanzapine paliperidone almost all of them are important :) loxapine thiothixene quetiapine molindone thioridazine Risperidone trifluoperazine Ziprasidone  Antipsychotics 3 Antipsychotics Typical Atypical 1st generation 2nd generation Side effects ★ ExtraPyramidal Symptoms (EPS): Sleepiness and slowness. ○ Stiffness and shakiness (Dystonia). Weight gain. ○ Uncomfortable restlessness (Akathisia). Increased chance of developing diabetes and ★Metabolic Syndrome. ○ (Pseudoparkinsonism). Decrease Libido. ○ Long-term use can produce movements of the face Some can affect blood pressure and make patient feel (Tardive Dyskinesia) and, rarely, of the arms or legs. dizzy. Feeling sluggish, slow in thinking, apathy, low In high doses, some have the same EPS and motivation (Negative symptoms). Parkinsonian side-effects as the older medications Problems with breast swelling or tenderness and (stiffness of the limbs) but less than typical. (Galactorrhea). “↑ Prolactin levels” Problems with breast swelling or tenderness and (Galactorrhea) but less than typical. Some can affect blood pressure and make patient feel Lowers seizure threshold, worsens QTc interval. dizzy. Decrease Libido. “Atypicals still can cause EPS but less than the typicals” Lowers seizure threshold, worsens QTc interval. “These side effects depend on the potency and dose of the drug used” Important Note, ★All Antipsychotics have these effects: 1- EPS → Typical > Atypical, High potency > Low potency. 2-QTc Prolongation. 3-Lowers seizure threshold. 4-↑ Prolactin levels. 5-Can cause NMS (Neuroleptic Malignant Syndrome). Clozapine High Potency typical antipsychotics: Neurological side effects Low Potency typical and atypical antipsychotics: many other side effects Metabolic side effects of atypical antipsychotics  Antipsychotics 4 These two drug cause worst metabolic side effects Worst in QT interval Classification of Antipsychotic drugs First-generation First-generation Second generation Antipsychotic (low potency) Antipsychotic (high potency) Antipsychotics “Doses are higher” “Doses are lower” aripiprazole Chlorpromazine Fluphenazine asenapine prochlorperazine Haloperidol Clozapine iloperidone thioridazine pimozide lurasidone thiothixene Olanzapine Quetiapine Risperidone paliperidone Ziprasidone Antipsychotics average Daily Doses in mg (not important ) Depot antipsychotics Lower numbers indicate higher potency Giving to patients who cant take the drug everyday specifically psychotic patient with poor insight Typical Atypical Injection every 2 to 4 weeks. Releases the medication slowly over this time. Haloperidol (5 – 15 mg) Risperidone (4 – 8 mg) Both typical and atypical. Thioridazine (100 – 300 mg) Olanzapine (10 – 20 mg) Indication: Poor compliance. Chlorpromazine (50 – 400 mg) Quetiapine (600 – 1200 mg) Patient preference. perphenazine (8 – 16 mg) Clozapine (100 – 600 mg) Pharmacological Treatment Algorithm Adapted from the Maudsley prescribing Guidelines (Taylor et al, 2005) if poor compliance is due to poor tolerability discuss with patient and change drug if poor compliance is related to other factors, consider a depot or compliance therapy change drug and repeat Either: above process Titrate as necessary to Agree choice of Asses over 6-8 weeks Clozapine minimum effective dose antipsychotics with patient consider both typical Adjust dose according to Or if impossible and atypical response and tolerability “if 2 drugs (multiple) do not work we start atypical antipsychotics antipsychotics use Clozapine. (Due to its side effects)” Continue at established effective dose  Antipsychotics 5 Extrapyramidal Symptoms (EPS) Very important for video cases/SAQ and MCQs Acute Dystonia Akathisia (Hours) (Days) Sometimes develop within 30 minutes Can lead to suicide Involuntary spasms or stiffness. “especially in Neck / Jaw Muscles” Motor restlessness; inability to sit still due to inner tension. Can be terrifying to the patient. Typically seen early in treatment or with dosage increases of Risk is higher in males and at younger age (Blocky muscles). antipsychotics (typical more than atypical). Is more likely to develop in patients treated with high-potency First Is the most common antipsychotic-induced movement disorder. generation antipsychotic with inherently low anticholinergic Symptoms increase in severity with increasing antipsychotic dose. activity (e.g., Haloperidol, Fluphenazine). Are a major cause of poor compliance to antipsychotic Laryngospasm and swelling of the tongue (can close the airway) medications. “It is very annoying to the patient” (Rare). ➔ Treatment is by adding a beta-blocker (effective for akathisia): Spasmodic torticollis (spasm of cervical muscles of the neck). ○ Propranolol 20–40 mg bid Trismus (spasms of the muscles of mastication). ○ Nadolol up to 80 mg/day Oculogyric crisis (eyes rolled back in a locked position). ○ Metoprolol up to 100 mg/day ➔ Treatment is by adding an anticholinergic agent: ○ Benztropine mesylate (Cogentin) 1–2 mg orally BID–TID or 1–2 mg intramuscularly on an as-needed basis. ○ Other options: Trihexyphenidyl, Procyclidine, and Diphenhydramine. Pseudoparkinsonism Tardive Dyskinesia (Weeks) (Years) Also referred to as parkinsonism. Literally means late-appearing (tardive) abnormal involuntary Symptoms can be identical to those observed in Parkinson’s movements (dyskinesia). “Takes ~5 years to develop that’s why it's very rare” disease: (TRAP) Is more likely to develop in patients who have experienced EPS. ○ Tremors at rest. Presents with involuntary movements characterized by a mix of ○ Rigidity in arms and shoulders. orofacial dyskinesia, tics, chorea (jerking movements), and ○ Akinesia (absence of movements) athetosis (writhing movements): ○ Postural instability (e.g., shuffling gait) Orofacial dyskinesia is the most common presentation and ○ Bradykinesia (slowness of movements) includes rhythmic movements of the lips (e.g., puckering, ○ Hypersalivation smacking), tongue (e.g., undulations, rolling motions, protrusions, ○ Mask like facies “fly catching” movements), jaw (e.g., chewing, side-to-side ○ Cogwheel rigidity movements, biting), and face (e.g., involuntary blinking, grimacing). ➔ Treatment is by adding a dopaminergic agent: Tongue fasciculations and periorbital movements are common ○ Amantadine (a dopaminergic agent) 100 mg orally bid (effective early signs, Involuntary movements of the extremities are less for parkinsonism and dystonia) common, Involvement of the esophagus, pectoral muscles, and “The treatment in this case is debatable, mostly we won’t ask you about it” diaphragm is rare but can be fatal. ➔ Treatment is by prevention. “if started we can’t treat it” ★Neuroleptic Malignant Syndrome (NMS) Fatal, can happen in any time of the drug course, especially for patients receiving Antipsychotics for the first time OR when we have to increase the dose. Can conceptually be characterized as “severe EPS (i.e., extreme Rigidity) with fever”. Possibly secondary to dopaminergic receptor blockade in the Substantia Nigra producing rigidity and fever. Can develop with any Antipsychotic medication. Presents with symptoms easily recalled with the acronym (F + ARGO): ○ F Fever ○ A Autonomic dysregulation (e.g., hypertension, tachycardia, urinary incontinence, diaphoresis) ○ R Rigidity (“lead-pipe”) ○ G Granulocytosis (as well as increased lactic dehydrogenase, liver function tests, ↑ ↑ ↑ ↑ Creatine Phosphokinase [CPK] “high in trauma patients”, and myoglobinuria) ○ O Orientation changes (confusion, coma) Can additionally present with acute renal failure (due to myoglobinuria), proteinuria, deep vein thrombosis, respiratory distress, and dehydration. Management: stop the drug then supportive. Any patient on Antipsychotics and presents with Fever,Rigidity and Confusion→ NMS.  6 Antidepressants Selective serotonin reuptake inhibitors (SSRIs) Monoamine oxidase inhibitors Citalopram, Escitalopram, (MAOIs) Fluoxetine, Paroxetine, Rasagiline,selegiline, Sertraline, and Fluvoxa. isocarboxazid, phenelzine , 3 tranylcypromine 5 1 44 21 Classes Norepinephrine-dopamine Selective serotonin reuptake inhibitors (NDRIs) norepinephrine reuptake inhibitors (SNRIs) 2 3 Bupropion (used in smoking Desvenlafaxine, Duloxetine, and cessation as well) Venlafaxine. Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Desipramine, Doxepin, Imipramine, Nortriptyline, and Protriptyline. Serotonin's pharmacological function across multiple domains Indications Full clinical response Depression Depression 4 - 6 weeks in major Obsessions Organic mood disorders depression Migraines OCD Up to 6 - 12 weeks in Anxiety Anxiety disorders: obsessive compulsive ADRs : including panic, social disorder Intestines phobia, and PTSD Nausea Premenstrual dysphoric Sexual disorder and impulsivity associated with personality disorders  Antidepressants side effect 7 Nausea (Most common S/E associated with SSRIs) Diarrhea Dry mouth Selective serotonin Anxiety, agitation, insomnia reuptake inhibitors Drowsiness, fatigue (SSRIs) Effects on sleep (during REM) Headache Sexual dysfunction (e.g., anorgasmia, ↓ libido and late ejection) Weight gain Selective serotonin norepinephrine Side effects are similar to SSRIs reuptake inhibitors Venlafaxine and Desvenlafaxine increase BP in high doses (SNRIs) Anticholinergic: - Cardiovascular: tachycardia, arrhythmia. - Dry mouth - Urinary retention - Constipation - Blurred vision - CNS: Drowsiness, somnolence, myoclonic twitches, tremors and paresthesia. Tricyclic antidepressants Endocrine: weight gain due to H1 blockade tendency to increase blood sugars. (TCA) Orthostatic hypotension: - α-1 adrenergic blockade, transient ( may not be dose dependent) Cardiac: “some patients try commiting suicide by overdosing (its toxic), so its not used very often nowadays” - Sinus tachycardia (common): Quinidine-like type 1A antiarrhythmic effect. Prolongation of PR, QT, wide QRS complex Common side effects: weight gain Orthostatic hypotension Sexual dysfunction Other side effects: Insomnia with daytime sedation “Nardil Nod” Monoamine Myoclonus, tremor and akathisia oxidase inhibitors Paresthesia – vitamin B6 deficiency-like (MAOIs) Mania – up to 35% in depressed bipolar and 4% in unipolar patients “Nobody uses them anymore” Uncommon and serious side effects: Hypertensive crisis with ingestion of foods containing tyramine “Cheese reaction / Tyramine reaction” Spontaneous hypertension (Parnate) Hepatotoxicity – especially hydrazine group Teratogenicity – increased incidence of malformations if taken in first trimester  Complications of Antidepressants 8 MAOIs Hypertensive crisis “Cheese Reaction” Acute cardiovascular effect with severe hypertension Result from potentiation of indirect sympathomimetic agents (tyramine) Interact with tyramine-containing food Related to inhibition of tyramine metabolism Tyramine is normally deaminated in GI mucosa by MAO enzyme Tyramine is absorbed and taken up by noradrenergic neurons Displaces the stored norepinephrine from the synaptic vesicles Norepinephrine is released and free to exert its vasopressive effect Before starting new serotonergic drugs or ceasing dietary restrictions (e.g., foods containing tyramine), MAOI therapy has to be stopped for at least 2 weeks. OTC drugs: Cold & cough remedies Decongestants Stimulants Appetite suppressants Dietary supplements Indirect acting sympathomimetic amines: Amphetamine Ephedrine Cocaine Pseudoephedrine Serotonin Syndrome Caused by an excessive enhancement of serotonin neurotransmission when two different serotonergic agents are combined Overstimulation of 5-HT1A & 5-HT2A Consists of a triad of: - Mental status changes: Confusion, delirium, hallucinosis “Myoclonus in SS, Rigidity in NMS” - Physical findings: tremor, Myoclonus, hypertonicity, hyperreflexia - Autonomic instability: Fever, Diaphoresis, BP instability Onset range from hours to days: 50% within 2 hrs, 25% after 24 hrs Most cases involve only minor symptoms & resolve quickly Serious complications: seizures, DIC, respiratory failure, hyperthermia and death Drugs that increase serotonin: SSRIs, TCA and MAOIs Buspar, Tryptophan, Lithium Narcotic analgesics: meperidine, tramadol, methadone and pentazocine...etc (morphine analogues are deemed relatively safe) Ecstasy and marijuana Sumatriptan and zolmitriptan (5HT1D agonist) Increased risk with: Concurrent use of two or more serotonergic drugs Switching from one serotonergic drug to another without tapering (For Switching between SSRI / TCAs and MAOI, it is recommended to follow switching guidelines to avoid serotonin syndrome) Antidepressant discontinuation syndrome ( SSRI ) Description: Symptoms caused by abrupt withdrawal or dose reduction of antidepressants taken for ≥ 4 weeks. Most frequently cited with paroxetine (also SNRI: venlafaxine) (short half life drugs) Term not to be confused with withdrawal as seen with addiction Clinical features: Flu-like symptoms, vertigo, dizziness and nausea jolt-like bursts several times throughout the day Timing: Occur within 1 to 3 days after abrupt discontinuation of the SSRI. Subsiding within two to several days after the last dose Treatment: Taper the SSRI very slowly or start another SSRI with long half life “like Fluoxetine” Antidepressants & Cytochrome P450 System: (Reference) “not imp” Antidepressants and mood stabilizers may be inhibitors, inducers or substrates of one or more cytochrome P450 isoenzymes Knowledge of their P450 profile is useful in predicting drug-drug interactions P450 Subfamily: (CYP1A2, CYP 2C9, CYP 2D6 and CYP 3A4) are especially important to antidepressant metabolism and drug-drug interactions  9 Mood stabilizers Mood stabilizers - Lithium, Valproic acid,Carbamazepine, Lamotrigine, Gabapentin, Topiramate ( what we are afraid the most about lamotrigine is Steven Johnson syndrome) - Used in the treatment of Bipolar disorder and similar conditions associated with impulsivity - Drug level measurements are available for many of them General information - Mechanism of action is not clearly understood - Common side effects: benign: nausea, diarrhea and lethargy , weight gain Hand tremor: mild and fine, worse with high dose, caffeine and neuroleptic , Hypothyroidism– up to 5% of patients (usually mild) , Polyuria (urine volume > 3 L/day) and polydipsia - up to 40% of patients on Li+ therapy, Nephrogenic diabetes insipidus (5 - 6 L/day) is uncommon - Side effects Usually mild, well tolerated and dose dependent - Before and during the course of the treatment we have to monitor 3 things: - ( thyroid function test for hypothyroidism , urinalysis and RFT :polyuria and polydipsia for nephrogenic diabetic insipidus , ECG For cardiac diseases ) - Treatment of tremor: ↓ dose , stop caffeine, add β-blocker or switch to slow-release Lithium Lithium - Lithium Toxicity: (Cause dehydration) “lithium is a salt” - Lethargy , Muscular weakness , Ataxia , Hyperreflexia, Coarse hand tremor Dysarthria , Myoclonus , Neurological signs and , seizures , Coma and death in high level - treatment: First thing is to stop the drug, based on the amount of lithium and - clinical manifestation and dialysis at > 3.0 mEq Therapeutic Level is (4 - 12) mg/ml Common side effects: Dizziness, sedation, ataxia, leukopenia and rash , weight gain Carbamazepine Dangerous side effects: 1-Agranulocytosis, 2- teratogenicity ( neural tube defect), 3-induction of hepatic metabolism Valproic Acid - therapeutic level is (40 - 100) mg/m - Common side effects: Nausea, diarrhea, ataxia, dysarthria, weight gain, slight elevation of hepatic transaminases (MCQ from Dr) - teratogenic (neural tube defects) should be avoided in pregnancy women Lady came to you and you want to start valproic acid what test should you do? pregnancy test Same applies for carbamazepine  10 Anxiolytics / sedatives Anxiolytics / sedatives Sedative: Calm down and treat agitation Hypnotic: Induce sleep Go to sleep fast, feel refreshed tomorrow !!! Anxiolytic: Reduce anxiety (Physical, emotional, cognitive) General definitions Types: Benzodiazepines , Barbiturates (not used) , Antihistamines , Beta-blockers ( relieve the physical symptoms of anxiety but the problem with it can cause thoughts block ‫ ﺗﻧﺢ‬,Buspirone , Zolpidem Mechanism of Action: - BDZ receptors & it linked to GABA-A receptor complex (bound to Cl channels) - BDZ enhance GABA effect “just like alcohol” GABA: an inhibitory neurotransmitter - Effects: Sedative, Hypnotic, Anticonvulsant, Muscle-Relaxant - Used to treat insomnia, parasomnias and anxiety disorders - Often used for CNS depressant withdrawal protocols (ETOH withdrawal) Benzodiazepines - Clinical Institute Withdrawal Assessment for Alcohol (CIWA) - Side effects : Somnolence and Cognitive deficits , Amnesia and Disinhibition, (BZD): Tolerance and Dependence (that’s why we don’t use it for more than 4 weeks) Dr notes: In clonazepam we are afraid of seizures because ↓threshold Xanax ( alprazolam ) is the most dangerous type (short half life) lorazepam, clonazepam we are afraid of metabolic syndrome Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine (used in dementia) Other Psychotropic Sympathomimetics: Methylphenidate, Dextroamphetamine (used in addiction) Anticholinergic agents: Procyclidine, Benztropine classes: Hypertensive crisis : Associated with MAOIs Neuroleptic malignant syndrome : Autonomic instability, severe EPS, delirium, ↑CK, ARF, Recall of the most myoglobinuria important side effects Serotonin syndrome : Restlessness, myoclonus, ↑reflexes, tremors, confusion. Due to Dr: very imp combination of serotonergic agents Agranulocytosis : (Clozapine, carbamazepine) Never combine them  11 Summary and general principles in psychiatry They are part of a comprehensive treatment plan Summary of Basic knowledge of medications is important in daily clinical practice Medications Role in Their prescription by the psychiatrist follows a systematic approach: Psychiatry: Choose a medication based on FDA approval Prescribing a Family or personal history of response psychotropic agent after Adverse effects vs. key symptoms diagnostic assessment: Starting dose Monitor side effects & clinical response Adjust dose if needed Check Compliance & bioavailability Review the diagnosis Is the dose appropriate? Failure of Response Is the duration of treatment long enough? What to do? Any ongoing substance abuse? Other drugs/preparation causing drug-drug Interaction? Individual Variations 1. After a trail of adequate length ( at least 2 months) nd adequate dose 2. Switch to another antidepressant and wait for 2-4 weeks , if no improvement If no improvement: 3. Augment with another agent  12 Cases from Dr.Ali Q1: A young (19 years old) patient presented to the ER and was Agitated/Psychotic, they gave him an injection (the name of the drug “haloperidol” may or may not be mentioned) to control his agitation. Afterwards he developed spasms/contractions. What happened to him? Acute Dystonia. How can we treat him? Benztropine (Or one of these drugs: Procyclidine, Diphenhydramine, Trihexyphenidyl). Q2: An in-patient patient in the psychiatry ward (or Px in clinic), he can’t sit still and has to move. What is the side effect? Akathisia. How to treat this? Propranolol. Q3: A patient is taking an some medication for some time and presents with tremors, akinesia, rigidity and postural instabilities. What is the side effect? Pseudoparkinsonism. (the doctor didn’t mention the case exactly, but only said that some Px presenting with parkinson’s like features and you should recognize it) Q4: A patient taking an antipsychotic drug presented with Fever, Rigidity and Confusion. What is your diagnosis? Neuroleptic Malignant Syndrome (NMS). What is the management of the Px in this case? Discontinue the drug. How would you confirm your diagnosis? order CPK. Q5: A bipolar/manic patient will be started on Lithium what are the investigations you would order before starting this drug? 1-Thyroid function test. 2-RFTs. 3- ECG. Q6: A female patient will be started on Carbamazepine, what investigations would you order? 1- Pregnancy test. 2-LFTs. 3-CBC. 4-RFTs (Extra) Q7: A patient taking a MAOI which drug would you avoid? Pseudoephedrine What can they cause together? A hypertensive crisis.  Team leader Saleh Aloraini Team members Abdulrahman Aljofan Hamad Alothman Faisal Alhussaini Sultan Alkassim Alwaleed Bin shaya Faisal Alshuaibi Faisal Bin moammar Abdullah Alyamani Mishari Alzoubi Talal Alanazy Abdulmajeed Namshah Yahya Alghamdi Abdulrahman bawazir Osama Alsaaid Abdulmalik Alduraibi Good luck!! Special thanks to 439 & 438 psychiatry teams