Psychopharmacological Agents PDF

4. Psychopharmacological agents Pharmacology Núria Casals 4. Psychopharmacological agents 1. Benzodiazepines: anxiolytic and hypnotic agents 2. Drug therapy of depression 3. Pharmacotherapy of psychosis and mania 4. Neuropathic pain 1. Benzodiazepines Therapeutic...

4. Psychopharmacological agents Pharmacology Núria Casals 4. Psychopharmacological agents 1. Benzodiazepines: anxiolytic and hypnotic agents 2. Drug therapy of depression 3. Pharmacotherapy of psychosis and mania 4. Neuropathic pain 1. Benzodiazepines Therapeutic uses – Anxiolytic reduce anxiety – Sedative / Hypnotics (to treat insomnia) for seizures – Anticonvulsant (status epilepticus, tetanus, febrile convulsions) – Preanesthetic (allow general anaesthetic dose reduction) – Centrally acting muscle relaxant (muscle spasms)  1. Benzodiazepines. Pharmacodynamics benzodiazepines reduce the excitability of neurons, leading to calming effects like reduced anxiety, sedation, and muscle relaxation. GABA Drug Cl- GABA Are enhancers of GABA’s effects - - -- GABA is the brain's main inhibitory neurotransmitter, meaning it calms the brain by -- reducing nerve activity. - Benzodiazepines act allosterically on GABA receptor to increase the effects of GABA The entrance of Cl- into the neuron hyperpolarizes the membrane and inhibits transmission inside of cell more negative 1. Benzodiazepines Pharmacokinetics ✓ Lipophilic. Cross BBB very fast ✓ Different routes of administration Completely absorbed after oral administration. Other routes: sublingual, rectal, parenteral ✓ Large volume of distribution. ✓ Extensively metabolized by hepatic CYPs A patient is very anxious when enters the dental setting and you decide to administer a benzodiazepine. Which route would you chose? intramuscular is a good route to take 1. Benzodiazepines Clasification based on their half-life: Short-acting agents (t1/2 2-4 hours) Triazolam Midazolam Intermediate-acting agents (t1/2 6-24 hours) Alprazolam (Trankimacin®) Lorazepam Long-acting agents (t1/2 > 24 hours) Diazepam (Valium®) Flurazepam 1. Benzodiazepines usage depending on half-life Shorter t1/2: Patients with sleep-onset insomnia but without significant daytime anxiety Elderly Longer t1/2 Patients who have significant daytime anxiety Patients receiving treatment for depressive/anxiety disorders 1. Benzodiazepines Adverse Effects ✓ Sleepiness, light-headedness, increased reaction time, motor incoordination, impairment of mental and motor functions and confusion They can affect driving ✓ Anterograde amnesia ✓ Irritability, agresivity (only in older people) ✓ At high doses, respiratory depression (special care in children and elderly people) The adverse reactions are more freqüent in older people Benzodiazepine overdosage Loss of consciousness Huge doses are rarely fatal unless other drugs are taken concomitantly. Ethanol is a common contributor to deaths involving benzodiazepines Antidote: Flumazenil (IV) = benzodiazepine receptor antagonist 1. Benzodiazepines: Dependence (no tolerance) In patients who have benzodiazepines on a regular basis for prolonged periods Withdrawal symptoms: temporary intensification of the problems that originally prompted their use (e.g., insomnia or anxiety), dysphoria, irritability, sweating, unpleasant dreams, tremors, anorexia, and dizziness Taper the dosage gradually when therapy is to be discontinued (to avoid a rebound effect) 1. Benzodiazepines (BZD) Management of anxiety Pharmacological effect since the 1st dose Duration of the treatment should be < 12 weeks In the elderly or in patients with liver disease, prefer BZD with fast elimination (lorazepam) or with short/intermediate half-life Management of insomnia Sleep hygiene: stablishing good habits and practices is always the first step Transient or short-term insomnia (3 weeks): A more complete medical evaluation is necessary.  Other hypnotics a) “Z compounds”: Zolpidem, Zaleplon Enhancers of GABA receptor (Antidote: Flumazenil) Preferred than BZD as hypnotics because: Lower risk of dependence (it appears in the long term) Short half-life (around 2,5 h). Less daytime drowsiness. Reduced impact on sleep architecture b) Antihistaminics (1st generation) – Sedation is a side effect used to treat insomnia c) Melatonin – It restores the circadian rhythm 2. Drug therapy of depression 2. Drug therapy of depression An overview ❑ Depression affects ≈10-15% of the population at some time in their lives. ❑ Approximately 10-15% of those with severe depression attempt suicide at some time ❑ Depressive episodes are characterized by - depressed or sad mood - diminished interest in normal activities Occurring most days for a - insomnia or increased sleep period of at least 2 weeks - significant weight loss or gain - feelings of guilt and worthlessness - suicidal ideation 2. Drug therapy of depression Clinical Considerations with Antidepressant Drugs “Therapeutic lag”: 3-4 weeks for the initial response Side effects appear at first doses After remission, a maintenance treatment phase is typical to avoid relapse, after which the drug is gradually withdrawn In some patients, a combination of different drugs must be needed Psychotherapy 2. Drug therapy of depression Neurotransmitters involved in depression: NE y 5HT Dopamine Norepinephrine (NE) Serotonin (5HT) Mechanism of action of antidepressants ( ) 2. Drug therapy of depression Classification of antidepressant drugs (depending on the mechanism of action) Main goal: To enhance neurotransmission of 5HT and NE Serotonin (5HT) Norepinephrine (NE) – Serotonin-norepinephrine reuptake inhibitors (SNRIs) TCA (affect the function of other neurotransmitters as well) New – Selective serotonin reuptake inhibitors (SSRIs) – MAO Inhibitors (MAOI). 2nd-line drugs 2. Drug therapy of depression MAOI SSRI SNRI TCA Atypical  2.1. Serotonin-norepinephrine reuptake inhibitors (SNRI) Tricyclic antidepressants (TCA): Amitriptyline Actions Block serotonin and norepinephrine uptake transporters Poor selectivity Adverse effects (Bind with low affinity histamine H1, muscarinic and α1 adrenergic receptors) Sedation Anticholinergic effects: blurred vision, dry mouth, tachycardia and arrythmias, constipation, difficulty urinating Orthostatic hypotension Weight gain Overdosage can cause death (narrow therapeutic window) Warning: Do not use adrenaline containing local anesthetics with patients taking TCA 2.2. Serotonin-norepinephrine reuptake inhibitors (SNRI) New SNRI: Venlafaxine, duloxetine Safety advantages over the TCA Less cardiac adverse effects than TCA Less sedation than TCA Side effects: Nausea, insomnia, nervousness, headaches, and sexual dysfunction Mild anticholinergic effects: dry mouth, dry eyes, intestinal effects (constipation) Dose reductions are suggested for patients with renal or hepatic impairment  2.3. Selective serotonin reuptake inhibitors (SSRI) Fluoxetine, paroxetine, sertraline, citalopram Improvement in safety margin compared to TCA and new SNRI and much safer in overdose Pharmacokinetics Oral once daily dosing Adverse effects: Not anticholinergic or cardiovascular effects!! No sedation Minor side effects (agitation in the first doses, decreased libido, nausea, dullness of intellectual abilities) Better patient compliance! Also used in anxiety, OCD, bulimia 3. Pharmacotherapy of psychosis and mania 3.1. Pharmacotherapy of psychosis Introduction Psychosis is a symptom of mental illnesses characterized by a distorted or non-existent sense of reality Schizophrenia has a worldwide prevalence of 1% Positive symptoms Hallucinations, delusions, disorganized speech, and disorganized or agitated behavior Negative symptoms Apathy, reduced talking Cognitive deficits 3.1. Pharmacotherapy of psychosis Psychosis is caused mainly by dopaminergic and serotoninergic overactivity Treatment is symptomatic It takes a time (days) until is fully effective Clasification: Typical Dopamine (first-generation) Atypical They block: Norepinephrine (NE) Serotonin (5HT) Low D2 effect  Antipsychotics-Adverse effects: Neurological motor dysfunction (extrapyramidal effects) Due to D2 antagonism. Characteristic of typical antipsychotics Soon after administration of drug (reversible, decrease with time) Acute dystonia (involuntary muscle spasms and contractions) Akathisia Parkinsonism Neuroleptic malignant syndrome (rare: rigidity, fever, tremor, fluctuating heart rate) Late-appearing syndromes (nonreversible) Tardive dyskinesias or dystonia (perioral tremor)  Antipsychotics. Other adverse effects Sedation Autonomic system Orthostatic hypotension Arrhythmia Anticholinergic effects Metabolism and endocrine system: Weigh gain Hyperprolactinemia (due to blockade of D2 receptors). It causes: Galactorrhea (milk production) Irregular menstrual cycles Infertility and sexual dysfunction  1. Typical antipsychotics (first generation drugs) Block dopamine receptors, mainly D2 Very effective against positive symptoms, not for negative ones Promote several side effects: neurologic, hormonal, etc HALOPERIDOL: – Potent antipsychotic used to treat psychotic crisis in hospitals or Mental Health centers (high therapeutic index when used for a short period) – (Antiemetic activity) – Administration route: oral, parenteral Adverse effects All side effects listed before, but: – Low incidence of anticholinergic effects – Low sedation 2. Atypical antipsychotics: Clozapine, Olanzapine, Risperidone, Quetiapine, Aripripazole, etc Tend to improve both the positive and negative symptoms, and cognition in schizophrenia. Also used for: bipolar disorder, acute mania, major depression, autism, etc Less side effects – Produce few motor side effects. Tardive dyskinesia is rare – No or mild hyperprolactinemia – Clozapine can cause agranulocytosis (0,8%) and seizures (2-4%) Improved compliance  Antipsychotics. Drug interactions Potentiate all CNS depressants (hypnotics, anxiolytics, alcohol, opioids) Block the actions of levodopa and direct dopamine agonists in parkinsonism and worsen the symptoms of Parkinson’s disease One of the main problems is drug compliance 3.2. Pharmacotherapy of mania and bipolar disorder Introduction Mania is a period of elevated, expansive or irritable mood with increased energy and and decreased need for sleep May be induced by medications or abuse substances Mania represents one pole of bipolar disorder: - Mania at any time → Bipolar I - Periods of hypomania + depression → Bipolar II (Bipolar disorder, commonly known as) Prevalence of bipolar I and II disorders: 3-4 % 3.2. Pharmacotherapy of mania Lithium carbonate Therapeutic uses -Treatment of acute mania and the prevention of recurrences of bipolar illness in adults or adolescents -Depressive patients who are inadequate responders to antidepressants Pharmacokinetics Oral administration Low therapeutic index → periodic determination of serum lithium concentrations is crucial NSAIDs and diuretics increase lithium levels in blood and toxicity 3.2. Pharmacotherapy of mania Lithium carbonate. Adverse effects CNS Effects. Fine postural hand tremor (incidence ranging from 15-70%) At peak serum levels: incoordination, ataxia, or slurred speech may occur → dosing Li+ at bedtime. Thyroid and Renal Effects. Compromised thyroid function: Hypothyroidism Diabetes insipidus (~60% of individuals experience some form of polyuria) Renal insufficiency (nephropathy) in the long term 3.2. Pharmacotherapy of mania Alternatives or adjuncts to lithium: Antiepileptics Atypical antipsychotic agentes Antidepressants 4. Neuropathic pain Causes: ✓ Diseases of the spinal nerve roots, dorsal root ganglia, and peripheral nerves ✓ Amputation ✓ Multiple sclerosis, stroke, posttraumatic myelopathy ✓ Infectious disease (postherpetic neuralgia) ✓ Idiopathic Nerve damage Symptoms and Signs ✓ Dysesthesias are typical (burning, tingling, prickling, or electric shock-like sensations) ✓ Pain may also be deep and aching ✓ Hyperesthesia, allodynia, and hyperpathia  Treatment of neuropathic pain Address underlying conditions Symptom management → Started at the minimum dose, with the dose gradually increased until an effect is noticed → Combination of different drugs. Addition of therapeutic effect but not side effects Drugs: ✓ Tricyclic antidepressants (TCA): Amitriptyline, imipramine ✓ Lower dose than for depression ✓ Anticonvulsants: Gabapentin, carbamazepine ✓ Lower dose that for convulsions ✓ Tramadol