Psychopharmacology and Other Biologic Treatments Chapter 8 Psychopharmacology

Psychopharmacology and Other Biologic Treatments Chapter 8

Psychopharmacology • Subspecialty of pharmacology that includes medications affecting the brain and behavior used to treat mental disorders including – – – antipsychotics mood stabilizers antidepressants antianxiety medications stimulants • Provides a basis for understanding specific biologic treatments of psychiatric disorders

Pharamacodynamics: Where Drugs Act • Four sites of action – Receptors (those sites to which a neurotransmitter can specifically adhere to produce a change in the cell membranes) – Ion channels – Enzymes – Carrier Proteins • Biologic action depends on how its structure interacts with a receptor.

Receptors • Types of Action – – Agonist: same biologic actin Antagonist: opposite effect • Interactions with a receptor – – – Selectivity: specific for a receptor Affinity: degree of attraction Intrinsic activity: ability to produce a biologic response once it is attached to receptor

Ion Channels • Drugs can block or open the ion channels • Example: benzodiazepine drugs facilitate GABA in opening the chloride ion channel

Enzymes • Enzymes catalyze specific biochemical reactions within cells and are targets for some drugs. • Monoamine oxidase is an enzyme that breaks down most bioamine neurotransmitters (NE, DA, 5 -HT). • Enzymes may be inhibited to produce greater neurotransmitter effect.

Carrier Proteins • Transport neurotransmitters across cell membranes • Medications may block or inhibit this transport. • Example: antidepressants

Efficacy and Potency • Efficacy - Ability of a drug to produce a response as a result of the receptor or receptors being occupied. • Potency - Dose required to produce the desired biologic response. • Loss of effect – desensitization (rapid decrease in drug effect) – tolerance (gradual decrease in the effect of a drug at a given dose) – can lead to being treatment refractory

Target Symptoms and Side Effects • Target symptoms: – Specific symptoms for each class of medication – No drug attacks such a target symptom • Side effects - Responses not related to target symptoms (Table 8. 1, 8. 1). • Adverse effects: Unwanted effects with serious physiologic consequences.

Drug Toxicity • Toxicity: Point at which concentrations of the drug in the blood stream become harmful or poisonous to the body. • Therapeutic index: Ratio of the maximum nontoxic dose to the minimum effective dose. • High therapeutic index: Wide range between dose at which the rug begins to take effect and dose that would be considered toxic. • Low therapeutic index - low range

Absorption • From site of administration into the plasma • Oral - (tablet and liquid) (Table 8 -3) – – Most Convenient Most variable (food antacids) • • First pass effect Decreased Gastric Motility (age, disease, medication) • IM - Short-and long acting • IV - Rarely used

Pharmacokinetics: How the Body Acts on the Drug • Absorption • Distribution • Metabolism • Elimination

Bioavailability • Amount of drug that reaches systemic circulation unchanged • Often used to compare one drug to another, usually the higher the bioavailability, the better.

Distribution • Amount of drug found in various tissues, especially the intended ones. • Psychiatric drugs must pass through blood-brain barrier (most fat-soluble) • Factors effecting distribution – Size of organ ( larger requires more) Blood flow ( more, greater concentration) Solubility (greater, more concentration) Plasma Protein (if bound, slower distribution, stays in body longer – Anatomic Barriers (tissues surrounding) – – –

Crossing the Blood Brain Barrier • Passive diffusion – Drug must dissolve in the structure of the cell – Lipid solubility is necessary for drugs passing through blood brain barrier (then, can also pass through placenta) • Binding to other molecules – Plasma protein binding – The more protein binding, the less drug activity. – Can bind to other cells, especially fat cells. Then are released when blood level decreases.

Metabolism • Process by which the drug is altered and broken down into smaller substances (metabolites) that are usually inactive. • Lipid-soluble drugs become more water soluble, so they may be more readily excreted. • Most metablism is carried out in the liver.

Cytochrome P 450 • Many process carried out by enzyme class Cytochrome P-450 – – – high affinity for fat-soluble drugs involved in metabolism of most psychiatric medications Example: SSRIs inhibitors of the subfamily P 4502 D 6

Elimination • Clearance: Total amount of blood, serum, or plasma from which a drug is completely removed per unit time. • Half-life: Time required for plasma concentrations of the drug to be reduced by 50%. • Only a few drugs eliminated by kidneys (lithium) • Most excreted in the liver – – excreted in the bile and delivered to the intestine may be reabsorbed in intestine and “re-circulate” (up to 20%)

Dosing and Steady State • Dosing: Administration of medication over time, so that therapeutic levels can be achieved. • Steady-state: – drug accumulates and plateaus at a particular level – rate of accumulation determined by half life – reach steady state in about five times the elimination half-life

Pharmacokinetics: Cultural Considerations • 9% of whites - genetically defective P-4502 D 6 • Asian descent – Metabolize ethanol to produce higher concentrations of acetaldehyde (flushing, palpitations) – Require 1/2 to 1/3 dose antipsychotics and more severe side effects • Cardiovascular effects of propranolol – Asian descent - more sensitive – African descent - less sensitive

Phases of Drug Treatment • • Initiation Stabilization Maintenance Discontinuation

Psychiatric Medications • Antipsychotic Medications • Movement Disorders Medication • Mood Stabilizers – – Antimania Antidepressants • Antianxiety and Sedative-Hypnotic • Stimulants

Antipsychotic Medications • Target symptoms: psychosis • Types – – Conventional Atypical • Absorption: variable – – – clinical effects seen 30 -60 min IM less variable (avoid 1 st pass) when immobile, less absorption • Metabolism: liver

Antipsychotic Medications • Target symptoms: psychosis • Types – – Conventional Atypical • Absorption: variable – – – clinical effects seen 30 -60 min IM less variable (avoid 1 st pass) when immobile, less absorption • Metabolism: liver • Excretion: slow – – accumulates in fatty tissues 1/2 life of 24 hours or more

Antipsychotic Medications (cont. . ) • Preparations – – – Oral IM Depot - haloperidol and fluphenazine • Side Effects – – Cardiovascular - orthostatic Hypertension Weight-gain: blocking histamine receptor Endocrine and sexual: block dopamine, interfere with prolactin Blood Dyscrasias - agranulocytosis

Antipsychotic Medications • Conventional – – Phenothiazines (Thorazine, Prolixin) Thioxanthenes (Navane) Dibenzoxazepines (Loxitane) Haloperidol (Haldol) • Atypical or Novel – – – Clozapine (Clozaril) Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon)

Antipsychotic Side Effects • • • Cardiovasular Anticholinergic Weight Gain Endocrine and Side Effects Blood Disorders Miscellaneous

Medication-Related Movement Disorders: Acute Syndromes • Can occur in 90% of all patients • Dystonia: involuntary muscle spasms, abnormal postures, oculogyric crisis, torticollis • Parkinsonism: rigidity, akinesia (slow movement), and tremor, masklike face, loss of spontaneous movements • Akathisia: Inability to sit still, restlessness

Movement Disorders: Acute (cont. ) • Etiology (acute): – Related to dopamine in nigrostrial pathway that increases cholinergic activity • Treatment – – Anticholinergic Medication for dystonia, parkinsonism (Artane and Cogentin) Akathisia does not usually respond to anticholinergic medication. Beta blockers have best success.

Movement Disorders: Chronic • Tardive Dyskinesia – Irregular, repetitive involuntary movements of mouth, face, and tongue, including chewing, tongue protrusion, lip smacking, puckering of the lips, and rapid eye blinking. Abnormal finger movements are common. • Symptoms – – Begin after 6 months, but also as antipsychotics are withdrawn Irreversible - controversy

Movement Disorders: Chronic • Etiology – – believed that chronic dopamine suppression in the EPS causes an overactivation of the system increases in antipsychotic meds, suppresses • Treatment – – prevention by using lowest possible dosage, minimize use of PRN, closely monitor individuals in high-risk groups monitoring tools

Mood Stabilizers: Antimania Lithium Carbonate • Action: uncertain, crosses cell membranes, altering sodium transport, not protein bound • Side Effects: thirst, metallic taste, increased frequency or urination, fine head and hand tremor, drowsiness, and mild diarrhea • Blood levels monitored (lithium toxicity - severe diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination, withhold)

Lithium Carbonate • Monitor creatinine concentrations, thyroid hormones, and CBC every 6 months. • Kidney damage may be a risk. • Thyroid function may be altered usually after 6 -18 months. Observe for dry skin, constipation, bradycardia, hair loss, cold intolerance. • Avoid during pregnancy.

Mood Stabilizers: Antimania Anticonvulsants • Valporate and derivatives (divalproex sodium - Depakote) • Carbamazapine (Tegretol) • Gabapentin (Neurontin) (least side effects) • Lamotrigine (Lamictal) • Topiramate (Topamax)

Anticonvulsant Mood Stabilizers • Only carbamazepine is approved for mania. • Used when patients have not responded to lithium • Pharmacokinetics – Highly protein bound, metabolized by P 450 system (potential drug-drug interaction)

Carbamazepine Side Effects • Dizziness, drowsiness, tremor, visual disturbances, nausea, and vomiting • Minimized by treating in low doses • Give with food • Weight gain • Alopecia (hair loss)

Antidepressants Table 8. 11, 12 Tricyclic: Tertiary Amines • • • Amitriptyline (Elavil) Clomipramine (Anafranil) Doxepine (Sinequan) Imipramine (Tofranil) Trimipramine (Surmontil)

Antidepressants Secondary Amines • • Amoxapine (Asendin) Desipramine (Norpramin) Nortriptyline (Aventyl, Pamelor) Protrypyline (Vivactil)

Side Effects -- TCAs • Most common uncomfortable side effects – sedation – orthostatic hypotension – anticholinergic • Others – – – • tremors, restlessness, insomnia, confusion pedal edema, headache, and seizures Blood dyscrasias Sexual dysfunction Adverse – cardiotoxicity

Antidepressants • Most antidepressants block the re-uptake of a neurotransmitter of one or more of the bioamines: serotonin, norepinephrine, dopamine. • SSRIs - selective to the serotonin

Serotonin Selective Reuptake Inhibitors SSRI – – Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox)

Side Effects -- SSRIs • • Headache Anxiety Transient nausea Vomiting Diarrhea Weight gain Sexual dysfunction

SSRIs • Usually given in morning, unless sedation occurs • Higher doses, especially fluoxetine, can produce sedation • Venlafaxine (Effexor), only mildly sedating. • Paroxetine associated with weight gain

Antidepressants Others • • • Mirtazapine (Remeron) Maprotiline (Ludiomil) Trazodone (Desyrel) Nefazodone (Serzone) Bupropion (Wellbutrin) Venlafaxine (Effexor)

Antidepressants Monoamine Oxidase Inhibitors (MAOIs) • Action: Inhibit enzyme responsible for the metabolism of serotonin, dopamine, norepinephrine, and tyramine. • Increases levels of norepinephrine and serontonin in the CNS • Interacts with food -- low tyramine diet (Table 18. 3)

Antianxiety and Sedative. Hypnotic Medication • Used for anxiety, not long-term • Benzodiazepines (Table 8. 14) – – – diazepam (Valium) lorazepam (Ativan) alprazolam (Xanax) • Nonbenzodiazepines – – busipirone (Bu. Spar) zolpidem (Ambien) • Side effects – – – Sedation and CNS depression Tolerance and dependence (Benzos) Avoid Benzo in elderly

Stimulants • Amphetamines • Used in narcolepsy, ADHD, and obesity

Electroconvulsive Therapy • Initiate generalized seizures by an electrical current • Short-acting anesthetic and muscle relaxant given • Repeat procedure 2 -3 times per week • Produces rapid relief of depressive symptoms • Side Effects-hypo or hypertension, bradycardia or tachycardia, and minor arrhythmias immediately after

Other Biological Treatment • Light Therapy (Phototherapy) – – Reset circadian rhythms Used for SAD • Nutritional Therapies