Vernon Rosario, MD, PhDAssociate Clinical Professor

Dept. of Psychiatry and Biobehavioral Sciences

Overview

• Neurotransmission & pharmacodynamics• Pharmacokinetics• Some medications affecting the brain and

behavior:o antipsychoticso mood stabilizerso antidepressantso antianxiety medicationso stimulants

Adapted from Steven A. Fink, PhD, Jarred von Snellenberg, PhD, Heidi Combs & MD Shamim Nejad, MD

Synaptic Transmission:Action Potentials

http://videosift.com/video/Brain-Synapses-and-Neurotransmission-3D-Animation

Pharamacodynamics:Where Drugs Act

• Four sites of actiono Receptors (those sites to which a

neurotransmitter can specifically adhere to produce a change in the cell membranes)

o Ion channelso Enzymeso Carrier Proteins

• Biologic action depends on how its structure interacts with a receptor

Receptors• Types of Action

o Agonist: same biologic actiono Antagonist: opposite effect

• Interactions with a receptor o Selectivity: specific for a receptoro Affinity: degree of attractiono 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

Potassium channel. Image Source Page: http://www.beckman.illinois.edu/news/Illinoisgating

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 (SSRI) on serotonin transporter protein

Image Source Page: http://scientopia.org/blogs/scicurious/2010/08/25/back-to-basics-3-depression-post-6/

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 o desensitization (rapid decrease in drug effect)o tolerance (gradual decrease in the effect of a drug at

a given dose)o can lead to patient being treatment refractory

Target Symptoms and Side Effects• Target symptoms

Specific symptoms treated for each class of medication

• Side effects Responses (+ or -) not related to target symptoms

• Adverse drug reaction Unwanted effects with serious physiologic

consequences.

Drug Toxicity• Toxicity

Point at which concentration of the drug in the blood stream becomes harmful or poisonous to the body.

• Image Source Page: http://www.beltina.org/health-dictionary/narrow-therapeutic-index-nti.html

Drug Toxicity• Therapeutic index

Ratio of the dose that produces toxicity in 50% to the dose that is therapeutically effective in 50%

• TD50/ED50 High therapeutic index: wide range between dose at which the

drug begins to take effect and dose that would be considered toxic

Low therapeutic index: low range

Image Source Page: http://quizlet.com/5151182/usmle-pharmacology-principles-flash-cards/

Pharmacokinetics:How the Body Acts on the Drug

• Absorption

• Distribution

• Metabolism

• Elimination

Pharmacokinetics

Blood BrainBarrier

P450 Enzymes

J van Snellenberg 2007

Absorption• From site of administration into the plasma• Oral - (tablet and liquid)

o Most Conveniento Most variable (food and antacids)

First pass effect Decreased gastric motility (age, disease, medication)

• IM - Short-and long acting• IV - Rarely used outside hospital

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

o Size of organ (larger requires more)o Blood flow (more, greater concentration)o Solubility (greater, more concentration)o Plasma protein (if bound, slower distribution, stays in body longer)o Anatomic barriers (tissues surrounding)

Crossing the Blood Brain Barrier• Passive diffusion

o Drug must dissolve in the structure of the cello Lipid solubility is necessary for drugs passing through

blood brain barrier (then, can also pass through placenta)

• Binding to other moleculeso Plasma protein binding o The more protein binding, the less drug activity.o Can bind to other cells, especially fat cells. Then are

released when blood level decreases.

Image Source Page: http://www.nanowerk.com/spotlight/spotid=19339.php

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 metabolism is carried out in the liver

Cytochrome P450 (CYP)

Largest class of enzymes catalyzing oxidation of organic substances in all living things • 11,550+ identified ; 57 in humans• High affinity for fat-soluble drugs• Involved in metabolism of most psychiatric medications• Inactivate drugs (or in some cases activate them)• Chemicals may increase or decrease CYP activity• Example:

o SSRIs inhibitors of the subfamily CYP2D6o Compounds in grapefruit juice inhibit CYP3A4o Tobacco induces CYP1A2

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 via the liver

o excreted in the bile and delivered to the intestineo 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: o drug accumulates and plateaus

at a particular level o rate of accumulation

determined by half lifeo reach steady state in about five

times the elimination half-life

Pharmacokinetics: Ethnicity

• 9% of whites - genetically defective CYP2D6• Asian descent

o Metabolize ethanol to produce higher concentrations of acetaldehyde (flushing, palpitations)

o Require 1/2 to 1/3 dose antipsychotics and have more severe side effects

• Cardiovascular effects of propranololo Asian descent - more sensitiveo African descent - less sensitive

Phases of Drug Treatment• Initiation• Stabilization• Maintenance• Discontinuation

Psychiatric Medications• Antipsychotic Medications• Movement Disorders Medication• Mood Stabilizers

o Antimanico Antidepressant

• Antianxiety and Sedative-Hypnotic• Stimulants

Antipsychotic Medications

• Target symptoms: psychosis• Types

o Conventionalo Atypical

• Absorption: variableo clinical effects seen 30-60 mino IM less variable (avoid 1st pass)o when immobile, less absorption of IM

• Metabolism: liver• Excretion: slow

o accumulates in fatty tissueso 1/2 life of 24 hours or more

Antipsychotic Medications• Preparations

o Oralo IMo Depot - haloperidol and fluphenazine

• Side Effectso Cardiovascular: orthostatic hypotensiono Weight-gain: blocking histamine receptoro Endocrine and sexual: block dopamine, interfere with

prolactino Blood dyscrasias: agranulocytosis

Antipsychotic Medications

• Conventionalo Phenothiazines (Thorazine, Prolixin)o Thioxanthenes (Navane)o Dibenzoxazepines (Loxitane)o Haloperidol (Haldol)

• Atypical or Novelo Clozapine (Clozaril)o Risperidone (Risperdal)o Olanzapine (Zyprexa)o Quetiapine (Seroquel)o Ziprasidone (Geodon)o Aripiprazole (Abilify)o Asenapine (Saphris)o Iloperidone (Fanapt)o Lurasidone (Latuda)o Paliperidone (Invega)

Antipsychotic Side Effects• Cardiovascular: arrhythmia, incr. heart rate

• Anticholinergic: dry mouth, dry eyes, imbalance, pupil dilatation, double vision, constipation, confusion, delirium

• Weight Gain• Endocrine: hyperprolactinemia > milk production, irregular periods,

hyperthermia, diabetes

• Blood Disorders: decr. white blood count

• Miscellaneous: jaundice, rash, photosensitivity

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• Extrapyramidal Symptoms (EPS) (11 min)

Movement Disorders: Acute (cont.)• Etiology (acute):

o Related to dopamine in nigrostrial pathway that increases cholinergic activity

• Treatmento Anticholinergic medication for dystonia, parkinsonism

(Artane and Cogentin)o Akathisia does not usually respond to anticholinergic

medication. Beta blockers have best success.

Movement Disorders: Chronic• Tardive Dyskinesia

o 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. More common in women and elderly.

• Symptomso Begin after 6 months, but also as antipsychotics are

withdrawno Irreversible - controversy

Movement Disorders: Chronic• Etiology

o believed that chronic dopamine suppression in the EPS causes an overactivation of the system

o increases in antipsychotic meds, suppresses• Treatment

o prevention by using lowest possible dosage, minimize use of PRN, closely monitor individuals in high-risk groups

o monitoring tools

Mood Stabilizers: AntimaniaLithium 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 (associated with cardiac defects and arrhythmia)

Mood Stabilizers: Antimania Anticonvulsants• Valporate and derivatives (divalproex sodium -

Depakote)• Carbamazapine (Tegretol)• Gabapentin (Neurontin) (least side effects)• Lamotrigine (Lamictal)• Topiramate (Topamax)

• Highly protein bound• Metabolized by the cytochrome P450 system• Side effects: dizziness, drowsiness, tremor, visual disturbance,

nausea, & vomiting

Anticonvulsant Mood Stabilizers• Only carbamazepine is approved for mania.• Used when patients have not responded to lithium• Pharmacokinetics

o Highly protein bound, metabolized by P450 system (potential drug-drug interaction)

CarbamazepineSide Effects

• Dizziness, drowsiness, tremor, visual disturbances, nausea, and vomiting

• Minimized by treating in low doses• Give with food• Weight gain• Alopecia (hair loss)

Antidepressants 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)

TCAs: Side Effects• Most common uncomfortable side effects

o sedationo orthostatic hypotensiono anticholinergic

• Otherso tremors, o restlessness, insomnia, confusiono pedal edema, headache, and seizureso blood dyscrasiaso sexual dysfunction

• Adverseo cardiotoxicity

Antidepressants• Most antidepressants block the re-uptake of a

neurotransmitter of one or more of the bioamines: serotonin, norepinephrine, dopamine

• SSRIs = Selective Serotonin Reuptake Inhibitors

Selective Serotonin Reuptake Inhibitors (SSRI)

• Fluoxetine (Prozac)• Sertraline (Zoloft)• Paroxetine (Paxil)• Fluvoxamine (Luvox)• Citalopram (Celexa)• Escitalopram (Lexapro)

SSRI: Side Effects• Headache• Anxiety• Transient nausea• Vomiting• Diarrhea• Weight gain• Sexual dysfunction

SSRIs• Usually given in morning, unless sedation occurs• Higher doses, especially paroxetine, can produce

sedation• Paroxetine associated with weight gain

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 (no cheese, liver, fermented or cured foods)

Antidepressants Others

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)o Venlafaxine (Effexor)o Desvenlafaxine (Pristiq)o Duloxetine (Cymbalta)

• Mirtazapine (Remeron)• Trazodone (Desyrel)• Nefazodone (Serzone withdrawn due to rare liver failure)• Bupropion (Wellbutrin)

Antianxiety and Sedative-Hypnotic Medication• Used for anxiety, not long-term• Benzodiazepines

o diazepam (Valium)o lorazepam (Ativan)o alprazolam (Xanax)

• Nonbenzodiazepineso busipirone (BuSpar)o zolpidem (Ambien)

• Side effectso Sedation and CNS depressiono Tolerance and dependence (benzos)o Avoid benzos in children & elderly

Psychostimulants

• This class of drugs, in low to moderate doses, generally have the following effectso Heightened mood (euphoria)o Increase vigilance and alertnesso Reduce fatigueo Alertness

• In order of prevalence of useo Caffeineo Nicotineo Amphetamines/Cocaine

Psychostimulants

• Amphetamine, etc (cont.)o Low to moderate doses

Facilitate performance on sustained attention tasks, and those requiring physical quickness or strength

Especially if fatigued (Benzedrine used extensively in WW II) Increased energy, concentration, alertness, self-confidence, and

mood Social interactions may be enhanced Suppresses appetite

o High doses generally interfere with performance Also can lead to dysphoria, social withdrawal, and depression

Psychostimulants

• Amphetamine, etc (cont.)o Extremely high doses or chronic use can lead to amphetamine-

induced psychosis Almost indistinguishable from paranoid schizophrenia

o Simple movements are often repeated for long periods E.g. continuous chewing, teeth grinding, tongue movement

o Chronic use leads to marked tolerance and, in chronic users, the administration of very high doses