General psychopharmacology

GENERAL PRINCIPLES OF PSYCHOPHARMACOLOGYDr Salman Kareem

1st yr Resident

Department of Psychiatry

PSYCHOPHARMACOLOGY

Psychopharmacology: The study of the effects of drugs on the nervous

system and on behavior.

Drug effects: The changes a drug produces in patient’s physiological

processes and behavior.

Sites of Action: The locations at which molecules of drugs interact with

molecules located on or in cells of the body, thus affecting some biochemical processes of these cells.

CLASSIFICATION Structure- Tricyclics Mechanism of Action – MAOI History – First generation, traditional. Uniqueness – atypical antipsychotics Major clinical applications

Anti depressentAnti psychoticsanxiolytics

PHARAMCOLOGICAL ACTIONS

PHARMACODYNAMICS What the body does to the drug

Receptor mechanismDose response curveTherapeutic indexDevelopment of toleranceDependenceWithdrawal phenomenon

MECHANISM

• 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

1. Synthesis2. Storage 3. Enzymatic destruction if not stored4. Exocytosis5. Termination of release via binding with autorecptors6. Binding to receptors7. Inactivated

Drugs are developed that address these actions as an AGONIST (mimic the NT ) or ANTAGONIST (block the NT)

Neurotransmitters Go through 7 steps

RECEPTORS• Types of Action

o Agonist: same biologic action eg benzodiazepines act benzodiazepine recognition site in the benzodiazepine GABA receptor complex

o Antagonist: opposite effect eg Flumazenilo Partial Agonist :Buprenorphineo Inverse agonist

• 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 receptoro Medications treating anti psychotics - blocks dopamine 2

receptors

MECHANISM

Poorly understood Drugs alter synaptic concentration of

dopamine, serotonin, nor epinephrine , histamine, gamma amino butyric acid or acetylcholine

Results from Receptor agonist, antagonist Interference with neurotransmitter uptake

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.

• Eg Lithium binds directly to enzyme inositol 1 phosphatase

CARRIER PROTEINS

• Transport neurotransmitters across cell membranes

• Medications may block or inhibit this transport

• Example: antidepressants (SSRI) on serotonin transporter protein

/

SIDE EFFECTS Unavoidable risks of medical treatment Probability of its occurence Impact on quality of life Cause

TCA’s – most common side effect caused by blockade of muscarinic acetylcholine receptors or histamine 2 receptors.

SSRI’s serotonion reuptake – cause nausea and sexual dysfunction

Anti psychotics – D2 blockage of drugs – Extra pyramidal side effects.

Benzodiazepine – agnostic action ataxia and daytime sleepiness.

Time course

adverse effects differ in terms of time of onset and duration . Some appears ate the end of the treatment

Nausea occuring with SSRI’s or venlaxafine eg

Sedation occuring with mirtazapine of

onset

Long term complications – Dopamine and other Dopamine receptor antagonists – Tardive Dyskinesia

MOST COMMON SIDE EFFECTS Somnolence - desirable adverse effect GI Disturbances - Sertraline most likely to

cause loose stools, Fluvoxamine most likely to cause nausea

Movement disorder Sexual dysfunction – most commonly

associated with the use of SSRI. Weight gain - atypical antipsychotics bec. of

disturbance in glucose and insulin metabolism

SIDE EFFECTS Glucose changes- atypical antipsychotics

because of disturbance in glucose and insulin metabolism

Hyponatremia – elderly patients more common by oxcarbamazepine

Cognitive impairment Sweating Cardiovascular Rash Urinary retention

POTENTIAL ADVERSE EFFECTS OFANTIDEPRESSANT THERAPY 0

4/1

0/2

02

3

19

Cardiac

Orthostasishypertensionheart block,tachycardia

Urogenital

Erectile dysfunction,ejaculation disorder,anorgasmia, priapism

Central Nervous System

Dizziness, cognitive impairment,sedation, light-headedness,somnolence, nervousness,insomnia, headache, tremor,changes in satiety and appetite

Gastrointestinal

Nausea, constipation,vomiting, dyspepsia,diarrhea

Autonomic Nervous System

Dry mouth, urinary retention,blurred vision, sweating

IDIOSYNCRANTIC AND PARADOXICAL RESPONSE When a patient expresses particularly unusual or

rare effects from a drug Eg some patients may be agitated when given a

benzodiazepine Spontaneous orgasm instead of anorgasmia Behavioural disinhibition - benzodiazepines

SAFETY Therapeutic index relative measurement of

toxicity or safety of a drug and is defined as ratio of median toxic dose to median effective dose.

High therapeutic index: wide range between dose at which the drug begins to take effect and dose that would be considered toxic eg SSRI

Low therapeutic index: low range eg LITHIUM

OVERDOSE Newer drugs have a wide margin of safety. Safest drug can have severe medical complication

especially when combined with other drugs

Suicide is a major concern

Attempt made to verify that the medicine is not hoarded.

Random pill container

Asking family members to dispense daily might be helpful.

Possible of accident ingestion of medication by children in household.

PHARMACOKINETIC ACTION What the body does to the drug

Time course of drug concentration in different parts of the body such as plasma , adipose tissue and CNs.

Explains or predicts the onset and duration of drug activity and intention between drugs that alter their metabolism or excretion.

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.

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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%)o BILE, FECES, and URINE are major routes of

excretion.

SUCCESS OF MEDICATIONS

Patient related factorsDiagnosis Past history of diagnosisConcurrent medical disorderLifestyleOverall medical statsGenetic factor

Diagnosis failure to diagnose a disorder diminishes the

likelihood of optimal drug selection.Produces worsening of symptomsTreatment failure for exacerbation of symptoms

should promp a reassesment of diagnosis Post treatment response Response in faulty members

Concurrent medical / psychiatric illness Thyroid disease not adequately treated Sleep apnea produces depression and cognitive

impairment. Kleine levin syndrome – mimics bipolar disorder Recreational drug, alcohol consumption and frequent

consumption of coffee can undermine psychotropic drug treatment.

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

Duration variesHigh rates of chronicity and relapseTherapeutic trial Continuation therapy

Frequency of visitsDetermined by clinical judgment.Maintenance therapy needs monitoring.

TREATMENT OUTCOMES Remission

Degree of improvement to below the syndromal threshold is defined as remission.

Response 50 percent or greater decrease from baseline on a

standard rating scale. Treatment failure

Anticipate Prompt reassesment Intolerance to side effects Appropriate dosage for sufficient for a length of time? Drug non compliance

THREE PHASES OF TREATMENT

Time

Sym

pto

m S

everi

ty

Normal

AcutePhase (3 months+)

ContinuationPhase (6-12 months)

MaintenancePhase (years)

Response

Remission

Relapse

Relapse Recurrence

> 50% STOP Rx

65 to 70% STOP Rx

Recovery

TREATMENT RESISTANCE

Some patients fail to respond to repeated trials of medication.

Tolerance Marked by a need, over time , to use increased

doses of drug for it to maintain a clinical effect.Decreased responsiveness occurs after repeated

doses. Sensitization

Reverse of toleranceSensitivity to a drug effect increases over time.

Withdrawal Development of physiological adaptation of a

drug ‘side effect’More abruptly it is stopped and the shorter its

elimination half life more likely the clinically significant withdrawal symptoms occur

Gradual tapering of medication.Benzodiazepines, SSRI (paroxetine)

COMBINATION OF DRUGS

“use of mutiple drugs should be avoided as possible” When two psychotropics drugs with the same

approved indications are used concurrently , this is termed as combination therapy.

Adding another drug with another indication is termed as augmentation.

Almost all patients with bipolar disorder take more than one psychotropic agent.

Medications are also given to counteract the side effects , to treat specific symptoms and as a temporary measure to transition from one drug to another.

SPECIAL POPULATION

Childrenhigh metabolism, low – slow, /kg

Pregnant and nursing women Avoid administering in them unless the

psychiatric disorder is severe. Paroxetine – FDA warning – cardiac malformation. Lithium – ebstein’s anomaly Carbamazepine, valproic acid – neural tube

defects. Lamotrigine – oral clefts. Psychotherapeutic drugs – overly sedated at

deliveryECT is good

Elderly patients – more susceptible to adverse effects and may metabolize

and excrete drugs more slowly. low metabolism , 1/3 adult dose, drug interaction and

medical state Medically ill patients

Medical disorder should be ruled out as a cause of psychiatric symptoms

Taking other medications can result in pharmacodynamic and pharmacokinetic interaction

Potentially increased sensitivity to adverse effects including increased or decreased metabolism and excretion of the drug.

NON APPROVED DOSAGES AND USES

Treat psychiatric disorders with drugs that are approved for non psychiatric conditions.Propanolol – social anxiety and lithium induced

tremorVerapamil for mania and treatment of MAOI

induced hypertensive crisis.Clonidine and guanificine for ADHD and PTSD.Levothyroxine for antidepressent augmentation

BLACK BOX WARNING

Prescribing information sometimes contains a black box warning to warn physicians about potentially important safety information

Strongest warning – more serious than just bolded text

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