View
1.520
Download
6
Category
Tags:
Preview:
DESCRIPTION
psychopharmacology
Citation preview
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.
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%)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
THANK YOU
Recommended