CHAPTER 36

Principles of Psychopharmacology Advances in the understanding of

brain functions have resulted in: More effective treatments Less toxicity More specifically targeted therapeutic

agents

Classification

Psychotropic drugs Antidepressants Antipsychotics Mood stabilizers Anxiolytics Hypnotics Cognitive enhancers Stimulants

Pharmacological Actions

Environmental and genetic factors that determine the body’s response to medications

Pharmacokinetics What the body does to the drug

Pharmacodynamics What the drug does to the body

Pharmacological Actions

Drug-neuron interaction Effect on neurotransmitter secretion

Profile of efficacy Tolerability Safety Risk-to-Benefit Ratio

Drug Selection

Drugs for particular disorders are similar in overall effects but differ in: Pharmacology Efficacy

Side/Adverse effects Effects on individual patients

See table 36.1-1, pgs 977-979

Drug Selection cont. Drug selection decisions are made on a case-by-

case basis Effectiveness of drugs depends on patient

variables Some drugs are uniquely helpful for certain

subgroups of patients No drug is universally effective No evidence indicating unambiguous superiority

of any agent as Tx for major psychiatric disorders Clozapine- Tx-refractory schizophrenia

Drug Factors: Pharmacodynamics Pharmacodynamic considerations

Receptor mechanisms Dose-response curve Therapeutic index Development of tolerance Dependence Withdrawal phenomena

Pharmacogenetic studies are beginning to identify factors linked to individual differences in Tx response and sensitivity to side effects

Drug Factors: Mechanisms

Psychotropic drugs: Poorly understood mechanisms of action Based on the drug’s alteration of synaptic

concentrations of neurotransmitters like: Dopamine Serotonin Norepinephrine Histamine GABA (GammaAminobutiric Acid) Acetylcholine

Drug Factors: Mechanisms

Results based on: Agonist/antagonist-Receptor interactions Interference with neurotransmitter reuptake Enhancement of neurotransmitter release Enzyme inhibition

Some Drugs have mixed action Some drugs can be agonists at one

receptors and antagonists at other receptors

Some drugs are partial agonists

Drug Factors: Mechanisms

Some psychotropic drugs produce clinical effects through mechanisms other than receptor interaction Lithium

Inhibits the enzyme: Inositol-1-phosphatase

Some effects are linked to specific synaptic effects Antipsychotics block Dopamine-2 receptors Benzodiazepine agonists- bind benzodiazepine and

GABA receptor complex

Side Effects

Side effects considerations Probability of its occurrence Impact on patients quality of life Time course Cause

Regardless of how common a side effect is it won’t necessarily occur in every patient.

Side effects can result from: Same pharmacological action responsible for it’s

therapeutic activity From an unrelated property

Side Effects

Side effects can vary according to: Pharmacological properties Dosage Patients health Interactions with concurrent therapies

Including OTC/Natural Dietary Supplements Other factors

With or without food Mixed with Alcohol Recreational drugs

Side Effects

Common side effects of psychotropic medications Somnolence GI disturbances Movement disorders Sexual dysfunction Weight gain Weight Loss Glucose changes Hyponatremia Cognitive imopairment

Cont. Sweating CV disease Rash

Side Effects

Idiosyncratic and paradoxical drug responses Rare- Happen in a very small percentage

of patients Not related to the pharmacological

properties of the drug Might be related to a gentically based

abnormal sensitivity

Therapeutic Index

Relative measure of the toxicity or safety of a drug The ratio of the median toxic dose to the median

effective dose

Median toxic dose Dose at which 50% of the patients experience a

specific toxic effect

Median effective dose Dose at which 50% of the patients have a specifies

therapeutic effect.

Safety: Overdose

Safety is always a consideration in drug selection.

Most newer agents have a wide margin of safety

Clinicians must recognize that some medications can be used to commit suicide

In cases where suicide is suspected, medications should not be prescribed in large numbers.

Accidental ingestion by other members of the family should also be a safety consideration.

Patient-Related Factors

Diagnosis Poor diagnosis affects optimal drug

selection Misdiagnosis can worsen the symptoms

Past-treatment response Selection of specific drug according to the

patient’s history of drug response Compliance, therapeutic response, side

effectsI If a drug has previously been effected it should

be prescribed again.

Patient-Related Factors

Past-treatment response For unknown reasons some patients fail

to respond to a previously effective agent

Response in family members Drug responses tend to cluster in

families This might be an indicator of agent

effectiveness on the patient’s relatives.

Patient-Related Factors

Concurrent Medical or Psychiatric Disorder Obtain information about coexiting medical

disorders Some non-psychiatric disorders may mimic

psychiatric disorders. Patients with thyroid disease may appear

depressed Sleep apnea produces depression and

cognitive impairment Klein-Lever syndrome can mimic bipolar

disorder

Patient-Related Factors

Concurrent Medical or Psychiatric Disorder. Cont. Addiction or substance abuse (recreational

drugs or alcohol) can complicate or undermine psychotropic drug treatment

These substances can possess significant psychoactive properties and might even be the source of the patient’s symptoms

Informed Consent and Patient Education

Trust and motivation to comply with medication regimen are essential components of successful treatment.

Inform patients about Treatment options Possible side effects Unique benefits of each treatment

Always consider risk-benefit ratio Thoroughly explain to the patient the

reason for treatment choice

Informed Consent and Patient Education

Important to develop strong clinician/patient therapeutic alliance

Document discussion and drug selection No need for signed informed consent

Successful engagement of patient and family in the treatment plan influences the success of the treatment

Instruct patient’s relatives about the reasons for treatment as well as expected and potential risks.

Dosing, Duration and Monitoring Dosing Plasma concentrations of many psychotropics

can vary up to tenfold Optimal dose for individuals is ultimately

determined by trial and error Some drugs demonstrate a relation between

increase in dose and clinical response Dose –response curve Potency

Relative dose required to achieve certain effects

Dosing, Duration and Monitoring Dosing, cont.

Drugs must be used in effective dosages for sufficient periods

Inadequate dosing increases risk of side effects and no therapeutic benefits

Time dosing, based on plasma half life of drug Dosing of psychotropic drugs, based on

measurements of plasma concentrations rather than receptor occupancy in the brain

Psychotropic drugs should be used continuously Except: drugs for insomnia, acute agitantion,

and severe situational anxiety

Dosing, Duration and Monitoring Duration of treatment

Depends on multiple variables Nature of the disorder Durantion of symptoms Family history Patient’s tolerance Medication’s benefits

3 phases of treatment Initial therapeutic trial Continuation Maintenance phase

Dosing, Duration and Monitoring Frequency of Visits Visits should continue until optimal

response to treatment is achieved Frequency of follow-up or monitoring is

determined by clinical judgment Monitoring is important even in stable

patients 3 months reasonable interval, 6 months for

long standing treatment.

Laboratory Tests and Therapeutic Blood Monitoring

Based on clinical circumstances and drugs being used

Routing testing is not required for most commonly used psychotropic drugs

No currently available laboratory test can confirm the diagnosis of a mental disorder

Pretreatment tests are used to establish baseline values to rule out medical problems that could be causing psychiatric disorders

Treatment Outcomes The goal of Psychotropic treatment is to

eliminate all manifestations of the disorder, enabling the patient to regain the ability to function well and enjoy life as fully as before he or she became ill.

Response and Remission Remission

Preferred outcome of a treatment Less likely to experience a relapse or recurrence

Response 50% or greater decrease from baseline on a standard

rating scale

Treatment Outcomes Treatment Failure

Medication ineffectiveness should be anticipated as part of initial treatment plan

A next-step strategy should be in place at initiation of treatment

Treatment Outcomes

Repeated drug failures should prompt patient reassessment. Was original diagnosis correct? Are observed symptoms related to original

disorder? Are they adverse effects of treatment? Were drug dosage and length of treatment

appropriate? Did a pharmacokinetic or pharmacodynamic

interaction with another drug the patient was taking reduce the efficacy of the newly prescribed drug?

Did the patient take the drug as directed?

Treatment Outcomes Treatment Failure, cont.

Most common reason for treatment failure is intolerance of side effects

Absorption and metabolism of drugs can vary greatly among patients.

Treatment Outcomes

Treatment Resistance Some patients fail to respond to repeated trials

of medication.

Tolerance The need over time to use increased doses of a

drug to maintain a clinical effect

Treatment Outcomes

Sesitization Increased Sensitivity to a drug

The reverse of tolerance

Withdrawal Physiological adaptation to a drug with a

subsequent risk of withdrawal symptoms.

Combination of Drugs

Acording to the American Psychiatric Association (APA) Avoid, if possible, the use of multiple

psychotropics. Even so simultaneous use of multiple

psychotropics is commonplace Inpatient prescription

Average 3 simultaneous psychotropics Fixed combinations have also become common

More than one medication contained in a single tablet

Combination of Drugscont. One of the advantages of fixed

combinations is: Patient treatment compliance

A disadvantage of fixed combinations: Clinician has less flexibilitiy in adjusting

dosages

Special Populations

Children ADHD and OCD are the only two disorders for

which there are drugs labeled for pediatric use Commonly used psychotropics have no

labeling for pediatrics Evidence of effectiveness of psychotropics on

children are mostly based on clinical findings rather than large clinical trials.

Higher metabolic rates in children may suggest higher doses than for adults.

It is always best to start with lower dosages and adjust as needed.

Special Populations

Pregnant and Nursing Women No assurances of risk free drugs administered

during pregnancy or lactation No psychotropic drug is absolutely

contraindicated during pregnancy Except those with known risks of birth defects,

premature births or neonatal complications. Paroxetine- Risk of cardiac malformations Lithium- Ebstein’s anomaly Carbamazepine & Valproic acid: neural tube

deffects Lamotrigine: Oral-Clefts

Special Populations Pregnant and Nursing Women

Administration of psychotropics on or near to delivery can cause oversedation in the newborn

Virtualy all psychotropics are secreted in milk No breast feeding recommended

Elderly Patients 2 concerns with elderly patients

1- increased succeptibility to adverse effects (cardiac)

Decreased metabolism, requiring dosage adjustment.

Special Populations Elderly Patients

Account for 1/3 of all prescription drug use High incidence of polypharmacy Nearly ½ of patients in long-term care facilities

are prescribed more than on psychotropic agent.

Psychotropics have been shown to be casually related to falls in patients Discontinuation reduces risk of falls about 40%

Psychotropic agents with possible adverse effects such as hypotension, cardiac conduction abnormalities, anticholinergic activity and respiratory depression should not be used

Special Populations

Medically Ill Patients Rule out medical disorder as a cause of the

psychiatric disorder Ex: neurological or endocrine disorders,

HIV/AIDS patients

Substance Abuse Discontinuation of substance abuse can

result in cravings and clinically significant psychological withdrawal symptoms

Placebos

For mild psychiatric disorders like mild to moderated depression and some anxiety, 30% of patients exhibit significant improvement or remission of symptoms on a placebo.