GENERAL PRINCIPLES OF PHARMACOLOGY

Pharmacology is the study drug effects on living systems

Most drugs alter central nervous system function by acting at the level of the individual nerve cell

GENERAL PRINCIPLES OF PHARMACOLOGY

The human brain contains approximately 20 billion neurons, each of which may share up to 100,000 synapses (connections) with other neurons

Groups of neurons in the brain have specific functions. For example, some are involved with thinking, learning, and memory. Others are responsible for receiving sensory information. Still others communicate with muscles, stimulating them into action

NEURON PHYSIOLOGY

Each neuron has a cell body, an axon, and many dendrites

The cell body controls all of the cell's activities

The axon extends out from the cell body and transmits messages to other neurons

Dendrites also branch out from the cell body. They receive messages from the axons of other nerve cells

GENERAL PRINCIPLES OF PHARMACOLOGY

Modulation of neuronal activity via neurotransmitters (i.e., communication between neurotransmitters) is a fundamental mechanism of brain function

The release of neurotransmitters, their mechanisms of action and their effect on target neurons are complex and still poorly understood.

Mechanisms of Drug Action

Drug administration can facilitate or inhibit neurotransmitter systems in the brain in several ways:

By altering the synthesis of the neurotransmitter By interfering with the storage of the neurotransmitter By altering the release of the neurotransmitter By interfering with the inactivation of the

neurotransmitter (by enzymes or reuptake) By interacting with receptors

Neurotransmitter Systems

gultamatergic

GABAergic systems

cholinergic

serotonergic

noradrenergic

dopaminergic

widely distributed

densely packed in circumscribed areas of brain which project to their target areas - lead to more circumscribed effects

Serotonin

Serotonin is linked to many brain functions due to the widespread serotonergic projections and the heterogeneity of the serotonergic receptorsExamples include:

Modulation of serotonergic receptors and the reuptake site is beneficial in the treatment of anxiety, depression, OCD, and schizophrenia

Blockade of serotonin receptors in the area postrema decreases nausea and emesis

Hallucinogens, such as LSD, modulate serotonergic neurons via serotonergic autoreceptors

Norepinephrine

Noradrenergic neurotransmission has implications for several brain functions

Noradrenergic projections modulate sleep cycles, appetite, mood, and cognition. These functions are typically the targets of antidepressant drugs

Dopamine

Dopamine affects several brain functions primarily by modulation of other neurotransmitter systems

Decreased dopaminergic functioning leads to Parkinson=s disease and extrapyramidal side effects

Dopaminergic projections are involved in the development of addiction to drugs such as ethanol, cocaine, nicotine and opiates

GENERAL PRINCIPLES OF PHARMACOLOGY

Psychotropic Medicationany drug prescribed to stabilize or improve mood, mental status, or behavior

includes medications typically classified as antidepressants, antianxiety, etc.

includes other medications not typically classified as psychotropic when such medication is prescribed to improve or stabilize mood, mental status or behavior (e.g., carbamazepine is usually an antiepileptic medication but can be prescribed for affective disorders)

includes herbal or nutritional substances when such substances are used to stabilize or improve mood, mental status, or behavior

Classification of Psychoactive Drugs

Various ways of doing thisBy the chemical grouping of the drug (e.g.,

barbiturates)

By the action of the drug (e.g., stimulants, dopamine blockers)

By the therapeutic use (e.g., antidepressant, antipsychotic)

the most common classification scheme is by therapeutic use

Names of Drugs

Trade, Proprietary or Brand Name usually a Acatchy@ name to emphasize the main function

such as Oblivon7 for a sleeping pill trade names written with an initial uppercase letter and often

carry the superscript 7 for registered trade name

Generic name written with lowercase initial letter and the name is derived from

the chemical structure of the drug

Pharmacokinetics

The time course and effects of drugs and their metabolites on the body (what the drug does to the body)

absorption distribution biotransformation half-life steady-state concentration excretion

Pharmacokinetics

Absorption the process whereby drug molecules enter the bloodstream affected by the route of administration and the particulars of

manufacture, such as the thickness of pill coating, type of filler substance, hardness of tablet

Distribution the movement of drug molecules through the bloodstream to the

site of action protein-binding affects distribution. The ratio of protein-bound to

unbound remains constant, so as unbound molecules pass out of the bloodstream other molecules become unbound

Pharmacokinetics

Biotransformation

the changes in the structure of drug molecules characteristically produced by enzymatic action in the liver

most drugs are converted into inactive metabolites, but some are changed to an active form.

some drugs are not metabolized and pass from the body unchanged

Half-life determined by measuring the amount of time required for a

given blood level to decline by 50%

Pharmacokinetics

Steady State Concentration the concentration of the drug when the amount administered is

equal to the amount eliminated per unit time

Excretion the process responsible for the removal of drug molecules and

metabolites from the body, usually in the urine. some variables that influence the rate of elimination include

genotype, age, drug history, and liver or kidney disease

Drug Effects

when a drug is used therapeutically, the desired action is termed the therapeutic effect

the effects of all drugs are dose-dependent the amount of drug that is administered determines both

qualitative and quantitative aspects of its effects very low doses - no observable effects high enough doses - toxic reactions

Side Effects

any other action is a side effect side effects may be adverse, beneficial, or innocuous

adverse drug reactions include toxic effects due to overmedication common side effects that appear at therapeutic dosages idiosyncratic side effects (e.g., allergic reactions) that are

not clearly related to dose

side effects vary from mild to life-threatening

side effects may develop insidiously over a long period of time or may occur in an idiosyncratic and unpredictable fashion

Side Effects

Behavioral Effects

Agitation and Restlessness Sedation Impaired memory Hostility, Disinhibition, Aggression Switch Mania Sleep disturbances Withdrawal Reactions

Side Effects

Cardiovascular Effects hypertensive reaction orthostatic hypotension cardiac conduction delays

Endocrine and Metabolic Effects hyperprolactinemia hypothyroidism nephrogenic diabetes insipidus hypercalcemia weight gain

Side Effects

Hematologic Reactions aplastic anemia agranulocytosis leukocytosis eosinophilia benign leukopenia thrombocytopenia

Hepatic effects changes in liver functions

Side Effects

Reproductive and Adverse Sexual Effects changes in libido priapism impotence ejaculatory and orgasmic disturbances

Renal and Genitourinary System Effects polyuria incontinence and enuresis urinary retention renal failure

Side Effects

Immunologic and Gastrointestinal Effects

xerostomia dysphagia (may result in aspiration and asphyxiation) gastroesophageal reflux nausea, vomiting and GI discomfort constipation or abnormal distension diarrhea

Convulsive effects

Side Effects

Neuromuscular Effects

myoclonus nocturnal myoclonus action (inaction) tremor of upper extremities acute extrapyramidal symptoms (including dystonia,

neuroleptic-induced parkinsonism, bradykinesia, akinesia, tremor, and rigidity)

akathisia tardive symptoms neuroleptic malignant syndrome

Side Effects

Monitoring Adverse EffectsRating scales general purpose side effect-specific scales

General medication strategies to deal with side effects Dosage reduction Drug change Adjunctive medication Drug discontinuation

Medication ManagementMedication Management

3 STAGES BASELINE: collection of medical information and

behavioral observations for later comparison with treatment. TITRATION: experimental process of trying different doses

or types of medication and evaluating therapeutic response and side effects.

MAINTENANCE: periodic monitoring of the child’s functioning on the optimal dose selected during the titration stage. Adjustments in the dose or drug may be made in response to changes in functioning or side effects.

Medication ManagementMedication Management

TRIAL PROCEDURES

OPEN (NON-BLIND): all those involved with the trial, including the child, parents, teachers, and physician, are aware of the type and dose of medication being used.

PLACEBO-CONTROLLED (BLIND): active medication and inactive placebo are identically packaged and those involved are unaware of which is being administered.

Psychopharmacology for Childhood Behavioral and Developmental Disorders

Medication is widely recognized as a key treatment for serious psychopathology and behavior problems in children and adolescents

the use of medication in children has dramatically increased in the community

the use of these treatments has outstripped current efficacy and safety data

Child PsychopharmacologyThe Challenge

individual differences in treatment response are common

resistant cases are common -- treatment-resistance may be more common in youth

most of this variability is unexplained

Role of MedicationRole of Medication

Medication is a single component of a broad treatment plan

Medication is usually considered when behavior interventions have been unsuccessful or the behavior is presumed to be of organic origin

The use of medication increases as the number and severity of the individual’s behavior problems increase

Medications are often used to treat specific diagnoses as well as specific target symptoms

PharmacotherapyPharmacotherapy

Commonly used classes of medications to treat psychiatric and behavior problems include:

antipsychotics stimulants

antidepressants antimanics

anxiolytics antiepileptics

selective norepinephrine reuptake inhibitors

PharmacotherapyPharmacotherapy

Considerations include:

indications effects on behavior

side effects effects on learning

dosing guidelines

Stimulants - IndicationsStimulants - Indications

Attention Deficit Hyperactivity Disorder ADHD with comorbid disorders (including

mental retardation, Fragile X Syndrome, Tourette Disorder)

Hyperactivity in developmental disorders narcolepsy adjunctive treatment in refractory

depression

Stimulant Medications• Stimulant medications are the most studied,

most commonly used first-line agents for ADHD treatment

• Stimulant medications improve:• core symptoms: inattention, impulsivity, hyperactivity• associated symptoms: cognition, on-task behavior, academic

performance, social function, defiance, and aggression

• Good response in preschoolers, school-age children, adolescents and adults

Stimulant Medications• two primary classes of stimulants

• amphetamines and methylphenidate (MPH)

• for ADHD• response rate for any one particular stimulant is

approx. 70%• no predictors of response have been identified• all stimulants are generally of comparable efficacy• there is significant individual variability in response

to a particular stimulant

Stimulant MedicationsMPH-based and amphetamine-based

stimulants have different effects at the neurotransmitter level

• MPH inhibits the activity of the presynaptic dopamine transporter protein involved in the reuptake of dopamine from the synaptic cleft

• Amphetamines have a dual effect – blocks the reuptake of dopamine and norepinephrine through inhibition of the dopamine transporter protein and also causing retrograde release of catecholamines (dopamine and norepinephrine) through the transporter

Stimulant Medications

In the treatment of ADHD:

• If initial stimulant does not work at the highest feasible dose, then an alternate stimulant should be recommended

• Sub-optimal responders to a given stimulant may benefit from a trial with an alternate stimulant

Stimulants - PreparationsStimulants - Preparations

methylphenidate (Ritalin, Methylin, Metadate) long acting preparations: Ritalin-SR, Ritalin LA, Methylin-ER,

Metadate-ER, Metadate-CD, Concerta * Methylin comes in an liquid and chewable tablet form

dexmethylphenidate (Focalin) long acting preparation: Focalin XR

dextroamphetamine (Dexedrine, Dextrostat) long acting preparation: Dexedrine spansules

mixed amphetamine salts products (Adderall) long acting preparation: Adderall XR

pemoline (Cylert)

Stimulants - Side EffectsStimulants - Side Effects

• most side effects are transient and dose dependent• common side effects include: insomnia, decreased

appetite, mild increase in heart rate and BP, weight loss, headache, nausea

• rare side effects include: behavioral rebound, psychosis, anxiety or depression

• dexmethylphenidate (Focalin) may have fewer side effects than MPH

• pemoline: liver toxicity

Concerta• Oros delivery system• Immediate release of MPH in overcoat of the tablet

(22%) followed by progressive 8-hour release by an osmotic pump from 2 separate drug subcompartments (78%) with increasing concentration of medication in the afternoon

• Designed to mimic TID IR MPH with a 12 hour duration

• 18, 27, 36, and 54 mg tablets• 72 mg tablets may be available soon

Ritalin LA• biphasic release bead technology using SODAS

(spheroidal oral drug absorption system)• designed to mimic BID MPH• 50% immediate release / 50% delayed release• bimodal release profile has smoother peaks and

troughs compared to BID IR Ritalin• 10, 20, 30, and 40 mg capsules can be sprinkled• same side effect profile as IR Ritalin• designed for 9-hour duration of efficacy

Metadate CD• Biphasic bead technology (Diffucaps)• 30% immediate release / 70% delayed release

(20 mg capsule = 6 mg initial / 14 mg delayed release)

• dispensed as a 30-capsule dose pack (6 rows of 5 tablets)

• 10, 20 and 30 mg capsule • designed for 9 hour duration of action• Metadate ER is a “branded generic” version of

Ritalin SR with wax matrix tablet design

Adderall XR• Longer acting version of Adderall with

Microtrol two-bead delivery system• 50% immediate release and 50% delayed

release• designed to parallel 4-hr BID Adderall dosing

but duration of action may extend beyond 8 hours (10-12 hours)

• capsules can be sprinkled (6 dosing sizes available: 5, 10, 15, 20, 25, 30 mg capsules )

Focalin• newest stimulant preparation to be approved

by the FDA• dexmethylphenidate – d-isomer of MPH

• d-isomer is clinically active• l-isomer is rapidly metabolized and degraded after

oral administration and has little, if any, pharmacologic activity

• short acting immediate release formulation with approx. 5 hr duration of action

• reportedly “smoother” response than MPH with fewer side effects (esp. insomnia)

Focalin XR• long-acting preparation of

dexmethylphenidate recently approved by the FDA (May, 2005) for adults, adolescents, and children

• available in a capsule form with the SODAS technology

Methylphenidate Patch• transdermal patch designed to be applied once

daily• MPH not subject to first-pass metabolism in

the liver• dose can be altered by changing the size of the

patch• duration of action controlled by removing the

patch which stops delivery of the medication

Long-Acting Stimulant Preparations

Formulation AM/PM effect (%)

Duration

Concerta18, 27, 36, 54 mg

OROS 30% IR

70% next 8 hr

12 hours

Adderall XR5, 10, 15, 20, 25, 30 mg

Microtrol two-bead system

50%/50% 10 - 12 hours

Metadate CD 10, 20, 30 mg

Diffucaps encapsulated beads

30%/70% 8 - 9 hours

Ritalin LA10, 20, 30, 40 mg

SODAS biphasic release beads

50%/50% 9 hours

Focalin XR5, 10, 20 mg

SODAS biphasic release beads

50%/50% 8 - 9 hours

Ritalin® LA 40 mg

Metadate® CD 60 mg (3 x 20 mg)

Concerta® 54 mg

Time (h)

0 5 10 150

5

10

15

20

Mea

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)Comparison of Extended-release Methylphenidate Dosage Forms

Ritalin® 20 mg BID

Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175-184.

Data on file, Novartis Pharmaceuticals.

Selective Norepinephrine Reuptake Inhibitor

Atomoxetine (Strattera)Highly selective blockade of the presynaptic

norepinephrine transporter (relatively more plentiful in the prefrontal cortex than the striatum)

• Increased concentration of norepinephrine in the anterior and posterior brain attentional systems

• Downstream increase in dopamine in the prefrontal cortex• Does NOT increase the concentration of dopamine in the

nucleus accumbens (abuse potential) or striatum (tics)

Selective Norepinephrine Reuptake Inhibitor

Atomoxetine (Strattera)Safety data• diastolic BP and heart rate increase in a statistically but not

clinically significant manner• 20% with decreased appetite - weight decreased in first 9-

12 weeks of treatment, then begins to catch up and parallel growth curve

• no significant lab or EKG changes• no exacerbation of tics or anxiety• insomnia not a significant side effect*** need to watch for abnormal liver function*** black box warning – may increase suicidal thoughts

Selective Norepinephrine Reuptake Inhibitor

Atomoxetine (Strattera)

• Several studies showed that once daily dosing strategy similar to twice-daily dosing

• Atomoxetine associated with improved evening and early morning parent ratings – single daily dose

• Non-controlled substance• First non-stimulant, FDA approved medication for

treatment of ADHD in children, adolescents and adults (November, 2002)

• May take up to 2-4 weeks to see optimal benefit

Antidepressants - IndicationsAntidepressants - Indications

major depressive disorder enuresis ADHD anxiety disorders (e.g., school phobia, separation

anxiety, panic disorder, and obsessive-compulsive disorder)

sleep disorders (night terrors) some cases of self-injury in individuals with

developmental disabilities

Classes of AntidepressantsClasses of Antidepressants Tricyclics

amitriptyline (Elavil) desipramine (Norpramin)

imipramine (Tofranil) nortriptyline (Pamelor)

Monoamine Oxidase Inhibitors (MAOIs)phenelzine (Nardil) tranylcypromine (Parnate)

Selective Serotonin Reuptake Inhibitors (SSRIs)fluoxetine (Prozac) fluvoxamine (Luvox)

paroxetine (Paxil) sertraline (Zoloft)

citalopram (Celexa) escitalopram (Lexapro)

Others bupropion (Wellburtin) trazodone (Desyrel)

venlafaxine (Effexor) nefazodone (Serzone)

Mirtazapine (Remeron)

Tricyclic AntidepressantsSide Effects

Tricyclic AntidepressantsSide Effects

Common: dry mouth, constipation, blurred vision, weight gain, sedation, mild liver and blood count changes

Rare: arrhythmias or tachycardia, induction of psychosis or mania

** SLOWING OF CARDIAC CONDUCTION

(baseline and maintenance EKG monitoring is required) Contraindicated in patients with cardiac conduction

disturbances Sudden discontinuation of the medication may result in flu-

like symptoms, an increase in behavioral problems or insomnia

Antidepressants - Side EffectsAntidepressants - Side Effects MAOIs: changes in blood pressure, weight gain, need to

follow dietary restrictions SSRIs: irritability, headaches, insomnia, nervousness,

drowsiness or fatigue, anorexia, nausea, or diarrhea(safer side effect profile, especially reduced risks of cardiotoxicity and lethality of overdose, compared to tricyclics)

bupropion: irritability, insomnia, drug induced seizures (with high doses)

trazodone: changes in blood pressure, sexual dysfunction

** recent concerns regarding antidepressants and increased risk for suicidal ideation in children/adolescents

Antipsychotics - IndicationsAntipsychotics - Indications

psychotic disorders

schizophrenia (exacerbations and maintenance)

mania (in conjunction with a mood stabilizer)

behavior disorders with severe agitation, aggressivity, and self-injury

dyskinetic movement disorders (e.g., Tourette disorder)

AntipsychoticsAntipsychotics

Traditional antipsychotics

Low potency: chlorpromazine (Thorazine)

thioridazine (Mellaril)

Intermediate potency: loxapine (Loxitane)

High potency: haloperidol (Haldol)

thiothixene (Navane)

AntipsychoticsAntipsychotics

New or Atypical Antipsychotics

clozapine (Clozaril)risperidone (Risperdal)olanzapine (Zyprexa)quetiapine (Seroquel)ziprasidone (Geodon)aripiprazole (Abilify) - DOPAMINE PARTIAL

AGONIST

Antipsychotics - Side EffectsAntipsychotics - Side Effects

Traditional antipsychoticsdystonia anticholinergic effects

akasthesia tardive dyskinesia

sedation endocrine disturbances

confusion malignant neuroleptic syndrome

Atypical antipsychoticsClozapine: risk of agranulocytosis

Antipsychotics - Side Effects

Extrapyramidal Sedation Weight

Gain

Anticholinergic Risk for Diabetes

Abilify +/- + +/- +/- -

Risperidal + ++ ++ + ?

Zyprexa +/- ++ +++ ++ +

Seroquel +/- ++/+++ ++ ++ ?

Geodon ++ ++ +/- + -

AntimanicsAntimanics

lithium carbonate (Lithobid, Eskalith) indications:

manic episodes of bipolar disorder unipolar depression/adjunct treatment

in major depressive disorder behavior disorders with extreme

agitation or aggression

Antimanics - Side EffectsAntimanics - Side Effects

sedation, confusion

electrolyte imbalances

gastrointestional distress

renal dysfunction

Classes of AnxiolyicsClasses of Anxiolyics

Benzodiazepinesalprazolam (Xanax)

diazepam (Valium)

lorazepam (Ativan)

Antihistamines diphenhydramine (Benadryl)

hydroxyzine (Atarax)

Atypical anxiolytics buspirone (BuSpar)

Anxioltyics - IndicationsAnxioltyics - Indications

anxiety disorders seizure control night terrors and sleepwalking acute management of severe agitation adjunct treatment in mania and refractory

psychosis Tourette disorder

Anxioltyics - Side EffectsAnxioltyics - Side Effects headache sedation and decreased cognitive performance behavior disinhibition gastrointestinal distress physical and psychological dependence (long-acting

benzodiazepines) rebound or withdrawal reactions (short-acting

benzodiazepines) blood abnormalities anticholinergic effects

AntiepilepticsAntiepileptics

carbamazepine (Tegretol) Ethosuximide (Zarontin) sodium valproate (Depakote) oxcarbazepine (Trileptal) topiramate (Topamax) gabapentin (Neurontin) lamotrigine (Lamictal)

Antiepileptics - IndicationsAntiepileptics - Indications

seizure control

bipolar disorder

adjunct treatment in major depressive disorder

severe behavior problems

Antiepileptics - Side EffectsAntiepileptics - Side Effects

sedation behavioral disinhibition, overexcitement blood abnormalities anticholinergic effects

Alpha-Adrenergic AgonistsAlpha-Adrenergic Agonists

These centrally acting antihypertensive agents have more recently been reported as alternative or adjunctive treatments for: ADHD Tourette disorder behavior disorders with severe agitation,

self-injury, or aggression adjunctive treatment of schizophrenia and

mania

Alpha-Adrenergic AgonistsAlpha-Adrenergic Agonists

Clonidine (Catapres)

• most common side effect is sedation• other side effects include:

hypotensionother cardiovascular effectsheadache and dizzinessstomach ache, nausea, vomiting

• available in a skin patch

Alpha-Adrenergic AgonistsAlpha-Adrenergic Agonists

Guanfacine (Tenex)

much more binding specificity than clonidine

most common side effects are:

lethargy (60%) insomnia (30%)

headache (40%) dizziness (20%)

Drug CombinationsDrug Combinations

although it is not uncommon in clinical practice, there are few reports in the literature concerning the simultaneous use of more than one medication

usually considered in

treatment-resistant patients

patients with comorbid diagnoses use of two different medications may permit lower doses

of each and decrease the potential for side effects further research is needed evaluating the overall safety

and efficacy of various drug combinations