GENERAL PRINCIPLES OF PHARMACOLOGY

1. 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

2. 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

3. 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 NEURON PHYSIOLOGY

4. 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.

5. 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

6. 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 Neurotransmitter Systems

7. Serotonin Serotonin is linked to many brain functions due to the widespread serotonergic projections and the heterogeneity of the serotonergic receptors Examples 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

8. 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

9. 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

10. GENERAL PRINCIPLES OF PHARMACOLOGY Psychotropic Medication any 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

11. Classification of Psychoactive Drugs • Various ways of doing this By 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

12. 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

13. 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

14. 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

15. 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%

16. 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

17. 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

18. 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

19. Side Effects Behavioral Effects • Agitation and Restlessness • Sedation • Impaired memory • Hostility, Disinhibition, Aggression • Switch Mania • Sleep disturbances • Withdrawal Reactions

20. Side Effects Cardiovascular Effects • hypertensive reaction • orthostatic hypotension • cardiac conduction delays Endocrine and Metabolic Effects • hyperprolactinemia • hypothyroidism • nephrogenic diabetes insipidus • hypercalcemia • weight gain

21. Side Effects Hematologic Reactions • aplastic anemia • agranulocytosis • leukocytosis • eosinophilia • benign leukopenia • thrombocytopenia Hepatic effects • changes in liver functions

22. 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

23. 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

24. 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

25. Side Effects Monitoring Adverse Effects Rating scales • general purpose • side effect-specific scales General medication strategies to deal with side effects • Dosage reduction • Drug change • Adjunctive medication • Drug discontinuation

26. Medication 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.

27. MedicationManagement 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.

28. 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

29. 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

30. Role 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

31. Pharmacotherapy Commonly used classes of medications to treat psychiatric and behavior problems include: antipsychotics stimulants antidepressants antimanics anxiolytics antiepileptics selective norepinephrine reuptake inhibitors

32. Pharmacotherapy • Considerations include: indications effects on behavior side effects effects on learning dosing guidelines

33. Stimulants - 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

34. 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

35. 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

36. Stimulant Medications MPH-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

37. 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

38. Stimulants - 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)

39. Stimulants - 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

40. 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

41. 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

42. 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

43. 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 )

44. 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)

45. 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

46. 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

47. Long-Acting Stimulant Preparations

48. Ritalin® 20 mg BID Concerta® 54 mg Metadate® CD 60 mg (3 x 20 mg) Ritalin® LA 40 mg Comparison of Extended-release Methylphenidate Dosage Forms 20 15 Mean d,l-methylphenidate plasma levels (ng/mL) 10 5 0 5 10 15 0 Time (h) Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175-184. Data on file, Novartis Pharmaceuticals.

49. 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)

50. 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