Download general principles of pharmacology

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
widely distributed
cholinergic
serotonergic
noradrenergic
dopaminergic
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 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
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 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
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
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 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
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.
Medication 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 Psychopharmacology
The Challenge

individual differences in treatment response are
common

resistant cases are common -- treatmentresistance may be more common in youth

most of this variability is unexplained
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
Pharmacotherapy
Commonly used classes of medications
to treat psychiatric and behavior
problems include:
antipsychotics
stimulants
antidepressants
antimanics
anxiolytics
antiepileptics
selective norepinephrine reuptake inhibitors
Pharmacotherapy
 Considerations
include:
indications
effects on behavior
side effects
effects on learning
dosing guidelines
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

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 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
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 - 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 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
Concerta
5, 10, 15, 20, 25,
30 mg
Metadate CD
10, 20, 30 mg
Ritalin LA
10, 20, 30, 40 mg
Focalin XR
5, 10, 20 mg
Duration
OROS
30% IR
12 hours
70% next 8 hr
Microtrol two-bead
system
50%/50%
10 - 12 hours
Diffucaps
encapsulated beads
30%/70%
8 - 9 hours
SODAS biphasic
release beads
50%/50%
9 hours
SODAS biphasic
release beads
50%/50%
8 - 9 hours
18, 27, 36, 54 mg
Adderall XR
AM/PM
effect (%)
Comparison of Extended-release
Methylphenidate Dosage Forms
Mean d,l-methylphenidate
plasma levels (ng/mL)
20
Ritalin® 20 mg BID
Concerta® 54 mg
Metadate® CD 60 mg (3 x 20 mg)
15
Ritalin® LA 40 mg
10
5
0
0
5
10
Time (h)
Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175-184.
Data on file, Novartis Pharmaceuticals.
15
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 912 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 - 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 Antidepressants

Tricyclics
amitriptyline (Elavil)
imipramine (Tofranil)

Monoamine Oxidase Inhibitors (MAOIs)
phenelzine (Nardil)

tranylcypromine (Parnate)
Selective Serotonin Reuptake Inhibitors (SSRIs)
fluoxetine (Prozac)
paroxetine (Paxil)
citalopram (Celexa)

desipramine (Norpramin)
nortriptyline (Pamelor)
fluvoxamine (Luvox)
sertraline (Zoloft)
escitalopram (Lexapro)
Others
bupropion (Wellburtin)
venlafaxine (Effexor)
Mirtazapine (Remeron)
trazodone (Desyrel)
nefazodone (Serzone)
Tricyclic Antidepressants
Side 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 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 - 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)
Antipsychotics
 Traditional
antipsychotics
Low potency:
chlorpromazine (Thorazine)
thioridazine (Mellaril)
Intermediate potency:
loxapine (Loxitane)
High potency:
haloperidol (Haldol)
thiothixene (Navane)
Antipsychotics
 New
or Atypical Antipsychotics
clozapine (Clozaril)
risperidone (Risperdal)
olanzapine (Zyprexa)
quetiapine (Seroquel)
ziprasidone (Geodon)
aripiprazole (Abilify) - DOPAMINE PARTIAL
AGONIST
Antipsychotics - Side Effects
Traditional antipsychotics
dystonia
anticholinergic effects
akasthesia
sedation
confusion
tardive dyskinesia
endocrine disturbances
malignant neuroleptic syndrome
Atypical antipsychotics
Clozapine: risk of agranulocytosis
Antipsychotics - Side Effects
Extrapyramidal Sedation
Abilify
Weight
Gain
Anticholinergic
Risk for
Diabetes
+/-
+
+/-
+/-
-
+
++
++
+
?
Zyprexa
+/-
++
+++
++
+
Seroquel
+/-
++/+++
++
++
?
Geodon
++
++
+/-
+
-
Risperidal
Antimanics
 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 Effects
 sedation,
confusion
 electrolyte
imbalances
 gastrointestional
 renal
distress
dysfunction
Classes of Anxiolyics

Benzodiazepines
alprazolam (Xanax)
diazepam (Valium)
lorazepam (Ativan)

Antihistamines
diphenhydramine (Benadryl)
hydroxyzine (Atarax)

Atypical anxiolytics
buspirone (BuSpar)
Anxioltyics - 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 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
Antiepileptics
carbamazepine (Tegretol)
 Ethosuximide (Zarontin)
 sodium valproate (Depakote)
 oxcarbazepine (Trileptal)
 topiramate (Topamax)
 gabapentin (Neurontin)
 lamotrigine (Lamictal)

Antiepileptics - Indications
 seizure
control
 bipolar
disorder
 adjunct
treatment in major depressive
disorder
 severe
behavior problems
Antiepileptics - Side Effects
sedation
 behavioral disinhibition, overexcitement
 blood abnormalities
 anticholinergic effects

Alpha-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 Agonists
Clonidine (Catapres)
• most common side effect is sedation
• other side effects include:
hypotension
other cardiovascular effects
headache and dizziness
stomach ache, nausea, vomiting
• available in a skin patch
Alpha-Adrenergic Agonists
Guanfacine (Tenex)

much more binding specificity than
clonidine

most common side effects are:
lethargy (60%)
insomnia (30%)
headache (40%)
dizziness (20%)
Drug 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