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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.

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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 pharmacology1
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

NEURON PHYSIOLOGY
general principles of pharmacology2
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
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

Neurotransmitter Systems
serotonin
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
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

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 pharmacology3
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
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
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
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
pharmacokinetics1
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
pharmacokinetics2
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%
pharmacokinetics3
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
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
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 effects1
Side Effects

Behavioral Effects

  • Agitation and Restlessness
  • Sedation
  • Impaired memory
  • Hostility, Disinhibition, Aggression
  • Switch Mania
  • Sleep disturbances
  • Withdrawal Reactions
side effects2
Side Effects

Cardiovascular Effects

  • hypertensive reaction
  • orthostatic hypotension
  • cardiac conduction delays

Endocrine and Metabolic Effects

  • hyperprolactinemia
  • hypothyroidism
  • nephrogenic diabetes insipidus
  • hypercalcemia
  • weight gain
side effects3
Side Effects

Hematologic Reactions

  • aplastic anemia
  • agranulocytosis
  • leukocytosis
  • eosinophilia
  • benign leukopenia
  • thrombocytopenia

Hepatic effects

  • changes in liver functions
side effects4
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 effects5
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 effects6
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 effects7
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
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 management1
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.
psychopharmacology for childhood behavioral and developmental disorders
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
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 medication
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
Pharmacotherapy

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

antipsychotics stimulants

antidepressants antimanics

anxiolytics antiepileptics

selective norepinephrine reuptake inhibitors

pharmacotherapy1
Pharmacotherapy
  • Considerations include:

indications effects on behavior

side effects effects on learning

dosing guidelines

stimulants indications
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
  • 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 medications1
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 medications2
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 medications3
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
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
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
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
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
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
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
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
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
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
comparison of extended release methylphenidate dosage forms

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.

selective norepinephrine reuptake inhibitor
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 inhibitor1
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 inhibitor2
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
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
Classes 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 antidepressants side effects
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
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
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
Antipsychotics
  • Traditional antipsychotics

Low potency: chlorpromazine (Thorazine)

thioridazine (Mellaril)

Intermediate potency: loxapine (Loxitane)

High potency: haloperidol (Haldol)

thiothixene (Navane)

antipsychotics1
Antipsychotics
  • New or Atypical Antipsychotics

clozapine (Clozaril)

risperidone (Risperdal)

olanzapine (Zyprexa)

quetiapine (Seroquel)

ziprasidone (Geodon)

aripiprazole (Abilify) - DOPAMINE PARTIAL AGONIST

antipsychotics side effects
Antipsychotics - Side Effects

Traditional antipsychotics

dystonia anticholinergic effects

akasthesia tardive dyskinesia

sedation endocrine disturbances

confusion malignant neuroleptic syndrome

Atypical antipsychotics

Clozapine: risk of agranulocytosis

antimanics
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
Antimanics - Side Effects
  • sedation, confusion
  • electrolyte imbalances
  • gastrointestional distress
  • renal dysfunction
classes of anxiolyics
Classes of Anxiolyics
  • Benzodiazepines

alprazolam (Xanax)

diazepam (Valium)

lorazepam (Ativan)

  • Antihistamines

diphenhydramine (Benadryl)

hydroxyzine (Atarax)

  • Atypical anxiolytics

buspirone (BuSpar)

anxioltyics indications
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
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
Antiepileptics
  • carbamazepine (Tegretol)
  • Ethosuximide (Zarontin)
  • sodium valproate (Depakote)
  • oxcarbazepine (Trileptal)
  • topiramate (Topamax)
  • gabapentin (Neurontin)
  • lamotrigine (Lamictal)
antiepileptics indications
Antiepileptics - Indications
  • seizure control
  • bipolar disorder
  • adjunct treatment in major depressive disorder
  • severe behavior problems
antiepileptics side effects
Antiepileptics - Side Effects
  • sedation
  • behavioral disinhibition, overexcitement
  • blood abnormalities
  • anticholinergic effects
alpha adrenergic agonists
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 agonists1
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 agonists2
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
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