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DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM (21)
Subcommittee:
William Martin (Kentucky) (Chairman)
Richard Eisenberg (Minnesota, Duluth)
Thomas Westfall (St. Louis Univ.)
Ezio Giacobini (Southern Illinois)
Harbans Lal (Texas Coll. Osteopathy)
Seymour Ehrenpreis (Chicago Med. School)
Warren Chernick (Hahnemann Med. School)
Joseph Goldfard (Mt. Sinai Med. School)
Louis S. Harris (Med. Coll. of Virginia)
Israel Hanin (Loyola University)
Claudio Cuello (McGill University)
Introduction to Neuropharmacology
Understanding of central nervous system pharmacology depends
upon prerequisite knowledge of neurochemistry, the physiology of
sleep and of pain and its modulation, psychopathology (neurosis,
psychosis, and affective disorders), and neuropathology. In many
medical schools, the pharmacology course is scheduled before some
or all of these prerequisites are achieved. In such instances,
the discussion of many centrally acting drugs in the pharmacology
course must be prefaced with the appropriate neurochemistry,
psychiatry, or neurology. Taking this into account, a core
curriculum in CNS pharmacology might require from 20 to 25 hours.
1. Neurotransmitters, receptors and neurochemistry (1.5)
A. Concepts
1) Anatomic pathway
2) Function
3) Cotransmitter
B. Classes
1) Acetylcholine (Ach)
2) Indoles (5HT)
3) Catechols (E, NE, DA)
4) Amino acids
a. Excitatory (glutamate and aspartate)
b. Inhibitory (GABA and glycerine)
5) Histamine
6) Peptides (Substance P, endorphins, enkephalins
and dynorphins, and other peptides - if not
covered with narcotic analgesics)
7) Purines (Adenosine, adenosine triphosphate)
2. General Anesthetics (2)
1) Define the terms "minimum alveolar concentration
(MAC)", "general anesthetics", "neurolept analgesia",
"dissociative anesthesia", and "epidural and
intrathecal opioid analgesia".
2) State the objectives of general anesthesia.
3) State the physical characteristics of inhalational
anesthetics which determine the rate of achievement of
equilibrium for a given partial pressure in repaired
air for alveoli e.g. brain tissues and other. Define
Ostwalds coefficients.
4) List the current theories of the mechanism of action of
general anesthetics.
5) List the methods by which inhalational anesthetics are
administered and factors that must be taken into
account when drugs are administered by inhalation.
6) Compare the inhalational anesthetics with respect to
their general properties, effects on various organ
systems, biostrasformation, disadvantages and
advantages.
7) Describe the mechanism by which intravenous induction
anesthetics produce anesthesia of rapid onset and short
duration.
8) Recognize or describe clinical conditions which render
general anesthesia more hazardous than other methods of
preparing the patient for surgery.
9) Compare various i.v. induction agents, compare toxicity
of anesthetics, recognize malignant hyperthermia and
know how to treat it.
10) Explanation of second gas effect and diffusional
hypoxia.
11) List the classes of drugs used as (a) pre-anesthetic
medications and (b) anesthetic adjuvants, and explain
their useful actions and their hazards. Discusstoxic
effects of pre-anesthetic medications (e.g. Midazolam).
Drugs to be considered:
ATROPINE
DANTROLENE
DIAZEPAN
EUFLURANE
PENTOBARBITAL
FENTANYL
HALOTHANE
ISOFLURANE
KETAMINE
MORPHINE
NITROUS OXIDE (N20)
PENTOBARBITAL
SUCCINYLCHOLINE
SUFENTANIL
THIOPENTAL
3. Local Anesthetics (1)
1) Mechanism of action. List the pharmacologic, chemical
and physiologic influence that determine the activity
of local anesthetics.
2) List the factors that influence the sensitivity of
different nerves to local anesthetics.
3) Describe the metabolism of amide and ester local
anesthetics.
4) List common toxic effects. What drugs are used to
treat the adverse effects of local anesthetics?
5) List routes of administration of local anesthetics.
6) What are the advantages of administering epinephrine
with local anesthetics?
7) What drugs are used to treat the adverse cardiovascular
and CNS effects of local anesthetics?
Drugs to be considered:
BENZOCAINE
COCAINE
LIDOCAINE
BUPIVACAINE
PROCAINE
4. Opioid analgesics, Agonist-antagonists, Antitussives and
Expectorants (3.0)
A. Narcotic Analgesics (2.0)
1) Describe the pharmacologic responses associated
with the stimulation of the various opioid
receptor subtypes, e.g., Mu, Kappa, Delta, etc.
2) Know which analgesics are partial agonists; their
advantages and disadvantages.
3) Describe characteristics of endorphins,
enkephalins, dynorphin, and substance P.
4) Describe the types of pain, pain pathways and
distribution of opioid receptors.
5) Describe mechanisms and sites of action of opioid
analgesics.
6) Describe the structure-activity relationships of
morphine, morphine surrogates and morphine
antagonists.
7) Know the pharmacologic actions of morphine on the
following systems:
a) CNS
b) Cardiovascular
c) G.I. tract
d) Biliary
e) Bronchi
f) Genitourinary
8) Contrast the analgesic effects of morphine with
those of the nonsteroidal antiinflammatory drugs.
9) List the sensory modalities that are not affected
by morphine.
10) Discuss drug dependence to morphine, e.g.,
tolerance and withdrawal to morphine.
11) List the contraindications for morphine and its
surrogates.
12) List the signs and symptoms of morphine (also
heroin) overdose and its management.
13) Describe tests for diagnosing acute and chronic
opioid intoxications.
14) Discuss the rationale of using mixtures of opioid
analgesics and NSAI drugs.
15) Indicate important drug interactions of morphine
and other narcotic analgesics with other types of
drugs.
16) State the means by which narcotics are
eliminated.
17) Describe the distribution of narcotics in the
body, including their ability to cross the
placenta.
18) Explain the rationale behind the use of methadone
to treat narcotic dependence.
19) Indicate the abuse liability of the different
narcotics.
20) State the reasons for caution in the use of
narcotics in patients suffering from cor
pulmonale.
21) Increase analgesic effectiveness of morphine and
meperidine due to elevated levels of unbound drug
in plasma.
Drugs to be considered:
CODEINE
D-PROPOXYPHENE
FENTANYL
DIPHENOXYLATE
HEROIN
MEPERIDINE
METHADONE
MORPHINE
B. Narcotic Agonist-Antagonists (0.5)
1) Describe the principle of relative potency and
know how to calculate equivalent doses.
2) Describe the principle of receptor dualism.
3) Describe the principle of competitive antagonism
as it applies to precipitated abstinence
syndrome.
4) Indicate the therapeutic use of opioid
antagonists.
5) Compare PENTAZOCINE, MORPHINE and NALOXONE.
Compare in respect to effect in elderly, e.g.
PENTAZOCINE is more likely to produce mental
confusion.
Drugs to be considered:
Agonists/Antagonists
BUTORPHANOL
NALBUPHINE
BUPRENORPHINE
Specific Antagonists
NALOXONE
NALTREXONE
PENTAZOCINE
C. Antitussives, Expectorants and Mucolytics (0.5)
1) Review cough reflex and cites of action of
antitussive drugs.
2) Discuss mechanism of action of antitussive drugs.
Drugs to be considered:
acetylcysteine
AMMONIUM CHLORIDE
Codeine
DEXTROMETHORPHAN
HYDROCODONE (dihydrocodeine)
GUAIFENESIN
POTASSIUM IODIDE
5. Drugs used in the treatment of motor disorders (1)
1) Describe the neural control of motor function
(pyramidal, extrapyramidal and cerebellar).
2) Discuss dysfunction of the basal ganglia and
Parkinson's disease. Discuss the influence of age on
dopaminergic receptors. Discuss drugs which can induce
Parkinson's disease.
3) Describe pathophysiology of Parkinson's disease.
4) Discuss the use of levodopa (pharmacological actions,
side effects, contraindications).
5) Describe the useful drug interactions in treating
Parkinson's Disease (diphenhydramine, amantadine,
bromocriptine).
6) Describe Huntinton's chorea and reciprocal relation to
Parkinsonism.
7) Describe the metabolism of levodopa and the use of
decarboxylase and MAO inhibitors in treating or
delaying the progression of Parkinson's disease.
8) Describe the mechanism of action of levodopa,
anticholinergics, and antihistaminics in relieving the
signs of parkinson's disease. compare the effects of
tremor and akinesia.
9) Describe the interaction of levodopa with
sympathomimetics, anticholinergics and amantadine.
10) Describe the interactions of anticholinergics with
phenothiazines.
Drugs to be considered:
AMANTADINE
BENZTROPINE
BROMOCRIPTINE
CARBIDOPA
DEPRENYL
DOPAMINE
LEVODOPA (1 DOPA)
TRIHEXYPHENIDYL
6. Antiepileptics (1 hr.)
1) Discussion of epilepsy (pathophysiology of a seizure,
incidence, etiology, and types of seizures).
2) Describe for each antiepileptic drug the interval
between time of administration and the onset of
pharmacological effects.
3) What are mirror foci, kindling, post-tetanic
potentiation and long term potentiation?
4) State the duration of action of each antiepileptic drug
and the means by which their pharmacological effects
are terminated.
5) Explain the influence of drug dosage on the rate of
elimination of phenytoin.
6) List the types of epilepsy and seizures for which each
drug is used.
7) Describe the mechanisms, where known, by which each
drug works as an antiepileptic and mechanisms where by
neuronal excitability can be enhanced and diminished.
8) List the types of drugs which may increase or decrease
the metabolism of phenytoin.
9) Describe the possible effects of chronic phenobarbital
administration on drug metabolism.
10) Explain the use to which serum drug levels may be put
to assist in adjusting the doses of some
antiepileptics.
11) Explain why multiple antiepileptics are used.
12) List the major toxicologic and teratologic effects of
the prototypical anticonvulsants.
13) Describe "status epilepticus"; its dangers and its
treatment.
Drugs to be considered:
acetazolamide
CARBAMAZEPINE
clonazepam
DIAZEPAM
ETHOSUXIMIDE
PHENOBARBITAL
PHENYTIN
PRIMIDONE
VALPROIC ACID
7. Hallucinogens (1 hr.)
1) Describe the mechanisms and sites of action, tolerance,
pharmacokinetics, effects on organ systems of the
different types of hallucinogens.
2) Discuss the social use and abuse of hallucinogens.
Drugs to be considered:
BELLADONNA ALKALOID (ATROPINE, scopolamine)
MARIHUANA
LYSERGIC ACID DIETHYLAMIDE (LSD)
MESCALINE
PHENCYCLIDINE
Drugs used in the treatment of psychiatric disorders
8. Antidepressants and Lithium (1 hr.)
1) Describe the concept of affect and how it can be
altered by drugs.
2) Give a description of affective disorders (unipolar and
bipolar depression, phobic and schizoaffective
disorders).
3) Describe the time course of response after initiation
of therapy with tricyclic antidepressants.
4) Describe the importance of metabolism to the
elimination of tricyclic antidepressants, and to the
formation of active metabolites for some agents. Learn
the influence of age on the formation of these
metabolites.
5) Describe the effect of tricyclic antidepressants on CNS
neurotransmitter systems including effects on
neurotransmitter receptors, receptor binding activity
and receptor regulation.
6) Explain the side effects and toxic effects of tricyclic
antidepressants on the basis of autonomic actions.
7) Describe the direct toxic manifestations of tricyclic
antidepressants on the CNS and myocardium with special
emphasis on the influence of old age.
8) Explain the principles of management of tricyclic
antidepressant overdose using a pharmacological
antidote and plasma pH adjustment.
9) Describe the interactions of tricyclic antidepressants
and monoamine oxidase inhibitors with CNS depressants,
sympathomimetic amines, and food stuffs.
10) Describe the time course for clinical response after
initiation of therapy for depression with MAO
inhibitors.
11) Describe the effect of MAO inhibitors on cellular
levels of 5-HT and catecholamines.
12) Describe the manifestations of overdose with MAO
inhibitors and the principles of overdose treatment.
13) Describe the chronic toxicities of MAO inhibitors
involving the liver, brain and cardiovascular system.
14) Describe and explain the interactions of MAO inhibitors
with biogenic amines and substances which release
biogenic amines.
Treatment of Mania - Lithium Carbonate
15) Describe the effects of lithium on CNS neurotransmitter
systems.
16) Describe the effects of decreased sodium intake or
diuretic drugs on the response to lithium.
17) Explain why there is a contraindication to the use of
lithium in patients with impaired renal function or
cardiovascular disease.
18) Discuss the value of plasma lithium determination in
assessing adequacy of dosage with lithium.
19) Describe the toxic effects of lithium and contrast its
acute and chronic toxicities.
20) What are the therapeutic indications for lithium?
Drugs to be considered:
AMITRIPTYLINE
DOXEPIN
IMIPRAMINE
PHENELZINE
TRANYLCYPROMINE
FLUOXETINE
LITHIUM CARBONATE
NORTRIPTYLINE
9. Antipsychotics (neuroleptics) (2 hrs.)
1) Discuss schizophrenia (epidemiology, symptoms,
etiology, biochemistry).
2) Indicate possible mechanisms of action of antipsychotic
drugs.
3) Review the major dopamine pathways and action and
effects of the antipsychotic agents phenothiazines,
butyrophenones.
4) List the acute and long-term effects of neuroleptics on
dopamine receptors.
5) List the pharmacological properties of antipsychotic
drugs.
6) Explain the effect of active metabolites of some
phenothiazines on the effective half-life of the parent
compound administered. Describe the effects of aging
on the metabolism of phenothiazines.
7) Explain the effect of hepatic microsomal enzyme
induction by phenothiazines on the steady-state plasma
concentration after prolonged administration.
8) Describe the behavioral effects of antipsychotic drugs
which are generally referred to as the neuroleptic
syndrome.
9) Describe the biochemical mechanism which may explain
the action of antipsychotic drugs at different levels
of the CNS.
10) Describe the clinical manifestations which may be seen
in patients treated with antipsychotic drugs and
explain these on the basis of the probable biochemical
mechanisms operating at different levels of CNS and
autonomic function.
11) Describe the endocrine and cardiovascular changes which
may be produced by antipsychotic drug therapy.
12) Describe the hypersensitivity reactions to
phenothiazines which may affect the liver, blood
elements and skin.
13) What is tardive dyskinesia; what drug produces it?
14) What is the neuroleptic malignant syndrome? How is it
treated?
Drugs to be considered:
CHLORPROMAZINE
HALOPERIDOL
PIMOZIDE
THIORIDAZINE
clozapine
10. Sedative-Hypnotics; Muscle Relaxants (1 hr)
1) List and describe the stages of sleep.
2) Discuss the pathophysiological basis of rigidity,
spasticity, muscle spasm (if not previously
discussed under motor dysfunction)
A. Barbiturates
3) Discuss the relationship between the chemical
structure of barbiturates and their
pharmacokinetics (absorption, distribution,
biotransformation, elimination).
4) Describe the actions of the barbiturates on the
CNS, (including tolerance), respiration,
cardiovascular system, kidney, and liver.
5) Discuss the consequences of barbiturate induction
of enzymes, specifically on aminolevulinic acid
synthetase (porphyria).
6) Give the clinical indications for the use of
barbiturates; discuss adverse reactions of
elderly persons to barbiturates (confusion,
restlessness, etc.)
7) Describe the interactions of barbiturates with
other CNS agents and their effects on the
metabolism of other drugs.
8) Describe the effects of ionization and lipid
solubility on tissue distribution and duration of
action of barbiturates.
9) Classify the clinically useful barbiturates
according to duration of action.
10) Describe the effects of altering urinary pH on
the rate of phenobarbital elimination.
11) Describe the effects of barbiturates on REM
sleep.
12) Describe acute barbiturate intoxication and its
treatment.
13) Indicate the effects of combining barbiturates
with alcohol and other CNS depressants on CNS
function.
14) Discuss the therapeutic ratio of barbiturates.
15) Describe the symptoms of barbiturate withdrawal
in a barbiturate dependent subject.
Drugs to be considered:
PHENOBARBITAL
PENTOBARBITAL
THIOPENTAL (if not previously discussed)
B. Non-barbiturate sedatives and hypnotics and central
skeletal muscle relaxants
1) Describe the mechanisms of elimination and the
effectiveness of hemodialysis as a means of
increasing the rate of elimination.
2) Describe the harmful effects which may ensue from
the use of sedative agents for the symptomatic
treatment of chronic anxiety stress.
3) List the signs of overdose of non-barbiturate
sedatives.
4) Describe the use of sedative hypnotics as adjunct
to anesthesia and their toxicity (e.g.
temazepan).
5) Compare the actions and toxicity of barbiturates
and benzodiazepines as sedative hypnotics.
Drugs to be considered:
chlorzoxazone
cyclobenzaprine
FLURAZEPAM
orphenadrine
TEMAZEPAM
CHLORAL HYDRATE
TRIAZOLAM
baclofen
11. Amphetamines, anorexigenic and analeptics (0.5)
1) Describe the metabolism and excretion of this group of
drugs and the effect of Ph.
2) Summarize the site and mechanism of action of
amphetamines.
3) Compare mode of action of amphetamine and fenfluramine.
4) List the toxic effects of amphetamines.
5) Give the therapeutic indications for amphetamines and
their efficacy in the treatment of narcolepsy,
attention deficit disorders and obesity.
6) Describe the mechanism of action of xanthines on the
CNS.
Drugs to be considered:
AMPHETAMINE
CAFFEINE
COCAINE
fenfluramine
EPHEDRINE
METHYLPHENIDATE
picrotoxin-emphasizes role of glycinergic transmission
strychnine
12. Benzodiazepines (anxiolytics, hypnotics and muscle relaxants
(2 hrs).
1) Describe the effects and mechanisms by which anxiolytic
agents exert their effects.
2) Compare the dependence liability, toxicity, side
effects, and therapeutic actions of benzodiazepines
with the barbiturates and non-barbiturate sedative
hypnotics.
3) What is the mechanism of action of benzodiazepines
(receptor types)?
4) Describe the interactions of the benzodiazepines with
other CNS depressants.
5) Describe the mechanism of action of flumazenil and its
uses.
6) Describe metabolic and distribution factors which may
effect the action of benzodiazepines including the
effect of old age.
7) Describe the pharmacology of buspirone and compare it
with the pharmacology of diazepam.
Drugs to be considered:
ALPRAZOLAM
chlorazepate
CHLORDIAZEPROXIDE
buspirone
DIAZEPAM
FLURAZEPAM
LORAZEPAM
TRIAZOLAM
TEMAZEPAM
13. Ethanol - alcoholism (1 hr).
1) Summarize the therapeutic applications of ethanol.
2) List the effects of ethanol on organs of the body.
3) Describe the relationship of ethanol to vasopressin
release.
4) Describe the pharmacokinetics of ethanol (distribution
including blood levels and legal limits, elimination,
and metabolism).
5) Describe the inhibition of ethanol metabolism by
disulfiram and its therapeutic implications.
6) Discuss the social aspects of ethanol abuse.
7) Describe the fetal alcohol syndrome.
8) List procedures used in treating acute and chronic
alcohol intoxication.
9) Summarize ethanol - drug interactions.
10) Discuss methanol (its source, chemistry, and
elimination).
11) Describe methanol and ethylene glycol toxicology and
their treatment with ethanol (explain the rationale).
12) Describe the elimination kinetics of the aliphatic
alcohols as a function of a saturable catabolic enzyme
system.
13) List the products of methanol and ethylene glycol
catabolism.
14) Discuss the value if dialysis in the treatment of
methanol and ethylene glycol intoxication.
15) Give the common effect of all aliphatic alcohols on CNS
function.
16) Describe the manifestations of ethanol intoxication on
the CNS depressants.
17) Describe the toxic effects and effect on lipid
metabolism associated with chronic excessive ethanol
ingestion.
18) Describe the effects on the body of methanol and
ethylene glycol intoxication.
19) List signs and symptoms of the ethanol abstinence
syndrome.
Drugs to be considered:
DISULFIRAM (ANTABUSE)
ETHANOL
METHANOL
ethylene glycol
14. Drug dependence (1.5)
1) Define and describe physical dependence and tolerance
on drugs.
2) Discuss the economic - social issues of drug
dependence.
3) Describe the personality characteristics of an
individual susceptible to drug dependence.
4) Describe the clinical characteristics of drug
dependence.
5) Describe the withdrawal and detoxification techniques
for different drugs of abuse.
6) Review the mortality and morbidity of dependence to
various drugs.
7) Define and describe physiological dependence.
8) Compare dependence on and associate abstinence signs of
opioids, CNS depressants and stimulants.
Drugs to be considered:
ETHANOL
COCAINE
MARIHUANA
HEROIN
PENTOBARBITAL
AMPHETAMINES
DIAZEPAM
LSD
15. Drugs and the law (1 hr).
1) Describe the role of the FDA concerning the purity,
safety and efficacy of drugs.
2) Discuss the comprehensive Drug Abuse, Prevention and
Control Act of 1970 and stat and local laws.
16. Pharmacology of migraine (0.5)
1) Describe the rates of onset of action of each prototype
drug used for the treatment of migraine headaches
following administration by the sublingual, oral,
rectal or parenteral routes.
2) Describe the duration of action of each prototype, drug
used to treat migraine.
3) Explain the means by which each drug prevents the
occurrence of migraine headaches or terminates their
attacks if they have stated.
4) Discuss the acute and chronic toxicity of each of the
following drugs.
Drugs to be considered:
CAFFEINE
CLONIDINE
ERGOTAMINE
5-hydroxytryptamine (5-HT)
METHYSERGIDE
NOREPINEPHRINE (NE)
PROPRANOLOL
PROSTAGLANDINS (carboprost, tromethamine, dinoprost,
dinoprostone)
Minimum list of drugs in CNS Pharmacology:
acetazolamide
acetylcysteine
ACETYLCHOLINE (ACH)
acetylcysteine
ADENOSINE
ADENOSINE TRIPHOSPHATE
+ALPRAZOLAM
AMATIDINE
+AMITRIPTYLINE
ammonium chloride
AMPHETAMINE
ASPARTATE
+ATROPINE
baclofen
BELLAADONNA ALKALOIDS
(ATROPINE, scopolamine)
BENZOCAINE
BENZTROPINE
BROMOCRIPTINE
+buspirone
BUPIVACAINE
BUPRENORPHINE
BUTORPHANOL
+CAFFEINE
+CARBAMAZEPINE
+CARABIDOPA
chloral hydrate
CHLORDIAZEPOXIDE
CHLORPROMAZINE (CPZ)
chloroxazone
CLONAZEPAM
CLONIDINE
+clorazepate
clozapine
COCAINE
+CODEINE
+cyclobenzaprine
DANTROLENE
DEPRENYL
+DEXTROMETHORPHAN
+DIAZEPAM
dihydrocodeine
DISULFIRAM (antabuse)
DIPHENOXYLATE
DOPAMINE
doxepin
+D-PROPOXYPHENE
dynorphins
endorphin
ENFLURANE
enkephaline
EPHEDRINE and pseudoephedrine
ERGOTAMINE
ETHANOL
ETHOSUXIMIDE
ethylene glycol
fenfluramine
FENTANYL
+FLUOXETINE
+FLURAZAPAM
GABA
glutamate
glycine
+GUAIFENESIN
HALOPERIDOL
HALOTHANE
HEROIN
HISTAMINE (5
hydroxytryptamine)
+HYDROCODONE
(dihydrocodeinone)
IMIPRAMINE
ISOFLURANE
KETAMINE
+LORAZEPAM
+LEVODOPA (1-DOPA)
LIDOCAINE
LITHIUM CARBONATE
LSD
MARIHUANA
MEPERIDINE
MESCALINE
METHADONE
METHANOL
METHYLPHENIDATE
METHYSERGIDE
MORPHINE
NALBUPHINE
NALOXONE
NALTREXONE
NITROUS OXIDE (N2O)
NOREPHINEPHRINE
+NORTRIPTYLINE
orphenadrine
PENTAZOCINE
PENTOBARBITAL
PHENCYCLIDINE
PHENEZINE
+PHENOBARBITAL
+PHENYTOIN
picrotoxin
PIMOZIDE
POTASSIUM IODIDE
PRIMIDONE
PROCAINE
+propranolol
+propoxyphene
prostaglandins (caraboprost,
tromethamine, dinoprost,
dinoprostone)
strychnine
substance P
SUCCINYLCHOLINE
SUFENTANIL
+TEMAZEPAM
THIOPENTAL
THIORIDAZINE
TRANYLCYPROMINE
+TRIAZOLAM
TRIHEXYPHENIDYL
VALPROIC ACID
PRIMARY DRUGS - All capital letters
SECONDARY DRUGS - Small letters
+Indicates that drug is listed in the 200 most commonly
prescribed drugs in 1989 (National Prescription Audit). All of
the first 100 and most of the second 100 of the top 200 drugs
prescribed are included in the document
