PHARMACOLOGY OF THE
CENTRAL NERVOUS SYSTEMS -Objectives
Dr. Robert L. Copeland, Jr.
Dr. Keith Crawford
Dr. V. John Massari
Dr. Sonya Sobrian
Dr. Martha Davila-Garcia
Dr. Walter Bland
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.
 | Neurotransmitters |
| Receptors |
| Neurochemistry |
 | Concepts |
1. Anatomic pathway
2. Function
3.Cotransmitter
| Classes
|
 | Indoles (5HT) |
| Catechols (E, NE, DA) |
| Amino acids |
| Excitatory (glutamate and aspartate) |
| Inhibitory (GABA and glycine) |
| Define the terms "minimum alveolar concentration (MAC)", "general anesthetic", "neuroleptic analgesia", and "dissociative anesthesia", and "epidural and intratheal opioid analgesia" |
| State the objectives of general anesthesia. |
| State the physical characteristics of inhalational anesthetics which determine the rate of achievement of equilibrium for a given partial pressure in respired air for alveoli e.g. brain tissues and other. Define Oswalds coefficients. |
| List the current theories of the mechanism of action of general anesthetics. |
| List the methods by which inhalational anesthetics are administered and factors that must be taken into account when drugs are administered by inhalation. |
| Compare the inhalational anesthetics with respect to their general properties, effects on varous organ systems, biotransformation, disadvantages and advantages. |
| Describe the mechanism by which intravenous induction anesthetics produce anesthesia of rapid onset and short duration. |
| Recognize or describe clinical conditions which render general anesthesia more hazardous than other methods of preparing the patient for surgery. |
| Compare various i.v. induction agents, compare toxicity of anesthetics, recognize malignant hyperthermia and know how to treat it. |
| Explanation of second gas effect and diffusional hypoxia. |
| List the classes of drugs used as (a) pre-anesthetic medications and (b) anesthetic adjuvants, and explain their useful actions and their hazards. Discuss toxic effects of pre-anesthetic medications (e.g. Midazolam). |
Drugs to be considered:
ATROPINE KETAMINE
DANTROLENE MORPHINE
DIAZEPAM NITROUS OXIDE (N2O)
ENFLURANE PENTOBARBITAL
FENTANYL SUCCINYLCHOLINE
HALOTHANE SUFENTANIL
ISOFLURANE THIOPENTAL
Local Anesthetics
| Mechanism of action. List the pharmacologic, chemical and physiologic influence that
determine the activity of local anesthetics. |
| List the factors that influence the sensitivity of different nerves to local
anesthetics. |
| Describe the metabolism of amide and ester local anesthetics. |
| List common toxic effects. What drugs are used to treat the adverse effects of local
anesthetics? |
| List routes of administration of local anesthetics. |
| What are the advantages of administering epinephrine with local anesthetics? |
| What drugs are used to treat the adverse cardiovascular and CNS effects of local anesthetics? |
Drugs to be considered:
BENZOCAINE
COCAINE
LIDOCAINE
BUPIVACAINE
PROCAINE
Sedative-Hypnotics: Muscle Relaxants
| List and describe the stage of sleep. |
| Discuss the pathophysiological basis of rigidity, spasticity, muscle spasm (if not
previously discussed under motor dysfunction) |
Barbiturates
| Discuss the relationship between the chemical structure of barbiturates and their
pharmacokinetics (absorption, distribution, biotransformation, elimination). |
| Describe the action of the barbiturates on the CNS, (including tolerance), respiration, cardiovascular system, kidney, and liver. |
| Discuss the consequences of barbiturate induction on enzymes, specifically on aminolevulinic acid synthetase (porphyria). |
| Give the clinical indications for the use of barbiturates; discuss adverse reactions of elderly persons to barbiturates (confusion, restlessness, etc.). |
| Describe the interactions of barbiturates with other CNS agents and their effects on the metabolism of other drugs. |
| Describe the effects of ionization and lipid solubility on tissue distribution and duration of action of barbiturates. |
| Classify the clinically useful barbiturates according to duration of action. |
| Describe the effects of atering urinary pH on the rate of phenobarbital elimination. |
| Describe the effects of barbiturates on REM sleep. |
| Describe acute barbiturate intoxication and its treatment. |
| Indicate the effects of combining barbiturates with alcohol and other CNS depressants on CNS function. |
| Discuss the therapeutic ration of barbiturates. |
| Describe the symptoms of barbiturate withdrawal in a barbiturate-dependent subject. |
Drugs to be considered:
PHENOBARBITAL
THIOPENTAL
PENTOBARBITAL
Non-barbiturate sedatives and hypnotics and central skeletal muscle relaxants
| Describe the mechanisms of elimination and the effectiveness of hemodialysis as a means
of increasing the rate of elimination. |
| Describe the harmful effects which may ensue from the use of sedative agents for the
symptomatic treatment of chronic anxiety states. |
| List the signs of overdoes of non-barbiturate sedatives. |
| Describe the use of sedative hypnotics as adjunct to anesthesia and their toxicity (e.g.
temazepam). |
| Compare the actions and toxicity of barbiturates and benzodiazepines as sedative
hypnotics. |
Drugs to be considered:
chlorzoxazone CHLORAL HYDRATE
cyclobenzaprine TRIAZOLAM
FLURAZEPAM baclofen
ophenadrine
TEMAZEPAM
Benzodiazepines (anxiolytics, hynotics and muscle relaxants)
| Describe the effects and mechanisms by which anxiolytic agents exert their effects. |
| Compare the dependence liability, toxicity, side effects, and therapeutic actions of
benzodiazpines with the barbiturates and non-barbiturate sedative hypnotics. |
| What is the mechanism of action of benzodiazepines (receptor types)? |
| Describe the interactions of the benzodiazepines with other CNS depressants. |
| Describe the mechanism of action of flumazenil and its uses. |
| Describe metabolic and distribution factors which may effect the action of benzodiazepines including the effect of old age. |
| Describe the pharmacology of buspirone and compare it with the pharmacology of diazepam. |
Drugs to be considered:
ALPRAZOLAM DIAZEPAM
chlorazepate FLURAZEPAM
CHLORDIAZEPOXIDE LORAZEPAM
buspirone TRIAZOLAM
TEMAZEPAM
Drugs used in the treatment of psychiatric disorders
Antidepressants and Lithium
| Describe the concept of affect and how it can be altered by drugs. |
| Give a description of affective disorders (unipolar and bipolar depression, phobic and
schizoaffective disorders). |
| Describe the time course of response after initiation of therapy with tricyclic
antipressants. |
| Describe the importance of metabolism to the elimination of tricyclic antidepressants,
and to the formation of active metabolites for some agents. |
| Describe the effect of tricyclic antidepressants on CNS neurotransmitter systems
including effects on neurotransmitter receptors, receptor binding activity and receptor
regulation. |
| Explain the side effects and toxic effects of tricyclic antidepressants on the basis of
autonomic actions. |
| Describe the direct toxic manifestations of tricyclic antidepressants on the CNS and
myocardium. |
| Explain the principles of management of tricyclic antidepressant overdose using a
pharmacological antidote and plasma pH adjustment. |
| Describe the interactions of tricyclic antidepressants and monoamine oxidase inhibitors
with CNS depressants, sympathomimetic amines, and food stuffs. |
| Describe the time course for clinical response after initiation of therapy for
depression with MAO inhibitors. |
| Describe the effects of MAO inhibitors on cellular levels of 5-HT and cathecholamines. |
| Describe the manifestations of overdose with MAO inhitiors and the principles of
overdose treatment. |
| Describe the chronic toxicities of MAO inhibitors involving the liver, brain and
cardiovascular system. |
| Describe and explain the interactions of MAO inhibitors with biogenic amines and
substances which release biogenic amines. |
| Describe the effects of lithium on CNS neurotransmitter systems. |
| Describe the effects of decreased sodium intake or diuretic drugs on the response to
lithium. |
| Explain why there is a contraindication to the use of lithium in patients with impaired
renal function or cardiovascular disease. |
| Discuss the value of plasma lithium determination in assessing adequacy of dosage with
lithium. |
| Describe the toxic effects of lithium and contrast its acute and chronic toxicities. |
| What are the therapeutic indications for lithium? |
Drugs to be considered:
AMITRIPTYLINE
DOXEPIN
IMIPRAMINE
PHENELZINE
TRANYLCYPROMINE
FLUOXETINE
LITHIUM CARBONATE
NORTRIPTYLINE
Antipsychotics (Neuroleptics)
| Discuss schizophrenia (epidemiology, symptoms, etiology, biochemistry). |
| Indicate possible mechanisms of action of antipsychotic drugs. |
| Review the major dopamine pathways and action and effects of the antipsychotic agents
phenothiazines, butyrophenones. |
| List the acute and long-term effects of neuroleptics on dopamine receptors. |
| List the pharmacological properties of antipsychotic drugs. |
| Explain the effect of hepatic microsomal enzyme induction by phenothiazines on the
steady state plasma concentration after prolonged administration. |
| Explain the effect of hepatic microsomal enzyme induction by phenothiazines on the
steady state plasma concentration after prolonged administration. |
| Describe the behavioral effects of antipsychotic drugs which are generally referred to
as the neuroleptic syndrome. |
| Describe the biochemical mechanism which may explain the action of antipsychotic drugs
at different levels of the CNS. |
| 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. |
| Describe the endocrine and cardiovascular changes which may be produced by antipsychotic
drug therapy. |
| Describe the endocrine and cardiovascular changes which may be produced by antipsychotic
drug therapy. |
| What is tardrive dyskinesia, what drug produces it? |
| What is the neuroleptic malignant syndrome? How is it treated? |
Drugs to be considered:
CHLORPROMAZINE THIOIDAZINE
HALOPERIDOL clozapine
PIMOZIDE
Opioid analgesics, Agonist-antagonists
| Narcotic Analgesics |
1) Describe the pharmacologic responses associated with the stimulation of the various opiod receptor subtypes, e.g., Mu, Kappa, Delta, etc.
| Know which analgesics are partial agonists; their advantages and disadvantages. | ||||||||||||||
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| Describe characteristics of endorphins, enkephalins, dynorphin, and substance P. | ||||||||||||||
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| Describe the types of pain, pain pathways and distribution of opioid receptors. | ||||||||||||||
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| Describe mechanisms and sites of action of opiod analgesics. | ||||||||||||||
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| Describe structure-activity relationships of morphine, morphine surrogates and morphine antagonists. | ||||||||||||||
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| Know the pharmacologic actions of morphine in the following systems: | ||||||||||||||
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| Contrast the analgestic effects of morphine with those of the nonsteroidal antiinflammatory drugs. | ||||||||||||||
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| List the sensory modalities that are not affected by morphine. | ||||||||||||||
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| Discuss drug dependence to morphine - e.g., tolerance and withdrawal to morphine. | ||||||||||||||
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| List the contraindications for morphine and its surrogates. | ||||||||||||||
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| List the signs and symptoms of morphine (also heroin) overdose and its management. | ||||||||||||||
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| Describe tests for diagnosing acute and chronic opioid intoxication. | ||||||||||||||
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| Discuss the rationale of using mixtures of opioid analgesics and NSAI drugs. | ||||||||||||||
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| Indicate important drug interactions of morphine and other narcatic analgesics with other types of drugs. | ||||||||||||||
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| State the means by which narcotics are eliminated. | ||||||||||||||
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| Describe the distribution of narcotics in the body, including their ability to cross the placenta. | ||||||||||||||
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| Explain the rationale behind the use of methadone to treat narcotic dependence. | ||||||||||||||
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| Indicate the abuse liability of the different narcotics. | ||||||||||||||
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| State the reasons for caution in the use of narcotics in patients suffering from cor pulmonale. | ||||||||||||||
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| Increase analgesic effectiveness of morphine and meperidine due to elevated levels of unbound drug in plasma. | ||||||||||||||
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Drugs to be considered:
CODEINE HEROINE
D-PROPOXYPHENE MEPERIDINE
FENTANYL METHADONE
DIPHENOXYLATE MORPHINE
| Narcotic Agonist-Antagonists |
| Describe the principle of relative potency and know how to calculate equivalent doses. |
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| Describe the principle of receptor dualism. |
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| Describe the principle of competitive antagonism as it applies to precipitated abstinence syndrome. |
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| Indicate the therapeutic use of opioid antagonists. |
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| Compare PENTAZOCINE, MORPHINE, and NALOXONE. Compare in respect to effect in elderly, e.g. PENTAZOCINE in more likely to produce mental confusion. |
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Drug to be considered:
Agonist/Antagonists Specific Antagonists
BUTORPHANOL NALOXONE
NALBUPHINE NALTREXONE
BUPRENORPHINE PENTAZOCINE
8. Drugs used in the treatment of motor disorders
| Describe the neural control of motor function (pyramidal, extrapyramidal and cerebellar) |
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| Discuss dysfunction of the basal ganglia and Parkinson's disease. Discuss the influence of age of dopaminergic receptors. Discuss drug which can induce Parkinson's disease. |
| Describe pathophysiology of Parkinson's disease. |
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| Discuss the use of levodopa (pharmacological actions, side effects, contraindications). |
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| Describe the useful drug interactions in treating Parkinson's Disease (diphenhydramine, amatadine, bromocriptine). |
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| Describe Huntington's chorea and reciprocal relation to parkinsonism. |
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| Describe the metabolism of levodopa and the use of decarboxylase and MAO inhibitors treating or delaying the progression Parkinson's disease. |
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| Describe the mechanism of action of levodopa, anticholinergics, and antihistaminics in relieving the signs of Parkinson's disease. Compare the effects on tremor and akinesia. |
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| Descrie the interaction of levodopa with sympathomimetics, anticholinergics, and amantadine. |
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| Describe the interactions of anticholinergics with phenothiazines. |
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Drugs to be considered:
AMANTADINE DEPRENYL
BENZTROPINE DOPAMINE
BROMOCRIPTINE LEVODOPA (1-DOPA)
CARBIDOPA TRIHEXYPHENIDYL
9. CNS - Stimulants
| Describe the metabolism and excretion of this group of drugs. |
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| Summarize the site and mechanisms of action of amphetamines. |
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| Compare the mechanism of action of amphetamine and fenfluramine |
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| List the toxic effects of amphetamines and cocaine. |
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| Give the therapeutic indications for amphetamines and their efficacy in the treatment of narcolepsy, attention deficit disorders and obesity. |
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| Describe the mechanism of action of strychnine, picrotoxin and tetanus toxin. |
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| Describe the mechanism of action of xanthines on the CNS. |
Drugs to be considered:
AMPHETAMINE EPHEDRINE
CAFFEINE METHYLPHENIDATE
COCAINE picrotoxin
fenfluramine strychnine
10. Antiepileptics
| Define epilepsy with respect to the pathophysiology of a seizure, incidence, etiology, and types of seizures). |
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| Describe for each antiepileptic drug the interval between time of administration and the onset of pharmacological effects. |
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| Know the first and second drugs of choice for each type and list the major side effects of the drug of first choice. |
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| State the duration of action of each antiepileptic drug and the means by which their pharmacological effects are terminated. |
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| Explain the influence of drug dosage on the rate of elimination of phenytoin. |
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| List the types of epilepsy and seizures for which each drug is used. |
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| Describe the mechanisms, where known, by which each drug works as an antiepileptic and mechanisms where by neuronal excitability can be enhanced and diminished. |
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| List the types of drugs which may increase or decrease the metabolism of phenytoin. |
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| Describe the possible effects of chronic phenobarbital administration of drug metabolism. |
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| Explain the use to which serum drug levels may be put to assist in adjusting the doses of some antiepileptics. |
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| Explain why multiple antiepileptics are used. |
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| List the major toxicologic and teratologic effects of the prototypical anticonvulsants. |
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| Describe "status epilpeticus"; its dangers and its treatment. |
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Drugs to be considered:
acetazolamide PHENOBARBITAL
CARBAMAZEPINE PHENYTOIN
clonazepam PRIMIDONE
DIAZEPAM VALPROIC ACID
ETHOSUXIMIDE
11. Ethanol - alcoholism
| Summarize the therapeutic applications of ethanol. |
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| List the effects of ethanol on organs of the body. |
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| Describe the relationship of ethanol to vasopressin release. |
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| Describe the inhibition of ethanol (distribution including blood levels and legal limits, elimination, and metabolism). |
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| Describe the inhibition of ethanol metabolism by disulfiram and its therapeutic implications. |
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| Discuss the social aspects of ethanol abuse. |
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| Describe fetal alcohol syndrome. |
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| List procedures used in treating acute and chronic alcohol intoxication. |
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| Summarize ethanol - drug interactions. |
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| Discuss methanol (its source, chemistry, and elimination). |
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| Describe methanol and ethylene glycol toxicology and their treatment with ethanol (explain the rationale). |
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| Describe the elimination kinetics of the aliphatic alcohols as a function of a saturable catabolic enzyme system. |
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| List the products of methanol and ethylene glycol catabolism. |
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| Discuss the value of dialysis in the treatment of methanol and ethylene glycol intoxication. |
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| Give the common effect of all aliphatic alcohols in CNS function. |
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| Describe the manifestations of ethanol intoxication on the CNS which are different from those of their CNS depressants. |
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| Describe the toxic effects and effect on lipid metabolism associated with chronic excessive ethanol ingestion. |
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| Describe the effects on the body of methanol and ethylene glycol intoxication. |
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| List signs and symptoms of the ethanol abstinence syndrome. |
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Drugs to be considered:
DISULFIRAM (ANTABUSE)
ETHANOL
METHANOL
ethylene glycol
DRUGS OF ADDICTION AND SUBSTANCE ABUSE:
12. Hallucinogens
| Describe the mechanisms and sites of action, tolerance, pharmacokinetics, effects on organ systems of the different types of hallucinogens. |
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| Discuss the social used and abuse of hallucinogens. |
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Drugs to be considered:
BELLADONNA ALKALOID (ATROPINE, scopolamine)
MATIHUANA
MESCALINE
LYSERGIC ACID DIETHYLAMINE (LSD)
PHENCYCLIDINE
13. Drug dependence
| Define and describe physical dependence and tolerance for drugs. |
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| Describe the clinical characteristics of drug dependence. |
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| Define the signs and symptoms of intoxification for the major drugs of abuse. |
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| Describe the withdrawal and detoxification techniques for different drugs of abuse. |
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| Review the mortality and morbidity of dependence to various drugs. |
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| Define and describe psychological dependence. |
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| Compare dependence on and associate abstinence signs of opioids, CNS depressants and stimulants. |
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Drugs to be considered:
ETHANOL PENTOBARBITAL
COCAINE AMPHETAMINES
MARIHUANA DIAZEPAM
HEROIN LSD
Minimum list of drugs in CNS Pharmacology
acetazolamide
acetylcysteine
ACETYLCHOLINE (ACH)
acetylcysteine
ADENOSINE
ADENOSINE TRIPHOSPHATE
+ALPRAZOLAM
AMANTIDINE
+AMITRIPTYLINE
ammonium chloride
AMPHETAMINE
ASPARTATE
+ATROPINE
baclofen
BELLADONNA ALKALOIDS
(ATROPINE, scopolamine)
BENZOCAINE
BENZTROPINE
BROMOCRIPTINE
+buspirone
BUPIVACAINE
BUPRENORPHINE
BUTOPHANOL
+CAFFEINE
+CARBAMAZEPINE
+CARBIDOPA
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
enkephalins
EPHEDRINE (and pseudoephedrine orphenadrine)
ERGOTAMINE
ETHANOL
ETHOSUXIMIDE
ethylene glycol
fenfluramine
FENTANYL
+FLUOXETINE
+FLURAZEPAM
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)
NOREPINEPHRINE
+NORTRIPTYLINE
PENTAZOCINE
PENTOBARBITAL
PHENCYCLIDINE
PHENELZINE
+PHENOBARBITAL
PHENYTOIN
picrotoxin
PIMOZIDE
POTASSIUM IODIDE
PRIMIDONE
PROCAIN
+PROPRANOLOL
+PROPOXYPHENE
PROSTAGLANDINS
(carboprost, tromethamine, dinoprost, dinoprostone)
strychnine
substance P
SUCCINYLCHOLINE
SUFENTANIL
+TEMAZEPAM
THIOPENTAL THIORIDAZINE
TRANYLCYPROMINE
+TRIAZOLAM
TRIHEXYPENDIDYL
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 this document.
Theories of Mental Illness
Learning Objectives
Be able to:
1. Identify the problems associated with determining the CNS pathology associated with mental illness.
2. State the Dopamine (DA) Hypothesis of Schizophrenia.
3. Know the central DA systems and receptor subtypes hypothesized to be involved in the etiology of schizophrenia.
4. Identify experimental and/or clinical evidence that would support or contradict the DA hypothesis.
5. Know the transmethylation hypothesis of schizophrenia.
6. Identify other neurotransmitters (interactional hypotheses) involved in the etiology of schizophrenia.
7. Identify physiological factors involve in etiology of schizophrenia.
8. Identify the different types of depressive disorders.
9. State the catholamine hypothesis of depression.
10. State the indole hypothesis of depression.
11. Know the neuroendocrine factors involved in depression.
12. Identify monoaminergic changes seen in depression.
13. Recognize the neurochemical systems involved in anxiety.
14. Know neurochemical systems involved in two-factor theories of shizophrenia and depression.