PHCL 764 PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM

Chapter 6 in Mosby

I. Anxiolytics, Sedatives and Hypnotics

A. Key Objectives

1. To understand the stages of central nervous system depression as they pertain to the actions of these agents.

2. To understand the classification of central nervous system depressants.

3. To understand the theories relating to the biochemical mechanism of action of anxiolytics, sedatives and hypnotics, with particular emphasis on the barbiturates and benzodiazepines.

4 .To understand the effects of these agents on the cardiovascular, respiratory and central nervous systems.

5. To know the advantages and disadvantages of each class relative to the others.

6. To appreciate why new drugs are being developed in this area.

B. Introduction and Definitions

1. Be able to define the following:

• sedation
• hypnosis
• anesthesia
• anxiolytic

2. Know the primary drugs and drug classes used to treat anxiety and sleep disorders over the past two thousand years.

3. Understand the clinical and pharmacological differences between ethanol, barbiturates and benzodiazepines.

C. Ethanol

1. Understand the metabolism of ethanol, its effects on major organs systems, contraindications for its use, and the acute and chronic toxicities associated with this substance.

2. Know the mechanism of action of disulfiram, its acute toxicity and primary use.

D. Barbiturates

1. Know how barbiturates are classified on the basis of their duration of action. Be able to give an example of each class.

2. Understand the mechanism of action of the barbiturates.

3. Understand the concept of physical redistribution as it pertains to the action of barbiturates.

4. Know the effects of barbiturates on major organ systems, with particular emphasis on hepatic function.

5. Be able to list the primary uses of the barbiturates.

6. Know the most common side effects and toxicities associated with barbiturates and the treatment of these conditions.

E. Benzodiazepines

1. Know the primary use of the following benzodiazepines:

• chlordiazepoxide
• diazepam
• oxazepam
• lorazepam
• alprazolam
• flurazepam
• triazolam
• clonazepam
• flumazenil
• midazolam

2. Be able to describe the mechanism of action of the benzodiazepines at a biochemical level and understand the concept of endogenous benzodiazepines.

3. Know the chief effects of the benzodiazepines on the major organ systems, as well as the primary side effects and toxicities associated with these agents.

F. Other Agents

• Understand the rationale, advantages and disadvantages of the following as anxiolytics:

• meprobamate, chloral hydrates, paraldehyde
• antipsychotics, antidepressants, antihistamines
• beta-blockers
• buspirone

G. Some Important Drugs

1. Benzodiazepine anxiolytics, hypnotics and antagonists

2. Barbiturate sedatives-hypnotics and anesthetics

3. Miscellaneous sedative-hypnotics

4. Non-depressant anxiolytic

5. Treatment of alcoholism

II. Antiepileptics

A. Key Objectives

1. To understand the different types of seizures and the drug classes most effective in their management.

2. To understand the proposed mechanisms of actions of antiepileptics.

3. To appreciate the more common side effects and toxicities encountered with antiepileptic therapy.

4. To gain a sense for the types of antiepileptics being developed.

B. Introduction and Definitions

1. Know the physiological and clinical differences between partial and generalized seizures and be able to cite examples of each class.

2. Know the primary drugs and drug classes used to treat epilepsy.

3. Know the characteristics of therapy, especially as they pertain to the drug interactions and chronic toxicity.

C. Mechanisms of Action

• Be able to define, at the biochemical and cellular levels, the proposed mechanisms of action of:

• Hydantoins, succinimides and oxazolidinediones
• Barbiturates and benzodiazepines
• Valproic acid and vigabatrin
• Acetazolamide

D. Drugs Used to Treat Grand Mal, Status Epilepticus, and Partial Seizures

• Be able to match the following agents with the types of seizures they are used to treat, their chief side effects and toxicities and potential for drug interactions:

• Hydantoins-Phenytoin
• Barbiturates-Phenobarbital and Primidone
• Benzodiazepines-Diazepam and Clonazepam
• Valproic Acid

E. Drugs Used to Treat Petit Mal (Absence) Seizures

• Know the chief side effects, toxicities and potential for drug interactions for the following:

• Oxazolidinediones-Trimethadione
• Succinimides-Ethosuximide
• Acetazolamide
• Valproic Acid

F. Some Important Drugs

1. Grand mal

2. Petit mal

3. Partial

III. General Anesthetics

A. Key Objectives

1.To understand the characteristics which determine the potency of general anesthetics and their rate of induction.

2.To understand the relationship between minimum alveolar concentration (MAC) and the Ostwald coefficient.

3.To understand the signs and stages of general anesthesia.

4.To appreciate the pharmacological and clinical differences among the inhalational anesthetics and between these agents and fixed anesthetics.

5.To understand the rationale for preanesthetic medications.

B. Introduction and Definitions

• Be able to define:

• General anesthesia
• Partial pressure (tension)
• Lipid solubility
• Ostwald coefficient
• Induction

C. Absorption and Elimination of General Anesthetics

• Understand the variables that influence the rates of induction and emergence from general anesthesia.

D. Anesthetic Potency

• Understand the concept of minimum alveolar concentration (MAC) and its relationship to the Ostwald coefficient.

E. Signs and Stages of General Anesthesia

• Be able to characterize the four stages of general anesthesia and their importance.

F. Comparison of Inhalational Anesthetics

• Know and understand the relationships outlined in Table 6.4.

G. Preanesthetic Medications

1. Understand the rationale for using preanesthetic medications in general, and the use of the following in particular:

• Anxiolytics/hypnotics: benzodiazepines
• Analgesics: opiates
• Antiemetics: phenothiazines
• Anticholinergics: scopolamine, glycopyrrolate

H. Fixed Anesthetics

1.Know advantages and disadvantages of fixed or I.V. anesthetics as compared to inhalational agents.

2.Know the uses and side effects of ketamine, thiopental, innovar and propofol.

I. Some Important Drugs

1. Fixed anesthetics

2. Gaseous anesthetics

3. Volatile anesthetics

IV.Local Anesthetics

A. Introduction

• What is the general mechanism of action of local anesthetics (LA)?
• What are the primary clinical uses of LA?

B. Basic Pharmacology of LA

• What are important chemical features that serve as a basis for differing pharmacokinetic and clinical efficacy?
• How are LA administered?
• Understand the factors that influence absorption of LA from the site of administration.
• What is the role of vasoconstrictor agents in the clinical use of LA?
• Be able to classify LA as either esters or amides.
• Be able to describe the differences in drug distribution between amide and ester LA.
• How does the metabolism of ester LA differ from that of the amide agents?
• What abnormal physiological factors might influence the rate of metabolism of LA?
• Be able to describe the effects of LA on ion channel function. Be able to describe effects of calcium and potassium ions on LA-induced neural block.
• Be able to describe the differing effects of LA on different nerve fibers.

C. Clinical Pharmacology of LA

• Be able to discuss the factors that influence which LA may be selected for a given procedure.
• What are clinical bases for adding a vasoconstrictor agent to a LA?
• Be able to describe the likely mechanism for the loss of LA effectiveness following repeated administration.

D. Toxicology

• Be able to describe the toxic effects of LA on

a. the central nervous system
b. the peripheral nervous system
c. the cardiovascular system
d. hemopoietic system

E. Some Important Drugs

V.Skeletal Muscle Relaxants

A. Introduction

• What are the two major drugs classes used as skeletal muscle relaxants?

B. Basic Pharmacology of Neuromuscular Blocking Drugs

• Be able to describe the underlying structural similarities between neuromuscular blocking drugs.
• Be able to describe the differing routes of elimination of the non-depolarizing neuromuscular blockers.
• Which non-depolarizing blockers are relatively longer vs. shorter in duration?
• What is the major depolarizing skeletal muscle blocker?
• Describe the basis of prolonged duration of succinylcholine blockade in a subset of patients. Indicate a test which may identify patients who may experience this effect.

C. Mechanism of Action

• What are mechanisms of actions for nondepolarizing blockers?
• Describe under what conditions acetylcholinesterase inhibitors may reverse the neuromuscular blockade of nondepolarizing blockers. What might be the clinical importance of this effect?
• What are the two phases of block that may accompany the use of depolarizing drugs?
• Why does the action of succinylcholine last longer than the naturally occurring transmitter acetylcholine?
• What type of paralysis is associated with depolarizing blockade?
• Be able to describe the conditions that may result in a phase II depolarizing blockade. What are the characteristics of a phase II blockade?

D. Clinical Pharmacology of Neuromuscular Blocking Agents

• What is the role of neuromuscular blockade as a part of surgical anesthetic protocols?
• Be able to describe the cardiovascular effects of the neuromuscular blockers.
• The use of depolarizing blockers may be associated with hyperkalemia, increases in intraocular pressure, increase in intragastric pressure, and muscle pain. Be able to describe these effects in more detail.
• Be able to discuss the interactions of neuromuscular blockers with anesthetics, antibiotics, local anesthetic and antiarrhythmic agents.
• Be able to describe the influence of myasthenia gravis, advanced age, severe burns on the pharmacological effectiveness of the neuromuscular blockers.

E. Other Uses of Neuromuscular Blockers

• Be able to describe the utility of neuromuscular blockers in control of ventilation in certain patients.
• Be able to describe the utility of neuromuscular blockers in treatment of convulsions.

F.Spasmolytic Drugs

• What is clinical spasticity?
• Be able to describe how drug therapy may improve some of the symptoms of spasticity.
• By what mechanism may diazepam (Valium) diminish spasticity? What neurotransmitter receptor is involved?
• By what mechanism may baclofen, a GABA-mimetic drug, diminish spasticity? How does the efficacy of baclofen compare to diazepam or dantrolene?
• How does dantrolene reduce spasticity? What is the role of dantrolene in the treatment of malignant hyperthermia?

G. SomeImportant Drugs

1. Neuromuscular blocking drugs

2.Spasmolytics

VI. Pharmacological Management of Parkinsonism and Other Movement Disorders

A. Introduction

• Be able to define tremor, chorea, athetosis, dystonia and tics.
• Abnormalities in what part of the brain is thought be associated with Parkinsonism.

B. Parkinsonism

• What are general presenting symptoms of Parkinsonism?
• What neurotransmitters are considered important in the pathophysiology of Parkinsonism?
• What drug classes may induce Parkinsonism?
• Be able to describe the chemical relationships between L-DOPA and dopamine and the basis for the pharmacological advantage of L-DOPA administration vs. dopamine administration.
• What are the neural locations of D1 and D2 receptors and which are most important in the actions of the dopamine receptor agonists?
• Be able to describe the pharmacokinetics of L-DOPA in the presence and absence of CarbiDOPA.
• Why may the best therapeutic results with L-DOPA be obtainable often during the first few years of treatment?
• Be able to describe adverse effects seen with L-DOPA administration, including gastrointestinal effects, cardiovascular effects, dyskinesias, behavior effects, and fluctuations in response.
• What are "drug holidays" with respect to L-DOPA administration?
• What is the nature of the drug interaction between L-DOPA and vitamin B6)?
• Be able to describe contraindications for the use of L-DOPA.
• Be able to describe the pharmacological basis for the action of bromocriptine.
• What are the prominent toxic reactions associated with bromocriptine use?
• What is pergolide?
• What is the role of the monoamine oxidase B inhibitor (MAO_B) selegiline (deprenyl) in the therapy of Parkinsonism?
• Describe the use of amantadine in the treatment of Parkinsonism.
• Be able to discuss the adverse effects associated with amantadine use.
• What are the centrally active antimuscarinic drugs that are useful in the treatment of Parkinsonism?
• Be able to describe the clinical use of the antimuscarinics in Parkinsonism.
• Describe the Adverse Effects and Contraindications associated with the acetylcholine blocking drugs.
• From the section on "Other Movement Disorders", be able to discuss the varied drugs that can lessen and worsen tremor, essential tremor, and intention tremor.
• What drugs may be useful in treatment of chronic multiple tics (Tourette's Syndrome)?
• What drugs may be useful in the treatment of acute dyskinesias or dystonias that may occur following initial administration of a phenothiazine?

C. Some Important Drugs

1. Antimuscarinics

2. Dopamine agents

3. Others

4. SELEGILINE (DEPRENYL)

VII. Antipsychotics and Lithium

A. Key Objectives

1. Understand the indications for these drugs.

2. Understand the dopamine theory of schizophrenia; data supporting and refuting.

3. Understand mechanisms and sites of action proposed for therapeutic effectiveness and for side effects.

4. Know side effects.

B. Introduction to Antipsychotics

1. Understand the terms: neuroleptic, phenothiazine, antipsychotic, antischizophrenic.

C. Major Classes of Antipsychotics

1. Know the following by generic name only (trade name):

• Phenothiazines: chlorpromazine (Thorazine), thioridazine (Mellaril) and fluphenazine (Proloxin)
• Buterophenones: haloperidol (Haldol)
• Dibenzodiazepine: clozapine (Clozaril); olanzapine (Zyprexa)

2. Understand differences between these drug classes with regard to strength of binding to dopamine receptors, therapeutic oral dosage, and side effects.

D. Therapeutic Effects and Side Effects

1. Understand 3 types of dopamine receptors.

2. Understand side effects: mild and severe; overdose.

3. Appreciate reasons for choosing one drug vs. another.

E. Lithium (Li)

1.Understand structure and proposed mechanism of action.

2.Indications for use.

3.Side effects: mild and severe.

F. Some Important Drugs

1. Antipsychotics

2. Treatment of bipolar depression

VIII. Antidepressant Agents

A. Key Objectives

1. Understand the 2 types of mood disorders (bipolar and unipolar) and their drug treatments.

2. Know the 3 classes of antidepressants and examples of each (TCA's, MAO-I's, Second Generation).

3. Know the indications for the antidepressants.

4. Understand proposed mechanisms of action for therapeutic effects and side effects for each of the 3 classes of antidepressants

5. Know the side effects, mild and severe, for each class.

6. Understand the pharmacological data that implicate neurotransmitter abnormalities as associated with/causal of the mood disorders.

7. Understand the advantages of the serotonin-selective reuptake inhibitors (SSRI's).

8. Understand the criteria for selecting one drug or class over another.

9. Know about the most important drug-food and drug-drug interactions of these drugs.

10. Know the symptoms of overdose and the treatments.

B. Outline of Antidepressants

1. Tricyclic antidepressants (TCA's)

• amitriptyline (Elavil)
• imipramine (Tofranil)
• desipramine (Norpramin, Pertofrane)
• doxepin (Sinequan)
• clomipramine (Anafranil) (also a SSRI)

2. Monoamine oxidase inhibitors (MAO-I's)

• phenelzine (Nardil)
• tranylcypromine (Parnate)
• clorgyline (specific for MAO type A)

3. Second generation antidepressants

• amoxapine (Asendin) (also a TCA)
• bupropion (Wellbutrin)
• trazodone (Desyrel)
• SSRI's

• fluoxetine (Prozac)
• clomipramine (Anafranil) (also a TCA)
• sertraline (Zoloft)
• paroxetine (Paxil)
• fluvoxamine (Luvox)

C. Some Important Drugs

1. Tricyclic drugs

2. Second-generation drugs

3. Second-generation — SSRI's

4. Monoamine oxidase inhibitors

IX. Opioid Analgesics and Antagonists

A. Basic Pharmacology of Opioid Analgesics:

• Be able to describe the pharmacokinetic features of the opioids, including absorption, distribution, metabolism and excretion.
• You should be able to discuss the mechanism of action of these agents, including shared features with the endorphins.
• What are the receptor sub-types for opioid agonists and what effects are mediated by each receptor sub-type.
• Which parts of the brain are most likely sites of analgesic action of opioids?
• What are the definitions of tolerance and physical dependence?
• Be able to describe CNS effects of opioids, including analgesia, euphoria, sedation, respiratory depression, cough suppression, miosis, truncal rigidity, and emesis.
• Be able to discuss peripheral effects, such as those on the cardiovascular system, GI tract, biliary tract, GU tract, Uterine effects, and neuroendocrine effects.

B. Clinical Pharmacology

• What are the major clinical uses of opioid analgesics?
• Be able to discuss specifics concerning application of opioids to treatment of cancer pain, obstetrical applications, renal and biliary colic.
• Discuss opioid use in acute pulmonary edema, cough suppression, diarrhea and in anesthesia.
• What are the major toxic effects of opioid analgesics?
• Be able to discuss the nature of tolerance, physical and psychological dependence associated with opioid agonists.
• What are the approaches to diagnose and treat opioid overdose? What is the role of naloxone?
• What are the major contraindications and cautions in the clinical use of opioids?
• Be able to discuss the major pharmacological properties of morphine, heroin, methadone, meperidine, fentanyl, codeine, oxycodone, diphenoxylate, loperamide, dextromethorphan, naloxone, naltrexone.
• Be familiar with the pharmacokinetics and pharmacodynamics of the pure opioid antagonist drugs naloxone and naltrexone.

C. Some Important Drugs

1. Analgesic opioids

2. Analgesic combination

3. Antitussives

X. Drug Abuse

A. Introduction

• Be able to define psychic dependence, physical dependence, addiction, tolerance, metabolic tolerance, and functional tolerance.

B. Opiates and Opioids

• What are the most commonly abused drugs in this group?
• What is the method of administration of these agents?
• What are the symptoms of opiate withdrawal?
• What are some examples of serious complications that may be associated with opiate dependence?
• Be able to describe the treatment options for management of opiate dependencies.

C. Barbiturates and Other Sedatives

• What are the major drug categories in this section?
• What are the effects seen with increasing doses of these drugs?
• What is the main pharmacokinetic classification of barbiturates and benzodiazepines?
• What are the patterns of drug abuse with sedatives?
• What are withdrawal symptoms seen with sedatives?
• Be able to discuss treatment principles as applied to sedative abuse.

D. Stimulants

• What are the major stimulant drugs of abuse?
• Be able to discuss the patterns of amphetamine abuse.
• Know the patterns of cocaine abuse.
• What are pharmacological approaches that are being considered for long-term treatment of stimulant abuse?
• Know the use of amphetamine and methylphenidate in the treatment of attention-deficit hyperactivity disorders (ADHD).
• Know the use of stimulants in the treatment of obesity

E. Hallucinogens

• What are the major drugs in this section?
• What is the neurotransmitter system that may be most affected by LSD?
• What receptor system may be involved in the mediation of the effects of phencyclidine?
• What are the main clinical effects of LSD, as compared to scopolamine and PCP?
• What are adverse effects (psychological and physical) associated with the use of hallucinogens?

F. Marihuana

• What is marihuana?
• What is the active cannabinoid in marihuana?
• What are stages of marihuana intoxication?
• What are the main characteristics signs of cannabis intoxication?
• What are health hazards that may be associated with marihuana use?
• What are therapeutic uses for cannabis?

G. Inhalants

• What are the categories of inhalants that are subject to abuse?
• Know the clinical aspects of abuse of nitrous oxide, ether and chloroform, industrial solvents and organic nitrites.
• What is the toxicity of chloroform?

H. Some Important Drugs

1. Barbiturates and other sedatives

2. Stimulants

3. Hallucinogens

4. MARIHUANA

5. Inhalants