NEUROPHARMACOLOGY



DRUG ABUSE

READING: Brenner, Chap. 24

Lippincott, Chap. 10

A. LEARNING OBJECTIVES:

1. Define a controlled substance and explain how the manufacure, distribution and use of such substances are controlled.

2. List the major drugs of abuse in the U.S. and their acute and chronic effects when abused.

3. Describe the mechanisms for drug tolerance and dependence associated with each abusable agent.

4. List the clinical manifestations of overdose, other adverse reactions, and withdrawal for each agent.

5. Describe the recommend treatment of overdose and withdrawal for each agent, and discuss methods for treating chronic substance abuse.

B. Overview and Definitions:

1. Factors related to drug abuse: perception of individual, social and/or economic consequences

a) Culture

b) Time and Situation

c) Law

2. The Controlled Substances Act: Regulates the manufacture, prescription, dispensing and availability of drugs with abuse potential

a) Schedule I - No medical use (e.g. heroin, LSD)

b) Schedule II - Medically useful agents with high potential for abuse

1) Opioid analgesics,

2) stimulants,

3) some barbiturates that are commonly abused

c) Schedule III - Less abuse potential

1) Misc. sed/hypnotics, barbiturates,

2) some opioid agonist/antagonists,

3) some stimulants

d) Schedule IV - Less abuse potential than II or III

1) Long-acting barbiturates, sed/hypnotics,

2) benzodiazepines

e) Schedule V - May be distributed without prescription but records must be kept

1) Narcotics used primarily for antitussive or antidiarrheal properties

3. ADDICTION - "A behavioral pattern of drug use, characterized by overwhelming involvement with the use of a drug, securing of its supply, and a high tendency to relapse after withdrawal" -WHO

4. Drug Dependence:

a) Physical dependence: is present when adverse physical or mental symptoms (abstinence syndrome) occur as a result of withdrawal of the drug.

b) Cross-dependence: refers to the ability of a drug to prevent withdrawal symptoms arising from chronic use of another drug. e.g. codeine was often used for this purpose in the past by heroin users when heroin was not available

c) Psychological dependence: book uses “Psychic dependence”; strong desire or craving for a drug, even in the absence of adverse symptoms of withdrawal; the reinforcing efficacy of a drug plays an important role here

5. Tolerance: larger or more frequent dose required for same effect after continued use

a) Metabolic Tolerance: Induction of drug metabolism with chronic use, such as with barbiturates

b) Pharmacodynamic Tolerance (Functional Tolerance): decreased sensitivity of affected system (e.g. receptor number, sensitivity), such as with opioid agonists (psychic tolerance)

c) Behavioral Tolerance: Performance of of some tasks may improve with chronic use, when compared with performance during first use; e.g. driving under influence of marihuana

d) Immune Tolerance: Development of antibodies to drug with chronic use lowers circulating concentration; not shown to be important for any abused drugs

e) Mechanism of tolerance, dependence and withdrawal:

1) Drug exerts specific effect

2) Homeostatic mechanism compensates for drug action (tolerance)

3) Removal of drug leads to overcompensation (withdrawal)

4) Continued use of drug is reinforced because withdrawal is prevented (dependence)

C. SPECIFIC ABUSABLE DRUGS:

1. Nicotine: responsible for most of the acute effects of cigarettes, cigars, smokeless tobacco

2. nicotine - primary reinforcement - absorbed by mucosa, acidic cigarettes by lung

tar - particulates remaining after extraction of nicotine and moisture

CO, ammonia, cyanide, alcohols and aldehydes, nitrosamines, polycyclic aromatic hydrocarbons

a) Acute effects:

1) Increased alertness, relaxation, decreased irritability, CNS stimulation and inhibition

2) Respiratory stimulation

3) Cardiovascular stimulation - catecholamine release

4) aggravation of angina and resp. problems (asthma) by sidestream smoke

b) Chronic effects:

1) increased risk of lung (90%) other carcinomas (bladder - 50%);

2) CV and pulmonary disease - 1/3-1/2 OF deaths due to CV disease, 85% deaths due to emphysema, COPD

3) Pregnancy - decreased birth weight, increased spontaneous abortion, perinatal mortality, SIDS

4) Sidestream smoke - Lung cancer equal to industrial pollution, increased CV and neoplastic diseases

c) Overdose:

1) Nicotine poisoning - nausea, headache, tremor, fasciculations

2) in children who eat tobacco could be life threatening

d) Dependence and withdrawal:

1) physical dependence (nicotine), psychological dependence - stronger than heroin, equal to cocaine

2) Although withdrawal syndrome is mild, craving is very compelling and long-lasting

a) anxiety, irratibility, decreased concentration

b) increased appetite

3) Anxiety, strong desire for tobacco

e) Nicotine preparations available for weaning tobacco users:

1) Nicorette® - chewing gum

2) Nicoderm® - skin patch

3) Nocotrol® - Inhaler

f) Bupropion (Zyban®) - mechanism unknown

3. CNS depressants: barbiturates, benzodiazepines, methaqualone

a) Acute effects: CNS depressant, loss of inhibitions, relaxation

b) Chronic effects: Social consequences - job, family

c) Overdose:

1) Severe medullary depression, cessation of respiration

2) Lethal dose for chronic users not much higher than for nonusers

d) Tolerance and dependence:

1) Slowly developing pharmacodynamic and metabolic tolerance

2) Cross-tolerance to alcohol, hypnotics, anesthetics, not narcotics

3) Physical dependence, psychological dependence, abstinence syndrome

4) Tolerance for medullary dependence does not keep pace with tolerance for other CNS effects

e) Withdrawal:

1) CNS stimulation - anxiety, tremor, nausea and vomiting, delirium and hallucinations

2) Seizures with chronic high level of dependence

3) Therapeutic withdrawal - after long treatment, weight loss, parasthesias and headache

f) Planned withdrawal:

1) Substitute long-acting

2) clonidine or propranalol

4. Alcohol: physical, psychological dependence; see ALCOHOL

5. CNS stimulants: amphetamine, methamphetamine, cocaine

a) Acute effects:

1) Stereotyped behavior, restlessness, insomnia, euphoria, anorexia

2) Toxicity: Paranoia, psychoses, seizures, arrhythmias, hypertension, CVA

b) Psychological and physical dependence - D3 receptor may be associated with the rewarding aspects of stimulant abuse, also associated with exploratory, novelty-seeking, risk-taking behavior

c) Specific formulations

1) "COKE" = cocaineHCl that can be insuffulated ("snorted") or injected i.v. - stimulant that is a vasoconstrictor

2) "CRACK" = smokeable form of cocaine free base

a) Peak circulating concentrations are achieved more rapidly

b) "rush" followed by rapid decline due to redistribution

3) "SPEED" = water soluble amphetamine, oral or i.v.

4) "ICE" = smokeable methamphetamine

5) “Cat” (methcathinone) = more potent and addictive than other stimulants, similar toxicities to amphetamines, eazy to synthesize

d) Abrupt withdrawal: causes a mild abstinence syndrome that includes hyperphagia, hypersomnolence; fatigue, irritability and depression may last for months

e) Treatment: after withdrawal: dopaminergic agonists or tricyclic antidepressants are being tested

6. Opioid agonists: heroin, morphine, meperidine, derivatives of fentanyl

a) Physical, psychological dependence, abstinence syndrome

b) Acute and chronic adverse reactions:

1) Anaphylactoid reactions

2) Foreign body emboli

3) Infection

c) Maintenance Treatment:

1) Opioid Agonists - methadone, L--acetyl-methadol

2) Antagonists - naltrexone (Dolophine®), also may be useful in treatment of alcoholics, others

7. Cannabinoids: marijuana, hashish, THC; a cloned receptor has been shown to activate adenylate cyclase through a G protein-coupled mechanism; an endogenous ligand has been found - anandamide - aracadonyl ethanolamide

a) Acute Effects:

1) Peripheral vasodilatation, tachycardia

2) Relaxation, heightened senses of touch, hearing, olfaction, body state, time

3) Visual hallucinations at high dose, sometimes paranoia

4) Diminished short-term memory, performance on multiple-step tasks, coordination

5) Temporal disintegration - loss of ability to carry out tasks requiring multiple mental steps

b) Chronic effects:

1) Possible suppression of cellular and humoral immunity - retarded monocyte maturation

2) All the effects of smoking on lung

3) Amotivational syndrome - mental dullness, apathy that accompanies chronic heavy use

c) Tolerance - little tolerance or physical dependence, long lasting metabolites

8. Psychedelics: LSD, mescaline, psylocybin, MDA, DOM ("STP"), MMDA, MDMA ("Ecstacy")

a) CNS stimulation, visual and auditory hallucinations, altered awareness of body,time and physical reality.

b) Euphoria or dysphoria ("bad trip") - set and setting, high suggestibility

c) Hypertension, tachycardia, pupillary dilatation, hyperreflexia

d) "Flashback" - recurrence of subjective effects of hallucinogenic drug long after use has ceased

e) Differences - duration, toxicities

f) Tachyphylaxis - varies, LSD cannot take constant dosage

9. Arylcyclohexylamines: PCP (phencyclidine, "angel dust"), ketamine

a) Acute effects: Dissociative anesthetics with strong anticholinergic properties

numbing of extremities, strong anticholinergic properties, psychosis with violent aggression in some cases. Some deaths due to overdose - hypertension, cholinergic

b) Chronic effects: chronic disorientation, personality changes, thought, memory and speech disturbances

c) Mechanism of action:

1) NMDA glutamate receptor antagonist

2) Sigma receptor antagonist

d) Overdose: cyclic coma, hypertension, seizures

1) continual nasogastric suction (gastric secretion), acidification of uring (drug is basic)

2) diazepam to curb CNS excitation and seizures, no antipsychotics

10. Inhalants: Anesthetic gases (nitrous oxide, "laughing gas"), alkyl nitrites, organic solvents, fluorocarbons, propane, butane

a) Organic solvents - liver, kidney, peripheral nerve and brain toxicity; bone marrow suppression and pulmonary disease

b) Fluorocarbons - asphyxiation, ventricular arrhythmias

c) Nitrites - vasodilitation, decrease BP and increased HR, methemoglobinemia with chronic heavy use

d) hydrocarbons - such as propane, butane - asphyxiation (huffing).

XII. GENERAL ANESTHETICS

READING: Brenner, Chap. 25

Lippincott, Chap. 11

A. LEARNING OBJECTIVES:

1. Define the terms “general anesthesia”, “minimum alveolar concentration” (MAC), “neuroleptanalgesia”, “dissociative anesthesia”, “epidural analgesia” and “intrathecal analgesia”.

2. Learn the major inhalational and IV anesthetic agents and describe their relative effects on general level of arousal, the cardiovascular system, CSF pressure, pain response.

3. Explain how the blood/gas partition coefficient determines the speed of onset and duration of action of inhalational anesthetics.

4. Describe the potential toxicities of these agents, including malignant hyperthermia and its treatment.

5. Discuss the known or hypothesized mechanisms of action of general anesthetic agents.

B. Overview:

1. Therapeutic use of general anesthesthetics: various degrees of unconsciousness, amnesia, analgesia, muscle relaxation

2. Mechanisms of action of inhalational anesthetics:

a) increased threshold for depolarization, decreased open time of nicotinic receptor

b) Meyer-Overton hypothesis -

1) higher the lipid solubility the higher the anesthetic potency;

2) specificity is elusive - xenon and argon both have activity;

3) volume of membrane-dissolved agent may determine effect

c) Anesthetics lower the temperature at which phospholipids undergo the gel to liquid crystal phase transition; may have effects on specific protein activities by interaction with boundary lipid or with hydrophobic domains of proteins

3. Physical Properties of Inhalation anesthetics: gases or volatile liquids

a) PT=P1+P2.....+PN (Dalton's law)

b) Partial pressure of a gas in a liquid is equal to partial pressure of gas above the liquid at equilibrium

c) Amount of gas dissolved in a liquid is proportional to the solubility of the gas in the liquid and the partial pressure (Henry's law)

d) Solubility is a property of the specific liquid and gas

[pic]

C. Factors regulating level of anesthesia: Equilibrium situation

1. Alveolar partial pressure - used to regulate partial pressure in CNS

2. Potency (MAC) -, or minimum alveolar concentration required to inhibit movement during a skin incision in 50% of patients)

3. Effects of two or more anesthetics are additive

[pic]

D. Factors regulating rate of anesthetic induction and emergence:

1. Tissue solubility: Blood/gas partition coefficient

a) A LESS soluble agent will induce more quickly when administered at its MAC than a more soluble agent

b) LESS soluble agent will lead to more rapid emergence

2. Ventilation

3. Blood flow

4. Methods for speeding induction:

a) Increase minute ventilation

b) Increase partial pressure of inhaled anesthetic (loading)

5. Diffusion hypoxia - (Fink phenomenon) - displacement of inspired air by anesthetic agent

E. Agents and conditions that affect dosage requirement:

1. Unaffected by pH, decreases with decreasing temperature and increasing age

2. Decreases with narcotics, benzodiazepines, other inhalation anesthetics

3. Increases in chronic alcoholics, acute amphetamine

4. Decreases in chronic amphetamine abuse

F. Judging depth of anesthesia:

1. Guedel's Signs: stages of anesthesia (ether,chloroform)

a) Analgesia

b) Excitement

c) Surgical anesthesia

d) Medullary depression

2. Modern agents:

a) rapid induction

b) signs may vary with agent(s) used

G. Preanesthetics:

1. Use:

a) decrease anxiety, promote cooperation,

b) perioperative amnesia,

c) relieve pre- and post-operative pain,

d) minimize side effects of anesthetic

2. Specific agents:

a) Sedative-hypnotics

b) Anxiolytics

c) Opioid agonists

d) Antiemetics

e) Anticholinergics

H. Nitrous oxide (N2O): MAC>100%, B/G solubility = 0.5, non-flammable but will support combustion

1. Therapeutic Use:

a) Gives good analgesia when combined with other potent inhalants

b) Alone - analgesia at 20%, hypnosis at 40% (minimally)

c) Produces little if any muscle relaxation

2. Effects on respiration: little effect alone at 50%, potentiates the effects of other respiratory depressants (CO2 response)

3. Cardiovascular effects:

a) Does not sensitize the heart to arrhythmogenic effects of catecholamines

b) Mild direct myocardial depressant

c) Sympathetic stimulation, with increased sensitivity of smooth muscle to epinephrine - good maintenance of blood pressure

4. Adverse effects:

a) Diffusion hypoxia, expansion of closed air spaces

b) Depression of bone marrow, megaloblastic anemia, possible spontaneous abortion after chronic exposure to trace amounts, teratogenic in animals

c) Increased cerebral blood flow, volume and CSF pressure

d) Nausea and vomiting in 10-15% of patients on withdrawal

I. Halothane (Fluothane®): MAC=0.75%, blood/gas solubility=2.3, potent volatile liquid at atmospheric pressure, non-flammable

1. Therapeutic Use:

a) Good analgesia only at high levels, little suppression of visceral reflexes

b) Little muscle relaxation (central effects); potentiates effects of non-depolarizing muscle relaxants

2. Effects on Respiration : reduces CO2 response, hypoxic drive, reduced tidal volume, increased rate

3. Cardiovascular effects:

a) Decreased cardiac output, contractility, rate

b) Hypotension

c) Sympathetic stimulation does not occur - may be diminished

d) Blood flow to all organs usually decreases

e) Increases automaticity of heart, potentiates arrhythmogenic effects of catecholamines, aminophylline, theophylline

4. Malignant hyperthermia - hypermetabolic reaction in skeletal muscle, Ca release SR

a) May be brought on by anesthetic, but usually seen following succinylcholine or other nondepolarizing agent

b) Muscular rigidity (not in all patients) tachycardia, tachyarrhythmia, hypertension, flushing then cyanotic mottling of skin, decreased blood pH, elevation of core temperature to as high as 110

c) Treatment - cease anesthetic administration, 100% O2, dantrolene, correct acidosis, cool patient

d) Pretreatment of susceptible patients with dantrolene

5. Other adverse effects:

a) CSF pressure: Cerebral bed loses autoregulation, increases

b) Hepatic function: Decreases hepatic function during anesthesia

1) Hepatic metabolism - 15% by removal of Br and Cl

2) Halothane hepatitis - hepatic necrosis possibly due to reactive metabolite

c) Depresses pharyngeal and laryngeal reflexes, dilates bronchioles, reduces salivary and bronchial secretions, pleasant odor

d) Relaxes uterus and inhibits uterine contractions above 0.5%

e) Interferes with oxytocic drugs, increased blood loss during parturition

f) Emergence - tremor, shivering, slight hypothermia

J. Enflurane (Ethrane®) - MAC=1.7%, B/G solubility=1.9; non-flammable volatile liquid

1. Therapeutic Use:

a) Rapid induction, pungent odor

b) Mild stimulation of salivation and bronchial secretions, suppresses laryngeal reflexes, causes bronchodilation

c) Better muscle relaxation than halothane, better analgesia

2. Effects on Respiration: depresses hypoxic and CO2 response to a greater extent than halothane

3. Cardiovascular effects:

a) similar to halothane, but no bradychardia and arrhythmias less common;

b) less sensitization to catecholamines

4. Other Adverse Effects:

a) CNS - Excitation, particularly in deep anesthesia or hypocarbia

1) Hyperventilation used to decrease CSF pressure

b) Obstetrics - relaxes uterus, increased blood loss during parturition, cesarean section and therapeutic abortion

c) Metabolism -

1)

2) more than 80% is eliminated unchanged as expired gas;

3) some metabolism (2.4% excreted in urine as nonvolatile fluorinated compounds, 0.5% as inorganic fluoride

4) possible liver toxicity

d) Shivering during emergence, little nausea and vomiting,

e) Teratogenic in animals, not known to affect human fetus

K. Isoflurane (Forane®): isomer of enflurane with similar properties; MAC=1.2%, B/G solubility=1.4

1. Therapeutic use: Marked muscle relaxation, reduce muscle relaxants to 1/3 normal

2. Respiration: Greater depression than halothane, less effect on rate

3. Cardiovascular effects:

a) Less depression of myocardium, may result in increased CO due to hypercapnia; does produce vasodilation and decrease blood pressure, sometimes tachycardia

b) No arrhythmias, no sensitization to catecholamines

4. Other adverse effects:

a) Does not induce seizures and convulsions

b) Hyperventilation may be used to decrease cerebral blood flow and pressure

c) No effect on hepatic function

d) Does not affect uterine contractions or increase maternal blood loss

L. Methoxyflurane (Penthrane®):

1. Therapeutic Use:

a) Slow induction and emergence, high analgesic potency

b) Used to use in obstetrics - self administration

2. Adverse effects:

a) Nephrogenic diabetes insipidis due to fluoride production from metabolism, irreversible renal failure

b) Excitement during induction

M. Desflurane (Suprane®) - Rapid onset and emergence, pungency causes breathholding, laryngospasm - not good for induction;

N. Sevoflurane (Ultane®) - low solubility, rapid induction and emergence, low pungency makes it OK for induction even in kids

O. Chloroform - arrhythmias, nephrotoxic and hepatotoxic

P. Diethyl ether, ethyl chloride, vinyl ether, fluroxene, cyclopropane and ethylene - not used because highly flammable or explosive

Q. IV agents other than barbiturates, benzodiazepines, narcotics

1. Etomidate (Amidate®)- minimal effects on cardiovascular system

a) Decreases cerebral blood flow, metabolic rate, and intracranial pressure so may be useful in neurosurgery

b) Has no analgesic effect

c) In about 60% of patients spontaneous muscle movements during induction

High incidence of nausea and vomiting

2. Propofol (Diprivan®) - IV - Nausea, vomiting, hypersensitivity to vehicle (fat emulsion vehicle does not have this property)

a) Decreased BP, some muscle movements

b) Rapid onset (less than 1 min) and recovery (4-8 min)

3. Ketamine (Ketalar®)- IV or IM

a) Therapeutic Use:

1) dissociative anesthesia

a) Good analgesia and amnesia

b) Not unconscious necessarily

2) Very rapid onset and short duration similar to thiopental

3) Little muscle relaxation

b) Adverse effects:

1) Does not depress and may stimulate cardiovascular system

2) Increased intracranial pressure

3) Psychic disturbances during emergence

R. Neuroleptanalgesia - combination of narcotic and butyrophenone

1. Therapeutic Use:

a) when patient must be awake and responsive during a procedure

b) Patient is typically detached and has no desire to move, but remains able to communicate and the intellect is relatively unaffected

2. Adverse effects:

a) Rigidity of respiratory and abdominal muscles may occur

b) Droperidol is antiemetic (DA receptor antagonist), alpha blocker, may produce parkinsonian symptoms on emergence

S. Neuroleptanesthesia - above combination with N2O or other general anesthetic

T. Balanced anesthesia - narcotic, ultra-short barbiturate, N2O and neuromuscular blocker

U. epidural opioid analgesia and intrathecal opioid analgesia: injection into epidural or spinal

XIII. LOCAL ANESTHETICS

READING: Brenner, Chap. 25

Lippincott, Chap. 11

A. LEARNING OBJECTIVES:

1. State the mechanism of action of local anesthetics.

2. List the factors that determine susceptibility of nerve fibers to blockade.

3. Define the factors that determine the duration of action of a local anesthetic.

4. Describe the major adverse effects of the local anesthetics.

B. Therapeutic Use:

1. Local anesthetics are agents that block neuronal conduction when applied locally to nerve tissue in appropriate concentrations

2. Can be applied locally, regionally, or epidural/intrathecally

C. Mechanism of action:

1. Block voltage-dependent sodium conductance - highest affinity for activated and inactivated states

2. Charged form is active, but cannot diffuse through tissues; site of action is the interior of the neuronal membrane

3. Clinically used LA have pKa of 7.7-8.9

D. Pharmacokinetics: systemic absorption is the mechanism for elimination in many cases

1. Intratissue distribution:

a) Volume and speed of injection, type of tissue

b) Fluid will flow along tissue planes, in CSF the specific gravity of the solution will determine the distribution

c) pKa of the LA, pH of tissue and injected solution, lipid solubility, Binding to tissue proteins

2. Susceptibility to blockade:

a) Use dependent blockade

b) Smallest fibers blocked first - fewer channels per unit length

c) Higher frequency fibers more sensitive

d) Myelin sheath reduces amount of drug entering neuron because of non-specific binding, increases amount required within neuron

e) Nerves deep within bundle fibers will be blocked last

3. Factors affecting systemic absorption:

a) Blood flow

b) Tissue binding and lipid solubility

E. Adverse effects:

1. Systemic toxicity: Plasma half-life and duration of action not necessarily related

a) First sign is usually circum-oral numbness, shivering, tremors;

b) progresses to seizures due to blockade of small inhibitory interneurons,

c) followed by profound depression of respiratory centers and coma

d) Systemic side effects are usually prolonged in LA with long plasma half-life

2. Cardiac toxicity: all LA are negative inotropic agents

3. Blood pressure: All cause arteriolar dilatation except for cocaine, which is a vasoconstrictor

4. Spinal and epidural anesthesia - blockade of sympathetic outflow from the spinal cord may increase hypotension

[pic]

Structures of some local anesthetics

F. Specific agents:

1. Classes:

a) Ester e.g. Procaine (Novocaine®), Cocaine -

1) cleaved by plasma cholinesterase, very short half-life

2) Allergic reactions to ester LA are fairly common

b) Amide e.g. Lidocaine (Xylocaine®) - metabolized by hepatic drug metabolizing enzymes

1) Much longer half-lives (hours rather than minutes)

2) Allergic reactions are rare

2. Selection of specific agent:

a) Prilocaine (Citanest®) -- metabolized to ortho-toluidine and nitroso-toluidine (methemoglobinemia)

b) Chlorprocaine (Nescaine®) - T1/2 very short in maternal and fetal blood

c) Bupivacaine (Bupivicaine®) - long duration, little neurologic effect on neonate, may cause CV collapse so not recommended for regional anesthesia; fetal bradycardia and death may result from obstetrical paracervical anesthesia

d) Etidocaine (Duranest®) - causes profound motor blockade

e) Cocaine - topical anesthetic for mucosal surfaces

1) causes intense vasoconstriction

2) cns stimulant - can cause euphoria, seizures and convulsions, hypertension, hyperpyrexia, tachycardia, arrhythmias and ventricular fibrillation

Addiction, 1

Amidate®, 13

Amphetamine, 4

Balanced anesthesia, 14

Bupivacaine, 17

Bupivicaine®, 17

Bupropion, 3

Cannabinoids, 5

Chlorprocaine, 17

Citanest®, 17

Cocaine, 4, 17

Dependence, 1

Desflurane, 12

Diprivan®, 13

Drug abuse, 1

Duranest®, 17

Enflurane, 11

Ethrane®, 11

Etidocaine, 17

Etomidate, 13

Fluothane®, 10

Forane®, 12

General anesthetics, 7

Halothane, 10

Inhalants, 6

Isoflurane, 12

Ketalar®, 13

Ketamine, 13

Lidocaine, 17

Local anesthetics, 15

LSD, 5

Marijuana, 5

Methamphetamine, 4

Methoxyflurane, 12

Nescaine®, 17

Neuroleptanalgesia, 13

Neuroleptanesthesia, 14

Nicoderm®, 3

Nicorette®, 3

Nicotine, 2

Nitrous oxide, 9

Nocotrol®, 3

Novocaine®, 17

PCP, 5

Penthrane®, 12

Phencyclidine, 5

Prilocaine, 17

Procaine, 17

Propofol, 13

Psychedelics, 5

Sevoflurane, 12

Suprane®, 12

THC, 5

Tobacco, 2

Tolerance, 2

Ultane®, 12

Xylocaine®, 17

Zyban®, 3

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