Pharm Ii - Substance Use Disorders

Front 1

Criteria for substance dependence

Back 1

A. Maladaptive pattern of substance use.
B. Clinically significant impairment or distress.
C. At least three of the following seven criteria during the year.
1. Tolerance (either)
a. Increased amounts of substance required for initial effect.
b. Markedly diminished effect with continued use of same amount.
2. Withdrawal (either)
a. Characteristic syndrome (observed).
b. Use of drug or similar one to avoid withdrawal symptoms (by history).
3. Drug is taken in larger amounts over longer periods of time than intended.
4. Persistent desire for and/or unsuccessful efforts to cut down or control use.
5. Significant time spent obtaining, using, or recovering from drug.
6. Important social, occupational or recreational activities are reduced because of substance use.
7. Continued use despite knowledge of persistent or recurrent harm caused or worsened by substance.

Front 2

Criteria for substance abuse

Back 2

A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:

1. Recurrent substance use resulting in failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household).
2. Recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use).
3. Recurrent substance related legal problems (e.g. arrest for substance-related disorderly conduct).
4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g. arguments with spouse about consequences of intoxication, physical fights).

Front 3

Nicotine: Acute effects

Back 3

1. May produce mild stimulation or sedation.
2. Reduces tension and anxiety.
3. Increases pain threshold.
4. Improves speed/accuracy of information processing.
5. Suppresses appetite.

Front 4

Nicotine: Chronic effects

Back 4

1. 85% of all lung cancer deaths.
2. 80% of all COPD deaths.
3. 30% of American cardiac mortality.
4. Increased risk of occlusive and hemorrhagic stroke.
5. Increased risk of various neoplasms.
6. Over 400,000 deaths annually for U.S., secondary to chronic tobacco use.

Front 5

Nicotine: Mechanism of Action

Back 5

1. Peripheral and central receptors bound.
2. Biphasic pharmacology. (low doses stimulate nicotinic receptors, high doses block nicotine receptors)
a. Low doses stimulate nicotine receptors.
b. High doses block nicotine receptors.
3. Autonomic and cardiovascular responses vary.

Front 6

Nicotine: Treatment delivery

Back 6

Nicotine replacement.
a. Gum.
b. Patch (transdermal).
c. Inhaler.
d. Nasal spray.

Front 7

Bupropion (Zyban, Wellbutrin)

Back 7

Used for Nicotine addiction treatment

a. Antidepressant with weak inhibition of NE and serotonin reuptake.
b. Produces dose-related stimulant effects.
c. Seizure risk--avoid in patients with previous seizures and with eating disorders.

Bupropion is for the smoke-we-on (because you smoke cigarettes and it's for treating Nicotine dependence)

Front 8

Mecamylamine

Back 8

a. Nicotine antagonist.
b. Efficacy not proven; may be useful in combination with nicotine replacement.

Front 9

Varenicline

Back 9

an alpha 4 beta 2 nicotinic acetylcholine receptor

a. Counteracts craving and nicotine withdrawal symptoms caused by dopamine depletion. Increases dopamine.
b. Has shown efficacy in large controlled trials both for achieving abstinence and maintaining it.
c. Prevents action of nicotine patch by blocking nicotine receptors.
d. Need slow dosage run up to prevent nausea.
e. Recent FDA warnings of increased suicidal ideation, depressed mood and agitation.
f. Safety in patients with serious psychiatric disorders such as schizophrenia, bipolar disorder and major depression unknown because they were excluded from the clinical trials.

Front 10

CNS stimulants - Sympathomimetics

Drugs in the amphetamine class

Back 10

Includes amphetamine, methamphetamine, phenmetrazine, pemoline.

Front 11

CNS stimulants - Sympathomimetics

Nonamphetamine

Back 11

Includes cocaine, methylphenidate, mazindol, nomifensine.

Front 12

CNS stimulants - Sympathomimetics

General Psychological Effects

Back 12

1. Euphoria, feelings of power, grandiosity.
2. Increased talkativeness.
3. Increased libido.
4. Increased vigilance (may progress to paranoia).
5. Delusions, hallucinations.
6. Delirium/confusion.

Front 13

CNS Stimulants-Sympathomimetics

General Abstinence (Withdrawal effects)

Back 13

1. Fatigue, lethargy.
2. Disturbed sleep, increased dreaming.
3. Apathy.
4. Depressed mood, sometimes suicidality.

Front 14

Cocaine:
Behavioral Effects

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Key effects are euphoria, increased energy, decreased appetite. Cocaine often used in binges with people sometimes taking it 48-72 hours straight.

Front 15

Cocaine:
Behavioral toxicity

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Behavioral toxicity is more likely to occur after repeated use due to sensitization. Behavioral toxicity can include paranoia, hallucinations (visual, auditory, or tactile – feeling of bugs crawling under the skin), and seizures.

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Cocaine:
Withdrawal symptoms

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Crash after binge: sleeping for 1-2 days, followed by long term symptoms (30-90 days) (anhedonia: no pleasure in usual activities--may be related to dopamine depletion), decreased energy, irritability, decreased concentration. The occurrence of these symptoms eventually leads to relapse.

Front 17

Cocaine:
CV system

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Increased heart rate, arteriolar vasoconstriction causing elevation of blood pressure, decreased cerebral blood flow resulting from vasoconstriction, cardiac arrhythmias

Front 18

Cocaine:
Source

Back 18

Coca paste is prepared from extracts of coca leaves. Cocaine hydrochloride is prepared from the paste while “crack” is usually prepared from the hydrochloride by adding baking soda, water and a heat source.

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Cocaine:
Addictive routes

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Smoked and intravenous are the most addicting routes. Euphoria (reinforcement properties of the drug) is related to how rapidly the drug reaches the brain. Smoked and intravenous cocaine take a matter of seconds to reach the brain. Chewed drug can be absorbed sublingually or swallowed. Swallowed drug is the slowest to reach the brain. Snorted cocaine is intermediate.

Front 20

Cocaine:
Oral Route

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Slowest, requiring 45-60 minutes to reach peak plasma levels. Bioavailability is 20-30%. There is first pass hepatic metabolism of 70-80% of a dose. Low rate of addiction

Front 21

Cocaine:
Intranasal Route

Back 21

Poor penetration of ionized form (cocaine HCl) through biologic membranes (nasal mucosa) and the vasoconstricting effect of cocaine on blood vessels in the mucosa accounts for low bioavailability (20-30%). Limits the amount of cocaine that can be taken by this route. Peak blood levels reached in 10-30 minutes, effect fades by 45-60 minutes

Front 22

Cocaine:
IV route

Back 22

Intravenous injection has 100% bioavailability, onset of activity within 15-30 seconds, with duration of 10-20 minutes. Rapidly reaches brain, highly addicting.

Front 23

Cocaine:
Smoking route

Back 23

Powdered cocaine HCL readily dissolves in water but cannot be smoked because heating destroys it by caramelizing it. Change it to the base form to make crack enables it to be smoked

Highly lipid soluble and absorbed rapidly, directly into pulmonary bed; 15 seconds for onset of effect, peaking in 5 minutes (similar to iv), also a rapid offset by 15 minutes resulting in immediate dysphoric feeling and craving for more cocaine. No limitation to the amount of cocaine that can be absorbed by this route other than toxic physiological and behavioral effects (hypertension, arrhythmias, seizures, etc.)

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Cocaine:
Metabolism

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Metabolism involves hydrolysis in the liver to benzoylecgonine which is excreted in the urine. Can be found in urine up to 10 days after a binge but 2 days is more common. Also hydrolyzed in the blood by cholinesterases.

Front 25

Cocaine:
Local anesthetic effect

Back 25

It can block conduction of the nerve impulse by decreasing the sodium current

Front 26

Cocaine:
CV effects

Back 26

Cocaine acts on peripheral autonomic nerves to prevent re-uptake of norepinephrine and dopamine and can potentiate the response of peripheral autonomic effectors to sympathetic activation. Responsible for cardiovascular effects

Toxicity: Myocardial infarction and arrhythmias resulting from coronary artery vasoconstriction, transient hypertension and stroke.

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Cocaine:
CNS effects

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Cocaine binds to the dopamine transporter to prevent reuptake and increases the amount of dopamine at the postsynaptic site. An important site of action is in the nucleus accumbens (dopaminergic neurons) which is associated with mood elevation and arousal, and reward (cocaine self-administration)

Toxicity: Seizures, hyperpyrexia, psychiatric symptoms including schizophrenia-like psychosis, personality disorders, anxiety, depression, paranoia.

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Cocaine:
Tolerance

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1. Receptors are downregulated because of excess dopamine in the synapse. After a binge, when regular amounts of dopamine are released, there is not as great an effect as normal, possibly responsible for anhedonia
2. The dopamine store is depleted because dopamine is not taken back up
2.

Front 29

Cocaine:
CV toxicities

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Myocardial infarction and arrhythmias resulting from coronary artery vasoconstriction, transient hypertension and stroke.

Front 30

Cocaine:
CNS toxicities

Back 30

Seizures, hyperpyrexia, psychiatric symptoms including schizophrenia-like psychosis, personality disorders, anxiety, depression, paranoia

Front 31

Cocaine:
Pulmonary toxicities

Back 31

Lung damage and pneumonia from smoking.

Front 32

Cocaine:
Ob/gyn related toxicities

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Pregnancy complications; premature labor and delivery, some effects on the fetus.

Front 33

Cocaine:
Nasal cavity toxicities

Back 33

Perforated nasal septum in snorters due to vasoconstriction and loss of blood supply to nasal tissue.

Front 34

Cocaine:
Oral orifice toxicities

Back 34

Cocaine vasoconstricts gums and numbs them; dental neglect.

Front 35

Cocaine:
Sexual issues

Back 35

Sexual dysfunction; initially an aphrodisiac but later results in loss of sexual interest, ejaculatory failure, impotence, orgasmic failure in females.

Front 36

Cocaine:
Treatment of Abuse

Back 36

a. Behavioral treatments such as cognitive-behavioral relapse prevention training and contingency contracting.
b. No effective pharmacological treatment to block effects of cocaine.
c. Current promising agents.
Disulfiram (beta-hydroxylase inhibitor).
Anti-convulsants: tiagabine, topiramate.
Stimulants: dextroamphetamine, modafinil.

Front 37

Amphetamines:
Mechanism of Action

Back 37

Both blocks dopamine reuptake and enhancing dopamine release into the synapse.

Amphetamine, like cocaine, also enhances the synaptic activity of serotonin and nor-epinephrine (NE).

Peripheral CV effects depend on NE.

Reinforcing effects depend on dopaminergic neurons in the mesencephalic VTA.

Role of serotonin variable.
a. Probably does not contribute to subjective effects of amphetamines.
b. Likely contributes to hallucinations/psychosis.

Front 38

Amphetamine:
Effects

Back 38

Amphetamines can produce much longer lasting effects than cocaine: 6-24 hours. The dose and duration is more related to stimulant-induced psychosis than psychiatric predisposition.

Tolerance to euphoric effect, no tolerance to psychomimetic effect.

Front 39

Heroin:
Routes of administration

Back 39

Intranasal or “snorting” - 5 minutes
Intravenous or “mainlining” - 1 - 5 minutes
Intradermal or “skin popping” - 5 minutes (variable)
Inhalation or “smoking” - 1 - 5 minutes

Front 40

Opioids:
Immediate effects

Back 40

a. “Rush”.
b. Analgesia.
c. Drowsiness, nodding off.
d. Unconsciousness.
e. Depression of respiration.
f. Constricted pupils.
g. Flushing of skin.
h. Itching.
i. Nausea and vomiting.
j. Spontaneous abortion.

Front 41

Opioids:
Associated risk of injection

Back 41

1. AIDS.
2. Hepatitis B and C.
3. Skin abscesses.
4. Sepsis.
5. Scarred veins.
6. Arthritis and other rheumatologic problems.
7. Bacterial infections

Front 42

Opioids:
Withdrawal Signs and Symptoms

Back 42

1. Piloerection “cold turkey”.
2. Rhinorrhea.
3. Yawning.
4. Perspiration.
5. Lacrimation.
6. Mydriasis.
7. Tremors.
8. Weight loss.
9. Muscle twitches, “kicking the habit”.
10. Restlessness.
11. Vomiting.
12. Hot and cold flashes.
13. Abdominal cramps.
14. Anxiety.
15. Diarrhea.
16. Severe craving.

Front 43

Opioids:
Chronic effects

Back 43

a. Tolerance
b. Constipation and sequelae
c. Opioid-induced hyperalgesia (increase in pain sensitivity)
d. Sexual effects
e. Sequelae of injection drug use and ingestion of adulterants added to "cut" heroin or of acetaminophen with prescription combinations

Front 44

Opioids:
Alleviating opioid withdrawal symptoms

Back 44

1. Benzodiazepines for insomnia, anxiety, muscle spasm (clonazepam, oxazepam commonly used).
2. NSAIDs for muscle and bone pain (ketorolac, oral NSAIDs).
3. Antiemetics (ondansetron, prochlorperazine).
4. Alpha-2 Agonists.
a. Reduce sympathetic hyperactivity by feedback inhibition of presynaptic neurons.
b. Clonidine.
c. Guanfacine.
d. Lofexidine
5. Anti-diarrheal Agents.
a. Loperamide.
b. Octreotide (an analog of sandostatin).

Front 45

Opioids:
Alleviating opioid withdrawal symptoms - insomnia, anxiety, muscle spasm

Back 45

Benzodiazepines (clonazepam, oxazepam commonly used)

Front 46

Opioids:
Alleviating opioid withdrawal symptoms - muscle and bone pain

Back 46

Ketorolac, oral NSAIDs

Front 47

Opioids:
Alleviating opioid withdrawal symptoms - Nausea and vomiting

Back 47

Ondansetron, prochlorperazine

Front 48

Opioids:
Alleviating opioid withdrawal symptoms - Sympathetic hyperactivity

Back 48

Alpha-2 Agonists.
a. Reduce sympathetic hyperactivity by feedback inhibition of presynaptic neurons.
b. Clonidine.
c. Guanfacine.
d. Lofexidine

Front 49

Opioids:
Alleviating opioid withdrawal symptoms - Diarrhea

Back 49

a. Loperamide.
b. Octreotide (an analog of sandostatin).

Front 50

Methadone maintenance

Back 50

1. Prevents heroin effects by producing tolerance (dose must be sufficiently high).
a. Methadone should be dosed at or above 70 mg/daily for maintenance.
b. Caution, if a nontolerant individual receives more than 40 mg of methadone, respiratory depression and death may result--check with treatment facility to verify dose.
2. Prevents withdrawal with once daily oral dosing.
a. Oral route of administration produces modest opiate effects.
b. Half-life is 15 to 40 hours.

Front 51

Methadone for Pain.

Back 51

There has been a major increase in methadone diversion and deaths secondary to increased use for pain relief. When methadone is used for analgesia, care needs to be taken when given to patients with minimal opioid tolerance. Physicians unfamiliar with methadone’s long half-life may prescribe initial doses that are too high or increase the dose too rapidly, especially if the patient complains of inadequate pain relief. This can result in a dangerous increase in plasma levels during the first week or so and unexpected deaths.

Front 52

Pharmacological treatment for opioid addiction:

Agonist maintenance

Back 52

Methadone
LAAM

"Legitimate Addict's Alternative to Methodone"

Front 53

Buprenorphine – Abuse Potential

Non-dependent opioid users

Back 53

Produces euphoria IV, not blocked by naloxone
Less euphoria sublingual because of slower onset

Front 54

Buprenorphine:
Metabolism

Back 54

Buprenorphine is metabolized by cytochrome P450-3A4

Examples of CYP450-3A4 inhibitors (may increase buprenorphine blood levels):
SSRI’s such as fluoxetine, paroxetine, and sertraline.
Anti-infectious agents such as erythromycin and ketoconazole.
Calcium channel blockers such as nicardipine and verapamil.
Retrovirals such as ritonavir.
Grapefruit juice.

Examples of inducers (may decrease buprenorphine blood levels):
Anti-epileptics such as carbamazepine, phenytoin, and phenobarbital.
Anti-tuberculosis agents such as rifampin.

Front 55

Buprenorphine:
Mechanism of Action

Back 55

Mixed agonist-antagonist maintenance.

a) partial agonist at mu receptor and kappa receptor antagonist.
b) Because it is a partial agonist, can be given with less adverse effects, e.g., has ceiling effect on respiratory depression.
c) Dose increases do not increase the pharmacologic effects at the ceiling but may increase the duration of action.
d) High affinity for mu receptors – displaces morphine and methadone.
e) Difficult for naloxone to displace buprenorpine and precipitate withdrawl.
f) Non-opioid dependent subjects have subjective effects when they receive acute dose of buprenorphine.
g) Buprenorphine does not fully block the reinforcing effects of heroin at lower buprenorphine doses.
h) Very slow dissociative rate from mu opioid receptor give rise to its prolonged therapeutic effects so can be given every other day.

Some of buprenophine’s properties may relate to its binding to the ORL-1 receptor (opiate-receptor like):
Endorphin and pure mu agonists do not bind to ORL-1.
May account for much of buprenorphine’s unique features, such as ceiling effect on respiratory depression and diminished mu agonist effects on mood and alertness.

Buprenorphine Butts out all of the morphine attached to the mu receptors.

Front 56

Buprenorphine – Abuse Potential

Physically dependent opioid users

Back 56

Effects on physically dependent opioid users vary by:
Level of physical dependence (buprenorphine can precipitate withdrawal by either route; naloxone will precipitate withdrawal by injectable route.
Time interval between agonist and buprenorphine (at least 12 hours after short acting opioid, at least 36 hours after methadone to avoid precipitated withdrawal).
Amount of acute buprenorphine dose (higher the dose of buprenorphine, the more likely to precipitate withdrawal).

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Buprenorphine

Formulations

Back 57

Subutex – buprenorphine alone.
Suboxone – buprenorphine plus naloxone (4:1 mixture). Causes illness if patient tries to abuse its use and does not take sublingually. Naloxone will not reach CNS sublingually, but will reach CNS if injected.

Front 58

Naltrexone.

Back 58

Antagonist maintenance.

Mu antagonist – blocks effects of opiates and in physically dependent individuals will precipitate withdrawals. Need to be off short acting opiates at least 5-7 days.
Most addicts not interested in using it; high drop-out rate.
Works best for those with extended pressure: doctors, probation, parole, etc.

Front 59

Nonpharmacological Treatment for opioid withdrawal

Back 59

Therapeutic community.
i. 24-hour-a-day residential treatment.
ii. 9-18, 24 months.
iii. Remedy social, economic, educational deficits.
iv. Long-lasting improvements in functioning.
v. High drop-out rate.

Front 60

CNS depressant

Back 60

Ethanol, like the sedative-hypnotic drugs and general anesthetic agents, is a generalized CNS depressant. This class of drug does not act selectively to depress any specific aspect or modality of CNS function but rather exerts a depressant effect on all parts of the CNS.

Front 61

Alcohol:

Mechanism of Action

Back 61

i. Enhancement of GABA mediated inhibition similar to the actions of the benzodiazepines.
ii. Inhibition of CA++ entry through voltage gated calcium channels.
iii. Inhibition of glutamate receptor function--especially at the NMDA receptor.

Front 62

Alcohol:

Effects on CV System

Back 62

a. Cutaneous vasodilation yields increased heat loss; flushing, feeling of warmth
b. A large number of studies, with large populations, have found that the regular consumption of moderate amounts of alcohol (2-3 drinks) associated with a reduction in the frequency of myocardial infarction in both males and females. Ischemic stroke may be reduced as well, while there is a suggestion of an increase in the occurrence of hemorrhagic stroke.
It has been hypothesized that these observations may be due to the following effects of ethanol:
i. Increased plasma levels of high-density lipoproteins (HDLs).
ii. Decreased platelet aggregation.

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Alcohol:

Effects on Renal System

Back 63

Increased Urine Output due to inhibition of release of antidiuretic hormone (ADH)

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Alcohol:

Effects on Sexual function

Back 64

Decreased Sexual Function.

Front 65

Alcohol:

Chronic effects on GI system

Back 65

a. Alcohol causes deposition of fat in the liver. May be due to the fact that oxidation of alcohol increases NADH:NAD+ ratio. It also mobilizes fat from other tissues.
b. Chronic ingestion of alcohol over years can produce cirrhosis, even with a well balanced diet. In most alcoholics, poor diet probably increases the severity of the problem.

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Alcohol:

Systems affected in chronic use

Back 66

GI, neurological, hematologic, cardiac, fetal alcohol syndrome

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Alcohol:
Fetal alcohol syndrome

Back 67

a. Increase in stillbirths and spontaneous abortions in women who consume 2-3 drinks/day.
b. Fetal alcohol syndrome (FAS)
i. The lowest level of daily consumption of alcohol that has found to produce FAS is 2.5 oz. of pure alcohol or 6.25 oz of 80 proof spirits.
ii. FAS characterized by CNS dysfunction, slowed growth, a characteristic facies and other malformations.

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Alcohol:
Early withdrawal symptoms

Back 68

Early symptoms (minor withdrawal).
a. Five to 10 hours after last drink.
b. Tremor (shakes).
c. Increased pulse, respiration, temperature, sweating.
d. Insomnia, including bad dreams.
e. GI upset, nausea, and anorexia.

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Alcohol:
Intermediate withdrawal symptoms

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Seizures (Rum fits).
a. Twenty-four hours after stopping drinking.
b. Grand mal type.

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Alcohol:
Late withdrawal symptoms

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Severe withdrawal and delirium tremens (DT’s).
a. Less than 5% of alcoholics.
b. Onset usually at 3 to 7 days after last drink.
c. More likely with intercurrent medical illness.
d. Confusion (delirium).
e. Hallucinations (distinct from alcoholic hallucinosis).
f. Severe autonomic dysfunction, including fever, elevated vital signs.
g. Mortality about 10 to 15%; care is supportive.

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Alcohol:
Detoxification

Back 71

1. Often inpatient hospitalization.
2. Crossover to benzodiazepine; role for anticonvulsant.
3. Gradual taper off benzodiazepine.
4. Nutritional supplementation.
5. Bridge to treatment.
6. Psychosocial intervention.

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Alcohol:
Medication for detoxification

Back 72

Disulfiram (Antabuse)
Naltrexone

Front 73

Disulfiram (antabuse)

Back 73

Disulfiram irreversibly inactivates aldehyde dehydrogenase, leading to accumulation (up to five to ten times normal levels) of the acetaldehyde metabolite of ethanol. Increased acetaldehyde leads to constellation of symptoms (the Antabuse-alcohol reaction). Reaction is proportional to dosage (levels) of both disulfiram and ethanol and persists for as long as alcohol is being metabolized (30 minutes to several hours).
i. Flushing.
ii. Pulsating headache.
iii. Respiratory difficulties.
iv. Nausea, copious vomiting.
v. Sweating, thirst.
vi. Chest pain.
vii. Vertigo.
viii. Orthostasis.
ix. Potential death.

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Ethanol metabolism pathway

Back 74

Ethanol + NAD+ → acetaldehyde + NADH + H+
i. Catalyzed by alcohol dehydrogenase (ADH).
ii. Rate-limiting step.
iii. ADH is primarily in the liver, also in the gastric mucosa.

Acetaldehyde → acetate (acetyl coenzyme A).
i. Occurs primarily in liver.
iii.
Very rapid.
iii. Catalyzed by the enzyme, aldehyde dehydrogenase.

Acetate → CO2 + H2O.

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Ethanol metabolism pathway

Heavy drinkers

Back 75

Ethanol + NADPH + H+ + O2 → acetaldehyde + NADP+ + 2H2O
i. This is catalyzed by the microsomal ethanol-oxidizing system (MEOS), a liver P450 system enzyme.
ii. MEOS can be induced by heavy alcohol consumption. This will accelerate ethanol metabolism as well as that of drugs metabolized by the same P450 enzymes.
iii. Other drugs may also induce the MEOS.

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Disulfiram (antabuse)

Problems

Back 76

i. Compliance
ii. Toxic reactions in individuals who drink.
iii. Works pretty well in those patients who take it.
iv. Improved compliance has been reported when family members are included in treatment/monitoring of compliance (Network Therapy).

Front 77

Naltrexone treatment

Back 77

May be effective in alcohol substance abuse

Front 78

Methanol

Back 78

Metabolized at a much slower rate than ethanol by alcohol dehydrogenase. End product is formaldehyde.

Toxic effects include (caused by formaldehyde metabolite):
1.
Severe acidosis, coma and death.
2. Blindness (if patient survives).

Treatment
1. Treat acidosis.
2. Ethanol - to slow metabolism of methanol to formaldehyde by competing for alcohol dehydrogenase.
3. Dialysis

Front 79

Barbiturates, benzodiazepines

Substance abuse

Back 79

Produce physiologic dependence (tolerance and withdrawal), like all sedative-hypnotic drugs

Cross-tolerance between alcohol, benzodiazepines, barbiturates

Withdrawal syndromes similar for these agents, but the onset, duration, and severity of these withdrawal syndromes depend, in part, on the half-life of the drug used

Barbiturate withdrawal is generally more severe in terms of autonomic instability, more frequently life-threatening, characterized more often by hallucinations and delirium (toxic encephalopathy), and may respond much more robustly to treatment with barbiturates (usually phenobarbital) with a dramatic resolution of symptoms

Vast majority of patients treated clinically with benzodiazepines do not develop any problems with addictive consumption of benzodiazepines; patients at greatest risk for benzodiazepine dependence are those with another substance use disorder

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Barbiturates, benzodiazepines

Treatment of substance abuse

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Typical approach is to use benzodiazepines for benzodiazepine withdrawal and barbiturates for barbiturate withdrawal.

Barbiturates may be used to manage benzodiazepine withdrawal, but benzodiazepines are generally ineffective for barbiturate withdrawal.

Substitution (typical) of longer acting agents (phenobarbital for barbiturate withdrawal, clonazepam or chlordiazepoxide for benzodiazepine withdrawal.

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Treatment of barbiturate withdrawal

Back 81

phenobarbital

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Treatment of benzodiazepine withdrawal

Back 82

clonazepam or chlordiazepoxide

Front 83

Marijuana

Route of administration

Back 83

Can be smoked or taken orally, rarely intravenous.
Average cigarette contains between 2.5 and 5.0 mg of which 50% absorbed. Smoking peak plasma level in 10 min, intoxication lasts 2-3 hours.

Disappears from plasma rapidly but high solubility in fat containing tissues such as brain and testes, slowly released over the next 30 days. Marijuana an be detected in urine for 3-4 weeks after the last dose.

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dronabinol [Marinol®]

Back 84

THC is available as a Schedule III oral drug, dronabinol (Marinol)

Oral drug version of marijuana that has a slower rate of onset, peak plasma levels 2-3 hours, effects last 6-8 hours.

Proposed Uses.
Antiemetic after cancer chemotherapy, appetite stimulant, muscle relaxant, to decrease ocular pressure in glaucoma (may do more harm than good by decreasing blood circulation to the eye), alleviation of neuropathic pain. Also for marijuana dependence

Looks most promising for antiemetic effect, appetite stimulating effect, treatment of spasticity secondary to multiple sclerosis (M.S.).

marinol...marine...think of sea slugs all sluggish and silly after getting high on pot!

Front 85

Marijuana

Mechanism of action

Back 85

Receptors for THC in brain (highly localized in cortex, hippocampus, cerebellum) CB-1 receptors. There is a natural substance that is a ligand for these receptors-anandamide. Its physiological function is not clear but it might regulate mood.

Also affects dopaminergic system and causes an increased extracellular dopamine in the nucleus accumbens (pleasure related area of the brain).

Heroin antagonist, naloxone, blocks dopamine enhancing effects of both heroin and THC which suggests that stimulation of specific cannabinoid receptors may affect dopamine transmission in the nucleus accumbens by activating the endogenous opioid system. Some of marijuana effects may be due to anandamide acting at THC receptors and some may be due to activation of endorphin system acting at the mu receptors.

CB-2 receptors generally located peripherally and not in the CNS may be responsible for other cannabinoid effects.

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Marijuana

Pharmacological Effects - CNS

Back 86

Mood changes; altered consciousness, mild euphoria, relaxation, increased followed by decreased social interaction, increased appetite. Impairs short term memory by affecting hippocampus. Interferes with distance perception.

Mild paranoia

Visual hallucinations at higher doses; anyone can become psychotic given enough THC (a dose response function) although most people do not get psychotic.

Associated with earlier onset of schizophrenia in vulnerable individuals and concern about possible psychosis in others, especially with early onset of use and continued heavy use.

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Marijuana

Pharmacological Effects - Physiological

Back 87

Dry mouth, red eyes, decreased motor coordination, tremors, decreased body temperature, decreased muscle strength and balance, decreased complex motor skills.

Less common: nausea, headache, nystagmus, lowered blood pressure, impaired immune system.

Acutely dilates bronchioles but chronically it constricts bronchioles and worsens breathing problems. Can lead to similar chronic effects as tobacco smoking. One marijuana cigarette deposits 4 times as much tar as a tobacco cigarette.

Increases heart rate, increases urinary frequency.

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Marijuana

Withdrawal

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Mechanism of withdrawal symptoms may be related to enhanced formation and release of corticotropin releasing factor (CRF). Withdrawal symptoms in humans after long-term use mimic all effects of stress (nervousness, anxiety, restlessness, sleep disturbances, trouble concentrating). "Physiological withdrawal manifested by psychological symptoms.”

Clear psychological dependence; compulsive drug seeking behavior that is likely to be mediated by effects on nucleus accumbens.

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Hallucinogens

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MDMA (methylenedioxymethamphetamine; “ecstasy”) is most common.
LSD (lysergic acid diethylamide)
Psilocybin (from certain mushrooms)
Mescaline (from the peyote cactus)
DMT (dimethyltryptamine)
DET (diethyltryptamine)
DOM (aka “STP”) 2,5-dimethoxy-4-methylamphetamine

These drugs do not really cause hallucinations, which is the perception of a sensory sensation in the absence of any stimulus. They actually cause illusions, misinterpreting existing stimuli.

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Hallucinogens

Mechanism of action

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Hallucinogens exert their effects by binding at the 5HT2A serotonin receptor.

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Hallucinogens

Tolerance

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Tolerance develops rapidly (after 3-4 days); therefore, addiction does not generally occur. Tolerance disappears quickly (one week). Cross tolerance occurs among the different hallucinogens.

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Hallucinogens

Dependence

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Physical dependence is not a problem, and there is no known withdrawal syndrome.

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Hallucinogens

Effects

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Causes increased awareness of sensory input; synesthesia-stimulate one sense and produce a reaction in another sense (hearing colors; seeing music); out of body experiences.

Flashbacks, weeks, months or years after the last use of the drug; a visual phenomenon, emotional reaction, seems like being under the influence of the drug even when the drug is not taken. (can be triggered by other drugs such as marijuana or by stress).

Intoxication.
a. Illusions.
b. Intense perceptions.
c. Rare hallucinations (usually visual).
d. Mystical feelings.
e. Dilated pupils.
f. Flushing.
g. Elevated heart rate and blood pressure.
h. Blurry vision.

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MDMA (Ecstasy)

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combination of mescaline and methamphetamine

Major Depression? Majorly Amazing "rush" first.

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MDMA (Ecstasy)

Effects

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Does not produce high like cocaine.
Can produce energized state, experienced first as a sudden amphetamine-like rush with increased sensory perception, followed by psychedelic effect, followed by adverse effects

Major Depression? Majorly Amazing "rush" first.

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MDMA (Ecstasy)

Adverse Effects

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Adverse effects (can last for a week or more after drug use).
i. Decreased ability to perform mental and physical tasks, decreased appetite.
ii. Inability to have sex, depressed mood; prolonged headaches.
iii. Heavy users have loss of serotonin axons that persists for months after last use; duration of axon loss is unclear as is its relation to amount of ecstasy used.

Suppression of thirst common which can lead to dehydration, hyperthermia, cardiac arrhythmias, and even death. Excess water intake to avoid this can lead to hyponatremia, seizures, and death.

Long-term adverse effects include sleep, mood, and anxiety disturbances, increased impulsiveness, memory and attention problems. Can last up to 2 years after last use.

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Hallucinogens

Toxic effects

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a. Psychosis.
b. Confusion, anxiety, panic.
c. Autonomic instability, including fever, shock, convulsions.
d. Flashbacks.
i. Spontaneous recurrence while sober of feeling/perceptions experienced while intoxicated; usually lasts only a few minutes.
ii. Persistent and chronic flashbacks suggest a separate psychiatric disorder.

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Arylcyclohexylamines

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Dissociative anesthetics

Phenylcyclidine (PCP)
Ketamine

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Phenylcyclidine (PCP)

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Dissociative anesthetics

Non-competitive antagonism at NMDA receptor complex. Act by blocking NMDA-associated calcium ion channel.

PCP binds sigma opioid receptor.

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Phenylcyclidine (PCP)

Effects

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Marked variability in responses.
a. Relaxation, euphoria.
b. Dysphoria, anxiety, emotional liability, paranoia.
c. Slowing of time perception.
d. Feelings of numbness.
e. Agitation, violence.
f. Tachycardia, flushing, drooling, miosis.
g. Dizziness, uncoordination, slurred speech, nystagmus.

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Phenylcyclidine (PCP)

Adverse Effects

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1. Psychosis.
2. Muscular rigidity.
3. Rhabdomyolysis.
4. Seizures.
5. Respiratory depression.
6. Hypotension.

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Phenylcyclidine (PCP)

Treatment of toxicity

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1. Benzodiazepines for sedation, muscle rigidity.
2. Treat elevated blood pressure cautiously.
3. Gastric suction (to reduce enterohepatic recirculation).
4. Acidification of the urine.
5. Diazepam for convulsions.

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Ketamine

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Arylcyclohexylamines - Dissociative Anesthetics.

Used clinically by anesthesiologists and experimentally for treatment of refractory depression.

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Sensitization

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Reverse tolerance
Prior exposure to a drug produces CNS adaptation leading to greater effects with the same dose (greater sensitivity).

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Tachyphylaxis

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Sometimes referred to as acute tolerance.
Subsequent doses of a drug produce progressively less effect.
a. Neurotransmitter depletion a common mechanism.
b. Binge stimulant use may produce measurable tachyphylaxis.

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L-alpha-acetyl methadol (LAAM)

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mu receptor agonist, treatment for morphine addiction

"Legitimate Addict's Alternative to Methodone"