Pharmacology of Abused Drugs 1-3 Flashcards Preview

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Flashcards in Pharmacology of Abused Drugs 1-3 Deck (70):
1

What is the neurobiological vs neuropharmacological model of addiction pathogenesis?

Neurobiological - medication will be effective in managing the neurobiology of addiction
Neuropharmacological - the addictive substance modifies the brain

2

What is the current predominant theory of addiction today?

Bio-Psycho-Social - multifaceted

3

What is a substance-induced disorder?

Intoxication / withdrawal / other substance/medication-induced mental disorder

4

How are substance use disorders classified now?

Based on 11 behavioral criteria, from mild (2+) to severe, with severe being 6+ criteria for SUD.

5

What are the 11 behavioral criteria for alcohol SUD?

1. More excessive use than intended
2. Persistent desire to control use
3. Lots of time dedicated to finding, taking, and recovering from the drug
4. Craving drug
5. Failure to meet obligations of life
6. Recurrent social / interpersonal problems because of drug
7. Activities are given up / reduced for drug
8. Use of alcohol where it is hazardous (i.e. DUI)
9. Continued use despite knowledge that it is causing problems
10. Tolerance
11. Withdrawal

6

What happens to alcohol use as you age?

Less binge-drinking with age, and more "current" use, although these parameters both peak around age 21-25

7

What are the three biggest predisposing factors for an alcohol use problem as you get older?

1. Age at first drink -> younger = much more likely

2. Family history of alcoholism

3. Male gender

8

What is the major source of opioids for non-medical use?

Prescription via doctor, or from a friend / relative who got it from a doctor
-> we are the problem

9

Is the prevalence of substance dependence changing over time?

No, despite our best efforts prevalence has been relatively flat

10

Who is at highest risk for developing a substance use disorder in general?

Those with co-morbid mental illness

11

What nucleus in the midbrain projects up into the cortex and is involved in addiction? Where does it project?

Ventral Tegmental Area - dopaminergic afferents

Projects to:
-Nucleus accumbens (reward center) - part of ventromedial striatum
-Ventral striatum (basal ganglia)
-Prefrontal cortex (impacts motivation)

12

What neurocircuit is the main contributor to reward reinforcement? What is its most important subcircuit?

Mesotelencephalic system

Mesolimbic system is subsystem which is VTA to Nucleus accumbens

Both pathways use dopamine

13

How do addictive drugs function within these neurobiologic systems?

They act as direct dopamine agonists feeding into the pathway, or indirect agonists (serve to increase the dopamine neurotransmitter in the synapse, i.e. how rivastigmine increases ACh)

14

How can opioids and benzodiazepines be addictive even if they are CNS depressants?

They can act preferentially on GABA interneurons to decrease the inhibition of VTA dopaminergic neurons to NAcc.

Disinhibition will lead to greater activation of dopamine pathway.

ALL addictive drugs increase dopamine delivery to NAcc.

15

How does the prefrontal cortex modulate limbic thinking and the rewards center?

Projects glutaminergic input onto the nucleus accumbens -> increased ability to have the mental will to suppress urges / emotional side of rewards.

PFC decision making is very important in control of urges

16

What are the functions of the anterior insular and cingulate cortexes with respect to emotional control?

Anterior Insular - more sensory in nature, control of visceral information coming in

Anterior cingulate cortex - more motor and limbic in nature - control the unpleasant experience of pain

Both are co-activated in response to various emotional stimuli and may play a role in fear and PTSD

17

How are other brain areas other than VTA to NAcc thought to play a role in addictive behavior?

Especially hippocampal and amygdalar inputs will modulate our stress response / learning, and change the likelihood of manifesting addictive behavior.

18

How does increasing dopamine and the various mechanisms of addictive drugs change the brain overtime? How does this explain the inheritance of addiction?

Leads to a change in gene expression which is conserved across all addictive drugs

This is often done via epigenetic mechanisms (changes in DNA acetylation / histones) that can persist overtime long after the stimulus is gone. Some of the propensity for these epigenetic changes may even be heritable -> some people are more prone to addiction.

19

Do antidepressants simply treat the symptoms of depression?

Actually no, there is some evidence that real meaningful changes of gene transcription can be reversed in various areas of the brain, with treatment

20

What is the neuroimmunopharmacologic perspective on stress and addiction?

In a high-stress, pro-inflammatory state, immune cells in the CNS actually promote addiction by releasing specific cytokines. Only in stress are these immune cells very active and can modulate limbic dopamine release.

>Reducing immune system can reduce withdrawal in rats

21

What is the opioid mechanism of immune-system interplay?

Opioids can actually bind the TLR4 receptors of microglia (inflammatory immune cells), and cause the release of cytokines which promote dopamine release (heightened reward).

22

What are tinctures, AWOL and powdered ethanol?

Tinctures - alcohol is mixed together with a drug in order to dissolve it. I.e. Robitussin

AWOL - Alcohol without liquid - an inhaled vapor

Powdered ethanol (cyclodextrins) - held in crystalline structure and can be eaten

23

What is the relative potency of ethanol? Where is it absorbed?

Quite low, requires ~13g serving to produce desired psychoactive effects

Absorbed rapidly in small intestines and slowly in the stomach. Does have some pulmonary absorption

24

What profession is most likely to be associated with alcohol dependence?

Painter's - inhalation of alcohol in paints (AWOL)

25

What is the distribution of ethanol and how does this relate to testing?

Distributes to total body water (but not fat), readily crosses BBB and placenta

Has no protein binding / sequestration, easily tested by a blood test

26

What is the elimination of ethanol and how does this relate to testing?

Metabolized in liver, although as much as 10% is excreted in urine, and 0.05% is exhaled in lungs -> basis of breathalyzer

27

Give two reasons why women have a lesser tolerance for ethanol than men?

1. More fat = less waterspace for ethanol to distribute

2. Men have far greater ethanol metabolism in the stomach than women

28

What drug can be used to inhibit alcohol dehydrogenase? What is it used for?

Fomepizole

Used to manage methanol and toxicity (ADH mediates toxic formic acid buildup)

29

How are MEOS enzymes different than regular alcohol dehydrogenase?

MEOS enzymes are inducible -> increase with high use levels

ADH is non-inducible

30

What is the mechanism of action of disulfiram?

Blocks oxidation of acetaldehyde to acetate - "antabuse"

31

What are the two main types of inhalants?

1. Hydrocarbons / Volatile solvents / gases

2. Nitrites

32

What are the acute and adverse effects of hydrocarbons?

Acute: Rapid onset euphoria, drunkness, headache / bloodshot eyes

Adverse: Anxiety, decreased appetite, tolerance / withdrawal symptoms

33

What are the acute and adverse effects of poppers and snappers?

Nitrites

Acute: Vascular / smooth muscle dilation, increase in cerebral blood flow

Adverse: Methemoglobinemia (amyl nitrite)

34

What are Roofies?

Flunitrazepam

35

What are GHB / GBL? What are they used for?

Gamma hydroxybutyrate

Gamma butyrolactone - longer-lasting precursor

Both are used as date rape drugs like roofies

36

What are the early and late mechanisms of acute ethanol intoxication?

Early - Excitation and arousal due to synaptic release of dopamine and NE

Late - Neuronal depression and reduced excitability due to enhanced GABA activity and decreased NMDA activity

37

How does alcohol exert its effects? Does it have an antagonist?

It affects boundary phospholipids around second messenger pathway receptors and influences -> changes in cation flux, adenylyl cyclase, and phospholipase C

-Has no pharmacologic antagonist

38

What is the eye finding associated with ethanol use?

Positional alcohol nystagmus - eyes will move due to lack of equilibration between the ECV and the fluid in the semicircular canals (alcohol has a lower specific gravity than water, and the two molecules are readily miscible)

39

What are the cardiovascular effects of ethanol use?

At high doses: labile blood pressure, arrhythmias, and stroke risk

Any dose: cutaneous vasodilation (flushing), and modest increase in HDL

40

What are the endocrine effects of ethanol use?

FSH/LH decrease, oxytocin increase (increased bonding)

Increased ACTH - cortisol levels

41

How does ethanol cause hypoglycemia?

Suppression of gluconeogenesis by accumulation of NADH (from oxidation of ethanol to acetaldehyde)

42

How does ethanol tolerance develop? What does this cause?

1. Pharmacodynamically - membrane changes occur to compensate for ethanol's effect on membrane phospholipids -> decrease GABA and increase NMDA levels back to normal

2. Metabolically - induction of MEOS (CYP450s 2E1, 3A4, and 1A2)

Causes dependence

43

What are the two stages of ethanol dependence + ethanol removal? How do they differ?

1. Abstinence syndrome - craving, hyperirritability, anxiety, tremor, insomnia, nausea, hallucination, and seizure (NMDA /GABA are no longer being depressed)

2. Delirium Tremens - About 3 days into abstinence, does not always occur -> confusion, disorientation, agitation, hyperpyresis (fever, dehydration)

44

What is used to treat alcohol overdose?

Only supportive therapy - ventilation, fluid, electrolytes

Flumazenil if co-administration of a benzodiazepine

45

What drugs can be given to blunt the withdrawal syndrome and prevent delirium tremens?

Substitutions: Benzos and Barbs
Symptomatic for seizures: Phenytoin, Gabapentin
Supportive: Thiamine (B1), NSAIDs

46

What are two alcohol anti-craving medications and how do they work?

Naltrexone - opioid antagonist, mechanism unclear

Acamprosate - NMDA antagonist + GABA-A agonist -> Second line due to frequent dosing

47

What is the chemical difference between powder cocaine and crack cocaine, and how is it functionally different?

Powder = cocaine HCl

Crack = Made by addition of bicarbonate to form a rock which can be smoked

48

What are diluents?

A reduction in purity of cocaine with drugs which look like or have similar effects, "stepping on" or "cutting" the drug
->i.e. procaine or lactose

49

What is the most rapid onset way to take cocaine?

Via inhalation (i.e. smoking crack)
-> IV administration is only slightly slower

50

What are the chemical properties of cocaine and where does it distribute? How is it metabolized?

Both hydrophilic / lipophilic, distributes to water and fat, but it rapidly metabolized by ester hydrolysis.

Has some active metabolites if N-demethylated in liver, but generally ester hydrolyzed by enzymes which can be induced in liver or exist in plasma.

51

What does a cocaine drug test look for?

Primarily the esterified breakdown products of cocaine

52

What eye findings are precipitated via cocaine?

Mydriasis + cycloplegia, can even precipitate glaucoma with long-term use

53

What is one very diagnostic hallucination that cocaine users experience in the long-term?

Tactile hallucinations - feel something creepy crawling under their skin

54

What is the final stage of longterm cocaine use?

Psychosis - with toxic paranoia, panic / hallucinations

Potential for seizures is also very high due to extreme CNS stimulation

55

What is most likely to kill you in cocaine overdose?

Anesthetic effect of cocaine causes a respiratory paralysis on brainstem, leading to death

56

Does tolerance occur in cocaine use? What is one special form?

Yes, acute and chronic tolerance will occur

Special form: Inverse tolerance -> lowering of seizure threshold and induction of schizophreniform manifestations

57

What is the triphasic withdrawal syndrome of chronic cocaine use?

1. Crash (hours) - huge depression, hypersomnolence, craving, and REM rebound

2. Subacute (weeks) - sustained depression (suicide may occur), dysphoria, lethargy, anhedonia

3. Extinction (months to years) - labile mood state, craving episodes due to personal triggers

58

How do we treat cocaine toxicity and withdrawal?

Toxicity - symptomatic management - maybe benzos to stop seizures

Withdrawal - cognitive behavioral therapy, no drugs have shown efficacy

59

What is the classic triad of opioid toxicity?

Coma, Respiratory Depression, Miosis

60

Why is tolerance for opioids safer than other drugs?

The LD50 rises with the ED50

61

What are the symptoms of opioid withdrawal?

opposite of opioid use:
mydriasis, hypertension, tachycardia, diarrhea, fever, insomnia, nausea, bone / muscle aches

62

What is the pill form of marijuana and why is the smoke form preferred?

Dronabinol

Because dosage of THC (delta9-tetrahydrocannabinol) can be perfectly controlled

63

What is the distribution of THC and how is this relevant to its halflife?

Widely distributed, highly protein bound (albumin, and lipoproteins alpha and beta) and accumulates in fat tissues -> acts as a depot to extend plasma half life

Half life is 19 hours but can take months to clear in chronic users

64

What is the effect of cannabinoids on learning?

State-dependent learning and amotivational syndrome

65

What are the effects of high end acute cannabinoid intoxication?

Anxiety, panic, delusions, depersonalization

66

What are the analgesia uses of cannabinoids?

Neuropathic and inflammatory pain

67

What are the effects of marijuana on temperature, appetite, nausea, and optical function?

Temperature: Hypothermia
Appetite: Increased
Nausea: Decreased (good for chemotherapy patients)
Optical function: Decreased intraocular pressure, may prevent glaucoma
Also suppresses REM sleep

68

What is the effect of cannabinoids on the immune system?

Suppresses it

69

What are the two subtypes of cannabinoid receptors and where are they present? What type of receptor are they? What is their general effect?

CB1 - Mainly in the brain
CB2 - immune cells mainly

They are GPCRs

General effect - CNS depression / decreased NT release

70

How do cannabinoids decrease NT release? Give an example cannabinoid that does this and what its derived from.

Anandamide - derived from arachidonic acid

Works by moving from post-synaptic to presynapic cell, inhibiting neurotransmitter release, then moving back to postsynaptic cell for degradation