Drugs of Abuse Flashcards
1
Q
Substance Use Disorder
A
- A problematic pattern of use leading to significant impairment or distress
- Pharmacological profile of the abused agent < Psychosocial aspects driving the abuse
- Cluster of cognitive, behavioral, and physiological sx indicating that the individual continues using the substance despite significant substance related problems
- Drug seeking behavior is a critical element of substance abuse disorder
2
Q
Innate Tolerance
A
Pre-existent tolerance due to genetic variability
Individuals w/ lower innate sensitivity to ethanol are at higher risk for alcoholism
3
Q
Acquired Tolerance
A
- ↓ Effect of a substance that develops after continued use
- Dose response curve shifts right ⇒ more substance is required to achieve the same effect
-
Drug toxicity curve shifts less than the psychopharmacological effect
- Ex. Opiods: brain respiratory centers tolerance < psychopharmacologic effects ⇒ pt ↑ dose to achieve the same effect ⇒ ↑ risk of respiratory depression
4
Q
Pharmacokinetic Tolerance
A
Body’s ↑ capacity to metabolize or excrete the drugs
Ex. chronic ethanol consumption ⇒ induction of the mixed ethanol microsomal oxidizing system (cytochrome p450 system) ⇒ ↓ levels of ethanol in the body
5
Q
Pharmacodynamic Tolerance
A
Refers to neuronal adaptation, resulting in a reduced response to the substance
Degree of tolerance via this mechanism is much greater than pharmacokinetic tolerance
6
Q
Short-term
Pharmacodynamic Tolerance
A
Refers to neuronal adaptation, resulting in a reduced response to the substance
Short-term tolerance ⇒ ∆ in neurotransmitter release or receptors
7
Q
Long-term
Pharmacodynamic Tolerance
A
Refers to neuronal adaptation, resulting in a reduced response to the substance.
Long-term tolerance ⇒ neuroadaptive changes 2/2 ∆ gene expression responsible for the action of the drug
May explain the cravings that occur after the drug has been discontinued
ETOH example:
- ETOH acutely ⊕ GABA receptors and ⊗ NMDA receptors
- Leads to dec. excitability
- Long-term exposure
- ∆ in subunit structure of GABA receptors ⇒ dec. sensitivity
- Phosphorylation of NMDA receptors ⇒ enhanced conduction Ca2+
- Changes are in the opposite direction of the acute effect
8
Q
Learned Tolerance
A
There are two types:
-
Behavioral Tolerance
- Changes in behavior to accommodate to the drug’s effects
-
Conditioned Tolerance
- Environmental cues associated w/ the drug, which elicit reflexive compensatory changes
- Ex. drug paraphernalia may elicit pre-emptory compensatory changes to counteract the drug
- A drug taken in a familiar environment may have a lethal effect if taken in an unfamiliar environment
9
Q
Physical Dependence
A
Related to tolerance and neuroadaptation
- Substance use disorders ⇒ need the drug to be present to maintain “near” normal functioning
-
Removal of drug ⇒ an acute w/d syndrome
- Lasts days while the system is re-equilibrating to the absence of drug
- Acute phase is mediated by signal transduction systems at the cellular level
- After the acute phase, a protracted w/d syndrome occurs which may continue indefinitely
- Manifested as craving for the drug
- Likely due to dysregulation of learning and reward systems in the brain
10
Q
Psychological Dependence
A
- This type of dependence is mediated by a common neuronal pathway that leads to reinforcement
- All drugs of abuse ↑ dopamine release from ventral tegmental area → nucleus accumbens
- Peak of dopamine release in the nucleus accumbens corresponds w/ peak drug effect on CNS
- Important in the brain reward pathway, ⊕ of nucleus accumbens reinforces motivated behavior and learning/memory via links to other parts of the brain
- Long-term dependence after w/d is over due to an
- *interaction between the reward and memory circuitry**
- Cues in the environment can generate intense cravings and relapse
11
Q
Substance Use Disorders
Factors
A
Variables affecting development:
-
Pharmacokinetics
- The more rapid the rise of drugs in the brain, the
- *greater activation of reward pathways**
- Heroin rapidly enters the brain ⇒ more addictive than morphine
- Cocaine:
- Chewing on coca leaves has a relatively low potential for addiction
- Inhaling extracted cocaine through the nasal mucosa is more reinforcing
- The most reinforcing and therefore, most addictive are intravenous injections or inhalation of smoked freebase
- This leads to the most rapid rise in cocaine concentration
-
Genetics
- Most studied in alcoholism
- Inheritance may account for 50-60% of variability in this disorder
- Polymorphisms in alcohol dehydrogenase and acetaldehyde dehydrogenase ⇒ ↑ levels of acetaldehyde ⇒ flushing and other sx which are aversive
- Individuals w/ this polymorphism would be less likely to develop alcoholism
- Most studied in alcoholism
-
Psychiatric Disorders
- Association between psychiatric disorders and substance abuse disorders
- Individuals w/ major depressive disorders are 2-3x more likely to have a substance abuse disorder
- A large proportion of addicts self-medicate to reduce distress associated w/ co-occurring psychiatric and medical disorders
- These conditions are then further exacerbated by the continued substance abuse
12
Q
Opioids
A
- CNS Depressant
- Multiple inputs into the reward circuits of the brain
- Opioids are co-abused w/ other drugs w/ different pharmacological actions
- Heroin + cocaine = “speedball”
- Shows significant tolerance
- Drug should be tapered when discontinued to avoid severe w/d sx
13
Q
Barbiturates and Benzodiazepines
A
- CNS Depressant
- Euphoric feelings occur early in intoxication and may contribute to the abuse potential
- Anxiolytic properties may also contribute to their abuse liability
- Often co-abused w/ other drugs, e.g. ethanol
- Combo w/ ethanol can cause respiratory depression and death
14
Q
Alcohol
A
- CNS Depressant
- Alcoholism is the most prevalent drug problem in the US, because it is readily available, affordable and legal
- It has complex mechanism of action, involving GABA, NMDA, and cannabinoid receptors
15
Q
Nicotine
Overview
A
CNS stimulant
-
Mechanism of Action:
- Activates nicotinic receptors in the body, CNS, periphery, and NMJ
- ⊕ of nicotinic receptors in VTA ⇒ dopamine release in the nucleus accumbens ⇒ activates reward pathway
- Inhaled and has a short half-life
- High addiction potential
-
CNS Effects:
- Nicotine is rapidly distributed into the brain
- ⊕ of nicotinic receptors in the CNS has anxiolytic effects, ↑ arousal, and suppresses appetite
17
Q
Nicotine
Withdrawal
A
- Leads to irritability, anxiety, autonomic arousal, and intense craving
- Treatment:
-
Nicotine replacement therapy
- Chewing gum, lozenges, or transdermal patches
-
Varenicline
- Partial agonist @ α4β2 nicotinic receptor
-
Bupropion (antidepressant)
- Enhances dopamine release in the nucleus accumbens
-
Nicotine replacement therapy
19
Q
Amphetamine/Cocaine
Mechanism of Action
A
CNS stimulant
-
Cocaine
- ⊗ Reuptake monoamines in the presynaptic terminal
- Most effective at blocking reuptake of dopamine
- Can also block NE and 5-HT transporters @ higher concentrations
-
Amphetamine
- Substrate for the monoamines transporter
- Enters the synaptic terminal ⇒ displaces primarily NE from the vesicles
- NE then exits the synaptic terminal through the reversal of the transporter
- Amphetamine causes the release of norepinephrine
- Other neurotransmitter systems are affected but less so
20
Q
Amphetamine/Cocaine
CNS Effects
A
-
Locus ceruleus contains noradrenergic cell bodies
- Diffuse projections throughout the brain
- Descending projections to the medulla and the spinal cord
- Cocaine and amphetamine enhance the actions of norepinephrine released from these projections ⇒ ↑ arousal and vigilance
- Also enhance the release of dopamine within the nucleus accumbens ⇒ activates the reward pathway
- Initial effects: profound sense of well-being, energy, and optimism
- Contributes to abuse potential
- Initial effects can progress to psychomotor agitation, paranoia and psychosis
- Cocaine has more euphoric effects initially d/t release of dopamine ⇒ effect is relatively short lived
- Cocaine can alter tactile sensation, causing the user to feel insects crawling below the skin ⇒ “cocaine bugs”
- Effects of amphetamine are more prolonged
- Initial effects: profound sense of well-being, energy, and optimism
22
Q
Methamphetaminea
A
CNS stimulant
- _Related to amphetamin_e, however, by comparison, it causes more dopamine release
- Crystal form of methamphetamine can be smoked, resulting, very rapid rate of dopamine release in the nucleus accumbens
- Enhances the abuse potential of the drug
- Cheap cost and wide availability have led to widespread abuse of this agent
24
Q
Caffeine
A
CNS stimulant
- A methylxanthine
- Found in many beverages and chocolate
-
⊗ presynaptic adenosine receptors ⇒ normally ⊗ release of dopamine and norepinephrine
- Results in enhanced dopamine/norepinephrine release ⇒ stimulatory effect
- Adenosine is thought to promote sleep, so caffeine works to counteract this effect
- W/d sx are mild, but may include lethargy, irritability and headache
25
Q
Cannabis
Mechanism of Action
A
Psychoactive Drug
- Active component is tetrahydrocannabinol (THC)
- Partial agonist at the cannabinoid receptor (CB1)
- THC mimics anandamide ⇒ endogenous ligand derived from arachidonic acid
- Made in activated dopaminergic neurons of VTA by diacylglycerol lipase
- Acts as a retrograde neurotransmitter on presynaptic GABAergic neuron ⇒ ⊗ their inhibitory action
- Disinhibition of these interneurons ⇒ release of dopamine within the nucleus accumbens
29
Q
Lysergic Acid (LSD)
A
Synthetic ergot derivative
-
⊕ serotonin-2 receptors in cortical layers ⇒ ↑ glutamate release
- Mesolimbic dopamine system is not targeted
- Usually causes visual hallucinations but may also cause other types
- Some report synesthesia ⇒ condition where one sensory modality assumes the characteristics of another
- Ex. colors may be heard
- Little effect on cognitive function or arousal
- Mood changes are usually pleasant but can be terrifying and cause a panic attack ⇒ “bad trip”
