Drugs of Abuse (Part 1) Flashcards
What are the 3 types of “Downers”?
- Opioids
- Alcohol
- Inhalants
What are the 5 types of “Uppers”?
- Cocaine
- Methamphetamine
- Ecstasy
- Nicotine
- Hallucinogens
What is the physiology of pleasure & reward?
DOPAMINE is imp. here
MesoLIMBIC pathway - contributes to pursuit & motivation
MesoCORTICAl pathway - drives feeding, sexual activity, & social interaction
What are Illicit &/or Addictive Drugs?
- Use of a substance to get “high” or be in a mentally altered state
- Psychoactive substances
- Many of these drugs activate the reward system (increase dopamine release)
What is Addiction or Substance Use Disorder?
A chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences.
* Health problems, disability, failure to meet major responsibilities at work, school or home
What is the Severe substance use disorder?
- Abstaining from drug use is not consistent
- Behaviour control is impaired
- Craving for drugs
- Diminished recognition of significant problems with one’s behaviours
- Emotional response is dysfunctional
What are the risk factors for substance use disorder?
- Age at time of drug experimentation (drug use changes the brain long term)
- Other medical conditions (mental health)
- Epigenetics
What is the current view of substance use disorder?
- drug addiction is a health problem
- it can be treated & prevented
When does the brain fully develop & what develops last?
age 20 & the Prefrontal cortex (decision making area)
What is the Harm Reduction Philosophy?
Harm reduction attempts to decrease the harmful consequences of illicit drug use to the individual, family, community, and society.
Example: safe injection sites, needle exchange programs
_______ or _______ of drug is fast & can create an intense “high” that many contribute to further drug seeking behaviour
Smoking
Injection
What is Physical dependence?
- The body needs the drug
- When a person stops using, they go through a withdrawal
- Tapering of the drug is required
What is Psychological dependence?
- The user believes they can not live without the drug
What is tolerance?
- No longer the desired response to drug
- More drug is required
- Development of tolerance is not substance abuse per se
- Tolerance for desired effect vs. drug toxicity
- Loss of tolerance with abstinence and lethality risk with resumption of drug use
What is Functional Tolerance?
- Pharmacodynamic tolerance
- Post-synaptic cell changes in CNS
- Desensitization of receptors (short term)
- Down regulation of receptors/signaling pathways (long
term) - Cross tolerance
– Where other similar drugs also no longer have a strong effect
–E.g.Methamphetamine&Cocaine
What is Metabolic Tolerance?
- Pharmacokinetic tolerance
- Increased drug metabolism due to repeated
exposure to drug - Enzyme induction
- Drug metabolism:
- CYP P450
- Glucuronidation
What is Reverse Tolerance?
- Can occur with drugs like alcohol and cocaine or amphetamines
- Behavioural sensitization to the drug (enhancement of (+) feelings)
- Often positive euphoric effects, which can drive
addiction - Locomotor activity is enhanced
What is withdrawal?
- Adverse symptoms that appear when a drug concentration drops in the body after prolonged drug use
- Person is likely to take the drug again to relieve the symptoms
What is the mech. of action of Opioids?
- Bind mu (μ) opioid receptors in the brain
- Mu1 receptors cause ANALGESIA
- Mu2 receptors cause RESPIRATORY DEPRESSION & EUPHORIA
What do Opioids do?
activate the reward system
- Tonic inhibition of VTA is blocked by opioids
- Increases dopamine output (from VTA)
- Mesolimbic and mesocortical activation
What are the routes of administration of Opioids?
- Heroin
- Injected, smoked or snorted
- Prescription opioids (codeine, oxycodone, fentanyl, etc.)
- Tablets or injection
- Heroin is highly lipophilic and rapidly absorbed
What is the metabolism of Heroin?
- Heroin is rapidly metabolized to morphine
- Glucuronidation in the liver is the key for morphine
metabolism - “High” usually lasts 1-2 hours
- All effects gone within 4 hours
What are the short term effects of Heroin?
- Euphoria (a ‘high’)
- Analgesia
- Respiratory depression
What are the long term effects of Heroin?
- Addiction/Dependence
- Tolerance (need higher amounts for same effect)
- Risk of an overdose
What is the Opioid withdrawal?
- Restlessness
- Yawning
- Sweating
- Anxiety
- Vomiting/Diarrhea
- Tachycardia
- Hypertension
- Muscle aches
- Lacrimation (tear formation)
What is Naloxone?
- Antidote for heroin overdose
- Binds Mu receptors with high
affinity - INVERSE AGONIST
- Induces opioid withdrawal at higher doses
- Administered intravenously, intramuscularly, and intranasally
What is the Tx for opioid use disorder?
- Methadone
- Full agonist (generates effect) - Buprenorphine
- Partial agonist (generates limited effect) - Naltrexone
- Antagonist (blocks effect)
What is Methadone?
- FULL OPIOID RECEPTOR AGONIST
- Meant to prevent withdrawal symptoms
- Very weakly activates the dopamine systems, so limited
euphoria - POTENTIAL FOR ABUSE, so patients in treatment typically only receive a daily dose. (TAPER)
What is Buprenorphine?
- PARTIAL AGONIST AT mu RECEPTORS
- Very high affinity for mu-opioid receptors (displaces other opioids)
- Less adverse effects (sedation, constipation)
- Given alone or with naloxone
- Can trigger withdrawal
What is Extended Release Naltrexone?
- Not currently available in Canada
- OPIOID RECEPTOR ANTAGONIST
- Given once a month as intramuscular injection
- Used in patients that have already gone through withdrawal
- Designed to REDUCE relapse by limiting opioid cravings and blocking effects if opioids are used
What is the most commonly used substance in society?
Alcohol
What is the cellular mech of action of Alcohol?
- Positive allosteric modulator of GABA receptors
- Hyperpolarizes the cell through increased Cl-
- Decreases glutamate binding to excitatory N- Methyl-D-Aspartate (NMDA) receptors
- Less neuronal excitation
What is Ethanol do to the Reward System?
- Reduces inhibition of VTA (more dopamine output).
- Increases endogenous opioids (endorphins).
- Inhibit glutamate neurons in the prefrontal cortex.
What are the short term effects of Alcohol?
- Low Doses
- Euphoria, excitation
- Vasodilation
– Feeling of warmth - Diuretic
– Decrease amount of vasopressin thus increasing the excretion of water - Higher Doses
- Slurred speech, sedation, ataxia
- Coma/Death (respiratory depression) (affecting respiration control in brainstem)
What are the factors affecting absorption?
- Concentration
- <10% beverages have low
concentration gradient - > 30% beverages increase intestinal mucous production
- Food in the stomach
- Prolongs gastric emptying; delays peak blood alcohol levels (opp. occurs if on an empty stomach)
What is the distribution of Alcohol?
- Alcohol is hydrophilic
- Enters all cells and tissues
- Distributes depending on water content
- This is influenced by:
- Age
- Sex
- Body weight
What is Alcohol Metabolism?
- 5% is excreted by kidneys or on the breath
- 95% is metabolized in the liver and stomach
ADH = alcohol dehydrogenase
ALDH = aldehyde dehydrogenase
What converts Ethanol –> Acetaldehyde?
ADH (alcohol dehydrogenase)
What converts Acetaldehyde –> Acetate?
ALDH (aldehyde dehydrogenase)
What is Oxidative EtOH metabolism?
- Acetaldehyde is highly reactive and toxic (underlies a lot of (-) effects of alcohol)
- Reactive oxygen species are produced
- NADH increases causing an imbalance in reduction-
oxidation (redox) state of liver cells (therefore, more likely to damage the liver cells) - More oxygen is consumed by the mitochondria to
replenish NAD+
What are the 2 of Ethanol Active Metabolites?
- Acetaldehyde
- Acetate
What is Acetaldehyde? What can it cause?
- Psychoactive compound with similar brain effects as alcohol (an intermediate in the breakdown of alcohol)
- Causes flushing
- Acetaldehyde-lysine adducts can cause an immune reaction and antibody formation. Leads to hepatoxicity.
- Forms carcinogenic DNA adducts.
- Inhibits mitochondria
- TOXIC
What is Acetate? What can it cause?
- Most acetate leaves the liver and is metabolized to CO2 in heart, skeletal muscle, and the brain
- Increases liver blood flow, DEPRESSES THE CNS (causing sustained sedation for ex)
- Acetate can also be converted to Acetyl-CoA and used as an ENERGY SOURCE
What causes a hangover?
- Dehydration
- Toxic effects of alcohol (acetaldehyde)
- Gastrointestinal disturbances due to acute inflammation from excessive alcohol
- Low blood sugar- alcohol inhibits gluconeogenesis and depletes body glucose stores
- Headache- caused by vasodilation
What are the Genetic Factors Influencing Alcohol Metabolism?
- Alcohol dehydrogenase (ADH)
- Aldehyde dehydrogenase (ALDH)
What are the Alcohol dehydrogenase (ADH) polymorphisms?
- Several different polymorphisms exist creating diversity in alcohol binding affinity and enzyme kinetics
- ADH1B*1- A slow ADH variant is prominent in most populations
- ADH1B*2-A fast ADH variant is found in almost 90% of Asian populations and 5% of European populations (rapidly metabolize ethanol to acetaldehyde)
- Associated with reduced alcohol abuse
What is a problem with Aldehyde dehydrogenase (ALDH)?
- 50% of people of Taiwanese, Chinese, and Japanese descent have a variant with no acetaldehyde metabolizing activity (cannot convert Acetaldehyde to Acetate, therefore have accumulation of Acetaldehyde & MUCH more (-) SE’s to alcohol - ex: extreme flushing, headache, GI problems etc.)
- More negative responses to alcohol (“alcohol intolerance”)
- 10 fold reduction in alcohol dependence (use disorder)
- particularly, if they also have rapid metabolite variant of ADH (therefore, rapidly converting ethanol –> acetaldehyde & then cannot metabolize that acetaldehyde)
______ have a smaller volume of distribution (higher blood alcohol concentration)
FEMALES
______ have very low levels of ADH in their stomach, so they absorb more EtOH into their bloodstream
FEMALES
____________ (estrogen and testosterone) increase the rate of alcohol dehydrogenase
Sex hormones
- Menstrual cycles and oral contraceptives may influence alcohol metabolism
What are the long term effects of Alcohol?
- Increases blood pressure, leads to heart failure (perhaps due to regular vasodilation occuring)
- LIVER DAMAGE
- 75% of deaths due to cirrhosis of the liver
- Increases risk of oral cavity, esophagus, and liver
cancer - Neurologic complications (b/c of affects to CNS)
What causes Tolerance?
Decreased sensitivity to the CNS depressant effects of EtOH
* Up-regulation of excitatory receptors (NMDA)
* Down regulation of GABA receptors
Requires more alcohol consumption for the same effect
What enhances ADH & CYP2E1 metabolism leading to more breakdown of alcohol?
Heavy drinking
Requires more alcohol consumption for the same effect
What is the Alcohol Withdrawal Timeline?
- Anxiety, insomnia, nausea, & abdominal pain
- High BP, increased body temp
- Hallucinations, fever, seizures, & agitation
When do Delirium tremens occur within the Alcohol Withdrawal Timeline? & for how long?
in Stage 3 for up to weeks if not treated
What happens after Chronic Alcohol & Withdrawal?
Reduced synaptic GABA activity (due to changes in receptor properties)
Reduced Cl- influx
Reduced inhibition of neuron
–> Anxiety, hyperexcitability
What is Glutamate signalling like during withdrawal?
Increased glutamate released from the presynaptic neuron
Reduced uptake of glutamate in glia cells
Glutamate levels in the synaptic cleft are elevated
More receptors are avail, receptors are more active
What are the Tx’s for Alcohol Use Disorder?
- Benzodiazepines (GABA receptor agonists)
- Disulfiram (inhibitor of aldehyde dehydrogenase)
- Acamprosate (blocks NMDA receptors while activating GABA receptors)
- Naltrexone (Opioid antagonist)
What are Benzodiazepines?
(GABA receptor agonists)
* Used to treat alcohol withdrawal symptoms (particularly
hallucinations, seizures and delirium tremens)
What is Disulfiram?
inhibitor of aldehyde dehydrogenase
* Causes acetaldehyde to accumulate after drinking leading to nausea, vomiting, palpitations, possible seizures
* Meant to deter drinking (makes them feel sick)
What is Acamprosate?
- Stabilize GABA and glutamate signalling after long term drinking
- Blocks NMDA receptors while activating GABA receptors
- Reduces withdrawal symptoms
- Reduces cravings, alcohol intake and avoid relapse of heavy drinking
- Not metabolized by the liver so it can be given to patients with liver disease or who continue to drink alcohol
(perhaps better for long term)
What is Naltrexone?
Opioid antagonist- blocks endogenous opioids in VTA and nucleus accumbens
(blocks rewarding feelings of drinking alcohol)
When is Naltrexone used?
May help to reduce alcohol intake and avoid relapse of heavy drinking
When should Naltrexone NOT be used?
with disulfiram because both are potentially hepatotoxic (b/c both have effects on the liver)
What happens if patients also abusing opioids take Naltrexone for drinking?
Patients also abusing opioids may go through withdrawal if taking naltrexone for drinking (imp. to know pt history prior)
What are the Common Household Chemicals that are Classes of Inhalants?
VOLATILE SOLVENTS
* Liquids that vaporize at room temp
* Glues, paint thinner, felt-tip markers, etc.
AEROSOLS
* Sprays that contain propellants and solvents
* Spray paint, deodorant and hair sprays, oil cooking sprays
GASES
* Butane lighters, propane tanks, etc.
* Most commonly abused is nitrous oxide which is found in whipping cream cannisters **
What is Inhalants mech. of action?
(the same as alcohol)
* Allosteric modulators of GABA receptors
* Blocker of NMDA receptors
* WEAKLY enhance dopamine release, contributing to
possible addiction
What are the Routes of Administration of Inhalants?
Inhalation: ENTERS BRAIN QUICKLY (WITHIN 10s)
* Sniffing” or “snorting” fumes from containers;
* Spraying aerosols directly into the nose or mouth;
* “Bagging” — sniffing or inhaling fumes from substances sprayed or deposited inside a plastic or paper bag
* “Huffing” from an inhalant-soaked rag over the mouth
* Inhaling from balloons filled with nitrous oxide.
What are the Pharmacokinetics of Inhalants?
- Intoxication only lasts a few minutes
- (therefore) Drives frequent use to continue effects
- Some metabolism in the liver, which generates toxic metabolites and contributes to liver toxicity
- Elimination- mostly through expired air
What are the short term effects of inhalants?
- Effects similar to alcohol intoxication
- Each class of inhalant causes slightly different effects
- Even single use or sporadic use can be very dangerous
(stresses heart & liver)
What are the short term effects of inhalants at higher doses?
- SEVERE ARRHYTHMIA leading to cardiac arrest- known as Sudden Sniffing Death Syndrome
- A LACK OF OXYGEN causing SUFFOCATION
- Severe seizures
- Coma
What are the long term effects of inhalants?
The brain
* Highly toxic
* Permanent damage
* MYELIN SHEATH that promotes axon conduction is degraded leading to MULTIPLE-SCLEROSIS-LIKE SYMPTOMS
* Neurologic syndromes with deficits in cognition, memory, movement control, etc.
- Toxic damage to most organs
What is Dependence & Withdrawal for Inhalants?
- Products with toluene and nitrous oxide are most likely to lead to some dependence
- OVERALL, LESS ADDICTIVE THAN OTHER DEPRESSANTS (but much more toxic)
- Heavy users report some withdrawal symptoms, but this seems to be related more to toxicity of use.
