Lecture 14: Drugs of abuse Flashcards
What is recreational drug use?
Use of a pharmacologically active agent (drug) for purposes other than its intended medicinal or other purpose.
Use of a substance/drug to get “high” or be in an mentally altered state
Psychoactive substances
Misuse vs abuse
Misuse: person taking drug to alleviate symptom but the drug they are taking doesn’t do that
Abuse: looking for drugs with main intention of getting high, not what drug is actually used for
Characteristics of addiction
Inability to consistently Abstain
Impairment in Behavioral control
Craving; or increased “hunger” for drugs or rewarding experiences;
Diminished recognition of significant problems with one’s behaviors and
interpersonal relationships; and
A dysfunctional Emotional response
How do addictive drugs cause addiction?
Activation of the mesolimbic dopamine system
Three classes: Gio protein-coupled receptors
Ionotropic receptors
Dopamine transporters
See figure
How do class I addictive drugs work?
Gio protein-coupled receptors
Block GPCRs responsible for recognizing GABA (inhibitory neurotransmitter)
With less GABA effect, neurons fire more easily = euphoria
How do class II addictive drugs work?
Ionotropic receptors
How do class III addictive drugs work?
Dopamine transporters
What is dependence? How is it influenced by withdrawal?
the state at which the user functions normally only when taking the drug
Withdrawal symptoms re-enforce dependence and are a response of the body to less drug
Physiological dependence example
withdrawal of alcohol from an alcoholic; life
threatening
Psychological dependence example
It implies addiction and pertains to desirable properties or “the high”
repeated crack cocaine use
drug seeking habits in spite of risks
repeated dosing related need to keep the “high”
What pathways play a role in cravings to use drugs again?
Dopaminergic pathways
Opioids and pathways for dependence
thought to have separate neurochemical pathways for physiological dependence versus psychological dependence
What is tolerance?
a state at which there is no longer the desired response to the drug
What is the progressive model of tolerance?
To achieve the desired response, more drug is required
Is tolerance addiction?
No, development of tolerance is not necessarily addiction
Tolerance to drug effect vs drug lethality
These two types of tolerance can differ and thus affect therapeutic index
What is reverse tolerance?
sensitization
can persist for years e.g. cocaine and
amphetamines
Impairing effects of a drug based on drug concentration
Impairing effects of a drug can be greater during rise to maximal concentration that in comparison on the downward slope: e.g. ethanol
What is functional tolerance?
aka pharmacodynamic tolerance
Change in post synapses of CNS
Desensitization of receptors (short)
Down regulation of receptors/signalling pathways (long_
What type of drugs cause functional tolerance
Psychoactive drugs
Hormones
Examples of post-synaptic receptors
G-protein
Ionotropic
Extrasynaptic proteins
What is cross tolerance in functional tolerance?
What hen multiple drugs affect the same receptor, tolerance to one drug may cause tolerance to another, different drug that acts on the same receptor
What is metabolic tolerance?
aka pharmacokinetic tolerance
Adaptation of the metabolic “machinery” to repeated exposure to a drug
Similar to drug resistance mechanisms
Enzyme induction
Drug metabolism (CYP P450, glucuronidation)
Cross tolerance in metabolic tolerance
If the enzyme affected by one drug also metabolizes other drugs, the metabolism of the other drugs can be affected
What is withdrawal?
a maladaptive behavioral change, with physiological and cognitive concomitants
Occurs when blood or tissue concentrations of a substance decline in an individual who had maintained prolonged heavy use of the substance
See figure
What is a person in withdrawal likely to do?
person is likely to take the substance to relieve or to avoid those symptoms
In what drugs are physiological signs of withdrawal obvious?
Alcohol
Hypnotics
Anxiolytics
Opioids
Sedatives
For what drugs are the physiological signs of withdrawal less obvious?
Amphetamines
Nicotine
Cocaine
Cannabis
Flow chart of events leading to addiction
See figure
What causes addiction?
Behavioural, environmental and biological factors
Similar to diabetes, cancer and heart disease
Using a drug may be a choice, but the effects (addiction) are not
Benefits of treating addiction as a disease?
Removes stigma
Standardization of diagnosis and therapy
Emergency department stats
See figure
Drug use among people in drug treatment by region of the world
See figure
People who inject drugs and HIV prevalence
High PWID, high HIV: south west africa, eastern and south-eastern europe
High PWID, low HIV: North america, central asia, Oceania
Low PWID, low HIV: africa, south asia, latin america, western and and central europe
See figure
Risk of different drugs
Most dangerous: opioids
How to diagnose abuse
DSM-V (questionnaire) - see figure
Laboratory testing
What can laboratory testing look for?
Indicates recent use
Not related to frequency or intensity (drugs can be stored in the body)
Monitor compliance
Determine extent of damage (ex: alcoholic lier disease)
Epidemiology (info for the future)
Drawback with laboratory tests to diagnose abuse
It is a targeted detection, so you can’t detect a drug for which you don’t have a test
Not related to frequency or intensity
Recreational drug classes
Alcohols
Cannabinoids
Cocaine
Amphetamine-like
Opioids
Sedative hypnotics
Hallucinogens
Antidepressants
Antipsychotics
Inhalants
Other: e.g. GHB, DMMA
What is a natural opioid?
Morphine
Natural vs synthetic opioid structure
See figure
Continum of opiates and opioids
Natural: opiates
Synthetic: opioids
See figure
Considerations with source of drug
Prescription vs street market
Considerations with scheduled drugs
Legal vs illegal highs
What are the endogenous opioids?
Enkephalins
Endorphins
Dynorphins (peptides)
Why are opioids used as recreational drugs?
Euphoric affect
Examples of opioids
Morphine
Heroin
Codeine
Dextromethorphan
Oxycodone
Hydromorphone
Fentanyl
Meperidine
Acetylfentanyl (designer drug)
How is an opioid chosen?
Route of administration
Availability
Duration of high
Potency
Side effects
Clinical use of opioids
Most efficacious analgesic drugs available
Side effects of opioids
Respiratory depression
Variable euphoric affect
Dependence
Prominent affect on GI tract
Miosis
How do opioids differ?
They are similar in pharmacology but differ in:
Duration of action
Oral availability
Relative potency
Adverse side effect profile
What is the potency of opioids related to?
Binding affinity for mu, kappa and delta receptors
Most are selective for mu receptor (exception: pentazocine)
Full vs mixed agonist
Desirable effects of opioids
Analgesia
Euphoria
Sedation
Relief of anxiety
Depress cough reflex
Undesirable effects of opioids
Dysphoria
dizziness
nausea
Vomiting
Constipation
Biliary tract spasm
Urinary retention
Withdrawal
Respiratory depression
What are common autopsy findings with opioid overdose?
Pulmonary congestion and frothing of mouth;
witnesses often comment that deceased was heavily snoring prior to death: blockade of respiratory centres to pCO2
Routes of administration of opioids
Oral:readily absorbed
IV
IM
Smoked
Intranasal
Transdermal: ++lipophilicity
What does lipophilicity of an opioid determine?
distribution and CNS levels
Higher lipophilicity drugs are better given transdermally
What does prolonged affect of opioids cause?
accumulation of drug/formation of active metabolites
What happens during first pass metabolism of opioids?
Glucuronidaton (liver) and renal elimination
Also undergo enterohepatic recycling
Mitigation strategies against opioid diversion and misuse
Screening tools to ID patients with substance use disorder
Use data from the prescription drug monitoring program (ID doctor shopping)
Use of urine drug screening (provides info on drug use not reported by patients)
Doctor-patient agreement adherence (personal contract)
Carfentanil in MB
Rise in overdose related deaths (4 deaths/week, now 1/month)
Post mortem blood conc of carfentanil: 0.03 to 13 ng/ml
Reports indicate accidental overdoses
Active abuse is on the rise (blotters)
What is naloxone?
Emergency antidote to opioid OD
Characteristics of naloxone?
Different admin routes lead to different concentrations in the blood
Hard to know how much to give to patient
See figure
Which part of the world has the highest cannabis usage?
Australia
Canada
France
Nigeria
See figure
Use of illicit drugs in youths (12-17)
Cannabis is most popular, followed by psychotherapeutics, followed by inhalants and hallucinogens
See figure
Variable effects of cannabis
Dysphoria (unease or dissatisfaction) to hallucination
Dependence and tolerance in cannabis use
1 in 9 first time users become dependent
Tolerance with chronic use
What is the major psychoactive constituent in cannabis?
THC
Route of administration of cannabis
Oral or smoked
What is CB1 linked to?
MAP kinase /adenylyl cyclase/K-channel-linked
What are the endogenous cannabinoids?
anadamide and 2-arachidonyl glycerol
Active ingredient in cannabis
Delta-9-tetrahydrocannabinol (THC)
Amount of THC in leaves, hashih and oil extract
Leaves: 2-5%
Hasish: 5-15%
Oil extract: >20%
CNS effects of cannabis
Euphoria
Lack of concentration
Motor function impairment (reaction time): driving under the influence
Impairment can persist after the perceived high has dissipated
Impaired attention, memory and learning
Users at heightened anxious state (CB1 in amygdala)
paranoia
CVS effects of cannabis
Increased HR
Decreased BP (vasodilation)
Respiratory effects of cannabis
Decreased RR
Bronchodilation
Lung damage (smoking)
Drug interactions with cannabis
Use with cocaine and amphetamines may lead to increased hypertension, tachycardia and possible
cardiotoxicity
Additive effect with CNS depressants (impaired driving enhanced with alcohol)
Cannabis PK (smoking)
rapid onset (minutes)
18-50% bioavailability
dynamics: # puffs, duration and volume of inhalation, hold
Cannabis PK (oral)
Slower onset (1-5 hours)
6-18% bioavailability
1st pass effect
Lipophilicity of THC
THC is lipophilic and undergoes enterohepatic circulation
Urinary THC half life
Urinary t1/2 of 11-carboxy-THC (as glucuronide)
3 days in chronic user
Issues with legalization of cannabis
Danger to kids (acute toxicity through edibles)
Harmful effects
DUI
Rates of paediatric marijuana calls in colorado (legalized marijuana) vs rest of US
Much higher in colorado
See figure
Harmful effects of marijuana
Short term: impaired short erm memory, impaired motor coordination, altered judgement (risk of sexual behaviours), paranoia and psychosis (high doses)
Long term: addiction, altered brain development, poor educational outcome, cognitive impairment, diminished life satisfaction and achievement, symptoms of chronic bronchitis, risk of chronic psychosis disorders in persons with predisposition
Marijuana and DUI’s
Volume of distribution in body is variable
Amount of THC in blood does not always correlate with behaviour
What are acceptable limits of THC in blood?
2-5 ng/ml
