Tolerance and Dependence on CNS active drugs (DONE) Flashcards
Definition of drug abuse
Administration of any pharmacological substance in a way which deviates from approved medical or social patterns
Self administration drug abuse
Excessive self medication
Abuse of drugs in sport
Patient non-compliance
Administration by others drug abuse
Over or mis-prescribing
Unnecessary counter prescribing
Excessive antibiotic addition to animal foodstuffs in factory farming
Tolerance definition
The need to employ increasing doses of drug in order to produce the same effect as on first exposure
Dispositional tolerance
Functional tolerance
Conditioned tolerance
Dependence definition
A state or condition where there is a compulsion to take a drug continually in order to experience its psychic effects and sometimes to avoid the physical discomfort of its absence
What is dispositional tolerance?
Adaptations in drug- ADME, less drug at active site so need to take more
e.g. barbiturates or alcohol- induce hepatic microsomal enzymes
What is functional tolerance?
Changes in properties and function of target tissue rendering it less sensitive to the substance Changes in receptor number Receptor uncoupling Exhaustion of modulators Tolerance at reuptake transporter
What are the different types of changes in receptor density?
Receptor down-regulation: usually with agonists on prolonged exposure
Receptor up-regulation: usually occurs with antagonists or low levels of endogenous agonist/ transmitter e.g. denervation
How does receptor up regulation differ between new drugs and tolerance?
Dug naïve- antagonist blocks endogenous transmitter or endogenous agonist
Tolerance- cell synthesises and inserts new receptors into cell membrane
How does receptor second messenger uncoupling differ between new drugs and tolerance?
Drug naïve- agonist stimulates adenylyl cyclase linked to G protein
Tolerance- repeated drug exposure uncouples enzyme from G-protein
How does receptor ion channel uncoupling differ between new drugs and tolerance?
Drug naïve- drug causes a change in ion flux to alter ion concentration and potential across membrane
Tolerance- receptor ion channel uncoupling impairs ion fluxes, ion concentration and potential across membrane
What happens in the exhaustion of mediators?
In some cases, tolerance is associated with depletion of intermediate substances
e.g. amphetamines and cocaine release neuronal NA, DA and other amines
These releasable transmitter stores can be depleted
Tolerance at reuptake transporters
Cocaine frequent use tolerance (dependence prone person):
Tolerance to inhibition of DA uptake i.e. transporters
Tolerance to NA uptake and positive chronotropic action
Probably longer term- some down regulation of DA receptors
Some exhaustion of DA stores
Conditioned tolerance
Repeated administration of drug in given circumstances
Psychological tolerance factor- variable
Psychological anticipation of drug effect
Conditioned response can lead to positive tolerance and negative tolerance
Negative conditioned tolerance
Reverse tolerance- abuser learns to enhance the so-called desired effect of the drug
Positive conditioned tolerance
Conditioned response opposite to that expected of drug- abuser learns to behave in opposition to the drug
High grade tolerance
Usually associated with functional tolerance
Person can take 10-20x the naïve dose
e.g. opioids, cocaine, CNS stimulants
Low grade tolerance
Sometimes dispositional tolerance
Person can take 2-3x the naïve dose
e.g. CNS depressants, alcohol, barbiturates
Acute vs chronic tolerance
Acute: develops after single exposure to drug, may develop during exposure to drug
Chronic: develops after several exposures to drug
Cross tolerance
Occurs when an increased amount of a second drug is required to produce the same effect after tolerance to a first drug has been established
Difference between abuse dependence and therapeutic dependence
Insulin dependent diabetic- wishes to avoid discomfort of its absence i.e. compulsion to take the drug
B-blockers- long term withdrawal causes hypertensive rebound i.e. compulsion to take the drug
Drug abstinence
Caused by drug taking cessation or antagonism by drugs
Severity depends on drug, dose or duration of use
Withdrawal relief and salience
Withdrawal relief- suppression of withdrawal symptoms by administration of a further dose of drug
Salience- compulsion to continue taking the drug in spite of all other considerations (legal, financial, health)
Classification of drugs of dependence
Alcohol Amphetamine Cannabis Cocaine Hallucinogen Khat Opioid Volatile solvent
Psychological dependence
Condition where there is an emotional or mental drive to continue taking drug to maintain a sense of well being
On drug withdrawal: emotional discomfort, ill-defined dissatisfaction, mild desire to take drug, intense craving for drug, drug seeking behaviour
Drug dependence and reward
Humans and animals engage in behaviours that are rewarding
Reward- pleasurable feelings that provide positive reinforcement so that the behaviour is repeated
Physical dependence
Altered or adaptive physiological state produced by repeated administration of drug
When drug (or metabolites) are necessary for continued functioning of certain body processes
Related to dose and pharmacological action of drug
On withdrawal of drug, physical and psychological signs
Opioid tolerance and dependence
Natural- opium alkaloids
Synthetic- heroin, pethidine, methadone
Endogenous- enkephalins, endorphins, dynorphins
Opioid receptors:
mu- central analgesia- euphoria, dependence
kappa- analgesia via receptors other than mu
sigma- analgesia- stress induced analgesia
Opioid tolerance
Tolerance develops to some opioid effects (not mioisis or constipation)
High grade tolerance
Mechanisms- some enzyme induction, receptor uncoupling
No change in receptor number or affinity
Withdrawal syndrome
Psychological craving Thermoregulatory disturbance Sexual disturbances Sympatho-adrenal overactivity GI reactions
Dependence mechanisms
Continual opioid inhibitory influence (on soma or terminals) causes hypertrophy of cells linked down stream
Withdrawal syndrome expresses overactivity of NA, ACh, DA and 5-HT
