PHA2022 DAB1-6

What is drug addiction?

Compulsive and out of control drug use despite serious negative consequences that is associated with high risk of relapse upon cessation

A 33 year follow up study on 581 addicts (started in 1962) that examined the status of patients in 1997 found that

- 284 dead due to overdose

- 241 (of the 297 living) still addicted

Addictive drugs include

- Opioids

- Alcohol, barbiturates, benzodiazepines

- Cannabinoids

- Caffeine

- Nicotine

- Cocaine, amphetamine

- LSD and MDMA

- PCP

Compared to healthy control, PET scan of a long term methamphetamine user demonstrates

Reduced dopamine activity

Two types of dependence

- Psychological dependence

- Physical dependence

How does psychological dependence occur?

Drug taking has pleasurable effects - POSITIVE REINFORCEMENT

How does physical dependence occur?

Development of tolerance causes unpleasant withdrawal symptoms (abstinence syndrome) that are alleviated when drug is taken --> NEGATIVE REINFORCEMENT

Reward and positive reinforcement is largely related to...

Psychological dependence (but not exclusively)

Negative reinforcement is associated with...

Physical dependence and withdrawal

Addictive drugs are both

Rewarding and reinforcing (positive and/or negative)

Interpersonal variables in drug use

- Mental and emotional wellbeing / psychiatric disorders

- Vulnerability to stress

- Metabolism

- Environmental variables

- Peer influences

What are the apparent three most important factors influencing first use of any illicit drug in Australia?

- Curiosity

- Peer pressure

- "To do something exciting"

Drugs that are strong positive reinforcers include

- Cocaine

- Amphetamine

- Morphine

- Heroin

Strong positive reinforcers tend to be associated with

Strong psychological dependence

Changes in brain levels of dopamine with positively reinforcing drug administration and withdrawal

- Drug causes large increase in dopamine

- Withdrawal causes large fall in dopamine (below control level)

Pathway for dopamine synthesis in brain

Tyrosine --> DOPA (via tyrosine hydroxylase) --> Dopamine (via DOPA decarboxylase)

Which dopaminergic pathway in the brain is most associated with drug reward / psychological dependence?

Mesocorticolimbic pathway

Which brain region is most involved in reward and positive reinforcement with drug use?

Nucleus accumbens

Addictive drugs can show _______ leading to ______

Tolerance and withdrawal, leading to physical dependence

What is tolerance?

Particular dose of drug demonstrates decreasing response with repeated use

Tolerance is also known as

Habituation or adaptation

What are the two types of tolerance?

- Pharmacokinetic tolerance

- Pharmacodynamic tolerance

Which drugs are associated with tolerance? Which are not?

- Morphine and heroin develop tolerance

- Cocaine and amphetamine DO NOT

How does pharmacokinetic tolerance occur?

Increased drug metabolism

How does pharmacokinetic tolerance to barbiturates develop?

Chronic barbiturate use increases microsomal enzyme levels and activity in liver, which increases metabolism of drug

How does pharmacodynamic tolerance occur?

Changes in drug target - generally downregulation of target receptor

Which type of tolerance is most associated with withdrawal?

Pharmacodynamic tolerance

What is the key defining feature of physical dependence?

A clear withdrawal (abstinence syndrome) when drug is discontinued

Which drugs demonstrate withdrawal?

- Morphine and heroin

Which drugs do not demonstrate withdrawal?

Cocaine and amphetamine

Why does withdrawal occur?

Chronic drug use causes adaptive changes (pharmaco-kinetic and/or dynamic) that are uncompensated for when drug is discontinued

How does pharmacodynamic tolerance develop to morphine?

- Morphine targets μ-opioid receptors (coupled to Gi)

- Chronic use upregulates adenylate cyclase

- Hence, activation of μ-opioid receptor by morphine less effectively inhibits cAMP formation from ATP in cell

Signs and symptoms of addictive phase of heroin use

- Warm flush and orgasm-like sensation

- Euphoria

- Feelings of tranquility

- Sleepiness

Signs and symptoms of initial heroin withdrawal phase

- Anxiety

- Craving

- Coughing

- Lachrymation

- Rhinorrhoea

- Yawning

- Shivering

- Sweating

Signs and symptoms of critical heroin withdrawal phase

- Dysphoria

- Rise in body temp. and cold skin

- Nausea, vomiting diarrhoea

- Muscular aches, cramps

- Piloerection

What is the general response of users to development of tolerance?

Use of higher dose

Cellular mechanisms of morphine withdrawal

- When tolerance develops, adenylate cyclase is upregulated (inhibited by morphine activation of μ-opioid receptors)

- When withdrawn, loss of inhibition, causing large increase in cAMP production, causing withdrawal symptoms

Acute abstinence is associated with _________, chronic abstinence is associated with _______

- Acute = withdrawal syndrome

- Chronic = craving

What is a sedative?

Drug with an anxiolytic/calming effect that has little or not effect on mental function

What is a hypnotic?

Drug that produces drowsiness, encouraging the onset and maintenance of sleep

Sedatives/hypnotics are used by what percentage of the population?

10-20% - most widely prescribed agents!

Increasing the dose of most sedatives beyond hypnotic effect (relaxed, less alert, sleepy) can lead to ______

Sedation/can be used as general anesthesia

General anaesthesia is

Loss of response to and perception of external stimuli

Stages of general anaesthesia

- Induction/analgesia (without amnesia)

- Excitement/delirium (amnesia, irregular respiration)

- Surgical anaesthesia (regular respiration, slowed pulse, loss of reflexes)

- Medullary paralysis (cardiorespiratory depression, death)

What percentage of the population has an anxiety disorder?

14.4%

Signs and symptoms of anxiety

- Unsettling feeling of apprehension

- Restless, agitation

- Tachycardia

- GI disturbances

- Sleep disturbance

- Sweating

Types of anxiety disorder (from most to least common)

- Post-traumatic stress disorder

- Social phobia

- Agoraphobia

- Generalised anxiety disorder

- Panic disorder

- Obsessive compulsive disorder

For a diagnosis of generalised anxiety disorder, symptoms must be...

Occurring on most days for at least 6 months

Transmitters that regulate the activity of the amygdala

- Noradrenaline

- GABA

- 5-HT

Functions of the amygdala

- Drives the fear response - recruits other brain regions!

Classes of sedatives and hypnotics

- Barbiturates

- Benzodiazepines

Example(s) of barbiturates

- Phenobarbitone

- Amylobarbitone

- Thiopentone

Barbiturates were used for sedation/anxiolysis/hypnosis from ____ until ____

From 1903 until 1960s

Key difference between dose-response relationship for barbiturates and benzodiazepines

Benzodiazepines have ceiling effect - response plateaus between hypnosis and general anaesthesia; barbiturate dose-response is linear, can lead to death due to cardiorespiratory depression

Compared to benzodiazepines, barbiturates have ________ potency and therefore can be used for _______

Barbiturates have higher potency and can therefore be used as general anaesthetics

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Why do barbiturates have higher toxicity than benzodiazepines

Barbiturates are less specific - additionally inhibit GLUTAMATE TRANSMISSION

Effects of ALL benzodiazepines

- Anxiolysis and reduce aggression

- Sedation (decrease time to achieve sleep and increase duration)

- Reduce muscle tone, coordination

- Anti-convulsant

Example(s) of benzodiazepines

- Diazepam

- Triazolam

- Chlordiazepoxide

- Temazepam

- Lorazepam

- Alprazolam

Half life of diazepam and use

Long (24-48 hours) - anxiety disorders

Half life of triazolam and use

Short (2-4 hours) - hypnosis

Metabolic pathway of diazepam

Diazepam --> nordazepam --> oxazepam --> glucuronide (via conjugation) - URINARY EXCRETION

Metabolic pathway of chlordiazepoxide

Chlordiazepoxide --> nordazepam --> oxazepam --> glucuronide (via conjugation) - URINARY EXCRETION

Metabolic pathway of temazepam

Temazepam --> oxazepam --> glucuronide (via conjugation) - URINARY EXCRETION

Metabolic pathway of lorazepam

Lorazepam --> glucuronide (via conjugation) - URINARY EXCRETION

Metabolic pathway of triazolam and alprazolam

Triazolam / Alprazolam --> hydroxylated metabolites - URINARY EXCRETION

Which benzodiazepines are hydroxylated

- Triazolam

- Alprazolam

Which benzodiazepines are conjugated to produce a glucuronide

- Diazepam

- Chlordiazepoxide

- Temazepam

- Lorazepam

Ultimately, benzodiazepine (or their metabolites) are cleared...

In the urine

Is zolpidem a benzodiazepine?

No - but same target!

Mechanism of action and effect of zolpidem

Selective for GABA-A receptors containing subunits associated with sedation BUT NOT ANXIETY

- Cause sedation but not anxiolysis

Effect of BDZs on sleep

- Decrease time to achieve sleep and increase duration

- Suppress REM sleep (causes rebound, worsened sleep on discontinuation)

Onset and duration of action of zolpidem

- Rapid onset

- Short duration (approx. 3-6 hours)

Do BDZs have efficacy for anxiety/insomnia beyond 4 months?

Uncertain (not well documented!)

Which class of drugs is more commonly used for long-term management of anxiety?

SSRIs

Adverse effects of BDZs

- Drowsiness

- Cognitive impariment

- Ataxia (impaired motor coordination)

- Anterograde amnesia

- Suppression of REM sleep

Association of BDZs with different types of dependence

Psychological - weak

Physical - strong (pharmacodynamic tolerance)

Because of their strong physical dependence potential, BDZs exhibit

Withdrawal symptoms!

Cause of BDZ tolerance

Downregulation of number/activity of GABA-A receptors

Signs and symptoms of BDZ withdrawal syndrome

- Anxiety and depression

- Sleep disturbance

- Tremor and shakiness

- Headache

- Seizure (reduction of GABAergic neuronal inhibition)

Withdrawal from BDZs is most severe when...

BDZ dose was high and the drug was short-acting

Long-acting BDZs exhibit withdrawal symptoms how long after discontinuation?

Weeks!

Common clinical uses of barbiturates

- General anaesthesia

- Anti-convulsant

Duration of action and uses of thiopentone

- Ultra short acting (10 mins)

- Induction anaesthetic

Duration of action and uses of pentobarbitone

- Short acting (6-12 hours)

- Anti-convulsant

How long do the fastest acting inhalation anaesthetics take to work?

Several minutes

Intravenous anaesthetics take how long to work?

10-20 seconds

Uses of intravenous anaesthetics

Effective for short or induction of anaesthesia BUT NOT MAINTENANCE

Why does i.v. thiopentone have rapid but short-acting effect?

Reaches brain within 10-20 seconds BUT short duration because drug is re-distributed throughout body (not because of metabolism!)

- Re-distributed from brain mainly to muscle and fat

Adverse effects of barbiturates

- RESPIRATORY DEPRESSION

- Drowsiness

- Cognitive impairment

- Ataxia

- Anterograde amnesia

- REM sleep suppression

Dependence potential of barbiturates

Similar to BDZs

- Psychological = weak

- Physical = strong

Tolerance to barbiturates is

- Pharmacokinetic AND

- Pharmacodynamic

Main source of opium is

Opium poppy (papaver somniferum)

Opium was introduced in western cultures as

Laudanum (ethanol extract of opium)

Chief alkaloid of opium is ____ and was isolated in ____

Morphine; 1803

Opium has been used in middle-eastern cultures for at least

5000 years

Opium contains at least how many different alkaloids

At least 20

Alkaloids in opium (in order of abundance)

- Morphine

- Codeine

- Noscapine

- Papaverine

- Thebaine

Types of opioid receptors

μ (mu)

δ (delta)

κ (kappa)

Clinically used agents targeting opioid receptors

- Morphine

- Pethidine

- Codeine

- Dextromethorphan

- Loperamide

- Naloxone