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Patterns of Drug Use in Australia

  • Tobacco:
    • 50% have had > 100 cigarettes
    • 20% daily use
    • 3% - use associated with “drug problem”; 20% main community problem
  • Alcohol:
    • 90% have used - most people have used them so the total damage is greater
    • 8% use daily (10% long-term “risky” or “high risk”; higher for short-term risk)
    • 8% - - use associated with “drug problem”; 20% main community problem
  • Illicit drugs:
    • 38% have used
    • 17% last 12 months
    • 88% - use associated with “drug problem”; 60% main community problem

What illicit drugs do Australians use?

  • Most people use marijuana
  • Then amphetamines, painkillers and E

Costs of Drug Abuse in Australia

  • difficult to quantify
  • Health costs, crime & violence (because people are addicted or dependent, so they don't have the money to buy the drugs they need), social disruption
  • Tangible social costs estimated at $18 billion But also raises money for the government
  • $5 billion from tobacco, $3 billion from alcohol
  • Drug induced deaths:
    • heroin OD & opioids
    • cancer & tobacco
    • accidental deaths (e.g. drink driving)

Includes protective effects (eg low dose alcohol)

Addiction

  • more than just tolerance and dependence; compulsive drug-taking and use, even in the face of negative health and social consequences (Am. Psychiatric Assoc., 1994)
  • “lifelong brain disease”
  • drug factors
    • speed of onset (mode of delivery, lipophilicity - cross the BBB easily = faster onset); cost & availability; potency (no quality control in illegal drugs)
  • user factors
    • genetics (metabolism, tolerance); risk takers; psychiatric problems
  • environmental factors
    • community attitudes; other sources of pleasure/reward; jobs, education
    • e.g. permissive community attitude towards alcohol (has a big impact in countries where it's associated with religion)
  • use continued for reward (euphoria) or reinforcement (avoid withdrawal)
    • possibility of treatment; multifactorial

Environmental and discriminative stimuli

  • These contribute to Early and Late drug-use problems
    • Noone sets out to become addicted to a drug in the first place
  • Aversive effects include hangover; and later, diseases.

Central reward: Dopamine

  • certain parts of brain when stimulated elicit pleasure
  • Mesolimbic dopaminergic pathway [reward pathway] dopaminergic neurons in ventral tegmental area project to nucleus accumbens and various pre-frontal and limbic regions
  • all drugs of addiction activate this DA pathway via different mechanisms, other pleasurable stimuli also activate pathway to some extent (especially if craving, eg hungry rats shown food)
    • and people addicted to food
    • other neurotransmitters: serotonin and noradrenaline
  • other neurotransmitter pathways involved, dopamine theory does not fully explain craving & addiction

Shifts in a dose-response curve with tolerance and sensitization

  • Tolerance: same dose of drug has less effect with repeated exposure (e.g. alcohol)
  • Sensitization: same dose of drug has more effect with repeated exposure (e.g. stimulants)
  • Can produce sensitisation by prolonged use of an antagonist (because the available receptor numbers increase --> a greater response than normal; therefore using an antagonist to treat addictions can have side effects e.g. unintentional overdose in naloxone for opioid)

Changes in dopamine release after daily injections of cocaine

  • Repeated cocaine dosing increases dopamine release for the same dose (sensitisation - 1)physiological response: increased expression of AMPA receptors on cell surface, and also 2) conditioned behavioural response... see below)
    • And after repeating cocaine dosing, providing a saline injection will result in a level of euphoria (conditioned behavioural response - animal is expecting the pleasurable response from last time).
  • Sensitization usually occurs with stimulants
    • Only occurs early on - eventually tolerance occurs

Pharmacological Treatment of Physically dependent individual

  • Ethanol
  • Nicotine
  • Opioids
  • Cocaine and other stimulants
  • Cannabinoids

Pharmacotherapy: can't stop craving (turn off the tap), but can treat acute overdose (with antagonists), minimalise withdrawal symptoms, and agents to help patient become abstinent. The patient remains at risk of relapse (it's a continual problem - doesn't just involve pharmacotherapy).

Ethanol Behavioural effects

Blood alcohol concentration (BAC) and clinical effects in non-tolerant individuals.

BAC (mg/dL) Clinical effect
50-100 Sedation, subjective "high"
100-200 Impaired motor function, slurred speech, ataxia
200-300 Emesis, stupor
300-400 Coma
>500 Respiratory depression, death
  • Marked individual differences:
    • eg1) learned tolerance in regular uses
    • eg2) females higher BAC from same dose vs males
    • eg3) higher BAC if higher proportion of body weight is fat
    • eg4) initial absorption rates higher if stomach empty

Alcohol Related Harm

See picture

Effects of alcohol consumption are dose-dependent

  • J-curve
  • Note that this is mortality
    • Relative risk of other diseases increases more rapidly than mortality
  • Error bars are massive with dose
  • Low dose: might be beneficial (lower rates of IHD), but binge drinking and being an alcoholic can greatly increase risk
  • reduced mortality relates to decreased risk of ischaemic heart disease in individuals (ie over 35yrs)
  • increased mortality predominantly liver cirrhosis, also some cancers, pancreatitis and accidents

Alcohol withdrawal syndrome

Need to do it in a hospital. Can cause death.

  • Alcohol craving
  • Tremor, irritability
  • Nausea
  • Sleep disturbance
  • Tachycardia
  • Hypertension
  • Sweating
  • Perceptual distortion
  • Seizures (6 to 48 hours after last drink)
  • Visual (and occasionally auditory or tactile) hallucinations (12 to 48 hours after last drink)
  • Delirium tremens (48 to 96 hours after last drink; rare in uncomplicated withdrawal)
  • Severe agitation
  • Confusion
  • Fever, profuse sweating
  • Nausea, diarrhea
  • Dilated pupils

Drugs used to treat alcohol addiction

Disulfiram

  • Aversion therapy
  • Blocks aldehyde dehydrogenase, the 2nd step in ethanol metabolism resulting in the accumulation of acetaldehyde.
  • Ethanol consumption results in flushing, tachycardia, hyperventilation, panic and distress.
  • Problems with patient compliance.
  • ARx when you take alcohol with the disulfiram
    • Asians have naturally low alcohol dehydrogenase

Metabolism of Ethanol

  1. Ethanol --alcohol dehydrogenase--> acetaldehyde
  2. Acetaldehyde --aldehyde dehyrdrogenase --> Acetic acid

Naltrexone and Acamprosate

  • Naltrexone is an opioid receptor antagonist that reduces alcohol induced reward via a mechanism involving mu opioid – receptors.
    • Gentler than disulfiram as they don't have negative effects
  • Acamprosate is a weak antagonist of NMDA receptors (also at GABA) which normalises disregulated neurotransmission and is used to help reduce craving.
  • Can be given in combination
  • Benzodiazepines are used to reduce withdrawal symptoms, eg oxazepam.
    • Short term ONLY.
    • Cross-tolerance (both act via GABA_A receptor): will swap dependences

Nicotine

  • nicotine rapidly absorbed and distributed into brain where it strongly binds to and activates central nicotinic acetylcholine receptors which generally excites neurons; rapidly metabolized although accumulates in heavy smokers.
  • some peripheral actions in the autonomic nervous system. Increased HR and BP
  • treatment: abstinence and replacement therapy; newer strategies – Varenicline, Bupropion
  • subtle behavioural but severe withdrawal and clear adverse health effects
    • mainly lung cancer and vascular disease; caused by carcinogenic tars

Nicotine withdrawal Symptoms

  • Irritability,impatience,hostility
  • Anxiety
  • Dysphoric or depressed mood
  • Difficulty concentrating
  • Restlessness
  • Decreased heart rate
  • Increased appetite or weight gain

Nicotine replacement therapy

  • Oral snuff, chewing tobacco, nicotine gum, patch
  • Administer nicotine without the carcinogens, and wean them off gradually

Pharmacological treatment of Nicotine dependency

  • Verenicline: Partial agonist at nicotinic receptors
    • So does stimulate receptors to some degree (get stimulation)
    • Competitive antagonist to a full agonist (nicotine) so they get less stimulation from that
  • Bupropion: Neuronal uptake inhibitor of noradrenaline and dopamine
    • Reduces withdrawal symptoms
      • Depression
      • Irritability
      • Anxiety
  • Rimonobant: CB-1 receptor antagonist; increases abstinence in rats. [withdrawn as anti-obesity drug]
    • increased risk of suicide

Opioids

  • The Opium poppy papaver somniferum is an annual herb native to Southeastern Europe and Western Asia.
  • Around the 8th Century Arab traders brought opium to India and China.
  • In 1806, Friedrich Serturner isolated a pure constituent of opium had the named morphine.
  • The main clinical use for opioids such as morphine is in the treatment of pain.

Opioid Receptor Classes

  • Mu- analgesia, respiration, cardio, intestinal transit, feeding, mood, thermoregulation, hormone secretion and immune function
  • Kappa - analgesia, diuresis, feeding, hormone secretion, immune function.
  • Delta - analgesia, mood, cardioregulation, immune function.
  • Endogenous opioids (endorphins, enkephalins, dynorphins)

Different opioid receptors identified in the 1970’s, cloned in the 1990s, 65% receptor homology

  • Kappa is dysphoric, the others are euphoric
Weak Moderate Strong
Codeine Oxycodone
  • Morphine
  • Pethidine
  • Methadone
  • Buprenorphine
  • Fentanyl
  • Heroin
  • Etorphine (elephant tranquiliser)

Heroin

  • Diacetyl morphine; metabolized to morphine; further metabolized in liver and excreted in urine.
  • Effects: intense rush followed by dreamy state, side effects (nausea, constipation) overdose & addiction
  • Effective dose: about 10 mg in inexperienced users, marked tolerance
  • Acute Toxicity: Opioid overdose leads to coma and marked respiratory depression, may be fatal.
  • Heroin is a pro-drug with 3 active metabolites:
    • 6-monoacetylmorphine
    • morphine
    • morphine-6 glucorinide

Morphine is also converted to morphine-3-glucorinide, but this is inactive

Characteristics of opioid withdrawal

  • Regular withdrawal
    • Craving for opioids
    • Restlessness, irritability
    • Increased sensitivity to pain
    • Nausea, cramps
    • Muscle aches
    • Dysphoric mood
    • Insomnia, anxiety
    • Pupillary dilation
    • Sweating
    • Piloerection ("gooseflesh") • Tachycardia
    • Vomiting, diarrhea
    • Increased blood pressure
    • Yawning
    • Fever
  • Protracted withdrawal
    • Insomnia, anxiety
    • Drug craving
  • Cyclic changes in weight, pupil size, respiratory sensitivity

Treating opioid dependence

  • Transfer patient to prescription opioid (cross tolerance)
  • Methadone
  • Buprenorphine
  • Alleviate withdrawal symptoms
    • Clonidine
  • Antagonists
    • Naloxone
    • Naltrexone

Methadone

  • Bioavailability > 85% (so can do it orally)
  • Metabolised in liver, mainly excreted in urine
  • Indication: moderate to severe pain, opioid maintenance programs (decreases rapid lows and highs seen with heroin)
  • Half life: 13 - 58 hrs

Differences in response to heroin and methadone

  • Much easier to maintain a patient in between euphoria and dysphoria using methadone (long half life) than heroin

Buprenorphine

  • Bioavailability 16%
  • Metabolised in liver, excreted in bile and urine
  • Indication: moderate pain
  • Partial agonist, May be used for opioid withdrawal
    • Acts as competitive antagonist of the agonist heroin
  • Half life: 6 - 9 hrs
  • Difficult because of patient compliance

Clonidine

  • Clonidine is an alpha2 adrenergic agonist which decreases adrenergic neurotransmission from the locus ceruleus.
    • Alpha 2 is presynaptic so decreases sympathetic outflow (Noradrenaline stimulating alpha2 agonist inhibits the release of more NA)
  • Reduces opioid withdrawal symptoms; nausea, vomiting, cramps, sweating , tachycardia and hypertension.
    • Because opioids inhibit the release of NA, so the body's homeostasis tries to do the opposite in withdrawal, so we target NA
  • It acts via a distinct receptor system to alleviate symptoms of opioid withdrawal, but does not reduce the craving for opioids.

Antagonists: Naloxone and Naltrexone

  • Major clinical use is the management of acute opioid overdose.
    • Reverses CNS and respiratory depression
    • Acts on all 3 receptors but highest affinity for mu
    • Naloxone: short half life compared to agonists. (Good to know what they've overdosed on, to match the half-lives. Need to monitor them)
  • Ultra rapid detoxification
    • put under anaesthesia, and then give them naloxone to put them under withdrawal; but this is expensive and anaesthetics are not without risk. The outcome is also no better than clonidine
      • long-term outcome is not good

Cellular Effects of cocaine: the dopamine hypothesis

  • Increases DA
  • Normally, DA is released into synapse, and is inactivated by reuptake via DA transporters
  • Cocaine blocks DA transporter, so DA builds up in the synapse gap
  • Makes you feel like wellbeing
  • Withdrawal is mild, but we want to treat the addiction

Cocaine Withdrawal

  • Dysphoria, depression
  • Sleepiness, fatigue
  • Cocaine craving
  • Bradycardia

Since cocaine withdrawal is generally mild, treatment of withdrawal symptoms usually is not required.

Pharmacological treatment of cocaine addiction

  • The major problem in treatment is not detoxification but helping the patient resist the urge to restart compulsive use.
    • Topiramate [anti-epileptic, increases GABA]
    • Baclofen [GABAB agonist]
    • Modafinil [stimulant, reduces euphoria]
    • Vaccine [experimental, cocaine binding antibodies]

Marijuana

  • Active ingredient THC (tetrahydrocannabinol) in different forms of cannabis
  • 7-TM domain, G-protein coupled receptors; CB1 and CB2
  • CB1: brain; mediates euphoric and most therapeutic effects
  • CB2: 50% homology; immunosuppressant effects

Marijuana Withdrawal Syndrome

  • Restlessness
  • Irritability
  • Mild agitation
  • Insomnia
  • Sleep EEG disturbance
  • Nausea, cramping

Not as addictive as opioid, Long-term: effects learning, memory, motor performance, schizophrenic in vulnerable persons, ?lung cancer

Marijuana: Treatment

  • Marijuana abuse and addiction have no specific treatments.
  • Heavy users may suffer from depression and respond to anti- depressants.
  • Rimonabant: CB-1 receptor antagonist [withdrawn as anti-obesity drug]