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'B33CNS - Pharmacology & Therapeutics > Reward/Drugs of abuse/Legal highs > Flashcards

Reward/Drugs of abuse/Legal highs Flashcards

1
Q

01:55

What does the WHO recommend drug dependence to be referred to as?

A
  • Abuse
  • Dependence
    »> NOT addiction, habbituation
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2
Q

What is dependence syndrome?

A
  • Strong desire or sense of compulsion to take substance
  • Difficulties in controlling use (amount, onset, termination)
  • Physical withdrawal state (?)
  • Tolerance (?); seen w/long term abuse
  • Progressive neglect of other interests, increasing time spent obtaining and taking substance
  • Persistence w/substance despite detrimental effects: social, cognitive, physical
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3
Q

What are the parallels between Social Attachment and Substance Abuse?

A
  • Social Attachment
    • Substance Abuse
  • Dating = ‘smitten’
    • Time set aside for getting and using substance
  • Sensation of time flying w/partner
    • Time increase; drug seeking behaviour, recovering
  • Loss of time with friends
    • Social, occupational and recreational activities reduced
  • Euphoria to contentment
    • Development of tolerance; reduced intensity
  • More time spent with partner
    • Dependence; induced increased in drug use
  • Separation anxiety
  • Physical or emotional abuse
    • Withdrawal; continued use despite recognition of problems
  • Anhedonia (inability to feel pleasure) and depression induced by loss or separation
    • Withdrawal-induced anhedonia and depression
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4
Q

What is the rat experimental model for brain reward pathways?

A
  • Rat is hooked up to tube w/indwelling catheter
  • Has access to a lever
  • Which is connected to programming + recording equipment and the infusion pump to administer the dose
    »> Learned behaviour, keeps pressing lever instead of grooming themselves etc.
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5
Q

Describe the brain reward pathway for dopamine, and where drugs of abuse act.

A
  • Many drugs of abuse increase DA release in the nucleus accumbens, NAC
  • Cell bodies of the (mesolimbic) DA pathway in the ventral tegmental area (VTA; in the midbrain, neurons run up and) terminate in the NAC
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6
Q

What drugs of abuse are involved DA increase in the NAC?

A
  • Opiates
  • Nicotine
  • Amphetamine
  • Cocaine
  • Cannabis
  • Ethanol
  • Ecstasy
  • PCP
  • Barbiturates
  • Caffeine
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7
Q

Which brain reward pathway do LSD (lysergic acid diethylamide) and Ecstasy (MDMA - 3, 4-methylenedioxymethamphetamine) act on?

A
  • Enhance serotonin (5-HT) function

- Hallucinogenic

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8
Q

Which drugs of abuse are NMDA antagonists?

A
  • Phencyclidine (PCP)
  • Ketamine
    »> Hallucinogenic
    »> Blocking excitatory mechanism
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9
Q

What is meant by the disinhibition of GABAa receptors by morphine/cannabinoids?

A
  • GABAa normally triggers downstream signalling to dampen down DA release from ventral tegmental area (VTA) to nucleus accumbens (NAC); GABA is inhibitory
  • However, morphine/cannabinoids (and endogenous enkephalins)
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10
Q

Describe how various drugs of abuse enhance the release of DA from VTA (ventral tegmental area) neurones.

A

P.206
Cocaine:
- Prevents reuptake of DA, thus more DA in cleft activating receptors = reward

Amphetamine:
- Same site of action as cocaine (end of VTA next to NAC)
- Taken up into the nerve ending and ‘kick out’ DA
»> NA is induced instead in PNS = tachycardia (same w/cocaine)

Morphine/cannabinoids:

  • Disinhibition of GABAa receptors
  • GABA normally results in dampening down DA release from VTA to NAC; inhibiting an inhibitor
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11
Q

What kind of studies were conducted to demonstrate how drugs of abuse affect DA release?

A
  • Microdialysis of the brain
  • Isotonic fluid perfused; ECF equilibrates through dialysis membrane = excess DA(?) transferred into dialysate
  • Can be examined upon collection from outlet tube
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12
Q

What does a faster and higher peak in brain DA levels mean for the person taking the drug of abuse? How does this affect ‘formulation’?

A
  • Faster and higher peaks in DA = greater the ‘rush’ (euphoria)

Formulation:
• IV heroin ‘better’ than methadone PO
• Snorting/inhaling cocaine better than chewing cocoa leaves
• Smoking cigarettes better than chewing tobacco

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13
Q

What is bromocriptine and what is it used for?

A

DA agonist:

  • Stopping breast milk production on medical grounds
  • Problems usually caused by not having the right amount of prolactin
  • Treating non-cancerous tumours in the brain (prolactinomas)
  • Treating Parkinson’s Disease (increases DA)
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14
Q

Why must special care be taken for DA agonists such as Bromocriptine and Ropinirole? (used for PD, stopping breast milk production, against prolactinomas etc.)

A

S/Es include potential addiction:

  • Risk of impulse control disorders; can include behaviours such as addictive gambling, excessive eating/spending, abnormally high sex drive etc.
  • Tell HCP if developing urgres
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15
Q

Name two narcotic analgesics and their degree of dependence liability.

A
  • Morphine (V. Strong)

- Heroin (V. Strong)

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16
Q

Name 4 General CNS depressants and their corresponding degree of dependence liability.

A
  • Ethanol (Strong)
  • Barbiturates (Strong)
  • Cannabis (Weak)
  • Anaesthetics (Moderate)
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17
Q

Name some psychomotor stimulants and their corresponding degree of dependence liability.

A
  • Nicotine (V. Strong)
  • Cocaine (V. Strong)
  • Amphetamines (Strong)
  • Caffeine (Weak)
  • Ecstasy (Absent ?)
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18
Q

Name some psychedelic agents and their corresponding degree of dependence liability.

A
  • LSD (Weak or Absent)
  • Mescaline (Weak or Absent)
  • Phencyclidine (Moderate)
19
Q

What is the degree of dependence liability of Benzodiazepine? What class of drug is it?

A

Anxiolytic (Strong)

20
Q

What is the mechanism of action of opiates? General effects? Give examples.

A
  • Agonists at GPCRs (mu receptors mainly)
  • Lower NT release in brain and periphery
Resulting in:
• Analgesia
• Euphoria 
• Positive reinforcement
• Respiratory depression
• Dysphoria (state of unease/general dissatisfaction with life)
• Sedation

E.g. morphine, heroin, methadone, codeine

21
Q

What are the acute and chronic effects of opiates?

A 
Acute:
• Euphoria
• Tranquility
• Miosis (excessive constriction of pupil of the eye)
• Drowsiness
• Itching
• Nausea

Chronic:

  • Anhedonia (lack of pleasure in life)
  • Constipation
  • Depression
  • Insomnia
  • Dependence
  • Nutritional status poor; danger of HIV and hepatitis from injecting
  • Significant tolerance; need to increase dose
22
Q

What are the withdrawal precipitates for opiates?

A
  • Craving
  • Insomnia
  • Restlessness
  • Diarrhoea
  • Muscle and bone pain
  • Vomiting
  • Cold flashes w/goose bumps (cold turkey)
  • Kicking movement (kicking the habit)
23
Q

When do withdrawal symptoms peak for opiates? What other complications involving withdrawal may occur?

A
  • Major withdrawal symptoms peak 48-72 hours after the last dose, subsiding after a week
  • Sudden withdrawal by heavily-dependent users occasionally fatal; although heroin withdrawal is considered less dangerous than alcohol or barbiturate withdrawal.
24
Q

Describe the mechanism of action of cocaine.

A
  • Increases catecholamine (DA, NA etc.) NT function by preventing re-uptake
  • DA most important for CNS behaviour
  • High conc. has anesthetic properties
25
Q

Describe cocaine’s main effects (+ effects in high doses), and the different routes of administration.

A

Effects:

  • Euphoria
  • Excitement
  • Increased capacity for work
High doses:
• Overactivity of the sympathetic system (reuptake blockade)
• Hypertension
• Tachycardia
• Hyperpyrexia
• Dilated pupil
• Palpitations

Routes:

  • Cocoa leaves chewed in Peru (cocaine HCl)
  • Snorted (hydrochloride; can cause perforation of nasal septum), or smoked w/tobacco
26
Q

Outline cocaine’s effect on dependence.

A
  • Little tolerance
  • Little PHYSICAL dependence
  • But, strong PSYCHOLOGICAl dependence (e.g. more cocaine was required to bind same number of sites at 50% neuronal uptake in dependent rats)
    »> Free base ‘crack’ can be smoked = v. rapid dependence
27
Q

Describe the mechanism of action of amphetamines. Give examples.

A
  • Release monoamines from neuronal storage vesicles
  • Block re-uptake transporters
  • Resulting in increased synaptic DA, NA and 5-HT

E.g. methamphetamine, dexamphetamine

28
Q

What are the general effects of amphetamine use?

A
  • Phenylethylamine drugs, produce increased wakefulness and concentration
  • In association w/fatigue and appetite
  • Some tolerance
  • Performance enhancing (sport/war)
    »> ‘Speed’
  • Increases cardiovascular tone; raised BP, tachycardia (sympathetic)
29
Q

What are the psychological effects of amphetamine use? What about with chronic use/high doses?

A

Psychological:

  • Euphoria
  • Increased libido
  • Energy
  • Self-esteem
  • Self-confidence
  • Aggression
  • Excessive feelings of power, obsession, paranoia

Chronic/high dose:
• Amphetamine psychosis can occur

30
Q

What are the parallels between amphetamines and pseudoephedrine?

A
  • Work in the same way, but just in the periphery (increases cardiovascular tone, raised BP, tachycardia)
    »> Banned in sport
31
Q

What is the active agent of cannabis? What is its mechanism of action?

A
  • Various preparations of Cannbis sativa
  • Active agent (THC); mimics effects so small endogenous lipid messengers e.g. anandamide (like enkephalins in opioids)
  • Inhibits wide range of NT release in the brain and periphery; via special Gi protein-coupled cannabinoid receptors
32
Q

What are the effects of cannabis use? Munchies?

A
  • Mild euphoric effect in moderate dose
  • Dysphoric in high doses (profound unease; particularly in naive users; ‘whitey’)
  • Context dependent
  • Stimulates appetite through actions on feeding centre in hypothalamus and possibly gut
  • Analgesic
33
Q

What is the risk of toxicity w/cannabis use?

A
  • Very low acute toxicity

- BUT, some concerns about precipitation of psychosis in chronic heavy users

34
Q

What is the drug abuse cost WRT crime, social security, NHS and justice for drug offenders?

A
  • £20 billion a year

- > £300 per person in England and Wales

35
Q

How does the annual spend per drug user differ between recreational use, Class A users and problem users?

A

Young recreation/older regular users:
- < £20 p.a.

Class A users:
- £2,030 p.a.

Problem users:
- £11,000 p.a.

36
Q

Why is treatment of drug users advantageous to the economy, as well as the drug user?

A

For every £1 spent on treatment, at least £5 is saved on health service and criminal justice costs.

37
Q

What is the pharmacological approach to treatment of opiate abuse? How is it given?

A
  • Agonist substitution; Methadone
  • Long-acting synthetic opiate agonist (onset of withdrawal 36-72 hr compared to 8-12 hr for heroin); administered PO for sustained period at dose sufficient to prevent opiate withdrawal (used appropriately)
38
Q

How does methadone work? What can it do for the user? Cessation?

A
  • Blocks effects of illicit opiate use and decreases opiate craving
  • Patient stabilised on adequate, sustained dosages can hold jobs, avoid crime and violence of street culture, reduced exposure to HIV by stopping needle sharing
  • Very low rate of complete cessation of heroin use in methadone patients e.g. 2 patients in 10 years
39
Q

How effective is NRT for smoking cessation?

A
  • Relatively ineffective in long-term smoking cessation; one year quit rates stand at 17% vs 10% placebo
  • No. of formulations: gum, patches, sprays etc.
  • Most difficult ‘drug’ to give up
40
Q

What do Champix (Varenicline) and Buprenorphine have in common?

A

Both partial receptor agonists:

  • Champix = nicotinic ACh (smoking)
  • Buprenorphine = mu-opioid (opioids)
41
Q

What antagonist treatments are availible for pharmacological therapy of drug abuse, and what are their criteria? Antibody therapy? Can their effect be overcome?

A

Naltrexone:

  • Not common (heavy addicts only)
  • Therapy for opiate addiction; patients must be detoxified and opiate-free for several days before naltrexone can be taken
  • Prevents precipitating opiate abstinence syndrome

Mecamylamine:

  • nACh receptor antagonist (nicotinic)
  • Blocks rewarding actions of nicotine and cue-induced craving

> > > Various attempts made to produce mAb (e.g. cocaine, nicotine that binds drugs of abuse in bloodstream; failed.
Antagonist effects can be overcome by increasing dose of drug
Patient non-compliance major problem

42
Q

What anti-craving medicines are availible? How do they work?

A

Acamprosate (Ca2+ salt of N-acetyl-homotaurine):

  • Registered for use as adjunct in maintaining abstinence in alcohol-dependent patients
  • Reduces alcohol consumption in alcoholic rats
  • Reduces neuronal excitability that occurs during alcohol withdrawal

Naltrexone:

  • Can be used in addition in opioid dependence, also reduces alcohol craving by interfering with positive reinforcement and possibly alcohol-conditioned cues
  • Possibly acts by blocking endogenous opioid disinhibition of GABA neurones in VTA, thereby reducing firing of DA releasing neurones
43
Q

What is the official position the HCP WRT to drugs of abuse and the user?

A
  • To help manage the condition
  • Not to ‘solve’
  • To not be judgemental

'B33CNS - Pharmacology & Therapeutics (13 decks)

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