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PY365 Substance Misuse > Pathophysiology, treatment and Pharmacology > Flashcards

Pathophysiology, treatment and Pharmacology Flashcards

1
Q

what is tolerance

A

refers to either very short term or long term kiss if agonist efficacy
- mainly attributed to LTD within reward circuit
- dependence and addiction are associated with tolerance

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2
Q

describe how acute tolerance can be observed

A

can be observed rapidly (seconds to mins) during the course of a single episode of opioid intoxication

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3
Q

describe how long term tolerance is observed

A

more substantial and emerges after days to weeks of substance misuse

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4
Q

what does tolerance result from

A

results from adaptive mechanisms at the level of the drug target receptors
- desensitisation and internalisation
as well as at the cellular, synaptic and network levels
- downregulation of signalling components

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5
Q

what is dependence

A

compulsive craving that develops as a result of repeated administration of a substance of misuse, mainly due to the positive reinforcing action

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6
Q

what is drug addiction

A

an uncontrolled craving for a substance and is manifested in drug seeking behaviours

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7
Q

what is the most well established site of action of addictive drugs

A

the mesocorticolimbic dopamine system

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8
Q

what are the 2 main factors that substance misuse is mainly attributed to

A
  1. positive reinforcement- reward circuit
  2. avoiding negative effects- withdrawal
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9
Q

give examples of drug related harms of substance misuse

A
  1. damaging quality of life- social impact
  2. liver damage
  3. neuropathy
  4. respiratory complications
  5. CV complications
  6. infections
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10
Q

describe the pathophysiology of alcohol ethanol

A
  1. ethanol mainly acts via activating GABA receptors
  2. leads to overall inhibitory effect including inhibiting GABAergic neurons
  3. inhibiting GABAergic neurons lead to less GABA production
  4. means less inhibition to dopaminergic neurons (disinhibition)
  5. therefore, increases dopaminergic neutron excitation
  6. ethanol leads to synaptic plasticity for dopaminergic and GABAergic neurons
  7. tolerance is induced
  8. dependance and addiction start
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11
Q

outline the major alcohol related harms in substance misuse

A
  1. liver damage
  2. respiratory depression
  3. CV complications
  4. nervous system
  5. infection
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12
Q

how does alcohol substance misuse affect liver

A

accumulated acetaldehyde leads to
1. increase fatty acids and lipogenesis and hence fatty liver
2. the formation of free radicals and reactive oxygen species leading to liver fibrosis

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13
Q

how does alcohol substance misuse affect respiratory depression

A
  1. potentiates and mimics GABA action leading to inhibitory effects on respiratory centres
    - respiratory failure
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14
Q

how does alcohol substance misuse affect cardiovascular system

A

causes hypertension, stroke, arrhythmia, cardiac hypertrophy

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15
Q

how does alcohol substance misuse affect nervous system

A
  1. depressing vital centres in the CNS
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16
Q

how does alcohol substance misuse affect infection

A

alcohol reduces key pulmonary defences against infection such as reducing mucociliary clearance, macrophage mobilisation and killing and clearance

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17
Q

explain why withdrawal effects occur in alcoholism

A
  1. mainly attributed to synaptic plasticity
  2. GABAergic receptors on dopaminergic and glutaminergic neurons are directly activated by high dose of alcohol
    - this initially leads to suppressing of dopamine and glutamate release
  3. LTP occurs in these suppressed neuronal synapses
  4. prolonged alcohol use leads to development of tolerance and physical dependance, which may result from compensatory functional changes by downregulation of GABA receptors
  5. therefore, alcohol is administered to calm and counteract the overexcited excitatory neurons
  6. in the absence of alcohol, withdrawal effects evolve by overstimulated potentiated and overstimulated dopaminergic and glutaminergic neurons
    - leading to symptoms such as delirium and seizures
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18
Q

name the drugs that can be used to treat alcohol misuse

A
  1. disulfiram
  2. acamprosate
  3. naltrexone
  4. benzodiazepines
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19
Q

what is the mechanism of action of disulfiram

A
  1. irreversible inactivation of liver ALDH and increases acetaldehyde concentration leading to disulfiram alcohol reaction
    - reducing alcohol induced CV complications
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20
Q

how does acamprosate work

A
  1. similar structure to that of amino acid neuromediators, such as GABA
  2. stimulates GABAergic inhibitory neurotransmission and antagonising excitatory amino acids, particularly glutamate
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21
Q

how does naltrexone work

A
  1. long acting specific opioid antagonist
  2. non aversive therapy and does not cause disulfiram like reactions
  3. reduces risk of a full relapse after having consumed a limited amount of alcohol and reduces the desire for alcohol during abstinence
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22
Q

what is the role of benzodiazepines

A

increases the inhibitory effects of GABA
- reducing neuronal excitability

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23
Q

describe the actions of methanol

A
  1. exerts similar CNS actions as ethanol
  2. exerts major health problems due to the metabolic product formaldehyde
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24
Q

what is the risk of formaldehyde

A

is toxic to the retinal and optic nerve
- causing permenant blindness

25
Q

what does the treatment of methanol toxicity involve

A
  1. ethanol
  2. fomepizole- inhibitor of ADH
26
Q

what are benzodiazepines and barbiturates

A

sedative and hypnotic agents and CNS depressants
- GABAergic drugs

27
Q

what is diazepam prescribed for

A

management of anxiety and insomnia

28
Q

give an example of a barbiturate

A

phenobarbital- used for management of severe epilepsy

29
Q

what can chronic use of BDZ and BARBs induce

A

GABAergic pathways (plasticity) leading to tolerance and withdrawal symptoms

30
Q

what are Z drugs

A

Zolpidem, zopiclone and zaleplon are non BDZ
- similar mechanism but different structure

31
Q

What is the treatment for BDZ misuse

A
  1. no approved treatment
  2. supportive therapies may be implemented
    - behavioural therapy
    - inpatient and outpatient treatments
  3. flumazenil is an antidote for BDZ toxicity
    - acts as BDZ receptors antagonist
32
Q

describe the mechanism of action of gabapentin and pregabalin

A
  1. bind at aS-2 subunit specific voltage gated calcium channels in the CNS
  2. reduce excitation of nerve cells leading to euphoria, relaxation and calmness
33
Q

what is the treatment of gabapentin and pregabalin misuse

A
  1. there is no approved treatment
  2. supportive therapies may be implemented
    - behavioural therapy
    - inpatient and outpatient treatments
34
Q

describe the pathophysiology of marijuana

A
  1. endocannabinoids are neurotransmitters that can indirectly affect dopamine signals by modifying the activity of other neurotransmitters such as GABA
  2. these molecules bind to cannabinoid receptors on the adjacent GABA neuron, reducing the amount of GABA it releases
  3. inhibiting GABA neurons boosts the dopamine signal in the reward synapse
35
Q

what is the treatment of cannabis misuse

A
  1. there is no approved treatment
  2. supportive therapies may be implemented
    - behavioural therapy
    - inpatient and outpatient treatments
36
Q

describe the pathophysiology of amphetamines

A
  1. they block the reuptake of monoamines, especially dopamine and noradrenaline transporters
  2. used to treat ADHD and narcolepsy
  3. can be used to override tiredness or for weight management
  4. common misused amphetamine- ecstasy (MDMA)
37
Q

what is the treatment for amphetamine misuse

A
  1. there is no approved treatment
  2. supportive therapies may be implemented
    - behavioural therapy
    - inpatient and outpatient treatments
38
Q

describe the pathophysiology of cocaine

A
  1. blocks the reuptake of monamines
    - dopamine, serotonin, and noradrenaline
  2. increasing dopamine in the synaptic cleft, increases the dopaminergic output in reward circuit
    - leading to euphoria
39
Q

what is the treatment of cocaine misuse

A
  1. there is no approved treatment
  2. supportive therapies may be implemented
    - behavioural therapy
    - inpatient and outpatient treatments
  3. CV toxicity and agitation may be treated with BDZ
  4. alpha blocker can treat alpha mediated hypertension but not tachycardia
40
Q

how do opioids exert their effects

A

exert their actions through 3 main receptors:
1. Mu receptors (MOP)- main target providing analgesia, euphoria and respiratory depression
2. Kappa receptors (KOP)- spinal analgesia and dysphoria without inducing dependence
3. Delta receptors(DOP)- peripheral analgesic receptors

41
Q

how do the MOP, DOP and KOP receptors work

A
  1. interact with the reward circuit through disinhibition:
    - inhibiting adenylate cyclase and reducing AMP synthesis
    - opening potassium channels
    - inhibiting the opening of voltage gated calcium channels
42
Q

what is a potent agonist for MOP, KOP and DOP

A

morphine

43
Q

what is the role of buprenorphine

A
  1. a partial agonist for MOP while acting as an antagonist for KOP and of weak activity towards DOP
44
Q

what is the role of methadone

A

a potent agonist for MOP and of weak activity towards KOP and DOP

45
Q

what is the role of naltrexone and naloxone

A

antagonists to all MOP, KOP and DOP, with more affinity to MOP

46
Q

describe the pathophysiology of opioids

A
  1. tolerance and addiction arise from the upregulation of the cellular components (LTP)- adenylyl cyclase, cAMP and PKA, which were initially suppressed by opioids
  2. LTP of adenylyl cyclase, cAMP and PKA in addition to dynorphin leads to severe withdrawal symptoms upon abrupt drug abstinence
    - dysphoria, diarrhoea
47
Q

describe how respiratory depression occurs in misuse of opioids

A
  1. MOP activation suppresses locus coeruleus noradrenaline neurons
    - suppressing medullary centres and respiratory rhythm
  2. the type I glomus cells in the carotid body are the bodies main sensors for hypoxia and hypercapnia
    - MOP activation inhibits carotid body activity through inhibiting dopaminergic and purinergic neurons
    - leading to slowly progressing hypoventilation and death
48
Q

what is the QT interval

A

the time between the start of the Q wave and the end of the T wave which is the electrical presentation of ventricular depolarisation and repolarisation in ECG

49
Q

how does prolongation of the QT occur

A

due to delayed repolarisation due to blocked or loss of function of the cardiac rapid rectifying K+ channel

50
Q

how can opioids lead to torsades de pointes

A

opioids block hERG channels leading to Torsades de pointes and arrhythmia

51
Q

describe the pathophysiology of opioids

A
  1. motility- excitatory motor neurons release ach and tachykinins
    - evoke longitudinal smooth muscle contraction
    - MOPR activation inhibits the release of ach and other peristaltic neurotransmitters
    - leading to decrease in normal propulsive activity
  2. fluid secretion- opioids bind to receptors and suppress ach and VIP release
    - resulting in decrease in chloride and water secretion into lumen
  3. sphincter tone- opioid induced dysfunction of anorectal function causing straining, haemorrhoids and increased contraction of the sphincter
52
Q

what is the mechanism of action of morphine

A

inhibits voltage gated calcium channels and activates potassium channels leading to inhibiting the release of NT from neuron

53
Q

describe the pharmacology of buprenorphine

A
  1. a potent ent but partial agonist of MOP showing high affinity but low intrinsic activity
  2. high potency and slow off rate
  3. ceiling effect due to partial agonism
  4. less dependence
  5. less respiratory depression
  6. less CV depression
  7. less constipation
  8. mainly excreted through enterohepatic circulation
54
Q

describe the pharmacology of methadone

A
  1. is a potent MOP receptor full agonist
  2. characterised by high extravascular compartment binding leading to slow release from extravascular reservoir into circulation
  3. increase duration
  4. less withdrawal
  5. not euphoric
  6. less risk of developing dependence and addiction
55
Q

describe the properties of naloxone as an opioid antidote

A
  1. a potent antagonist of opioid receptors
  2. used to reverse action of opioids
  3. IV
  4. rapid onset
  5. rapid hepatic metabolism
  6. short duration
56
Q

describe the properties of naltrexone as an opioid antidote

A
  1. oral antidote of opioids
  2. longer duration of action- up to 24 hrs
57
Q

describe the pathophysiology of nicotine

A
  1. different routes of administration
  2. activating presynaptic nAch receptors, leading to activation of VTA dopaminergic pathway
  3. nicotine induces nicotinic receptors up regulation
  4. nicotine stimulate presynaptic receptors, mediating the release of almost all neurotransmitters
    - leading to side effects
58
Q

outline the treatment of nicotine misuse

A
  1. NRT is a medication that provides a low level of nicotine, without the tar, carbon monoxide and other poisonous chemicals present in tobacco smoke and preventing withdrawal symptoms
    - nicotine gum
    - nicotine patches

PY365 Substance Misuse (10 decks)

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