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Drug Action - LIFE206 > Antidepressants and recreational drugs > Flashcards

Antidepressants and recreational drugs Flashcards

1
Q

Abnormalities of serotonergic (and NA) neurotransmission

A
  • The monoamine hypothesis of depression predicts that the underlying pathophysiologic basis of depression is a depletion in the levels of serotonin, noradrenaline, and/or dopamine in the CNS (long term).
  • Resulting in underactivity of serotonin and NA synapses
  • A number of antidepressants target the serotonergic (and NA) and neurotransmission system → block receptor that takes up serotonin
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2
Q

Bipolar disorder (depression with mania)

A

average age of onset around 30

significant concordance (30-90%) in twin studies

identity of the non-genetic factors is not known, but could include childhood experience, stress and illness

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3
Q

Unipolar depression

A

average age of onset of 35-45 and an incidence of 9-15%

genetic component, with ~25% of cases having familial links

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4
Q

Elevated mood

A

mania

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5
Q

Lowered mood

A

depression

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6
Q

Unipolar deppression

A

low mood

defined as suffering from five or more of these symptoms daily for at least two weeks

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7
Q

Bipolar

A

low mood and elevated mood → variable time course and response to therapy

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8
Q

Physical symptoms of depression

A

significant weight change (+-5% in a month)
sleep disturbance
fatigue/loss of energy

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9
Q

Emotional symptoms of depression

A

depressed or irritable mood
reduced interest in pleasurable activities
psychomotor agitation
loss of self worth, excessive guilt
diminished ability to think
suicidal thoughts

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10
Q

Usual symptoms of mania

A
  • unnaturally elevated mood
  • over-activity
  • loss of inhibitions, irritability
  • loss of sleep and appetite
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11
Q

Mania symptoms occurring in ~10% of patients

A
  • delusions
  • hallucinations
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12
Q

Manic episodes

A

treated separately from depressive episodes - different drugs used

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13
Q

Early Therapeutics: Monoamine Oxidase Inhibitors

A

among the first antidepressants to be introduced

target enzyme at synapse that would have otherwise broken down the monoamine neurotransmitter (serotonin) to increase concentration of neurotransmitter at the synapse

use declined due to side-effects and the advent of more effective drugs

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14
Q

Tranylcypromine

A

irreversible block of MAOI
Non-selective

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15
Q

Moclobemide

A

reversible block
MAO-A selective
Block oxidative amine deamination of 5-HT & NA

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16
Q

Monoamine oxidase

A

expressed in mitochondria of presynaptic neurone

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17
Q

Monoamine oxidase inhibitors - mechanism of action

A

Blocking breakdown of 5-HT and NA increases their levels at the synapse.

This is expected to increase release of these transmitters.
therefore receptor activation should increase.

MAO-A is more selective for serotonin & NA (selective action reduces side-effects).

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18
Q

Monoamine uptake inhibitors

A

target transporters - reuptake proteins

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19
Q

Tricyclic antidepressants (TCAs)

A

Dibenzazepines

e.g. imipramine

(non-selective for NA/5-HT uptake).

desipramine

(selective for NA uptake)

Dibenzcycloheptenes

e.g. amitriptyline

(non-selective for NA/5-HT uptake).

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20
Q

Monoamine reuptake inhibitors - mechanism of action

A

inhibit serotonin or NA transporter expressed at synaptic gap at presynaptic neurone

Blocking reuptake of 5-HT and NA from the synapse prolongs monoamine signalling at the synapse

Therefore as with MAOIs, this should lead to an increase in receptor activation.

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21
Q

Selective Serotonin Reuptake Inhibitors (SSRIs)

A

Monoamine uptake inhibitors: high affinity for serotonin transporter, traget with higher affinity than tricyclic antidepressants

e.g. fluoxetine (prozac)

sertraline

(selective for 5-HT uptake)

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21
Q

Other reuptake inhibitors

A

SNRIs: “SN” stands for “serotonin-noradrenaline”

e.g. venlafaxine, a non-specific reuptake inhibitor (May also block DA uptake)

NRIs: i.e. noradrenaline-selective.

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22
Q

Reuptake inhibitors

A

block monoamine transporters

23
Q

SERT

A

a type of monoamine transporter protein that transports serotonin from the synaptic cleft to the presynaptic neurone by undergoing conformational change

SSRIs bind at central binding pocket of transporter (substrate binding pocket) to inhibit serotonin transporter

24
Antidepressants can be classified as
- Tricyclic antidepressants (TCA) - Non-selective transporter block - Reuptake inhibitors - Selective transporter block - serotonin-selective (SSRIs) - noradrenaline (NRIs) - serotonin & noradrenaline (SNRIs)
25
Noradrenergic and Specific-Serotonergic Antidepressants (NaSSAs) e.g. mirtazapine
act as antagonist at specific receptors expressed at the synapse (both at pre and postsynaptic neurone) - specifically, a2AR & various 5-HT receptors (mainly 5-HT2 & 5-HT3) Prevents the negative feedback effect of synaptic NA on 5-HT and noradrenaline neurotransmission Increases the concentration of 5-HT and NA in the synaptic cleft This enhances signalling at certain NA and 5-HT synapses.
26
St John’s Wort (hypericins)
Evidence as an effective antidepressant is limited Potential for drug-drug interactions as it is an inducer of metabolism enzymes (CYP450)
27
Manic episodes
treated with mood stabilisers
28
Lithium (Li2CO3)
most widely used mood stabiliser mechanism of action may result from inhibition of phosphatidyl inositol (PI) metabolism narrow therapeutic window means it is toxic at high doses
29
Antipsychotics
can be used where schizophrenia-like symptoms (e.g. hallucogenic) are evident
30
Anti-convulsants (e.g. valproate, gabapentin)
effective in some cases
31
Treating depression
- Variation in symptoms makes treatment complex. - A combination of psychotherapy and antidepressant drugs is normally used.
32
Antidepressants can be classified as
- Monoamine oxidase inhibitors (MAOIs) - Block bioamine breakdown - Tricyclic antidepressants (TCA) - Non-selective transporter block - Reuptake inhibitors - Selective transporter block - serotonin-selective (SSRIs) - noradrenaline (NRIs) - serotonin & noradrenaline (SNRIs) - Noradrenergic and Specific-Serotonergic Antidepressants (NaSSAs) - Selective antagonist of adrenergic and 5HT receptors - Antipsychotics - Adjunctive treatment
33
First line therapy
Serotonin selective reuptake inhibitors (SSRIs)
34
Problems with current antidepressants
- Only around half of patients are fully responsive to current drugs - drugs only work in around 2/3 of patients - Drug treatments can take several weeks to take effect - side effects
35
Side effects of antidepressants
- Monoamine oxidase inhibitors (MAOIs) - atropine-like*, ‘cheese reaction’† postural hypotension, tremors - Tricyclic antidepressants - atropine-like*, sedative, postural hypotension, dysrhythmias (in overdose) - Reuptake inhibitors - nausea (also true of latest MAOIs) - St John’s Wort - induces metabolism of other drugs (*e.g.* oral contraceptives, anti-HIV drugs) * dry mouth etc.: due to action at muscarinic receptors † Hypertensive effects from ingested tyramine
36
Caffeine
- Caffeine and other methylxanthines, e.g. theophylline found in tea and coffee are psychostimulants. - They act as competitive antagonists at adenosine A1 and A2A receptors. - It has been suggested that caffeine consumption may protect dopaminergic neurones against the degeneration found in Parkinson’s disease.
37
Nicotine
- neuroactive substance in tobacco. - agonist at nicotinic acetylcholine receptors (nAChRs expressed throughout the brain), exerting its CNS effects through the a4b2 subtype. - These receptors are involved in cognition and the dopamine reward pathway. Nicotine desensitises nAChRs, leading to an increase in their surface expression, but reduction in their responsiveness - Patients suffering from schizophrenia almost invariably smoke, leading to the suggestion that it is a form of self-medication.
38
Ethanol
- has physiological effects in both the CNS and periphery (also as a diuretic). - acts as a general CNS depressant. Pharmacological effects resemble volatile general anaesthetics. - Acts via GABAA receptors, inhibiting NMDA receptors, 5HT3 receptors, L-type voltage-gated Ca2+ channels. It also activates the dopaminergic reward pathway. The opiate receptor antagonist naltrexone inhibits ethanol consumption and craving in alcoholism.
39
Psychostimulants: Cocaine and amphetamine
Both of these drugs are capable of inducing a psychosis that resembles schizophrenia (positive symptoms). -work by potentiating monoaminergic transmission through inhibition of dopamine, 5-HT and noradrenaline reuptake transporters. -Amphetamines (Speed) also promote the release of these neurotransmitters into the synaptic cleft. - The euphoria produced by amphetamine and cocaine is primarily related to their effects on dopamine.
40
Hallucinogens: LSD and mescaline
partial agonists at 5HT2A receptors (specific serotonin receptor which affect memory and perception) - derivatives are used therapeutically in the treatment of migraine.
41
Hallucinogens: phencyclidine and ketamine
channel blocker at NMDA receptors (a class of ionotropic glutamate receptor). Ketamine - off label use for treatment resistant depression – fast acting
42
Marijuana and Cannabinoids
potential therapeutic role as an analgesic agent, particularly in multiple sclerosis, in the treatment of glaucoma and to treat the nausea associated with cancer chemotherapy main psychoactive ingredient is D9-tetrahydrocannabinol (THC), which is an agonist at the GPCR CB1 cannabinoid receptor. This is located in brain areas associated with cognition (cerebral cortex) and memory (hippocampus).
43
Cannabinoids receptor ligands (Endocannabinoids)
Endogenous agonists for the CB1 receptor have been identified: anandamide and sn-2 arachidonylglycerol (2-AG). development of cannabinoid antagonists has shown that cannabis produces dependence and leads to withdrawal effects.
44
Cellular actions of cannabinoids
Activate GIRK channel - K+ out of cell Activates MAPK pathway - altered gene expression Inhibits adenylyl cyclase - less cAMP Inhibits Ca2+ influx channels CB1 (GPCR) receptor activation inhibits neurotransmitter release via inhibition of Ca2+ entry and hyperpolarisation due to activation of potassium channels
45
THC and mental health
association has been identified between cannabis use and the appearance of psychoses or schizophrenia risk of developing these conditions is approximately doubled in cannabis users It is not known whether this association is due to: - THC inducing or worsening psychoses in susceptible individuals, or; - Individuals who are susceptible to psychoses being more likely to become regular cannabis users. ink between CB receptors and schizophrenia symptoms may involve the “dopamine reward pathway”
46
Drug abuse
self-administration of drugs beyond the approved cultural norms
47
Dependence
a state in which “an organism only functions normally in the presence of a drug” (NIDA)
48
Addiction
a state in which “an organism engages in a compulsive behaviour” (NIDA). This is what is thought to involve the dopamine reward pathway
49
Tolerance
the need for significantly increased doses to achieve the same effect, or a reduction in effect when doses are constant
50
Withdrawal effects
generally oppose the normal effects of the drug. Dependence is evident when withdrawal leads to renewed drug taking.
51
Dopamine reward pathway
involved in 2 specific brain areas - nucleus accumbens (NAc) and ventral tegmenral area (VTA) signals at VTA inhibits NAc drugs of abuse activate this pathway different drugs have different effects at NAc and VTA
52
Inhibitory effet on NAc
nicotine alcohol stimulants PCP (phenylcyclidine) need to inhibit the NAc system to get euphoria - DA release
53
VTA
signals to NAc and inhibits it
54
Stimulatory effect on VTA
nicotine opiates alcohol?
55
Plasticity
reduces the effect of the drug through changes in protein expression patterns (e.g. through reduced receptor density) Drugs that inhibit a response could similarly lead to a compensatory effect in the opposite direction Changes can also occur at the cellular and anatomical levels (driven by changes in protein expression). Plasticity is key for tolerance and dependence
56
Withdrawal
when drug is removed, response will fall below the normal level (until the plasticity has time to reverse plasticity and receptor expression reduced leading to withdrawal effects due to tolerance and dependence

Drug Action - LIFE206 (12 decks)

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