Drug dependence

Question 1

What is substance dependence not?

Answer 1

Misuse.
Misuse is when the drug is used for the wrong indication, at the wrong dose or for the wrong period of time.

Question 2

What is drug dependence?

Answer 2

Dependence on opiate drugs - heroin, pethidine, morphine.
You only know you are dependent when you stop using the drug.
This causes physical withdrawal syndrome, then psychological withdrawal syndrome.

Question 3

What is physical withdrawal syndrome symptoms?

Answer 3

Anxiety
Insomnia
Cramps
Tachycardia
Piloerection
Diarrhoea

Question 4

What is physical withdrawal syndrome?

Answer 4

The motivation to avoid the symptoms is extreme, people perform extreme behaviours to avoid having withdrawal.
After 3-4 weeks the physical symptoms will wane.

Question 5

What is psychological withdrawal syndrome?

Answer 5

Compulsive behaviour
Anxiety
These symptoms can last a lifetime.
There are neurobiological changes that mean you are likely to become dependent on a drug again later in life.

Question 6

What are the origins of drug dependence?

Answer 6

Drug variable - drugs that you can become dependent on activate the mesolimbic dopamine pathway which produces reward and makes you feel good. Opiates produce more activation.
User variable - absorption and metabolism rates of drugs vary, partly due to genetics.
Environmental variable - peer pressure means you are more likely to take recreational drugs.

Question 7

What is tolerance?

Answer 7

Your ability to not be affected by a drug.
Can be innate or acquired.

Question 8

What is innate tolerance?

Answer 8

Genetics determine how rapidly you metabolise a drug.
Low metabolisers of alcohol have slow metabolism, so are more affected by alcohol, this is affected by ethnicity.

Question 9

What is acquired tolerance?

Answer 9

If you continue drinking alcohol, you increase your ability of CYP450s to metabolise alcohol, and so more is required to have the same effect.
Behavioural - learn to modify behaviour and appear normal when under the influence drugs in order to maintain social standing.
Can be pharmacodynamic.

Question 10

What is pharmacodynamic acquired tolerance?

Answer 10

Opiates bind to GPCRs, which inhibits adenylate cyclase, so reduces cAMP levels.
Chronic administration of opiates causes the body to recognise the continuous inhibition of adenylate cyclase, so it upregulates expression of adenylate cyclase.
So more opiate is required to inhibit adenylate cyclase.

Question 11

What are the opiates?

Answer 11

Morphine, is a big molecule with several aromatic rings.
Heroin is a synthetic derivative of morphine that is more lipophilic, so cross the blood brain barrier more easily and increases the rush.
Pethidine is a synthetic, single ring structure, but still activates the opioid receptors.

Question 12

How are opiates administered?

Answer 12

Injectable infections by contaminated needles cause HIV, hepatitis B and C. staphylococcus aureus causes endocarditis - heart valve infection. Infections can spread and cause sepsis.
Street pharmacy - opiates aren’t regulated. The structure of heroin and morphine engages mast cells to release histamine which cause welts where the drug is injected. The drug might contain caustic cleaning products which mimic these welts.

Question 13

What is the VTA?

Answer 13

The ventro tegmental area, which is the cell body area for the mesolimbic dopamine pathway.
This is the other main dopamine pathway, in addition to the Nigro striatal pathway.
The VTA signals to the nucleus accumbens, the major part of the mesolimbic pathway. The amygdala and prefrontal cortex also receive dopaminergic innervation via this pathway.
The mesolimbic pathway when activated increases dopaminergic transmission and increases motivation.

Question 14

How do opiates affect the mesolimbic dopamine pathway?

Answer 14

Opiates disinhibit the mesolimbic pathway.
Agonists - heroin, morphine, pethidine - inhibit GABAergic neurones, which normally inhibit dopamine release in the VTA.
So GABA stops inhibiting, and dopamine levels are increased.

Question 15

What is the treatment of opiate overdose?

Answer 15

Naloxone
Methadone + psychotherapy.

Question 16

What is naloxone?

Answer 16

Naloxone is a competitive antagonist of opiate receptors, that quickly reverse opiate action.
But it has a short half-life of 30-60 minutes, whereas morphine and heroin have a half-life of many hours.
So naloxone is continuously delivered by IV so that it is not metabolised and removed too quickly.
Can make someone regain consciousness.

Question 17

What is methadone?

Answer 17

Opiate agonist - causes a small rush after oral administration.
Upon dosing, if the individual then injects heroin, there is little additional effect.
It has a very long half-life.
Gradually reduce the dose of methadone over weeks as a way to wean off opiates.

Question 18

What is psychotherapy?

Answer 18

Drug weaning is dependent on the motivation of the individual to not take opiates.
Psychotherapy should be used alongside to tell them they are having effect.
But the success rate is low.

Question 19

What is caffeine?

Answer 19

Stimulant
Withdrawal syndrome of lethargy, irritability, anxiety and headache.

Question 20

What is the mechanism of caffeine?

Answer 20

Phosphodiesterase inhibitor, so inhibits metabolism of cAMP, therefore cAMP increases.
cAMP activates neurones - stimulant.
Caffeine also antagonises the adenosine receptor.
Adenosine is normally inhibitory of the brain, so blocking this stimulates brain activity.

Question 21

What is cocaine?

Answer 21

A strong stimulant.
Cocaine hydrochloride is a salt, sniffed or rubbed on gums.
Crack cocaine is a free base so has a lower melting point, is smoked. This passes across the large surface area of the lungs and rapidly increases in plasma.

Question 22

What is the mechanism of cocaine?

Answer 22

Inhibits catecholamine uptake, mainly of dopamine, but also adrenaline and noradrenaline.
This facilitates dopamine neurotransmission, so the mesolimbic pathway is more active and there is more reward and pleasure.

Question 23

What are the symptoms of cocaine use?

Answer 23

Cocaine blocks noradrenaline and adrenaline uptake.
When you snort cocaine, it facilitates sympathetic activity in the nose, so causes vasoconstriction and reduced blood flow.
This causes tissue necrosis - the nose septum is lost.

Question 24

What is cocaine withdrawal?

Answer 24

Withdrawal can be eased with tricyclic antidepressants.
These block catecholamine reuptake, noradrenaline, as well as serotonin (not a catecholamine).
Manage withdrawal related depression, but do not treat cocaine dependence.

Question 25

What is amphetamine?

Answer 25

Stimulates release of catecholamines - noradrenaline, adrenaline and dopamine. Releases dopamine, and then blocks its uptake, so increased activation of the mesolimbic pathway which increases reward.

Question 26

What is overdose of amphetamine treated by?

Answer 26

Neuroleptics, which are dopamine antagonists, so block the postsynaptic dopamine receptors. This reduces the effect of dopamine, such as reducing hallucinations.

Question 27

What is NMDA?

Answer 27

Amphetamine derivative that releases 5-HT (serotonin). NMDA activates the 5-HT 2B receptor, causes thickening of heart valves and can lead to cardiovascular issues such as myocardial infarction. Associated with brain lesions.

Question 28

What are psychedelics?

Answer 28

e.g. LSD, psilocybin, which is metabolised to active psilocin, these are 5-HT A2 agonists. This causes people to hallucinate, and senses change - taste sound. People can become psychotic, have flashbacks, especially if they are predisposed.

Question 29

What is the therapeutic use of psychedelics?

Answer 29

Acute dosing has a neuroplastic effect. Can be used to have long term effects on patients with drug resistant depression. Potential usage in treatment of depression, anxiety and PTSD.

Question 30

What is cannabis?

Answer 30

Sedative e.g. tetrahydrocannabinol. Lipid soluble - rapidly cross the blood brain barrier and lungs.

Question 31

What is the effect of low doses of cannabis on the cannabinoid receptor?

Answer 31

CB1 receptor, causes euphoria, uncontrollable laughter, sharpened sensory awareness. The CB2 receptor is found on immune cells, activation could have anti-inflammatory effects.

Question 32

What is the effect of high doses of cannabis?

Answer 32

Dream-like state and ptosis - droopy eyelids. Few users seek treatment for cannabis dependence, despite cannabis tobacco being highly carcinogenic (more than nicotine).

Question 33

What are benzodiazepines?

Answer 33

Potentiates GABA A receptor action by acting on allosteric sites, so facilitates inhibitory action. GABA A receptor is the main inhibitory receptor in the brain, via Cl- conductance which hyperpolarises the neurone. Barbiturates and alcohol also act on the allosteric sites.