cheat sheet # 1

Question 1

What is the relevance of the route of administration ?

Answer 1

The relevance of the route of administration is that faster the route the more reinforcing the effecting (increasing abuse potential), often times faster routes also tend to have shorter duration leading to more severe withdrawal (e.g. heroine IV v. methadone oral)

Question 2

what are the types of routes of administration ?

Answer 2

Iv
inhalation
intranasal
oral

Question 3

Explain IV . What is it ? and what it does?

Answer 3

Iv is the fastest route of administration out of the 3 others route

It goes directly into blood circulation to heart and to brain. (fast and very reinforcing)

Question 4

List from fastest to slowest routes of administrations

Answer 4

Fastest: IV (injection), Inhalation/Smoking, Snorting, Oral, IM (intramuscular)

Question 5

inhalation (smoking)

how it works

Answer 5

• Absorbed into lungs (large surface areas dense with capillaries), passes to heart and fast action to brain through carotid artery

Question 6

intranasal

Answer 6

• Passes single epithelial layer in nose, direct access CSF by passes blood brain barrier

Question 7

Oral

Answer 7

• Stomach -> Intestine –> Liver (1st pass metabolism broken down and excreted)
• Enzymes in stomach can break down drug
• Drug can be absorbed into blood through stomach wall or intestine (more surface area more opportunity to be absorbed)

Question 8

absorption ?

Answer 8

Cell membrane are complex lipids and only lipid soluble substance can passively diffuse
easily through membrane.

Question 9

Stomach lining and intestinal wall

Answer 9

• blood circulation; body has capillaries with gaps and transporters that allow water soluble molecules to cross

Question 10

Brain (blood brain barrier

Answer 10

• extracellular space –> postsynaptic neurons; brain has capillaries (blood brain barrier) without gaps and transporters, therefore, ONLY sufficiently lipid soluble molecules can cross

Question 11

for drugs, what kind of solubility it has to produce a more potent effect on the brain ?

Answer 11

The more lipid soluble a substance, the more potent the substance to produce a psychoactive effect (brain effect

Question 12

Drugs differ in their lipid solubility depending

Answer 12

: 1) how alkaline or acidic the drug eg. Aspirin weak acid, 2) alkalinity or acidity of the solution the drug interacts with (eg. Stomach strong acid)

Drug Weak Acid + Strong Acidic Solution (stomach) == weak and strong create a neutral charge = non-ionized =lipid soluble = passes blood brain barrier (DON”T THINK BEYOND THIS ONE EXAMPLE)

Question 13

1. Binding of the drug

Answer 13

• Drugs will either bind to blood plasma and travel to target neurons or it will bind to inactive sites (depot binding) eg. Fat, bone.
• Individuals vary in how much drug will bind to inactive sites (depot binding)
• Drugs that bind to inactive sites it reduces the initial concentration of the drug available to produce a psychoactive effect (brain effect)
• Inactive binding is only temporary and eventually the drug will return to blood stream (but the concentration is low). This is why people have drugs in their systems days after taking the drug.

Question 14

1. Inactivation

Answer 14

• CYP450 family of enzyme responsible for breaking down psychoactive substances
• Can be found in liver, stomach etc.

Question 15

Enzyme Induction

Answer 15

• the more you take the drug the stronger the enzyme becomes and more likely the drug will be broken down. This is a mechanism of tolerance. Enzyme induction produces cross-tolerance with certain drugs eg. Smoking and antidepressants. The more you smoke and develop a tolerance due to break down by enzyme induction, the less effective antidepressants are.

Question 16

Enzyme Inhibition

Answer 16

• the more you take a drug the more like the enzyme is not to break down the drug. This is a mechanism of sensitization. Enzyme inhibition produces cross-sensitization with certain drugs e.g. grapefruit juice and certain medications. If you drink grapefruit juice and take the medication you will become more sensitive to the effects of the medication, which can be dangerous

Question 17

Enzyme Competition

Answer 17

• two different drugs will compete for the enzyme, this could lead to an elevated level of one of the drugs eg. Alcohol and valium. If alcohol binds and saturates all the enzymes, then nothing is breaking down the valium and this leads to elevated levels (which can be dangerous ie. depressing breathing)

Question 18

*Pharmacokinetic Tolerance

Answer 18

after repeated use you need more drug to produce the same effect as when you first started taking the drug.

Question 19

*Pharmacokinetic Sensitization

Answer 19

after repeated use (some drugs this can happen quite quickly) you become more sensitive to the drugs effect and need less drug to produce the same effect.

Question 20

Pharmacokinetic Cross-tolerance

Answer 20

the tolerance one develops for a drug will extend to another substance (even if you have never taken the drug before). Cross-tolerance usually only happens between drugs of a similar class ie. CNS stimulants, CNS depressants etc. However, this isn’t always the case……. (why it is complicated)

Question 21

excretion - first order kinetics

Answer 21

• Period of time for 50% of the drug to be removed eg. Fluoxetine half-life 2-3 days, cocaine half-life 1-2 ours. Longer time period/longer half life means the drug remains in the system longer and can increase the abuse potential. This is relevant for two reasons: 1) methamphetamine more abuse potential because it has a longer half life than amphetamine and cocaine, 2) longer half life is important for drugs like methadone because there are less severe withdrawal effects and people don’t have to take the substance as often. UNDERSTANDING HALF LIFE IS IMPORANT – it impacts the addiction potential and it impacts the degree of withdrawal (which makes it principle for withdrawal eg. Methadone is an opioid agonist, but it is taken orally (slower absorption = less rewarding) and has a longer half-life – less severe withdrawal and is a better substitution for heroin.

Question 22

Zero-Order Kinetics

Answer 22

• the rate of breakdown and excretion is constant regardless of the amount of the substance eg. Alcohol rate 1.5 hours for almost 1 standard drink. Alcohol binds and saturates the enzymes, so the more you drink the longer it will take to leave the system.

Question 23

Affinity-

Answer 23

how well the drug/neurotransmitter binds to the post-synaptic receptor (lock and key analogy)

Question 24

efficacy

Answer 24

when the drug is bound does it produce an effect (opens the door analogy)

Question 25

partial agonist

Answer 25

high affinity and low efficacy (e.g. buprenorphine for heroin use). Buprenorphine binds to the opioid receptor and prevents heroin from binding (this is a plus). It binds and only has minimal efficacy (which reduces the severity of the withdrawal and reduces the likelihood of euphoric effects).

Question 26

antagonist

Answer 26

high affinity and no efficacy (e.g. naloxone to address heroin overdose). It is a competes with heroin to bind to the opioid receptor and when it does bind it does nothing, which stops the overdose. The only problem with competitive antagonists is that you just need to take more of the agonist and this will undue any benefit of the antagonist (e.g. Take more heroin after naloxone and you render the naloxone ineffective).

Question 27

Excitatory Neurotransmitters (glutamate):

Answer 27

when glutamate binds to the post-synaptic receptor it opens the ion channel in the receptor leading to an influx of sodium. When sodium enters the neuron, it makes it more positive (voltage) and leads to depolarization – increasing the likelihood of an action potential firing

Question 28

Inhibitory Neurotransmitters

Answer 28

when GABA bins to post-synaptic receptor it opens the ion channel in receptor leading to an influx of calcium or potassium. When calcium or potassium (potassium is a positive ion, but there is a high concentration in the cell so when you open it the potassium flows out making the cell more negative) enters the neuron, it makes it more negative (voltage) and leads to hyperpolarization – decreasing the likelihood of an action potential firing.

Question 29

Tolerance

Answer 29

When you take a substance repeatedly your body gets an overabundance of a neurotransmitter into the system eg. Cocaine (blocks the reuptake transporter of all monoamines, but mostly for dopamine resulting in huge amounts of dopamine being left in the cleft) results in too much dopamine in the cleft. Your brain doesn’t like being overwhelmed by neurotransmitter and develops a neuroadaptation called downregulation. Downregulation means there is a reduction in the number of dopaminergic post-synaptic receptors (homeostasis). With fewer post-synaptic receptors (and if the person continues to take the same amount of cocaine and doesn’t increase their dose) the brain feels like it is receiving the same level of dopamine as before the cocaine use. However, the person doesn’t want the same level of dopamine, they want to have the same effects they experienced when they started taking cocaine. Therefore, the take more cocaine to produce the same effect the first experienced === tolerance.

Question 30

monoamine reuptake transporter

Answer 30

the transporter is found on the axon terminal and its job is to take drugs/neurotransmitters out of the cleft and return it to the vesicles to be used later – this is a homeostasis function to prevent too much NT staying in the cleft for too long activating post synaptic receptors.

Question 31

Withdrawal

Answer 31

After you have developed tolerance and your post-synaptic receptors have downregulated the individual might decide to stop using the substance. Continuing with the cocaine example, when there is less dopamine now available and fewer post-synaptic receptors, your brain is receiving minimal amounts of dopamine (way lower then your original base line before drug use) and treats this as a deficiency. Dopamine deficiency produces the experiences of dysphoria, depression, lethargy etc. The withdrawal symptoms are a rebound effect. Before you take cocaine, you have a baseline (the natural amount of dopamine your brain produces). You take cocaine this increase the dopamine levels well above your natural baseline (euphoria, energy, arousal), but when you stop taking it your brains dopamine levels are now below baseline as your natural state (deficiency dysphoria, lethargy). Your brain goes from having too much stimulation (cocaine use) and then registers a rebound effect – too little stimulation (stop using after developing tolerance). Withdrawal is the period of time the neuroadaptation remains in the brain (downregulation) in the absence of the substance.

Question 32

Negative Reinforcement/Dependence

Answer 32

Withdrawal is unpleasant, and, in some cases, this leads people to use more of the drug to stop the negative withdrawal experience = negative reinforcement (the removal of an unpleasant stimuli/withdrawal increases the likelihood of the beh/drug seeking beh). The continued use of the substance to stop the negative effects of withdrawal is called drug dependence.

Question 33

Positive Reinforcement

Answer 33

A pleasant stimulus that increase the likelihood of behavior. You take a drug, it feels good, you take it more.

Question 34

Brains Reward Circuit

Answer 34

pathways rich with dopaminergic neurons which are associated with a pleasant high/euphoria/reward) 1. Nigrostriatal Pathway (Substantia Nigra Caudate-Putamen) • Motor movement eg. Cocaine release dopamine in nigrostriatal pathway and produces increased energy and movement 2. Mesolimbic Pathway (Ventral Tegmental Area Nucleus Accumbens) • Reward/high/euphoria • Salience (focused attention to drug compared to anything else in environment) • Change in value system – drug has more value and things that were previously rewarding lose their value 3. Mesolimbic Pathway (Ventral Tegmental Area Prefrontal Cortex) • Motivation

Question 35

Any drugs thhat produces a euphoria or a high activates which neurons ?

Answer 35

activates dopaminergic neurons in the mesolimbic pathway.

Question 36

Opioid receptors

Answer 36

Opioid receptors (are rewarding in and of themselves ie. endorphins are great) can also be found in the ventral tegmental area. Opioid are an inhibitory neurotransmitter, but they activate GABA which is also inhibitory in the mesolimbic pathway. When you inhibit an inhibitor, you remove the breaks in the mesolimbic pathway resulting a flush of dopamine release. GABA plays a key role in regulating your reward pathway.

Question 37

GABA (breaks in brain)

Answer 37

inhibitory neurotransmitter. The function of a GABA agonist (sedative hypnotics) is to produce relaxation, sleepiness, reduces the experience of anxiety. Too Much GABA – coma, stop breathing, death Too little GABA – convulsions, seizures

Question 38

Glutamate

Answer 38

Glutamate (gas pedal in the brain) – excitatory neurotransmitters. Major role in learning and memory. Too Much Glutamate- high levels are dangerous in the brain and can produce cell death/neurotoxic effects (apoptosis/necrosis the cell swells and bursts because the channels are open too long and the ions flow in and make cells burst) Too Little Glutamate – impairs learning and memory, formation of new memories

Question 39

Serotonin (SSRI blocks the reuptake and leads to more serotonin in the cleft)

Answer 39

* Mood – less serotonin people experience depression * Appetite- take SSRI (more serotonin) increases appetite * Sexual Beh – take SSRI (more serotonin) decreases sexual libido and can lead to development of sexual dysfunction * Pain and Sensitivity – less serotonin more sensitive to pain (physical and psychological) * Anxiety – more or less serotonin is associated with anxiety (it is complicated) * Aggression – more or less serotonin is associated with aggression (it is complicated)

Question 40

Norepinephrine

Answer 40

* Arousal, attention, vigilance | * Sympathetic Nervous System – fight or flight system activates a stress and anxiety system