TASK 1

Question 1

Pharmacodynamics

Answer 1

Drug on body - which receptors a drug acts on

Question 2

Pharmacokinetics

Answer 2

Body on drug - what your body does to the drug

(includes bioavailability: routes of administration, absorption and distribution, binding (depot binding), inactivation/biotransformation, excretion)

These factors are in work simultaneously. The drug effect will not only depend on bioavailability but also on how fast the drug reaches its target, the history of drug use and nonspecific factors

Question 3

Bioavailability

Answer 3

amount of drug available in the blood to bind at specific target sites to elicit drug action

Question 4

routes of administration

Answer 4

ENTERAL METHODS: uses the gastrointestinal tract. Slow in onset and produce variable blood levels of the drug

• Oral or rectal administration
• to be effective, the drug must dissociate in the stomach and pass stomach walls to reach blood capillaries and must be resistant to stomach acid

PARENTERAL METHOD: do not use the alimentary canal (e.g. injection, pulmonary, topical administration)

• Intravenous injection
• Intramuscular injection
• Intraperitoneal injection - drug given though abdominal wall
• Subcutaneous: hormone administration
• topical: intranasal administration: can have local and systemic effects (avoid first-pass metabolism and pass into the blood stream)
• epidural injections

Question 5

Drug absorption

Answer 5

drug concentration: determined in part by individual differences in age, sex and body size

Cell membranes are made of phospholipids (fat) that prevents many drugs from passing through the layers

a) Lipid-soluble drugs: they move through cell membranes by passive diffusion, leaving the water in the blood or stomach and entering the lipid layers of membranes
- Moving through membranes happens from higher to lower concentration (concentration gradient determines the speed)
- It increases the absorption of the drug into the blood

b) most drugs are not lipid soluble because they are weak acids or weak bases that can become ionized when dissolved in water (form two charged particles)
- Do not pass blood-brain barrier when ionized (if a drug cannot pass blood-brain barrier, it doesn’t have any effect on behavior)

Question 6

Drug distribution

Answer 6

Once the drug has entered the blood, it is carried through the body within 1 or 2 minutes and can have action at any receptor site

• Higher concentration of the drug will be found in heart, brain, kidney and liver due to higher blood flow

a) has an effect once it reaches side of action
b) most of the drug will be elsewhere = side effect

Question 7

Blood brain barrier

Answer 7

Distinct morphology of brain capillaries are found in there. They have intracellular clefts with tight junctions which are supported by glial cells and make sure nothing enters the brain and CBF

• Not complete, so several areas are not isolated from material in the blood (area postrema in the medulla –> causing vomiting)
• drugs that are ionized don’t pass the barrier

Question 8

Placental barrier

Answer 8

found between the blood circulation of a pregnant mother and that of her fetus. It exchanges nutrients, O2, Co2, fetal waste products and drugs
- Lipid soluble drugs pass easily, water soluble substances not

Question 9

First-pass metabolism

Answer 9

Drug in the gastrointestinal tract goes to liver, which breaks down the drug
A certain amount of drug will be inactivated or metabolized
- other routes may not be subject to first-pass metabolism

Question 10

Depot binding

Answer 10

drug binding also occurs at drug depots, which are inactive sites where no effect can be seen

• Drug depots include plasma protein, muscle and fat
• the binding is irreversible, so it binds until the blood level drops and then continues to circulate in the plasma

It has effects on the magnitude and duration of drug action:
1. reduces the concentration of the drug at the site of action –> delayed effects & Individual differences in depot binding explain individual reactions to the drug

2. Binding to these sites is nonselective, so many drugs compete for these sites. Such competition may lead to higher-than-expected free drug blood level, producing an overdose
3. Bound drug molecules cannot be altered by liver enzymes - it prolongs the time the drug is in the body (THC use can be detected for a long time - stored in fat)
4. They can be responsible for terminating the action of a drug

Question 11

biotransformation

include routes of elimination and metabolism

Answer 11

routes of elimination:

1. primarily kidneys via urine (often must be transformed to active metabolites to be excreted)
2. lungs
3. bile/intestine
4. skin (sweat)

Metabolism: done in liver by microsomal enzymes (lack specificity and alter many drugs that are highly lipid soluble to less lipid soluble drugs - active metabolites)

a) Phase 1: nonsynthetic modification: modification of drug by oxidation, reduction or hydrolysis to have a less lipid soluble drug in the end
- use P450 CYP

b) Phase 2: synthetic modification: combination of drug with some small molecule –> psychoactive drug deactivation

Question 12

Rates of elimination

Answer 12

Half life: the amount of time required to remove 50% of the drug in the blood: it determines how often a drug should be taken max. otherwise the drug will remain in the blood and the next dosage is taken anyways
• goal: to maintain the plasma concentration at a constant desired level for a therapeutic period BUT the target concentration is achieved only after multiple administrations
• steady-state plasma level: desired blood concentration of drug achieved when the absorption distribution phase = equal to metabolism or extinction phase

First order kinetics: drugs are metabolized proportionally to the amount of drug present

Zero order kinetics: drug molecules are cleared at a constant rate regardless of drug concentration

Question 13

Renal excretion

Answer 13

The primary organ of elimination is the kidney, as drugs are usually eliminated in the urine
- As filtered materials pass through the kidney tubules, necessary substances are reabsorbed into the blood. Reabsorption of water lead to an increase in the drug concentration in the tubules - many drug molecules are reabsorbed into the blood

Question 14

Stage in life of a neurotransmitter

Answer 14

1. Biosynthesis- Production of NTM occurs through an enzyme facilitate process
2. Storage: NTM into vesicles prepares them for the release
3. Release: Increasing release facilitates action of NTM, preventing release blocks its action
4. Receptor activation:NTM bind to PSN by binding to its receptors. There are specific receptors for each NTM
   Drugs can mimic the action of NTM and bind to the receptors:

a) Agonists: drugs that activate NTM receptors
b) Antagonist: drugs that bind to the receptor and prevent the binding of an actual NTM - blocking NTM function
c) Partial agonists: demonstrate efficacy that is less than that of a full agonist but more than that of an antagonist
d) Inverse agonist: initiate a biological action opposite to that produced by an agonist
e) Autoreceptor: located at the presynaptic neuron and when activated or blocked regulate the biosynthesis and release of the NTM. It senses the amount of NTM in the cleft
o Stimulate autoreceptors: biosynthesis and/or release are reduced
o Block autoreceptors: biosynthesis and/or release are increased

5. Inactivation
   a) Reuptake: transporters actively remove the NTM from the synapse
   b) Enzymatic inactivation: NTM is transformed into a compound that can no longer interact with the receptors

Question 15

Receptor types (intra vs. extracellular)

Answer 15

1. Intracellular receptors: in the cytoplasm or in the nucleus. Most hormones use this
   - alter cell functioning by triggering changes in expressing genetic material and produce differences in protein synthesis
2. Extracellular receptors can be ionotropic or metabotropic

Question 16

Types of extracellular receptors

Answer 16

Ionotropic receptors/ ligand-gated ion channels: simplest signal transduction mechanism. They are large protein complexes with a central ion channel that are activated by NTM.

• Ions are unequally distributed between the inside and outside of the neuron, electrical changes can lead to EPSP or IPSP
• rapid response
• Made of multiple protein subunits, so the pharmacology and function of the receptors can vary depending on the specific subtype that make it up

GOAL of psychopharmacology: create drugs that bind only to one subtype of receptors to get a selective response

Metabotropic receptors/G-protein-coupled receptors:
Complex and can affect the cell electrically and chemically
- A single protein makes up the receptor, but there may be different variants of that protein
- Slower response
1. NTM activates receptor
2. G-protein is modified and triggers internal neuronal events
- can activate enzymes that modify neurons on LT (second messenger system)
- EPSP or IPS depends on the channel activated

Question 17

Receptor modification

Answer 17

• Up-regulation: increase in receptors
• Down-regulation: decrease
  It takes 1-2 weeks to initiate a modification in number, while changes in sensitivity due to second messenger functions are way faster

Question 18

Ligand

Answer 18

any molecule that binds to a receptor with some selectivity

Question 19

Factors influencing drug metabolism

Answer 19

1. Enzyme induction: when used repeatedly drugs cause an increase in liver enzymes, leading to faster biotransformation
   •. explains cross tolerance: increase rate of metabolism for all drugs modified by the same enzyme
   • When drug use is terminated, enzymes decrease again
2. Enzyme inhibition: some drugs inhibit the action of CYP enzymes, reducing the metabolism of other drugs taken at the same time that are metabolized by the same enzyme–> prolonged effect and toxicity (MAOi is an example)
3. Drug competition: occurs for drugs that share a metabolic system: enzyme molecules are limited –> an elevated concentration of either drug reduces the metabolic rate of the second
4. Grapefruit juice: inhibits biotransformation of many drugs metabolized by CYP 450
   - 24 hours
   - inhibits first-pass metabolism (more drug in blood)
5. Individual differences: • genes: asians are slow metabolizers (different enzymes)
   • Level in nutrition or liver function
   • Age: older people have a reduced ability to metabolize drugs, similar to children under 2 years
   • Gender: stomach enzymes that metabolize alcohol before it reaches the blood stream are less effective in women than in men  women will have a higher concertation of alcohol in the blood

Question 20

Tolerance

Answer 20

• Some drugs induce tolerance frequently while others don’t.
• Not all behavioral effects demonstrate tolerance equally: vomiting when inducing morphine show tolerance, but other effects of the drug do not

TYPES OF TOLERANCE:

1. Acute tolerance: tolerance that develops during a single administration
2. Metabolic tolerance: new enzymes are built - increased metabolism –> more drug needed
3. Pharmacodynamic tolerance: receptors down-regulation: a certain amount of drug has fewer receptors to act on = less effect. Compensatory upregulation occurs when receptor activation is chronically reduced.
4. Behavioral tolerance:
   a) classical conditioning
   b) operant conditioning: tolerance due to learning: if a person is rewarded when their movements while being intoxicated match their movements while sober – tolerance develops faster
5. State-dependent learning: tasks learning in the presence of a psychoactive drug may subsequently be performed better in the drugged state

Question 21

Sensitization

Answer 21

enhancement of drug effects after repeated administration (more receptors)

• It is dose-dependent and the interval between the treatments is important
• Cross-sensitization can happen
• Conditioning plays a role
• Cocaine and amphetamine are examples of drugs that induce tolerance for some effects (euphoria) and sensitization for others

Question 22

Alcohol absorption

Answer 22

alcohol is absorbed from the gastrointestinal tract into the circulation. It travels down the esophagus into the stomach, from the stomach into the small intestine, to the liver, from liver to heart and from heart through the body, including the lungs and brain.
- alcohol is water soluble, passing easily through lipid membrane

Factors affecting absorption:

a) food consumption: absorbed more rapidly on an empty stomach
b) volume: large volume of alcohol consumed will lead to a rapid increase in blood-alcohol concentration (BAC)
- max BAC occurs before absorption is complete –> completion may take hours after drinking stops

Question 23

Alcohol distribution

Answer 23

The larger the body water content, the more dilute any amount of alcohol will become

• Tissues with greatest blood supply and capillaries receive it more rapidly (because blood consists of water)
• When it has been equally distributed, it reaches an equilibrium

FACTORS AFFECTING DISTRIBUTION:

a) gender differences: metabolism differs (muscle cells have more water than fat cells - women have less water = women have higher BAC)
- estimate of body water: height, weight, age

Question 24

Metabolism / Elimination of Alcohol

Answer 24

lining of stomach contains alcohol dehydrogenase ADH (also found in liver)

• responsible for 10% first-pass metabolism
• ADH oxidizes most alcohol in the liver: ADH produces acetaldehyde, which is transformed by ALDH to acetyl coenzyme A, which is broken down to carbon dioxide and water.

Two major types of aldehyde dehydrogenase (ALDH):

1. ALDH1: high acetaldehyde concetrations are required for the cell to become active
2. ALDH2: low levels are required for the cell to become active (Asians lack active ALDH2, so they cannot metabolize alcohol very well)

Hepatic metabolism: Alcohol is oxidized by two families of enzymes found in the liver:

1. ADH – 90% is metabolized by ADH
2. P4150 (MEOS) consists of 2 enzymes:
   a) cytochrome p350 reductase
   b) cytochrome 2E1 isozyme: can metabolize other drugs as well (important for drug-alcohol interaction)
   - plays a limited role in the metabolism of alcohol in occasional drinkers, but in chronic heavy drinkers increase this enzyme up to 10x

Question 25

Alcohol testing

Answer 25

Widmark equation: Extrapolate what the BAC was at the time of a specific incident prior to the time the specimen was collected

• takes amount of alcohol ingested, body weight, elimination rate, time since start of drinking into account (+ widmark factor)

Breath analysis: concentration of alcohol in blood = concentration of alcohol in breath
Problem: it assumes that alcohol is distributed equally in every person (50% error rate)

Question 26

Dose response curve

Answer 26

used to evaluate receptor activity. It describes the extent of biological or behavioral effect produced by the given drug concentration. It takes on a classical S-shape.

• Low doses: drug effect is slight because only a few receptors are occupied. As the dose increases, the effect increases.
• ED50 (50% effective dose): effect in 50 % of persons
• LD50: lethal effect for 50% of the persons
• Drug efficacy: activity that occurs between the drug and receptor interaction – refers to the maximal effect a drug can produce regardless of the dosage prescribed

Question 27

Potency

Answer 27

The absolute amount of drug necessary to produce a specific effect. Differences can be seen when comparing ED50 across the different drugs (for some drugs, more substance needs to be taken to achieve ED50 than for other drugs)

• one wants the largest difference between the toxic effect and 50% effectiveness

Question 28

Therapeutic index

Answer 28

Used to calculate drug safety: highest value = safest option

TI= TD50 (toxic effect in 50% of individuals)/ED50 (effective for 50% of individuals)

Question 29

Competitive antagonist

Answer 29

compete with agonists for the binding sites. They can be displaced from those sites by an excess of agonists, because increased concentration of active drug can compete more effectively for the fixed number of receptors
- The presence of an antagonist can diminish the potence of the agonist: cancel each other out

a) Noncompetitive antagonists: drugs that reduce the effects of agonists in ways other than competing for the receptor
b) Physiological antagonism: 2 drugs that act in 2 distinct ways but interact in such a way that they reduce each other’s effectiveness in the body (additive effects)
c) Potentiation: combination of.2 drugs produces effects that are greater than the sum of their individual effects

Question 30

Drug effects

Answer 30

Alterations in physiological or psych. functioning

• specific drug effects: can be explained biologically (receptors)
• unspecific drug effects: based on unique characteristics of the individual (mood, expectation, placebo believe)