Test 1- Pharmcodynamics

Question 1

Pharmacodynamics

Answer 1

refers to the effects of drugs and their mechanism of action within the body. If pharmacokinetics are what the animal does to the drug then pharmacodynamics are what the drug does to the animal.

Question 2

Therapeutic effects

Answer 2

Which is what we want

Question 3

Side effects

Answer 3

Which are secondary to the intended effect and may be good or bad

Question 4

Adverse effects

Answer 4

Which are unintended and unwanted, this includes NOT producing a desired clinical effect. The study and monitoring of adverse effects is called pharmacovigilance.

Question 5

Toxic effects

Answer 5

Responses to a drug that are harmful to the health or life of the animal.

Question 6

Physical interactions:

Answer 6

Nonspecific drug effects such as:

1. Osmotic diuretics:
2. Antacids (direct neutralizers):
3. Radioactive iodine

Question 7

Osmotic diuretics:

Answer 7

these molecules move through the body dragging water with them by osmosis until they are excreted.

Mannitol moves through the body dragging water with them until excreted in the urine

Question 8

Antacids (direct neutralizers):

Answer 8

Given orally they directly interact with acid in the GI

tract, a form of physiologic antagonism.

 Calcium carbonate tablets

Question 9

Radioactive iodine:

Answer 9

The iodine is actively concentrated in the thyroid (as all iodine is) and the radiation will destroy all tissue within 2-3mm causing focal, controlled destruction

 I-131 concentrates in the thyroid gland, the radiation will destroy all tissue within 2-3mm

Question 10

Biological interactions with drugs:

Answer 10

Receptors (signal-transduction) – specific recognition sites for a ligand

1. Ionotropic receptors:
2. Metabotropic receptors
3. Kinase-coupled receptors
4. Nuclear receptors / Transcription factor receptors
5. Receptor subtypes
6. Receptors can undergo up- or down-regulatio

Question 11

Ionotropic receptors:

Answer 11

LIGAND GATED ION CHANNELS

o These receptors are composed of several proteins embedded in the cell membrane creating a pore or tunnel. They are usually ligand-gated meaning that something has to bind to them causing a change in shape or ‘opening’ that allows a large influx of ions.

o Drugs can bind to these to activate them or prevent them from opening. This type of channel is often involved in fast neurotransmission (on the order of milliseconds).

• Nicotinic ACh receptors
• GABAA receptors

Question 12

Metabotropic receptors

Answer 12

• G-protein coupled receptors or 7TM (seven transmembrane) receptors
• These transduce an extracellular signal to an intracellular one by activating the

G-protein second messenger system.
-The drug binds to the receptor on the outside of the cell causing G-proteins inside the cell to bind to the receptor and take up GTP, which gives them enough energy to move to a target enzyme or channel to cause an action.

• Use of these type of systems allow signal amplification and specificity
• These are common receptor types for secretory and smooth muscle functions (eg. muscarinic ACh receptors) where the changes occur over seconds.

Question 13

Kinase-coupled receptors

Answer 13

o These transmembrane proteins have an extracellular receptor portion and an intracellular portion that has enzymatic activity (kinase domain).

• Phosphorylation and activation of proteins which then activate effectors
• There are enzymatic domains other than kinase
• Insulin receptors are of this type. Generally these are growth promoting hormones and factors—- METABOLIC CHANGES INSIDE THE CELL—- LONGER DURATION

Question 14

Nuclear receptors / Transcription factor receptors

Answer 14

o Receptors are actually located in the cytoplasm but after the ligand binds the receptor they translocate to the nucleus of the cell and bind to a response element within the DNA to initiate specific gene transcription.- alters gene transcription
o Steroids and thyroid hormones are examples of these. New protein production starts over the course of hours.

Question 15

Receptor subtypes

Answer 15

o Endogenous neurotransmitters often bind to more than one type of receptor.

The same signaling molecule can then cause different effects or have different affinity in different tissues or species.

-Adrenergic receptors for example, there are different subtypes (α, β) and differences in these subtypes between species.

Question 16

Receptors can undergo up- or down-regulation

Answer 16

o Up-regulation is an increase in the number of receptors resulting in an increase

in the effect of the drug
o Down-regulation of the number of receptors and therefore a reduction in effect

• Down-regulation can be achieved by internalizing the receptors in lysosomes, recycling them, sequestering, or degrading.
• This may be part of the normal cellular metabolism (e.g. insulin) or can occur as part of developing tolerance (a gradual decrease in responsiveness to a drug over days to months) or tachyphylaxis (an acute tolerance to a drug).

Question 17

Biological interactions:

Non-receptors

Answer 17

1. Voltage-gated ion channels
2. Enzymes
3. Carrier proteins

Question 18

Voltage-gated ion channels

Answer 18

o Blocking of ion channels can occur by the drug molecule physically obstructing the channel to impair ion movement

• Local anesthetics like lidocaine blocking Na+ channels

o The drug may also modulate the opening and/or closing of the channel

-Calcium channel blockers - amlodipine

Question 19

Enzymes

Answer 19

o Drugs can be analogs that compete with the real substrate for binding to the enzyme (acetylcholinesterase inhibitors or organophosphates do this by binding to the active site of acetylcholinesterase)
o Prodrugs where the drug needs to be metabolized to its active form
o Drugs can also act as false substrates which will lead to the formation of abnormal metabolites instead of the active product that normally would have been produced

-Sulfonamides to Dihydropteroate synthase works on the sulfa instead of on PABA and does not produce it’s normal metabolites (nucleic acids)

Question 20

Carrier proteins

Answer 20

 Some small polar molecules do not cross cell

membranes and require transport proteins

 Altering these proteins can remove molecules from their site of action and thus ending their effects

 Fluoxetine is a selective serotonin reuptake inhibitor

 Omeprazole targets the Na+/H+ proton pump in the gastric parietal cell

Question 21

ligand

Answer 21

A ligand is anything that binds to a recognition site (this can be an endogenous ligand like a neurotransmitter or a drug). At any point if a ligand is bound to a receptor it prevents other ligands from binding as long as it is sitting there.

Question 22

Agonist:

Answer 22

• Mimics the effect of the endogenous ligand
• There are differences in affinity and efficacy of agonists

o Full agonist: binds to the receptor to elicit a maximal response
o Partial agonist: will bind to the receptor but not cause as much effect as a full agonist, it does prevent anything else from binding to the receptor while it is ‘docked’ there.
This translates to a lower efficacy and is sometimes called a ceiling effect
o Reverse agonist: will bind to the receptor and cause the opposite effect as the endogenous ligand would (note that this is different from an antagonist)

Question 23

Antagonist (or ‘neutral agonist’)

Answer 23

Binds to the receptor but does nothing on its own, however it sits there and prevents anything else (like an agonist) from binding and thus blocks the receptor.

Question 24

Competitive antagonism

Answer 24

Competitive antagonism (most common) is when the antagonist ligand binds and releases as long as it is present and so if the antagonist is present as well as an agonist they will compete for the binding, who binds more often will be determined by concentration and affinity. Generally if you increase the concentration of either the agonist or antagonist enough you give that one a competitive advantage and can sometimes overcome the effect of the other.
-This can be reversible or irreversible (a great example are the carbamate and organophosphate toxins, they both bind to acetylcholinesterase and antagonize it but carbamate does so reversibly and organophosphates do so irreversibly)

Question 25

Irreversible competitive antagonism

Answer 25

Irreversible competitive antagonism is sometimes referred to as non- competitive because technically the receptors are never free, the competing ligand really doesn’t have a chance to bind there once the antagonist is present.

Question 26

Non-competitive antagonism

Answer 26

Non-competitive antagonism generally refers to a ligand that interacts somewhere other than the receptor but causes a change in the receptor (ie. shape change) that blocks its ability to bind to the normal ligand.

Question 27

Mixed agonist-antagonist

Answer 27

Acts as an agonist in one type of receptors and as an antagonist on other types of receptors

Butorphanol acts as an agonist at κ opioid receptors and as an antagonist at μ opioid receptors

Question 28

Non-receptor antagonism

Answer 28

Chemical antagonism: Two drugs chemically inactivate each other

Pharmacokinetic antagonism: A drug alters ADME of another drug & reduces its effect

Physiologic antagonism: Drugs have opposite effects that cancel each other out

Question 29

Quantification of drug response:

Answer 29

Drug response can be measured and will typically give a curve. Plotted on semi-log paper (log of concentration by response %) it will appear as a sigmoidal curve, the straight portion of which typically falls in the range between 20% and 80% response. This usually corresponds to the therapeutic range.

Question 30

Efficacy

Answer 30

o The maximal effect a drug can have (e=1 is a full effect)
o A partial agonist may never be able to achieve full efficacy (ceiling effect)

Question 31

Potency

Answer 31

o Comparison of the concentration of two drugs needed to induce the same magnitude effect

o A partial agonist could be more potent (eg. can achieve a sub-maximal effect at a lower dose than a full agonist)

Will be intergrated into dose

Question 32

EC50 (Effective Concentration 50%)

Answer 32

o This is the concentration at which a drug produces 50% of its maximal effect
o Only applies to in vitro preparations as we can’t get this kind of measurement in the animal

o It is useful to compare the efficacy of different ligands (ie. full agonists vs partial agonists).

Question 33

ED50 (Effective Dose 50%)

Answer 33

o Dose that produces a result (usually the desired effect) in 50% of the animals
o This is an in vivo, observed effect
o (Note that EC50 and ED50 are not interchangeable and do not mean the same thing)
o The LD50 is the dose which kills 50% of animals (it’s a special kind of ED50 where the effect is death)

Question 34

The therapeutic index

Answer 34

The therapeutic index is the ratio of LD50 to ED50
o A high therapeutic index indicates a safe drug – the two curves will be wide apart so that if 100% of the animals are demonstrating the effect at a dose for which 0% of animals are showing toxicity you have a very safe drug.

o A narrow or low therapeutic index indicates a more dangerous drug – at doses close to those required for efficacy in some animals toxicity may be seen in others (the two curves will be close or even overlap each other).

 In humans they compare harmful dose instead of toxic dose

Question 35

Onset of action

Answer 35

o The time required after drug administration for a response to be observed

o Also called the latent period

Question 36

Duration of action

Answer 36

o The length of time that a drug is effective (from onset of action until termination of action)

Question 37

Gs

Answer 37

Type 2: G-protein coupled (Metabotropic)

Gs – couples to adenylate cyclase
 Increases cAMP which activates kinase A which

phosphorylates cellular constituents.

Question 38

Gi/o

Answer 38

Gi/o – couples negatively to adenylate cyclase

 Decreases cAMP, can close Ca++ and K+ channels.

Type 2: G-protein coupled (Metabotropic)

Question 39

Gq

Answer 39

Gq – couples to phospholipase C-β (PLC-β)

 Increasing IP3 which increases Ca++ release from SER

Type 2: G-protein coupled (Metabotropic)

Question 40

Maximal effect (ceiling)

Answer 40

Point at which increasing concentration does not yield greater response

Question 41

narrow therapeutic index

Answer 41

A narrow therapeutic index (small number, close to 1) means that the dose required to cause death is close to the dose required to have a therapeutic effect.

Question 42

wide therapeutic index

Answer 42

A wide therapeutic index means that the dose required to cause death is much higher (often many times higher) than the dose required to have a therapeutic effect.

Question 43

Standard Safety Margin

Answer 43

Standard Safety Margin is a more conservative measure. It looks at the dose required to produce a therapeutic effect in ALL animals relative to the dose required to produce a hazardous effect.

Question 44

Lidocaine blocks

Answer 44

Na+ channels

Question 45

Are G-coupled proteins inhibitory or exictatory?

Answer 45

BOTH!

Question 46

affinity

Answer 46

how much the ligand wants to bind to the receptor

higher affinity will bind more to the receptor site

Question 47

efficacy

Answer 47

What happens when the ligand bind to the receptor

full, partial, or inverse agonist