Pharmacodynamics

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Drugs

What is Pharmacodynamics?

The effects of drugs on the body

What is Pharmacokinetics?

The study of how the body interacts with drugs

What are the 3 different ways that drugs can be named? Describe each

1. Chemical Name

   1. Describes the drug using chemical nomenclature

2. Generic (Non-Proprietary) Name

   1. The name of the drug by the producing company

   2. Ex: Acetaminophen

3. Trade (Proprietary) Name

   1. Names that are owned exclusively by one company

   2. Ex: Tylenol (a type of Acetaminophen)

T/F: Once manufacturers choose a trade name for a drug, they cannot rebrand that drug

False, they can, even if they. change the drug into an entirely new product they do not have to change the name

What are receptors?

They are molecules that bind to endogenous or exogenous ligands

What is Allosteric Binding?

Ligands that alter a receptors confirmation by binding nearby to it

What are the 4 major types of receptors? What is the main function of each?

1. Ligand-gated ion channels

   1. Regulate ion flow through cell membranes

2. G-protein coupled receptors

   1. Send 2° messengers into cells to trigger a certain outcome (stimulatory/inhibitory)

3. Tyrosine Kinase receptors

   1. Activation (phosphorylation) of cellular enzymes and proteins

   2. Mostly used by hormones/growth promoters

4. Intracellular Receptors

   1. Alters DNA transcription

   2. Ligands are lipophilic (steroids/thyroid hormones) and can enter the cell and bind to receptors within the cell

   3. Response can take days

A receptor that allows Na+ into and out of the cell would likely be what type?

Ligand Gated Ion Channel

A receptor that is activated by thyroid hormones within the cell is likely what type?

Intracellular Receptor

When a Drug binds to a receptor on an enzyme, what are the 3 potential outcomes?

1. Block/Activate normal enzyme function

2. Produce false metabolites

3. Activate a prodrug

When a Drug binds to a transmembrane receptor, what are the 3 potential outcomes?

1. Mimic/Block the normal effect of endogenous molecules

2. Indirectly affect endogenous molecule concentration at receptors

3. Change endogenous molecule uptake

Two important terms of drug-receptor interactions are affinity and intrinsic activity, define both terms, describe the difference between the two

• Affinity

  • Describes the tendency of a drug to bind with its target receptor and the strength of its connection

• Intrinsic Activity

  • Occurs after the drug binds to the receptor

  • It describes the amount of response that occurs when a drug binds to the receptor

The most ideal drug is specific and selective, what does this mean? Is this feasible?

• Specific means it binds to one or a few receptors

• Selective means the drug only has its intended effects (ie no side effects)

  • This is achieved by the drug only binding to its intended receptor and not any others

• This is rare, most drugs bind to multiple receptors with a stronger affinity for one of them

Which is more likely to cause side effects, non-specific drugs or specific drugs? Why?

• Non-specific drugs

  • They bind to a wider range or receptors with less affinity for one particular receptor

  • This gives them the greatest probability to cause side effects

What is the difference between efficacy and intrinsic activity?

• Efficacy describes the ability of the drug to produce the maximal desired effect

• Intrinsic activity describes the ability of the drug to cause a response at the receptor (cellular) level

T/F: Receptors can have variable intrinsic activity, why or why not?

• True

  • If the receptor can take multiple ligands, then it has the potential to send out one or more 2° messengers, resulting in different cellular responses

What are stereoisomers and what role do they play in pharmacokinetics?

• They are chemicals that share the same molecular formula but vary in their 3D shape

• The main type are Enantiomers

  • These are chemicals that are mirror images of each other (Think of it like holding out your L and R hand and making an L in both)

• Drugs are made with racemic mixtures, meaning they have both variants (L and R) that can bind to to the different variants of receptors

What risk do racemic mixtures of drugs pose?

They can bind to different receptors and cause very different effects or side effects

What are the 3 different theories of dose-response quantification? Briefly describe each theory

1. Occupancy Theory

   1. The response of a tissue/organ is proportional to the # of receptors bound and activated by a drug

2. Two-State Model

   1. Receptors exist in a dynamic equilibrium between active (tensed) and inactive (relaxed)

   2. Agonists bind to the receptors in their active state which shifts the equilibrium towards active

   3. Inverse Agonists bind to receptors in their inactive states and shift equilibrium towards the inactive

3. Rate Theory

   1. Receptors can be bound or unbound by a ligand but neither causes a reaction

   2. The reaction stems from the binding of the ligand to the receptor (the important part is the initial contact between ligand and receptor)

What are the 4 important characteristics of the drug-concentration relationships?

1. Efficacy

2. Potency

3. Slope

4. Variablity

Define Efficacy

The ability of a drug to produce the desired effect

It is more important for a drug to be ______ than potent

Efficacious

Define Potency

The concentration of a drug required to elicit the desired effect

What is a drug-response curve used to represent?

How close the relationship is between effectiveness of a drug and toxicity in relation to the dosing

If a dose-response curve has overlying lines, what does that indicate about the dosing range of the drug?

It indicates that there is not a very safe dosing range between effectiveness and toxicity

T/F: All drugs work the same for every animal of the same species

False, they can vary wildly

What factors can contribute to the variable responses to a certain drug in patients?

1. Administration route

2. Drug concentration at the receptor site

3. Drug interactions

4. Disease type and severity

5. Age

6. Tolerance

7. Gender

What is the difference between an Agonist and an Inverse Agonist?

• An Agonist mimics the effects of endogenous substances when they bind to a receptor, the “activate“ receptors

• An Inverse Agonist binds to inactive receptors and stabilizes them in the inactive confirmation, preventing activation

What is the difference between a partial agonist and a full agonist?

One produces a maximal response and the other produces a sub-maximal response (lower intrinsic activity)

What is the term that goes with this description?

Agonists that bind to receptors (mainly GPCRs) that can stimulate different pathways/responses but are favorable towards one particular pathway

Biased Agonists

What is the term that goes with this description?

The interaction between two drugs that results in the response of one being decreased when the other drug is present

Antagonism

What are Receptor Antagonists and what role do they play in receptor activation/inactivation?

• They are ligands that have an affinity for a recpetor but when they bind they do not change the confirmation of the receptor to active/inactive

• They reduce the effect of other agonists/ligands by competing for the

T/F: Receptor Antagonists have no clinical effect if no Agonist/Ligand is present

True

What are the 3 different types of Antagonists? Describe each

1. Reversible Competitive Antagonist

   1. Don’t bind permanently to the receptor

   2. Bind to the same site on the receptor as the ligand

   3. Surmountable (If there is more agonist it can be overcome)

2. Irreversible Antagonists

   1. Competitive/Non-Competitive forms

   2. Form permanent bonds with receptors

3. Non-Competitive Antagonists

   1. Bind allosterically to receptors, preventing agonist from binding

T/F: Antagonists alter the receptor equilibrium (active/inactive), but Agonists don’t

False, it’s reversed

What is the difference between a Physiological and a Chemical Antagonist?

• A Chemical Antagonist prevents the Agonist from binding to a receptor by modifying/sequestering the Agonist so that it can no longer bind to the receptor

• A Physiological Antagonist just cancels out the effect of another drug (similar to the definition of Antagonism )

What type of Antagonism is depicted on the L and R?

• L

  • Competitive Antagonism

• R

  • Non-Competitive Antagonism

  • Decreases each time because as the Antagonist increases, the response decreases because the Agonist can’t fight the antagonist for a spot since the antagonist binds allosterically

T/F: Drug action can change over time

True!

Refractory

Loss of therapeutic efficacy over time

Tolerance/Tachyphylaxis

Loss of efficacy of a drug due to continuous/repeated use

What is Receptor Attenuation? What can cause it?

• The loss of receptor response

  • The desensitization of receptors

    • Receptors remain in cell membrane but are deactivated

  • Down-regulation of receptors

    • # of receptors decreases either by decreased synthesis or internalization

What are some causes of increased responsiveness to a drug?

• Altered pharmacokinetics (how the body interacts with the drug) leading to a greater concentration of drug at the target site

• Increased # of target receptors

What is the Therapeutic Index?

• A measure of a drugs safety

• It’s a comparison of the average dosage that produces toxicity and the average dosage that produces the desired response

There is no such thing as a perfect drug, but what are the 10 properties of an ideal drug (in order of importance)?

1. Efficacy

2. Safety

3. Specificity

4. Reversible Actions

5. predictability

6. Ease of administration

7. Freedom from drug interactions

8. Inexpensive

9. Chemical Stability

10. Generic product available