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Colin CPR II > DSA - Intro to Pharmodynamics > Flashcards

DSA - Intro to Pharmodynamics Flashcards

1
Q

What is pharmacodynamics and how is it different from pharmacokinetics?

A

Pharmacodynamics is the effect of drugs on the body

  • Drug Receptors
  • Dose-response curves
  • Mechanisms of drug actions

Pharmacokinetics is the effects of body on drugs

  • Absorption
  • Distribution
  • Metabolism
  • Elimination
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2
Q

What is a receptor?

A

Receptor is a specific molecule in a biological system that plays a regulatory role.

Receptor interacts with a drug and initiates the biochemical events leading to drug effects

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3
Q

What is a ligand?

A

In the field of pharmacology, it is a molecule, such as a hormone or a drug, which binds to and interacts with a receptor

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4
Q

What is an Inert Binding Site?

A

A component of the biologic system to which a drug binds WITHOUT CHANGING ANY FUNCTION

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5
Q

What is a covalent bond?

A

Irreversible bond seen in some ligand-receptor interactions.

Drug removal/receptor re-activation requires re-synthesis of the receptor or enzymatic removal of the drug

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6
Q

What is a non-covalent bond?

A

Reversible bond seen in some ligand-receptor interactions

Most drugs bind to receptors via Non-covalent bonds.

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7
Q

What are 3 types of non-covalent bonds and rank them according to their strength

A

Ionic Bonds
- Electrostatic interaction between positively and negatively charged ions

Hydrogen Bonds
- Electrostatic bond between the net positive charge of hydrogen atoms in many functional groups and the net negative charge of an electronegative atom

Hydrophobic Interactions
- Between hydrophobic regions of the drug and hydrophobic regions of the receptor

Ionic Bonds > Hydrogen Bonds > Hydrophobic Interactions

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8
Q

What is affinity?

A

Affinity is a parameter describing the interaction of a drug with a receptor

The affinity of a drug for a receptor describes how readily and tightly that drug binds to its receptor.

High Affinity = Good drug-receptor interaction; LESS drug needed to produce a response

Low Affinity = Poor drug receptor interaction; MORE drug needed to produce a response

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9
Q

What is KD?

A

KD is a parameter describing affinity

KD = Dissociation Constant (unit = molar concentration)
- Drug concentration at which 50% of the drug receptor binding sites are occupied by the drug

The lower the KD, the HIGHER the affinity of a drug for a receptor

The higher the KD, the LOWER the affinity of a drug fro a receptor

KD = ([L][R]) / [LR]

[L] = Molar concentration of Ligand (drug)
[R] = Molar concentration of Receptor
[LR] = Molar concentration of Ligand-Receptor Complex
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10
Q

What is selectivity?

A

Selectivity is a parameter describing the interaction of a drug with a receptor

Selectivity is a property of a drug determined by its affinities at various binding sites

  • It is measured by comparing affinities of a drug to different receptors
  • A more selective drug would affect fewer targets over a specific concentration range (therapeutic range)
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11
Q

What is intrinsic activity?

A

Intrinsic activity describes the ability of a drug to change a receptor function and produce a physiological response upon its binding to a receptor.

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12
Q

What are agonists?

A

Agonists bind to a receptor and stabilize it in a particular conformation (usually, the active conformation), producing a physiological response

The ability to produce a physiologic response implies it has Intrinsic Activity

There are three Types of Agonists:

  • Full Agonists
  • Partial Agonists
  • Inverse Agonists
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13
Q

What are antagonists?

A

Receptor antagonists bind to the receptor but DO NOT change its function.

However, they prevent activation of the receptor in the presence of an agonist

Thus, antagonists DO NOT have Intrinsic Activity

  • They do not change the function of the receptor upon binding
  • They have no pharmacological effect in the absence of an agonist

There are three types of Antagonism:

  • Pharmacologic Antagonism
  • Chemical Antagonism
  • Physiologic Antagonism
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14
Q

What is a Full Agonist?

A

Agonist that:

  • Fully activates receptors
  • Produces a maximal pharmacological effect when all receptors are occupied
  • Has maximal Intrinsic Activity
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15
Q

What is a Partial Agonist?

A

Agonist that:

  • Partially activates the receptor upon binding
  • Produces a sub-maximal pharmacological effect when all receptors are occupied
  • Has intrinsic efficacy that varies depending on the drug , but is always sub-maximal
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16
Q

What is an Inverse Agonist?

A

Agonist that produces an effect opposite to a full or partial agonist

  • Decreases receptor signaling
  • Decreases response at receptors with a significant level of constitutive receptor activity
  • Intrinsic activity is present and related to the inhibition of receptor function
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17
Q

What is Pharmacologic Antagonism?

A

AKA Receptor Antagonism

Action at the same receptor as endogenous ligands or agonist drugs

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18
Q

What is Chemical Antagonism?

A

A form of Non-Receptor Antagonism

When chemical antagonist makes the other drug unavailable

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19
Q

What is physiologic antagonism?

A

A form of Non-receptor Antagonism

Occurs between endogenous pathways regulated by different receptors

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20
Q

What is a competitive antagonist?

A

Antagonist competed with endogenous chemicals or agonist drugs for binding of the receptor

Can be displaced from the receptor by other drugs (effects are surmountable)

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21
Q

What is a non-competitive antagonist?

A

Receptor inactivation is NOT surmountable

Two Types:

  • Irreversible Antagonists: Irreversibly bind to and occlude the agonist site on the receptor by forming covalent bonds
  • Allosteric Antagonists: Bind to a site other than the agonist site to prevent or reduce agonist binding or activation of the receptor
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22
Q

Describe the Dose-Response curve for a Competitive Antagonist

A

In the presence of a competitive antagonist, higher concentrations of agonist are required to produce a given effect

Thus the agonist concentration required for a given effect in the presence of an antagonist is shifted to the right.

High agonist concentrations can overcome inhibition by a competitive antagonist

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23
Q

Describe the Dose-Response curve for a Non-Competitive Antagonist

A

In the case with an irreversible (noncompetitive) antagonist, higher concentrations of agonist CANNOT overcome inhibition.

Thus reduces the maximal effect te agonist can achieve.

However the EC50 (Concentration of agonist required to achieve half maximal effect) may not change.

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24
Q

What is a Dose-Response Curve?

A

A graph quantitatively representing the relationship between a drug and its effects

Can be plotted arithmetically or logarithmically

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25
Q

What is an arithmetically plotted Dose-Response Curve?

A

When a plot of drug dose (mg) on the x-axis against arbitrary drug effect values on they-axis, you typically get a HYPERBOLIC CURVE

26
Q

What is a logarithmically plotted Dose-Response Curve?

A

More commonly, a concentration effect curve is represented by graphing the logarithm of the drug dose on the x-axis vs the response values on the y-axis.

In this case, you get a SIGMOIDAL CURVE

27
Q

What is Emax?

A

The maximal effect that can be produced by the drug

Represented by the greatest y-value plotted

28
Q

What is the ED50?

A

Effective Dose 50

The dose of drug that produces 50% of its maximal effect

29
Q

What is a graded response?

A

Answers the question “How much?”

Magnitude of a response varies continuously

Typically represents the mean value within a population or a single subject

30
Q

What is a quantal response?

A

All or none; Yes-No; Binary responses

Answers the questions:

  • Does the response occur or not?
  • In how many?

Requires a pre-defined response (e.g., death, falling asleep, 10% reduction in blood pressure)

Used to examine the frequency of (i.e., number of individuals showing) a response within a large population

31
Q

What is a Non-Cumulative Quantal Dose Response Curve?

A

Represents the number or % of individuals responding at a specific dose of a drug and ONLY at that dose

Will show a bell curve where the x-axis represents increasing drug doses and the y-axis represents the % or number of responsive individuals to the drug.

32
Q

What is Cumulative Quantal Dose Response Curve?

A

Represents the number or % of individuals responding at a dose of a drug AND at all doses lower than that dose

Will show a sigmoidal curve where the peak point in the curve is at y-value representing 100%
- X-axis is the dose and y-axis is the percent of individuals responding

33
Q

Cumulative Quantal Dose Response Curves and determining drugs safety (median effectiveness, toxicity, and lethal dose)

A

A cumulative quantal dose-response curve can be used to determine the median effectiveness of a drug, the median toxic dose, and the median lethal dose.

The dose at which 50% of individuals have achieved peak effectiveness of a drug is the median effectiveness (ED50)

The dose at which 50% of individuals have achieved a toxic effect of a drug is the median toxic dose (TD50)

The dose at which 50% of individuals have died as a result of a drug is the median lethal dose

34
Q

What is the Therapeutic index?

A

Therapeutic Index (TI) is a value that is calculated by taking the Median Toxic Dose (TD50) and dividing it by the Median Effective Dose (ED50)

TD50/ED50 = TI

The greater the TI value, the safer the drug

35
Q

What is the Therapeutic Window?

A

The range of doses of a drug of its concentration in a bodily system that provides for the safe and effective therapy

Drugs with a wider therapeutic window are safer than those with a narrow therapeutic window

36
Q

What is Drug Potency?

A

Potency describes the amount of drug required to produce a specific pharmacological effect

Drugs with higher affinities for a receptor (lower KD) tend to be more potent

Represented by ED50

The lower the ED50, the more potent the drug

Determines the drug dose that will be used clinically

37
Q

What is Drug Efficacy?

A

Efficacy describes the maximal pharmacological effect that a drug can produce

Represented by the Emax

The greater the Emax, the more efficacious the drug

Efficacy is related tot he total number of receptors available to bind a drug

Determines the magnitude of clinical effect

38
Q

What are drug targets and what are the major categories of drug targets?

A

Drug targets are important regulatory proteins in the existing cell signaling pathways

There are 5 major classes of drug targets:

  • Membrane Receptors
  • Nuclear Receptors
  • Ion channels
  • Transport proteins
  • Enzymes
39
Q

What is signal transduction?

A

Process by which cells transmit, receive, and respond to information from their environment and from each other

40
Q

What are the components of cell signaling?

A

Ligand

  • Biologically active molecule interacting with a receptor
  • endogenous ligands (hormones, neurotransmitters)
  • Exogenous ligands (drugs)

Receptors
- Protein molecule transmitting the signal to the target cells

Intracellular Signaling

  • Mechanisms within the target cell
  • Protein Kinases
  • Transcription Factors
41
Q

What are protein kinases?

A

Protein kinases are enzymes that modify proteins by covalently ATTACHING a phosphate group to an amino acid residue

This action is called Phosphorylation

Examples:

  • Serine-Threonine Kinases
  • Tyrosine kinases
42
Q

What is the protein Phosphorylation/Dephosphorylation cycle?

A

Phosphorylation (adding Phosphate group) changes the conformation of the protein, its activity, binding to other proteins, or localization within the cell

Dephosphorylation (removal of the phosphate group) will do the opposite.

Many enzymes undergo a cycle of Phosphorylation/Dephosphorylation

43
Q

What are protein phosphatases?

A

Protein phosphatases are enzymes that modify proteins by REMOVING a phosphate group from an amino acid residue

This action is called Dephosphorylation

44
Q

What is a transcription factor?

A

Transcription factors are proteins that bind to specific DNA sequences and thereby control the transcription of genetic information from DNA to RNA

Promote (activaators) or inihibit (repressors) the recruitment of RNA Polymerase to specific genes

Defining feature of TFs: presence of a DNA-binding domain

TFs bind to enhancer or promoter regions of DNA that are usually adjacent to the coding sequence of the regulated gene

The specific DNA sequence they bind to is called response element

45
Q

What is a GPCR?

A

G Protein Coupled Receptor

It is a transmembrane protein with topolgy of a typical serpent

Polypeptide chain snakes across the membrane 7 times (amino end is extracellular, carboxyl end is intracellular)

Hydrophobic transmembrane segments are designated by Roman Numerals (I-VII)

Agonist approaches the receptor from the extracellular fluid and binds to a site surrounded by the transmembrane regions of the receptor, especially around the third cytoplasmic loop connecting transmembrane regions V and VI.

Lateral movement of these helices during activation exposes an otherwise buried cytoplasmic surface of the receptor that promotes Guanine nucleotide exchange (receptor bound GDP is exchanged for GTP) on the G protein and thereby activates the G protein

The receptor’s cytoplasmic terminal tail contains numerous serine and threonine residues whose hydroxyl (-OH) groups can be phosphorylated.

This phosphorylation is associated with diminished receptor-G protein coupling and can promote receptor endocytes

G proteins are heterotrimeric, consisting of Alpha, Beta, and Gamma subunits

46
Q

What is the G protein cycle?

A

Activation cycle of a heterotrimeric G protein by a G protein coupled receptor receiving a ligand

The agonist activates the receptor, which promotes release of GDP from G-alpha protein, allowing entry of GTP into the nucleotide binding site

In its GTP-bound state (G-alpha-GTP), the G protein regulates activity of an effector enzyme or ion channel

The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state

47
Q

What are the G Protein families?

A

Gs
Gi
Gq
G(12/13)

48
Q

What are the down stream targets of Gs proteins?

A

Adenylyl Cyclase (all isoforms)

Src tyrosine kinase

AC activation causes the formation of cAMP from ATP

Src TK activation

49
Q

What are the down stream targets of Gi?

A

Adenylyl Cyclase (isoforms 13, 5, and 6)

Src tyrosine kinase

AC Inhibition

Src TK activation

50
Q

What are the down stream targets of Gq?

A

Phospholipase C (beta)

PLC activation

51
Q

What are the down stream targets of G(12/13)?

A

Rho GTPase activation

Cytoskeletal rearrangements

52
Q

How are G Protein Receptors Desensitized?

A

In the event of a prolonged presence of agonists, the cAMP response produced by GPCR activation becomes reduced (aka desensitization; takes only a few minutes)

If the agonist is removed, after a short time (several to 10 min), cells recover full responsiveness to subsequent agonist addition (resensitization)

Resensitization fails to occur or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period

53
Q

How are G Protein Receptors Downregulated?

A

Agonist binding to receptors initiates signaling by promoting receptor interaction with Gs proteins located in the cytoplasm

Agonist-activated receptors are phosphorylated by a GPCR kinase (aka GRK), preventing receptor interaction with Gs and promoting binding of a different protein, Beta-arrestin (aka Beta-Arr) tot he receptor

The receptor-arrestin complex binds to coated pits, promoting receptor internalization

Dissociation of agonist from internalized receptors reduces Beta-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase) and return of receptors to the plasma membrane

Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes, promoting receptor down-regulation rather than resensitization

54
Q

What is the cAMP second messenger pathway?

A

Key proteins include hormone receptors, a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P’ase), which remove phosphates from substrate proteins.

Activated Gs activates AC

AC converts ATP into cAMP

cAMP activates PKA (promoting downstream actions)

PDE hydrolyzes cAMP into 5’-AMP

P’ase reverses the actions of PKA

55
Q

What is the Ca2+-phosphoinositide signaling pathway?

A

Key proteins include hormone receptors, G protein (Gq), a phosphoinositide-specific phospholipase C (PLC), protein kinase C (PKC), substrates of the kinase, calmodulin (CaM), and calmodulin-binding enzymes, including kinases, phosphodiesterases, etc.

PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol; IP3, inositol triphosphate.

Activated Gq activates PLC

PLC breaks apart PIP2 into IP3 and DAG

IP3 promotes the release of intracellular Ca2+ stores

Calmodulin interacts with Ca2+

DAG activates PKC

PKC phosphorylates downstream proteins

56
Q

What is Receptor Tyrosine Kinase signaling?

A

RTKs are receptors with intrinsic tyrosine kinase activity

They transmit the action of a number of growth factors (ligands):

  • IGF-1 (insulin like growth factor-1)
  • Insulin
  • VEGF (vascular endothelial growth factor)
  • EGF (epidermal growth factor)
  • NGF (nerve growth factor)
  • PDGF (platelet-derived growth factor)
57
Q

What is the mechanism of action of Receptor Tyrosine Kinases?

A

Receptor polypeptide has extracellular and cytoplasmic domains

Upon binding EGF, the receptor converts from its inactive monomeric state to an active dimeric state, in which two receptor polypeptides bind non-covalently

The cytoplasmic domains become phosphorylated on specific tyrosine residues, and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins

58
Q

What are Receptors coupled to Janus Kinases?

A

Receptors coupled to JAKs, a family of cytosolic tyrosine kinases

Transmit the effect of a number of hormones and cytokines

  • Growth hormone (somatotropin)
  • Erythropoietin
  • Leptin
  • Interferons
  • Interleukins-2 to 10, 15

Activate JAK-STAT pathway

59
Q

What is the JAK-STAT pathway?

A

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers.

However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) moleucles.

STAT dimers then travel to the nucleus, where they regulate transcription.

60
Q

What are nuclear receptors?

A

Nuclear receptors are ligand-activated transcription factors that modulate gene expression

Ligands are lipophilic molecules that are able to cross cell membranes

  • Steroid hormones
  • Thyroid hormone
  • Vit D, Vit A
  • Lipid mediators, such as free fatty acids and their products

Steroid receptor family

  • Androgen receptors (AR)
  • Estrogen receptors (ER, alpha and Beta)
  • Progesterone receptors (PR, A, and B)
  • Glucocorticoid receptors (GR)
  • Mineralocorticoid receptors (MR)

These hormones produce their effects after a lag period

The effects can persist after the agonist concentration has been reduced to zero

Colin CPR II (12 decks)

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