[3] NEW Pharmacodynamics Flashcards
Actions/effects of drugs on the body
Pharmacodynamics
Specific molecules with which drugs interact to produce changes in the function of the system
Receptors
Determine the quantitative relations between dose or concentration of drug and pharmacologic effects
Receptors
Receptors are selective in _______ characteristics
Ligand-binging
Receptors mediate actions of both pharmacologic _____ and ______
Agonist and Antagonist
Specific binding region of the macromolecule
Receptor Site/ Recognition Site
High and selective affinity to the drug molecule
Receptor Site/ Recognition Site
What are the 4 Classification of Receptors
- Regulatory proteins
- Enzymes
- Transport proteins
- Structural poteins
Classification of Receptors:
Subserve specific physiologic functions
Regulatory Proteins
Classification of Receptors:
Catalyzes/facilitates metabolic processes
Enzymes
Classification of Receptors:
In cell membrane, the raw material of our metabolism is needed to be transported into the cell because we metabolize inside the cell
Transport Proteins
Classification of Receptors:
Cytoskeleton of framework - Cellular Anatomy
Structural Proteins
Classification of Receptors:
Best-characterized drug receptors
Regulatory Proteins
Classification of Receptors:
Mediates the action of endogenous chemical signals like neurotransmitters, autocoids, and hormones
Regulatory Proteins
Classification of Receptors:
Inhibited or activated by binding a drug
Enzymes
Classification of Receptors:
Membrane receptors for digitalis
Transport Proteins
Classification of Receptors:
Micro and macro anatomic, the receptor for colchicine, an anti-inflammatory drug used for gout
Structural Proteins
Molecules that translate the drug-receptor interaction into a change in cellular activity
Effector
True or False:
A single molecule may incorporate both the drug binding site and the effector mechanism
True
What are the 5 Basic Transmembrane Signaling Mechanism
- Lipid soluble drug
- Transmembrane receptor protein
- Stimulates Protein tyrosine kinase
- Ligand-gated transmembrane ion channel
- Transmembrane receptor is coupled with an effector enzyme by G protein
Modulates production of an intracellular second messenger
G protein
What is the 1st messenger
Drug
Give me the G protein of the ff:
high adenylyl cyclase -> high cAMP
GS and Golf (Olfactory epithelium)
Give me the G protein of the ff:
low adenylyl cyclase -> low cAMP
Gi1, Gi2, Gi3
Give me the G protein of the ff:
high phospholipase C -> high IP3 diacylglycerol, cytoplasmic Ca2+
Gq
Give me the G protein of the ff:
high cGMP phosphodiesterase -> low cGMP (phototransduction)
Gt1, Gt2
Give me the G protein of the ff:
Opens cardia K+ channels -> low heart rate
Gi1, Gi2, Gi3
What are the 3 Intracellular 2nd messengers
- cAMP or Cyclic Adenosine Monophosphate
- Calcium and phosphoinositides
- cGMP or Cyclic Guanosine Monophosphate
2nd messenger that mediates hormonal responses
cAMP or Cyclic Adenosine Monophosphate
2nd messenger that mobilizes stored energy of carbohydrates in the liver
cAMP or Cyclic Adenosine Monophosphate
2nd messenger that conserves water by kidneys mediated by vasopressin
cAMP or Cyclic Adenosine Monophosphate
2nd messenger that bind to receptors linked G proteins while others bind to receptors tyrosine kinases
Calcium and phosphoinositides
In calcium and phosphoinositides, _______ produces an activated effect towards the production of the intended response of that receptor system
Calmodulin complex
2nd messenger has few signaling roles in a few cell types like intestinal mucosa and vascular smooth muscle cells
cGMP or Cyclic Guanosine Monophosphate
2nd messenger that causes relaxation of vascular smooth muscles by a kinase-mediated mechanism that results in dephosphorylation of myosin light chains
cGMP or Cyclic Guanosine Monophosphate
Response of a particular receptor-effector system is measured against increasing concentration of a drug
Graded Dose-Response Curve
Quantifies the response of the drug to each specific dose
Graded Dose-Response Curve
On the Graph of the response versus the drug dose:
x-axis:_______
y-axis:_______
x-axis: dose
y-axis: response
True or False:
The smaller the EC50, the greater the potency of the drug
True
The maximal response that can be produced by a drug
Emax
The presumption is that all receptors are occupied
Emax
The basis of the characterization for full and partial agonist
Emax
Concentration of drug that produces 50% of the maximal effect
EC50
True or False:
EC50 and Potency are inversely proportional
True
The total number of receptor sites and all receptors have been occupied
Bmax
The total receptor occupancy
Bmax
Measure of the affinity of a drug for its binding site on the receptor
KD
Concentration drug REQUIRED to bind 50% of the receptors
KD
True or False:
Smaller KD = Greater affinity of drug-receptor
True
Represents the concentration of free drug at which half-maximal binding is observed
KD
Curve of Emax
Hyperbole
Curve of Bmax
Logarithmic Sigmoid Curve
Basis for drug potency
EC50
On the Graph of the agonist dose-response curve:
x-axis:_______
y-axis:_______
x-axis: agonist dose
y-axis: agonist effect
True or False:
On the agonist dose-response curve, the lower the curve the higher the concentration of the antagonist
True
Transduction process between the occupancy of receptors and the production of specific effect
Coupling
Elicated by a full agonist and spare receptors
Coupling
“Downstream” biochemical events that transduce receptor occupancy into cellular response
Coupling
Also known as receptor reserve
Spare Receptors
Maximal drug response is obtained at less than the maximal occupation of the receptors
Spare Receptors
Drugs with low binding affinity for receptors will be able to produce full response even at low concentration
Spare Receptors
Compare the concentration of 50% maximal EFFECT (EC50) with concentration of 50% maximal BINDING (KD)
Spare Receptors
Concentration of 50% maximal EFFECT
EC50
concentration of 50% maximal BINDING
KD
True or False:
KD > EC50 with spare receptors
True
True or False:
The actual number of receptors may exceed the number of effectors available
True
Non-regulatory molecules of the body
Inert Binding Sites
Binding with these molecules will result in NO DETECTABLE CHANGE in the function of the biological system
Inert Binding Sites
Also known to buffer the concentration of the drug
Inert Binding Sites
Binds to the receptor and directly or indirectly brings about an effect
Agonist
Produces less than the full extent, even when it has SATURATED the receptors
Partial Agonist
Acts as an inhibitor in the presence of a full agonist
Partial Agonist
Binds but do not activate the receptors
Antagonist
Blocks or competes with agonist
Antagonist
What are the 4 Classification of Antagonists
- Competitive Antagonist
- Irreversible Antagonist
- Chemical Antagonist
- Physiologic Antagonist
Inhibits and competes agonist receptor
Competitive Antagonist
Bonds to the receptor REVERSIBLY without activating the effector system
Competitive Antagonist
An antagonist that shifts to the right horizontally on the dose axis
Competitive Antagonist
True or False:
In Competitive Antagonists, effects are overcome by adding more agonists
True
True or False:
In Competitive Antagonists, increase the median effective dose (ED50)
True
Therapeutic Implication of Competitive Antagonist:
The _________ produced by the competitive antagonist depends on the concentration of the ANTAGONIST
Degree of inhibition
Therapeutic Implication of Competitive Antagonist:
The _________ to a competitive antagonist depends on the concentration of the AGONIST that is competing for binding to the receptor
Clinical response
Binds with the receptor via Covalent Bonds
Irreversible Antagonist
An antagonist that makes the receptor unable to bind the agonist
Irreversible Antagonist
An antagonist dependent on the RATE OF TURNOVER of receptors
Irreversible Antagonist
An antagonist that moves downward but has no shift of curve in the dose axis
Irreversible Antagonist
An agonist that binds to a site on the receptor separate or different from the agonist binding site
Negative Allosteric Modulators
Does not depend on interaction with the agonist’s receptor
Chemical Antagonism
Drug that interacts directly with the drug being antagonized to remove it or to prevent it from reaching it target
Chemical Antagonism
Makes use of the regulatory pathway
Physiologic Antagonism
An antagonist that has less specific effects and is less easy to control
Physiologic Antagonism
Binds to a different receptor producing an effect OPPOSITE to that produced by the drug it is antagonizing
Physiologic Antagonism
Response gradually diminishes even if the drug is still there after reaching an initial high level of response
Receptor Desensitization
Cells use more than one signaling mechanism to respond to the drug
Structure-Activity Relationship
Graph of the fraction of a population that shows a specified response to increasing doses of drug
Quantal Dose Response-Curve
It forms sigmoid curve, has minimum dose required to produce a specific response that determines each member of the population
Quantal Dose Response-Curve
The formula of Quantal Dose Response-Curve
TW = MTC -MEC
MEC - Minimum Effective Therapeutic Conc.
MTC - Minimum Toxic Conc.
Formula for Estimate Therapeutic Index
LD50 / ED50
Formula for Estimate Therapeutic Window
Minimum Toxic Concentration - Minimum Therapeutic Effective Dose/ Concentration
Median effective dose
ED50
50% manifested desired therapeutic effect
ED50
Median toxic dose
TD50
50% manifested toxic effects
TD50
Median lethal dose
LD50
Represents an estimate of the safety of the drug
Therapeutic Index
Dosage ranges between the minimum effective therapeutic concentration or dose (MEC) and the minimum tox concentration or dose (MTC)
Therapeutic Window
More clinically relevant index of safety
Therapeutic Window
Maximal Effect, an agonist can produce if the dose is taken to very high levels
Maximal Efficacy (Emax)
Determined mainly by the nature of receptors and its associated effectors
Maximal Efficacy (Emax)
Maximal Efficacy (Emax) is measured with [1]________ and not with [2]_________
[1] Graded dose-response curve
[2] Quantal dose-response curve
Amount of drug needed to produced given effect
Potency
Potency: Graded dose-response curve, the used dose is ____
the dose is EC50 and 50% of the maximal effect
Potency: Quantal dose-response curve, the used dose are_____
ED50, TD50, and LD50 variables in 50% of the population
True or False:
With a graph of concentration and response, the lower the curve is the more potent it is. On the other hand, the higher it is the more greater the maximal efficacy the drug has
True
Response to the drug is unknown or unusual
Idiosyncratic Response
Intensity of the drug is decrease, and large dose of the drug is need to have an effect
Hyporeactive Response
Intensity of the drug is increased or exaggerated
Hyperreactive Response
Decreased sensitivity acquired as a result of exposure to the drug
Tolerance
Tolerance develops after a few doses
Tachphylaxis
Reason for Varied Drug Responses:
- decrease drug absorption
- inhibited drug distribution
- increased elimination of the drug
Alteration in conc. of the drug
Reason for Varied Drug Responses:
- occurs when foreign or exogenous ligands are introduced
Variation in the con. of the endogenous ligands (especially for antagonistic patterns)
Reason for Varied Drug Responses:
- down-regulation
- up-regulation
Alteration in number or function of receptors
Reason for Varied Drug Responses:
- drug taken for a long time then abruptly discontinued
Overshoot phenomenon or Rebound hypertension
Give the drug that acts on the disease of the patient, no drug causes a single specific effect only, drugs are selective but never specific
Clinical Selectivity
What to do to avoid toxic effects
- Give low doses
- Carefully monitor the patient
- employ ancillary procedures
- use a safer drug
True or False:
high Emax = high efficacy
True
True or False:
low EC50 = high potency
True
Mechanism of Pharmacodynamics
Additive
Synergism
Potentiation
Antagonism
Mechanism of Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
What are the 5 Patient Factors
- Intrinsic drug clearance
- Genetics
- Gender
- Concurrent diseases
- Diet
What are the 4 Drug Specific Factors
- Dose
- Route of Administration
- Drug Formulation
- Sequence of Drug Administration
What are the two types of drug interaction mechanism
Altered Absorption
Altered Metabolism
Cholestyramine inhibits the effect of digoxin when combined with it
Altered Absorption
What are the 6 Pharmacokinetics Mechanism
- Gastrointestinal Absorption
- Altered Drug Distribution
- Altered Excretion
- Drug Distribution
- Metabolism of Drugs
- Renal Excretion
Pharmacokinetics Mechanism:
It binds or chelates, alters gastric pH, alters gastrointestinal motility, and affects transport proteins
Gastrointestinal Absorption
Pharmacokinetics Mechanism:
Competition for plasma protein binding, displacement from tissue binding sites, and alterations in local tissue barriers
Altered Drug Distribution and Drug Distribution
Pharmacokinetics Mechanism:
Probenecid inhibits the secretion of acids
Penicillin inhibits the excretion of probenecid
Altered Excretion
Pharmacokinetics Mechanism:
Induced or inhibited by concurrent therapy
Metabolism of Drugs
Pharmacokinetics Mechanism:
Are weak acids or weak bases may be influenced by other drugs that affect urinary pH
Penal Excretion
What are the Pharmacodynamic Mechanisms
- Additive
- Synergistic
- Potentiation
- Antagonism
The response elicited by combined drugs is equal to the combined response of the individual drugs
[ 1+1=2 ]
Additive
[same receptor = additive effects]
The response elicited by combined drugs is greater than the combined responses of each individual
[ 1+1=3 ]
Synergist
In synergist, ____ removes the cell wall
Penicillin G
In synergist, ____ inhibits the production of protein
Gentamicin
Drug which has no effect enhances the effect of the second drug
[ 0+1=2 ]
Potentation
Drug inhibits the effect of another drug
[ 1+1=0 ]
Antagonism
Pharmacodynamics Mechanism:
Keyword: equal
Additive
Pharmacodynamics Mechanism:
Keyword: greater >
Synergism
Pharmacodynamics Mechanism:
Keyword: enhances
Potentiation
Pharmacodynamics Mechanism:
Keyword: inhibits
Antagonism
Selectivity can be measured by comparing:
Binding affinities and ED50
