Pharmacology Flashcards
What type of receptors signal using 2nd messengers?
G protein-coupled receptors
In a system with no spare receptors, what fraction of receptors would be estimated to be occupied at a drug concentration 10-fold lower than the EC50 value?
9.1%
B=(Bmax x C)/ (C+Kc)
B/Bmax = C/(C+Kc)
Kc=1/2 max
C=1/10 Kc
B/Bmax = (1/10 Kc)/ (1/10 Kc + Kc) B/Bmax = (1/10)/(11/10) = 1/11 = 0.0909 B/Bmax = 9.1%
_____ block the orthosteric drug binding site of a receptor
Competitive antagonists
Nature of drugs
Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Action of drug on body:
- Receptors, effectors
- Dose-response curves, spare receptors
- Agonists, partial agonists, biased agonists, antagonists, inverse agonists
- Signaling mechanisms
- Receptor regulation
Pharmacokinetics
Action of body on drug:
- Movement of drugs in body
- Absorption
- Distribution
- Elimination
Signaling mechanisms for drug effects
- Transmembrane diffusion
- Transmembrane enzyme receptors
- Ligand-gated transmembrane receptors
- Transmembrane channels
- G-protein coupled receptors
Transmembrane diffusion
Bind to intracellular receptor
Transmembrane enzyme receptors
Outer domain provides the receptor function while inner domain provides the effector mechanism
Ligand-gated transmembrane receptors
- Ligand binding
- activate cytoplasmic tyrosine kinase (JAKs)
- Phosphorylation of STAT molecules that regulate transcription
Transmembrane channels
Gated open or closed by binding of drug to receptor site
G protein-coupled receptors
Use a coupling protein to activate a separate effector molecule
Dose-response curves
Relation b/t drug dose/concentration (x) and drug effect (Y)
- If dose = linear, curve = hyperbolic
- If dose = log, curve = sigmoidal
EC50
Dose/concentration at which effect is half-maximal (1/2 Emax)
Emax
Maximal effect of drug (peak of curve)
Dose-binding curves
Relation b/t drug/concentration (X) and % receptors bound
- If dose = linear, curve = hyperbolic
- If dose = log, curve = sigmoidal
Kd
Concentration at which 50% of receptors are bound
Bmax
Maximal number of receptors bound
Spare receptors
If system has spare receptors, EC50 is lower than Kd –> to achieve 50% of maximal effect, less than 50% of receptors must be activated.
Clinical: need less drug for response in system
Graph: Effect < binding
Drug potency
Concentration (EC50) or dose (ED50) required to procure 50% of maximal effect
Drug efficacy
Concentration required for drug to bind all receptors
Potency vs Efficacy (Graphically)
More potency to the left: less concentration required to reach EC50
More efficacy to the top: highest peaks = highest number of receptors bound
What is more important: efficacy or potency?
Generally, efficacy.
Agonist
Activate receptor
Types of agonism
Full or partial
Full vs Partial agonist: dose-response
- Same EC50
- Emax - full (higher) > partial (lower)
Full vs Partial Agonist: Competition
Maximal binding curves
- full will bind more than partial at lower concentrations
- as concentrations of both inc, full binding dec while partial binding inc
- Curves cross
- at highest concentrations, partial binds more than full
Full vs Partial Agonist: Titration
Dose-response curves
- Constant dose of full agonist starting at Emax concentration
- Titrate in the partial starting low and inc
- Partial competes will full in binding
- Full dec while partial inc
- Partial only increases to partial Emax
Inverse agonism
- Lessens receptor signal
- Must have receptor with BASAL ACTIVITY
- Will reduce basal activity (sigmoidal below)
Types of antagonists
Competitive, Irreversible, Non-Competitive
Which two antagonists compete with orthopedic (main) binding site in receptor?
Competitive and Irreversible
Competitive antagonist
Shift sigmoidal dose-response curve to the right
- Emax is the same
- EC50 increases
Irreversible antagonist
Shift peak of sigmoidal dose-response curve down
- Emax decreases
- EC50 is the same
Non-Competitive Antagonist
Binds to allosteric site to lower the efficacy of agonist that binds to orthosteric receptor site.
Shift peak of sigmoidal dose-response curve down
- Emax decreases
- EC50 is the same
Agonist treatment
Leads to receptor DOWN regulation
Antagonist treatment
Leads to receptor UP regulation
Desensitization
Reduced response due to continued presence of agonist
Resensitization
If agonist causing desensitization is removed after a short time, cell recover full responsiveness to more agonist.
Down-regulation
Sometimes, repeated/prologed exposure of cells to agonist promotes down-regulation instead of desensitization
Therapeutic index
= LD50/ED50
LD50 = lethal dose
What form of a weak acid/base can partition across cell membranes?
Neutral form
Charged drugs are ___ readily excreted than lipid-soluble drugs
More because they don’t pass membrane (aka, not reabsorbed) so can be filtrated
Can charged drugs get trapped in urine?
Yes, not reabsorbed into cells
Lipid-soluble drugs are excreted ___ ____
More slowly
Weak acids and bases can be removed from circulation by ___
Altering urine pH
The process by which the amount of active drug in the body is reduced after administration and before entering the systemic circulation.
First-pass effect
Volume of distribution (Vd)
a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid
Volume of distribution vs. location in body
If Vd > 42 L, drug is mostly in tissues
If Vd < 42 L, drug is mostly in circulation
The half-life is ___ regardless of the plasma concentration
The same
Zero-order elimination
Process that describes how plasma concentration of high doses of ethanol, phenytoin, and aspirin are reduced over time
The distribution of a drug through the body depends on ____ and ___
Blood flow and drug solubility
Weak acid
H2COOH –> H2COO- + H+
Neutral acid –> anion + proton
Weak base
NH3+ –> NH2 + H+
Cation –> neutral base + proton
What happens to weak acids/bases in acid?
Acid = low pH = high [H+]
Favors protonated/neutral acid and cation/protonated base
What happens to weak acids/bases in base?
Base = high pH = low [H+]
Favors deprotonated/anion acid and deprotonate/neutral base
What form of weak acids/bases is favored if pH>pKa?
pH>pKa = BASIC so deprotonated form favored:
- anion acid
- neutral base
Which form of weak acid/base is more lipid soluble?
Neutral:
- protonated acid
- deprotonated base
Under what pH level is a weak acid more lipid soluble?
Low pH = acidic = favors protonated weak acid = neutral form
Under what pH level is a weak base more lipid soluble?
High pH = basic = favors deprotonated weak base = neutral form
What form of weak acid/base accelerated drug excretion?
To accelerate, need to be less lipid soluble so drug stays in circulation (aka, not cross lipid membrane) –> to avoid absorption in cells, need to be charged
Under what pH conditions are weak acids charged?
High pH = basic = favors deprotonated weak acid = anion
What what pH conditions are weak bases charged?
Low pH = acidic = favors protonated weak base = cation
Methods of transmembrane signaling
- Lipid-soluble ligand crosses membrane to act on intracellular enzymatic activity
- Ligand binds extracellularly to transmembrane receptor protein with intracellular enzymatic activity
- Transmembrane receptor binds and stimulates intracellular tyrosine kinase
- Ligand-gated transmembrane ion channel
- Transmembrane receptor protein stimulated G protein that modulates intracellular 2nd messenger production
Desensitization
Response of receptor diminished over times (s or min) even in continued presence of agonist
Can desensitization be reversed?
Yes, happens rapidly
GPCR Second Messengers
- Cyclic Adenosine Monophosphate (cAMP)
- Phosphoinositides and Calcium
- Cyclic Guanosine Monophosphate (cGMP)
Major Routes of Drug Administration
- Oral
- IV
- IM
- Nasal
- Cutaneous
ADME
- Absorption
- Distribution
- Metabolism
- Elimination
What is the chemical composition of most drugs and why?
Weak acids or bases
- Bc pH regulates their lipid solubility
Henderson-Hasselback Equation
Log (protonated/unprotonated) = pKa - pH
pKa
pH where 1/2 of drug is charged
When are weak bases charged?
pH < pKa
When are weak acids charged?
pH > pKa
pH values in body for drug absorption
- Stomach: 2.0
- Intestine: 8.0
- Blood: 7.4
- Urine: 6.5
Drug distribution
Influenced by drug binding:
- If drug binds strongly to protein in vascular compartment, will be harder for it to go to extravascular space
Volume of Distribution (Vd)
= Amount of drug in body / Concentration in the blood
Units = Volume
How does Vd change if there is greater drug binding in vascular space?
Decrease
How does Vd change if there is greater drug binding in extravascular spaces?
Increase
Drug Clearance
How drug is cleared from the body
Clearance (CL)
= Rate of elimination / Plasma concentration (Cp)
Unite = Volume per unit time
Is clearance relatively constant of a broad range of plasma concentrations?
Yes
The elimination rate is rapid at first and then ___ as concentration decrease.
Slows
Systemic Clearance
= Clearance of kidney + clearance of liver + other clearance
Half-life
Time required for half of the drug to be eliminated
= (0.693 X Vd) / CL
Units = Time
Note: need to have Vd and CL provided –> these are not calculated!
Steady-State concentration
100% Plasma concentration of drug
How long does it take to reach steady-state in terms of half lives?
In Half-Lives: 1 = 50% 2 = 75% 3 = 87.5% 4 = 93.75% 5 = 96.875%*******
A drug is said to have reached the steady-state plateau after 5 half-lives (actually 97% of plateau)
First-Order Elimination
*More common
Rate of elimination (units per hours) is proportional to concentration
Time (X) vs Concentration (Y) = Negative exponential
Zero -Order Elimination
The rate is constant and independent of concentration
Time (X) vs Concentration (Y) = negative linear
First Pass Effect
Non IV administered drugs: part of dose is lost in feces via gut and in metabolism via liver before entering systemic circulation
Bioavailability (F)
Percentage of drug in circulation
For IV administration, F = 1 or 100%
Loading dose
Dose needed to achieve therapeutic steady state immediately –> amount in the body immediately following the loading dose
= V X TC
V: Volume of distribution
TC: therapeutic/target concentration
Dosing rate (IV)
= Rate of elimination = CL X TC
CL: Clearance
TC: therapeutic/target concentration
Dosing rate (non-IV)
= Dosing rate/F
= (CL X Desired plasma concentration) / F
Dosing rate: rate of elimination or CL X TC
F: bioavailability
Maintenance dose
Dose over internal of time to maintain drug plasma concentration at therapeutic/target steady-state
= Dosing rate X Dosing interval
= ((CL X Desired plasma concentration)/F) X Dosing Interval
Drug metabolism
- Phase 1 reactions
- Phase 2 reactions
- Genetic factors
- Induction of drug metabolism
- Inhibition of drug metabolism
Phase 1 Drug Metabolism
Convert drug to a more polar metabolite by introducing or unmasking a functional group such as -OH, -NH2, -SH
Phase 2 Drug Metabolism
Creates highly polar conjugates between Phase 1 function groups and endogenous substrates such as glucoronic acid, sulfuric acid, acetic acid, and amino acids
Drug metabolism enzymes
Phase 1: cytochrome p450
Phase 2: processed with sulfate or gluco
Pharmacogenomics
Most people metabolize drugs normally, but some:
- Metabolize too fast –> less drug in blood –> inc dose
- Metabolize slower –> more in blood –> dec dose
Drug metabolism usually results in a product that is (Less/more) lipid soluble than the original drug.
Less
Pharmacokinetics concepts
- Volume of distribution + CL –> Half-Life
- Clearance + Vd –> Half-Life
- Bioavailability –> First Pass Effect
- Dosing –> Maintenance or Loading
Surmountable antagonism
Competitive bc more agonist could push out and decrease effect of antagonist.
As concentration of antagonist increases, EC50 inc but Emax stays the same. At higher and higher concentrations of antagonist, EC50 will continue to increase and Emax will also start to decrease bc antagonist is overwhelming agonist.
Insurmountable antagonism
Non-competitive bc no matter go much agonist is added, it cannot overcome effect of the agonist.
As antagonist increases, Emax will decrease while EC50 stays the same bc antagonist does not bind at orthosteric site.
How do we know if there are spare receptors?
Using an irreversible antagonist, as more of it is added, Emax will stay the same while EC50 increases because not a lot of agonist is needed to reach Emax, so there are spare receptors. But, as antagonist continues to be added, there is a point where EC50 stops decreasing and Emax decreases instead bc the antagonist is not blocking the spare receptors.
