Intro to Pharming Flashcards
What does a lower Kd mean
It means that less drug is needed for activation. It is a measure of affinity/potency
high on rate and low off rate
What is the fold difference between minimal activation (10%) and max activation (90% response)
81 fold or 2 log units
Response Equation
DR Complexes/ Total Receptors = [D] / [D] + Kd
Potency
compares the concentrations of drugs needed to get 50% of maximal effect (EC50)
think a more potent drug is lower on the x acis because less drig is needed for the same effect
Efficacy
the measure of the maximal effect. Not all drugs lead to maximal effect. Ex: a partial agonist you never get maximum activation and is less efficacious
Is efficacy or potency more important?
efficacy is more important because a less potent drug with high effiacy will produce better results than a less efficacious drug with high potency
What are the types of receptors
1) ionotropic receptors (ion channels
2) metabolic teceptors (g proteins, kinases)
3) Transcription factors (alter gene expression- steroid hormones)
Examples where effects may not be proportional to receptor binding
1) complex interactions (cascades of 2nd messengers)
2) spare receptors- only need to activate a small fraction of receptors to get a max response (NMJ)
3) Tolerance/Desensitization- previous exposure to a drug may causes decreased effects
agonists
bind and activate receptors, get a dose response curve
antagonist
bind and dont activate receptor. Flat dose response curve. If given with an agonist, you get a shift dose that leads to a decrease in potency
Partial agonists
binds receptors and induced a partial activation (non-maximal)- lower efficacy
Spare Receptors
excess number of receptors for maximal effect. Only need to activate a fraction to get the maximal response. Causes a dose-response curve to be altered. ED50 is lower than Kd because you will get 50% binded at a lower dose
Dissociation Constant
the measure of affinity/potency (kd)
also the ratio of off rate receptor binding to the on rate
a smaller kd will bind the receptor longer
drugs with a very small kd may act for a longtime
Population curve
similar curve to individual dose response curve but contain frequency distribution that depends on the variability of response in the population that gives the sum of responsers
Therapeutic Index
important for toxicity, tell you that LD50/ED50. Not based on receptor binding but the variation in the population
How might there be changes in receptor window?
-Effects of drug diminished by repeated uses
-Down regulation in the number of receptors
-upregulation: overstimulation leading to an increase number of receptors such as seen in denervation hypersensitivity
-Sick animals (diminished organ failure)
What does parenteral drug admin depend on
1) form of the durg
2) perfusion of site of injection
3) perfusion of target organ (central compartment of peripheral
Pros and Cons of Intravenous administration
Pros: can give irritating solutions due to rapid dilution, can give large volumes
Cons: Dont give oils, suspensions
Bolus
initial high concentration of drug that moves to less perfused organs later. This redistribution decreases the blood concentration
When is steady state reached in constant infusion
4 half lifes
Pros and Cons of subcutaneous administration
Pros: prompt absorption for aqueous solutions, some suspensions, impants
Cons: cant give large volumes or irritants
Pros and Cons of Intramuscular administration
Pros: prompt absorption for aqueous solutions, slow and sustained for repository, moerate volumes, some oily vehicles and irritatns
What method of administration is about as fast as IV
Intraperitoneal
Why is oral absorption variable
Depends onL
1) Form of drug (capsules or those that dissolve)
2) Movement across a membrane/mucosa
3) Absorption from stomach
4) Bioavailability
What crosses membranes the best?
Lipid soluble drugs, depends on pH
How many transporters are there
2,000
What are absorbed from acid environments? Stomach and acidic urine
Weak acids
What are absorbed from basic environments? Small intestine and basic urine
Weak bases
First pass effect
oral drugs enter the portal circulation after absorption and pass through the liver sinusoids where the drug is metabolized and also secreted into bile
Bioavailability (F)
the fraction of drug that is absorbbed and escapes first pass elimination
AUCoral / AUC iv (if the dose and elimination are the same)
Volume of distribution
the apparent volume of distribution that depends on lipid solubility, binding to proteins, penetration of CNS and other compartments
Very big if it binds ti lipid, tissues, and proteins
C= Amound od drug in body/ Vd
Albumin
a plasma protein that binds drugs with low affinity. Only free drug can bind the receptors. Liver disease may impact binding as decreased proteins may lead to increased levels of free drug
Phase 1 Reactions
usually inactivated drugs
Cytochrome P450 system that adds a reactive group (usually oxidation) Usually increases water solubility
Phase 2 reactions
Conjugation that adds groups to make them more water soluble and easier to excrete
Filtration at the glomerulus
bounded to plasma protein wont enter urine
Filtration at the proximal tubule
uses transporters that removes some drugs that escapes filtration by the glomerulus
some may be resorbed from urine later if pH causes them to be uncharged
Zero order kinetics
same amount of drug eliminated/hour regardless of drug concentration.
Steady State
after the drug reaches equilibrium of uptake vs elimination, it maintains a steady state concentration. input =output. Reached in about 3.5-4 half lifes
if you increase the dose rate leads to a proportional increase in steady state plasma concentration
Repeated doses
Time to steady state is independent of dosage
Proportional to dosage, inversely proportional to dose interval
Proportional to bioavailability and inversely proportional to clearance
Causes of fluctuations in Repeated doses
Fluctuations are proportional to dose interval (double fluctuations would be twice as large)
Fluctuations inversely proportional to half-life (increased half life decreases fluctuations
decreased by slow absorption
*Dosing twice as often with half the dose decreases the fluctuations
Blood levels are half what you want, how do you increase?
Double the dose or cut the dose interval to half
Half life of drug is 2 hours, If you give at constant rate when will it reach an effective state concentration
8 hours
You are concerned with toxicity due to fluctuations, how do you fix this?
Cut the dose interval to half and dose to half to keep the dose rate the same
Causes of 50% variability in drug clearance
changing the glomerular filtration rate (renal dz, shock , etc.)
Induced/inhibited liver enzymes
Causes of 30% variability
fat animals that have a different percentage of fluids than lean animals, may vary in percentage bone and muscle
Variation in pharmacodynamics
variation effect at a fixed concentration.
transporter
ATP binding cassettes- pumps that remove drugs from cells ATP used
SLC solute carriers use secondary active transport, may used facilitated transprt
work on oppoSITE SIDES OF CELL AND ENABLES EFFICIENT DRUG ELIMINATION INTO URINE AND BILE
Adverse Drug Reactions
1) Lack of efficacy (giving too little, pharmacokinetic variability, pharmacodynamic variability)
2) Side effects, depends on drug binding same receptors in a different organ/system
3) Alletgic responses (not dose dependent
4) Toxic drug reaction, activate receptors with too high a dose (wrong receptors, too much,
