Exam 1 Flashcards
Important characteristics of receptors
- bind due to high affinity, so low amount of drug is required to cause an effect and the effect will take longer to end
- effect depends on the drug that binds to the receptor
Law of mass action as it pertains to drug binding
Doesn’t matter how much is given, drug effect is proportional to how much drug bind to receptors (Kd)
Kd
- Dissociation constant ([D][R])
- Kd is the drug concentration needed to bind 50% of receptors
- Measures affinity/potency of a drug
- Fraction of the receptor bound (bound receptors/ total receptors)
EC__
Effective concentration to see ___% of max effect
Which is more potent? Smaller or bigger Kd?
Smaller - will bind to receptor longer, thus act for longer time
Potency
Compares drug concentrations needed to get 50% of max effect (EC50)
Efficacy
Measures maximal effect (because not all drugs achieve max activation of receptors)
Full agonist
Causes max activation of receptors at a high dose
Partial agonist
Does not achieve max activation of receptors at a high dose (less efficacious drug)
Which is more important: Efficacy or potency?
Efficacy
Less potent drug with high efficacy = better results than high potency, less efficacious drug
Buprenorphine vs. Morphine
B - potent, partial agnoist with high affinity binding (so smaller dose will cause moderate analgesic effect, but it lasts longer) (if follow with morphine, B won’t dissociate, so likely will just have moderate pain relief)
M - less potent full agonist with lower affinity binding (so doesn’t last as long, but stronger analgesic effect)
Agonist
Has an effect on the receptor
Antagonist
Binds to receptor but doesn’t have an effect, blocks effect of agonist
Alone, doesn’t cause a dose response curve/effect, just flat horizontal line
What if an agonist and a competitive antagonist are both given?
Dose response curve shifts to right
Greater dose of agonist required to get same effect
What if an agonist and a non-competitive antagonist are both given?
Dose response curve is shorter/pushed down (decreased max effect) - agonist is made less efficacious (still binds but antagonist still stops receptor from responding)
Classes of signal transduction pathways
Ionotropic (ion channels, fast)
Metabotropic (G-prot)
Transcription Factors (change gene expression)
Enzyme-linked
Name 3 situations where drug binding to receptor isn’t proportional to drug effect
- 2nd messenger cascades
- Spare receptors
- Tolerance/desensitization
Spare receptors
Max response occurs even when agonist doesn’t fully occupy all available receptors (e.g. NMJ)
-alters dose response curve
Tolerance/desensitization
- previous/repeated exposure to drug may increases tolerance, decreasing drug effect
- partly due to a decrease in number of receptors
Partial agonist
Less efficacious, induce partial (non-max) activation when bind to receptor
Naloxone
- potent, partial opioid antagonist
- reversal for morphine or buprenorphine
- will reverse morphine faster than buprenorphine
Complex model of receptor binding
- some receptors shift between active/inactive without binding of drug to stimulate shift
- Assume some receptors are active without having bound drug
- drug binding will “stabilize” receptors by causing them to remain in active or inactive state
Inverse agonist
- binds to same receptor as agonist, but stabilizes it as inactive
- reduces effect opposite that of the agonist
How do spare receptors affect ED/C50
- EC50 will be lower than Kd
- with more spare receptors, a lower concentration will cause effect
Quantal/Population cumulative distribution curve
- not a true dose response curve
- curve made based on frequency distributions seen in a population
- measures if animal responded to drug or didn’t at each point
- NO predictive value to graph
use of population curves for toxicity studies
Used to estimate drug safety by determining therapeutic index
Therapeutic index
LD50/ED50 = TI
Compares dose/concentration that causes effect with dose/concentration that causes toxic effect
What therapeutic index number is considered safe?
> 10
larger TI = safer drug
Standard safety margin
% by which the ED99 must be increased before an LD1 is reached
Therapeutic window
Window where many patients get a good response and only a few toxic effects occur
Tachyphylaxis
acute drug desensitization
occurs after initial dose or after series of small doses
Down regulation
A decrease in the number of receptors responding to a drug, making cells less sensitive to the drug
What determines drug concentration?
drug (g) / volume (l)
Central compartment organs
- brain, spinal cord, retina
- well perfused, drug has rapid effects
Peripheral compartment organs
- skin, muscle, fat
- not well perfused, drug has slower effects
Advantages of parenteral drug administration (vs. oral)
-avoids lack of uptake issues with GI
-avoids elimination by the liver
aka you know it’s in there
-rate of uptake into blood usually faster
Advantages of oral drug administration (vs. parenteral)
-rate of uptake into blood usually slower
IV administration
- absorption circumvented
- fast
- provides bolus
- constant rate of infusion leading to steady state
- can give irritating solutions (b/c rapid dilution) or large volumes
- don’t give oils or suspensions
Bolus
Initial spike of drug into blood
Drug in central compartment first, then rapidly moves to peripheral
Once in peripheral compartment, slow decrease b/c removed only by elimination
steady state
- constant level of drug in the blood
- Only at this state does animal get full benefit of the drug.
Subcu administration
- aqueous solutions absorbed promptly
- repository, slow sustained release
- don’t give large vol, irritants
IM administration
- aqueous solutions absorbed promptly
- repository, slow sustained release
- can give moderate volumes, some oils, some irritants
IP (peritoneal)
- mostly useful for lab animals
- FAST
- don’t give irritants
Pulmonary administration
- must be non-irritating aqueous drugs given in gas form
Bioavailability (F)
- fraction of oral drug that is absorbed, escapes first pass elimination and makes it into systemic blood
- F = Area under curve oral / AUC iv
Oral administration
- bioavailability variable (GI blood –> liver –> elimination)
- usually slower onset
- typically more economical, safe, convenient
- not usually used for Rum
- multiple doses required to reach a steady state
Drug absorption from gut depends on
drug form and solubility
Who moves better across membranes:
lipid soluble vs. polar
small vs. large
lipid soluble > polar (uncharged vs. charged)
small > large (polar water can cross b/c small)
What drug type is best absorbed in stomach
acidic environment so lipid soluble drugs and weak acids (uncharged) best absorbed
What drug type is best absorbed in SI?
basic envornment so weak bases best absorbed
First pass effect
- Drugs given orally primarily absorbed in stomach, GI
- Portal circulations from these organs go to liver where drugs are metabolized or secreted into bile
Vd (volume of distribution)
- If you know this, you can determine what the drug concentration will be in the blood
or amount of drug in the body - very variable depending on drug characteristics (solubility, is it protein bound, CNS penetration etc)
- greater Vd = more likely to redistribute into other compartments
What can penetrate BBB?
non-polar drugs
What drug types deposit in fat? bone?
fat - lipid-soluble drugs
bone - tetracyclines
What happens when drug binds to plasma protein?
- albumin & plasma proteins bind drugs with low affinity
- only free drug can bind receptors
- plasma concentration of drug doesn’t = concentration of actively working drug
How can liver disease affect free drug circulation?
Liver has decreased protein production –> less bound drug, more free drug in circulation
Phase 1 reaction
- in liver
- Cytochrome P450 oxidizes/hydrolyzes/reduces drug (typically inactivating them)
- usually makes it more water soluble for easier excretion
2 main routes of drug elimination
Metabolized in liver
Excretion by kidney
P450’s
- Nonspecific
- Can be induced by other drugs to increase rate of drug elimination
- things like grapefruit juice can inhibit their function
Phase 2 reaction
- Conjugation of drugs in the liver
- makes them more water soluble for easier excretion in kidney
How does filtration move drugs from blood to urine
- at level of glomerulus
- small molecules –> urine
- only drug bound to plasma protein (albumin) isn’t filtered
How does secretion move drugs from blood to urine
- at the level of proximal convoluted tubules
- cells of pct’s secrete organic acids or bases drugs into urine via transporters
- if pH of urine causes these drugs to uncharged form, some may be reabsorbed back into blood by diffusion
How does the liver eliminate drugs?
- put into biliary system via transporters
3 measures of elimination
Clearance
Half Life
Rate constant of elimination
Clearance
-vol of drug cleared by an organ per unit time (CL = Clrenal + CLliver + CLother)
If clearance is decreased 50%, what does that do to drug half life?
doubled
Half-life
- Time to reduce drug concentration to half the original concentration
- decreased clearance = longer half life
Rate of constant elimination
Kel = 0.693/half life time
Inversely proportional to half life
1st order kinetics
- Drugs normally eliminated by 1st order
- the more drug you have the faster it is eliminated
zero order kinetics
- Few drugs eliminated by zero order
- same amount eliminated per hour regardless of concentration (e.g. alcohol)
Bolus vs. infusion
Bolus - drug all at once, bit of redistribution, plasma level depends on clearance
Infusion - slow, plasma levels low then approach steady state
steady state
after drug reaches equilibrium of uptake vs. elimination, it maintains a steady state of plasma concentration (assuming dose kept same)
reached in ~4 half lives (time NOT dose dependent)
continuous infusion vs. repeated doses and steady state
Both reach steady state in ~4 half lives
Repeated doses acts same, just with fluctuations
Steady state levels are proportional to ___ and inversely proportional to ____
- dosage (doubled dosage = doubled level of steady state) or bioavailability
- dose interval (e.g. q 4 hrs) or clearance
Fluctuations to steady state level are proportional to ___ and inversely proportional to ___
- dose interval (short interval = small flux)
2. half life
Blood levels of a drug are ~1/2 what you want. How can you increase the average blood level to twice the original level/
double the dose or cut the dose interval to .5
How can you reduce the fluctuations without changing average drug concentrations?
Cut the dose interval of the drug to ½, and also reduce the dose to ½ to keep the average concentration the same.
The clearance is estimated to be ½ of normal. What changes could you make in the recommended dose to get the optimum blood level?
With decreased clearance, the blood levels would approach twice normal.
You could cut the dose to ½ or double the dose interval.
Giving a concentration-dependent antibiotic (want brief periods of high drug levels)
higher doses with longer dose interval
Giving a time-dependent antibiotic (longer periods of use at minimal levels)
lower dose with shorter dose interval
Loading dose
Shortens the time to get to steady state concentration
What adds variability to drug effect?
blood concentration
effect through receptor
Pharmacokinetics
variability in blood concentration
3 factors that contribute to 9-fold range in blood concentration of drug
Clearance - kidney function, GFR, RAA system varies
Vol of distribution - different percent of fluids, bone, muscle in different animals
Bioavailability - blood levels vary
pharmacodynamics
variations in effect at a fixed concentration
changes in receptors/activation may increase variability
What molecule types can cross membranes without a transporter?
hydrophobic molecs (uncharged acid/base forms) small molecules (NO, H2O)
P glycoprotein
- ATP binding casette transporter
- saturable
- removes ivermectin from the brain, may also transport digoxin, etc.
- “white feet don’t treat” - collies etc. with decreased production of p glycoprotein & ivemectin toxicity
Type I hypersensitivity
allergy –> atopy –> anaphylaxis
Atopy
allergen is having an effect somewhere else in the body that where the reaction is happening
2 methods for causing toxic drug reaction
- too high of dose activates too many receptors or activates wrong low-affinity receptors
- non-receptor mediated - nasty compounds formed during metabolism in liver (e.g. acetaminophen) that hurt the liver
How can a 2nd drug interfere and cause adverse reaction?
- if animal has increased or decreased/inhibited cytochrome P450
- inhibition of p glycoprotein transporter (= drug accumulation)
- can displace original drug bound to proteins- bad or gets eliminated
Pharmacology (vs. toxicology)
- Compound given intentionally, not damaging
- study of potions
- receptor mediated effects that end when compound gone
Toxicology (vs. pharmacology)
- compound not given intentionally, damaging
- study of poisons
- receptor and non-receptor mediated effects, with changes/damage persisting after toxin is gone
receptor mediated toxicity
- drug binds to important receptors/enz, disrupt activity –> damage, death
- +/- excitotoxicity
- or low affinity binding to abnormal receptors when drug is in excess
- e.g. HAB’s, insulin toxicity in cats - seizures
excitotoxicity
overstimulation of normal receptors = disruption
-e.g. glutamate excess kills neurons
non-receptor mediated toxicity
- not very selective, potent
- much larger amounts required
- toxic metabolites formed
- e.g. ethylene glycol, acetaminophen
Why should you give drugs based on surface area?
Metabolic rate changes more similarly to SA (vs. weight)
Exotherms and drugs
- lower metabolic rate
- drug half life depends body temp
In what animals is drug half life the shortest? longest?
- rum, EQ
2. cats
What do cats have poor conjugation of?
Glucuronic acid - half life of aspirin extended
what drug types does the rumen trap?
hydrophobic bases (e.g. ivermectin)
Charged vs. uncharged groups and urine excretion
charged - better excreted in urine
uncharged - can be resorbed back into body
How much liver damage is required to overwhelm metabolism of drugs?
> 80%
what animals are tricaine methanesulfonate (MS-222) approved for use in?
Fish (or clove oil)
Amphibians (or Iso)
