Test 3 - Pharmacology - I and II Flashcards
What is pharmacokinetics?
The actions of the BODY on drugs
What is pharmacodynamics?
The actions of DRUGS on the BODY
*Act on receptors
What is an agonist?
Drug or natural ligand -Activates Rc (receptor) -can be selective or not -Examples —Neurotransmitter —Hormone —Drug that mimics a ligand
What is an antagonist?
Something that binds the receptor, but does not activate it
—Interferes with agonist
—Shifts dose-response to the right
—Most drugs are these, except antibiotics
*If enough agonist is present, then the agonist will start to bind and activate the receptor
What is a competitive inhibitor?
An antagonist that binds the active site on a receptor and competes with the agonist at that site
What is an allosteric activator?
Binds the receptor at a site separate from the agonist site
—Potentiates effects
What is an allosteric inhibitor?
Binds the receptor at a site separate from agonist site
—Noncompetitive
—Actions often reversible
—This changes the active site and decreases the Rc’s affinity for the agonist
Ra = ?
Ri = ?
In the absence of drugs, the two isoforms are in Eq and what is favored?
Active receptor
Inactive receptor
**Ri
What is a full agonist?
High affinity for the Ra conformation, and Ra-D = much larger effect
What do partial agonists do?
Produce lower response than full agonists
—Don’t get to same plateau as full agonists do
—Doesn’t stabilize Ra-D as well as full agonists
What is an inverse agonist?
Not the same as an antagonist
—Greater affinity for Ri
—Acts like a sponge, less Ra available, so less activity occurs
What is a conventional agonist?
Equal affinity for the Ra and Ri, no change in constitutive activity
What is Kd?
Infinity constant
—Conc of drug to get 50% of receptors bound
What is EC50?
Effective conc for 50% of drug’s max effect
What is IC50?
Inhibitory conc
—Antagonist conc
On graphs of inhibition, compare and contrast competitive inhibition with non competitive inhibition.
Comp inhib
—EC50 shift to right (higher dose of agonist necessary for desired effect)
Noncomp inhib
—Plateau of desired effect is greatly diminished, but EC50 does not move
T/F - When mixed, a full agonist can be displaced by a partial agonist, and the total response is decreased.
TRUE
Name and describe the 3 types of drug receptor interactions.
Additive (Summative)
—1+1=2
—Net effect is the sum
—Example: ibuprofen + acetaminophen
Synergistic (Supra-additive)
—1+1=5
—Net effect is greater than the sum
—Example: alcohol + sleeping pill
Antagonistic (Infra-additive)
—1+1=0.5
—Net effect is less than the sum
—Example: Antidotes
What is a chemical antagonist?
Does NOT involve a receptor
—(+)protein counteracting effects of a drug that is (-) charged
What is a physiological antagonist?
Involves endogenous regulatory pathways mediated by different receptors
Define efficacy.
Greatest effect that can be had
—Low efficacy - 12%
—High efficacy - 100%
Define potency.
Relative concentrations of 2 or more drugs that produced the same effect.
Potency = position on graph. More left on the graph, more potent.
—Higher potency drug will require low amount of drug to get to EC50
What is desired, a less steep or more steep drug curve?
LESS steep
The curve most left on the graph is what?
Most potent
The highest achieving drug curve on the graph is what?
Most efficacious
*Look in pics for the graph that will probably be on the test
What 2 factors govern drug action?
Affinity
—Measure of the tightness that a drug binds to the receptor
Intrinsic activity
—Ability of a drug, once bound, to generate an effect
T/F - A drug with a high therapeutic index is desired.
TRUE
TI = TD50/ED50
TD50 = Toxic dose in 50% of population
ED50 = Efficacious dose in 50% of population
*So a high therapeutic index is desired because if 100 pills of drug X are toxic to 50% of population, and the efficacious dose for 50% of the population is 1 pill, then that drug is good. However, if 2 pills of drug X are toxic to 50% of population, and the efficacious dose for 50% of population is 1 pill, then that is not desired because the room for error is too much
What is the loading dose?
An initial large amount of drug given to increase concentration of that drug in the blood.
*Next would be keeping the drug in a safe range of conc in the blood to have its effects
Safe drugs have a ________ margin of safety.
WIDE
*True definition is the amount of drug lethal to 1% of animals divided by amount of drug that causes beneficial effect in 99% of animals
What does parenteral mean?
Not by way of intestine or GI tract
What are the most common modes of parenteral drug administration? (3)
IV - Most rapid, easy to titrate and can enter direct circulation immediately
Intramuscular - Rapid, sometimes painful
Subcutaneous (SubQ) - Not rapid, smaller volumes req’d compared to intramuscular, sometimes painful
What does enteral mean?
By way of intestine or GI tract
What are the most common enteral types of drug administration?
Buccal/sublingual
Oral - Most common and convenient, most unpredictable, absorption via duodenum, first pass metabolism
Rectal - Soln or suppository, less first pass effect than oral
Initial distribution of drug into tissue is determined by rate of ______ ________.
Blood flow
The conc of drug at a particular site is related to __________.
Affinity
Gastric ________ time can play a role in drug metabolism.
Emptying
Other types of drug administration. (3)
Inhalation - Very rapid (close to IV timing)
Topical - surface, e.g. skin, mucus membranes, eye drops
Transdermal - control and continuous release
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
What is a drug?
Substance that brings about a change in biological function
What is a medicine?
A subset of drugs used for selective, therapeutic effects
What is an xenobiotic?
Chemical not synthesized in the body
*Xenos means stranger
“Xenos Things”
What is a side effect?
Any unintended effects
*Not always maleffects
Absorption is affected by 4 factors. Name them.
Route of administration
Blood flow
Drug characteristics
Cell membrane characteristics (diffusion or active transport)
Name 5 drug characteristics.
Lipid solubility
Size of molecule - Little stuff gets into more places than big stuff
Formulation - excipients (filler ingredients in drugs) EX - some excipients act like a lattice that allow a prolonged drug release if desired
Concentration
Acidity - Acidic drugs are non-ionized in the stomach and diffuse across membranes while basic drugs are not well absorbed in stomach
Two types of passive transfer.
Filtration
Simple diffusion - lipid soluble drugs across lipoprotein membranes
Two types of specialized transport.
Active transport - ATP required
Facilitated diffusion - channel req’d
What is bioavailability and what is it affected by and what mode of administration = 100% bioavailability?
The fraction of unchanged drug reaching the systemic circulation (If bioavailability is high, then a lot of the drug gets to the site)
Affected by:
Dissolving of drug in the GI tract
Destruction of drug by the liver
100% : IV administration
When considering drug distribution and clearance, a lot of factors need to be thought of including the amount of drug necessary to have effects in a system that is emptying and has extra vascular compartments in addition to the vascular compartment.
SWEET!
The volume of distribution is what?
Measure of the apparent space in the body available to contain a drug.
*Vd = amount of drug in body/conc of drug in the plasma or blood
**This volume can exceed any physical volume in the body b/c it is the volume necessary to contain the amount of drug at the conc found in the blood
Give me a clear example of small Vd.
100% of drug in 3 L of plasma, lets say 100 mg/3 L (found in the plasma sample), that is 33 mg/L. Well, Vd = dose (mg or g)/conc of drug (g/L or mg/L). That would be 100 mg/ 33 mg/L = 3 L.
*However, body is made up of multiple compartments. Plasma 3 L, Extracellular 14 L, total H2O 42 L.
**So, if we get big #’s for Vd, then drug is accumulating in some other compartment than the blood. Small #’s for Vd, drug is mostly in the blood.
Give me a clear example of big Vd.
100 mg dose given, but plasma sample only shows 1 mg of drug/3L, that is 0.33mg/L. So, 100 mg/0.33 mg/L = 300 L. Vd = 300 L. That is the volume of drug needed in the blood to equal amount of drug in the (lets say fat) compartment.
Total body water is what?
Extracellular water is what?
Plasma is what?
- 6 L/kg
- 2 L/kg
- 04 L/kg
**Based off 70 kg male
Half life equation?
T1/2 = 0.693 * Vd/clearance
Clearance = ??
Clearance = rate of elimination (mg/min)/conc of the drug (mg/mL)
*So, units of clearance are in mL/min
**Clearance is the volume of fluid cleared of drug from the body per unit of time
Drugs are generally eliminated in what ways?
Mostly in the urine
—Some in feces
—Lungs excrete volatile compounds (breathalyzer)
—Salivary glands, sweat, and hair small amount
Tell me about drugs and renal elimination.
Many drugs are filtered thru the glomerulus to enter the renal tubules.
Once in tubules, drugs may be reabsorbed back into the blood thru renal tubule cells —Reabsorption favors the highly soluble agents
Active transport thru renal tubular cells also affects the rate of renal elimination
What are 2 examples of Solute Carrier Transporters (SLC)?
OCT
—Organic cationic transporters
OAT
—Organic anionic transporters
What does P-glycoprotein (P-gp) do?
Transports drug molecule from cells back into the intestinal lumen for excretion
Assuming 1st order kinetics, ________% of drug is eliminated after ________ half-lives.
95
4.5
Explain zero order kinetics.
Constant amount of drug eliminated per unit time. This takes place independent of drug concentration involved in process.
*Graph looks like a straight declining line
Explain first order kinetics.
Process that is directly proportional to the drug concentration involved in the process.
100% (of drug) goes down to 90%. It goes down another 10%, but it is 10% of 90 now, so 9. So, it drops to 81%. Pattern continues. 10% of 81 is 8.1, so it drops to 72%, etc.
*Graph looks like the steep slide at Seven Peaks
Drug metabolism
Phase I has three possibilities. Name them.
Drug goes directly to conjugate of phase II.
Drug metabolite with modified activity and then goes to conjugate.
Inactive drug metabolite and then goes to conjugate.
Drug Metabolism
Phase II is what?
Conjugates passing onto to elimination phase.
*Break down to H20 soluble to be excreted in the urine
Give me 4 important concepts about drug metabolism.
It often inactivates drug, but sometimes activates
Generally makes drugs more hydrophilic and thus more easily excreted in the urine
Usually make substances less toxic, but sometimes more toxic
Phase II can PRECEDE phase I, but it’s more common to go from I —> II
What are microsomes?
Purified liver endoplasmic reticulum
*Rough microsomes contain ribosomes
**Smooth microsomes contain mixed function oxidase (monooxygenases)
What are some examples of monooxygenases?
NADPH-cyp450-oxidoreductase
Cyp450
What is Cyp450?
Cytochrome p450
—enzyme responsible for drug interactions in the liver.
**Drugs can inhibit or induce p450. If inhibited, then less drug is metabolized. If induced, then more drug is metabolized
What are the main engines of drug metabolism?
P450 and p450 reductase
Phase I of hepatic metabolism includes what 3 things?
Oxidation
Reduction
and/or Hydrolysis
Phase I metabolites that are ___________ are excreted, and all other metabolites go on to Phase II.
Hydrophilic
Tell me what cytochrome p450 actually.
Heme-containing enzymes primarily found in liver hepatocytes and small intestine enterocytes
*Each enzyme is referred to as an isoform
What are the 2 most common isoforms of cytochrome p450?
CYP3A4
—Most abundant in human liver and intestine
CYP2D6
What is a substrate?
Drug that is the target of a particular enzyme
What is an inducer?
Something that increases the activity of a particular p450 enzyme
***This increases metabolism and clearance of a drug
What is an inhibitor?
Something inhibits the activity of a particular p450 enzyme
**This decreases metabolism and clearance of a drug
Phase II of hepatic metabolism consists of 4 processes. Name them.
Glucuronidation
Acetylation
Glutathione conjugation
Glycine conjugation
**These processes make drugs more hydrophilic
*There’s also sulfation, methylation, and water conjugation
Give me 4 factors that affect hepatic drug metabolism.
Microsomal enzyme inhibition (many drugs inhibit CYP450)
Microsomal enzyme induction
Plasma biding protein (drugs highly bound will not enter liver and will have a longer 1/2 life)
Liver disease
What are pharmacogenomics?
The study of genetic factors that underlie variation in drug response
