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The rate of drug transfer = (Permeability
coefficient)(Surface area of contact)(concentration gradient)
(Permeability coefficient)*(Surface area of contact)*(concentration gradient)
study of what the drug does to the body
study of what the body does to the drug
Generic Name of Ranitidine (histamine receptor blocker)
(Diffusion coefficient)*(Partition coefficient)/membrane thickness
A measure of lipophilicity; a large value of PC indicates higher solubility in lipids. So better absorption. i.e. (conc. of unionized drug in octanol)/(Conc. of unionized drug in buffer)
Molecules with HIGH partition coefficients (5)
- Many drugs
Molecules with LOW partition coefficients (3)
- Ionized molecules
the pH at which the drug is half ionized.
First Pass Effect
The removal of a drug from portal circulation by metabolic enzymes in the liver so that amount reaching the systemic circulation is less than the amount absorbed across the GI tract. Also happens in the walls of the intestine which is rich in drug metabolizing enzymes. Many drugs cannot be given ORALLY because of significant first pass effect.
Measures how efficient absorption is. It's the fraction of the administered drug that reaches the systemic circulation. It signifies the extent of absorption and first pass effect. i.e. if 100 mg drug is administered orally and 70 mg is absorbed into blood, the bioavailability (F) is 0.7.
Example of drug that binds to eye
Chlorpromazine to melanin
Example of drug that binds to fat
Example of drug that binds to lungs
Example of drug that binds to bone
Apparent Volume of Distribution
Measure of the extent of drug distribution. It is the volume that a drug SEEMS to distribute into. Not an actual volume. It is a measure of the tendency of a drug to move out of the blood plasma to some other site.
It is the: (total amount of drug [mg])/(Plasma concentration [mg/L])
Volume of Interstitial Fluid
Volume of Intra-cellular Fluid
Total volume of body fluids
Phase I of metabolism
- biotransformation reactions: oxidation, reduction, and hydrolysis
- polar groups introduced, more water soluble, less lipophilic
- location: ER
Phase II of metabolism
Conjugation reactions catalyzed by transferases (i.e. glucoronyl, glutathione, sulfo-, specific amino acid transferases.
location: usually cytoplasm but DOMINANT REACTION GLUCORONIDATION occurs in ER
- reactions most often abolish biological activity and add more polarity
- very water soluble
The main function of glucuronic acids is to combine with other substances such as drugs, toxins, and hormones, and either carry them to other parts of the body or eliminate them. This combining, known as conjugation, makes the substances more water-soluble and easier to pass out of the body through the urine. The process also makes it easier for these substances, primarily hormones in this case, to be released in whatever location in the body they are needed.
What do you use to conjugate (inactivate) a drug
- glucoronic acid
- acetyl coA
- amino acids
Conversion of an inactive drug to active drug by metabolism
P450 polymorphism. Those lacking CYP2D6 expression will be...
- slow metabolizers of beta-adrenergic antagonists, neuroleptics, antidepressants and codeine.
- Increased amphetamine toxicity can occur in patients with decreased CYP2D6 activity.
Drug induced elevation of CYPs
- EtOH induces CYPE1
Drug-induced inhibition of CYPs
- Quinidine inhibits CYP2D6
- VOLUME of blood from which a drug is completely and irreversibly removed PER UNIT OF TIME. NOT concentration. Unit is mL/min (volume/unit time). I.e. kidney can get rid of a drug in X mL of blood in one hour. So the clearance is X mL/hr.
- It is also the rate of elimination/plasma concentration
- QxE (Q is blood flow, E is extraction ratio)
- What was taken out of liver divided by what was there in the first place. (Cin-Cout)/Cin
- i.e. if the ratio is 1, the entire drug is cleared by liver
Elimination of most drugs follows ____order kinetics
first; the rate is proportional to the amount of drug. dA/dt=-kA
Creatinine is used for...
to estimate GFR (Glomerular filtration rate). Creatinine is produced by the muscle and filtered by kidney. There's almost no active secretion nor reabsorption. It depends on the body weight, age, and sex.
Example of potential drug interactions for proximal tubule secretion
Probenecid, an inhibitor of active secretion of organic ions, can block active loss of penicillin, causing increases in antibiotic level in plasma
Three ways of drug elimination by the kidney
- Glomerular Filtration (passive)
- Active secretion (proximal tubule--carrier mediated organic cations/anions are transported this way)
- Passive reabsorption (collecting duct)
Common filtration rate (approximately)
Common plasma flow
If you have a lot of weak acid drugs (i.e. aspirin), how do you eliminate the drug?
Weak acids are RE-absorbed to the body at low pH. You should increase pH with sodium bicarbonate to increase drug excretion.
If you have a lot of weak base drugs, how do you eliminate the drug?
Weak bases are RE-absorbed into the body at high pH. You want to decrease urinary pH so it can be excreted. I.e. Ammonium chlorideleads to increased drug excretion
Conditions for drug excretion
What kind of things are excreted in bile?
large polar molecules (many drugs conjugated with glucoronic acid)
- the volume of blood from which a drug is IRREVERSIBLY removed PER UNIT OF TIME. unit is mL/min.
- If kidney or liver can rid drug from 100 mL of blood in 1 hour, then the clearance is 100 mL/hour
- CL=Q*E= Q*(Cin-Cout)/Cin
- What was taken out of the liver divided by what was there in the first place. I.e. 10 mg/mL goes into liver. 4 mg/mL goes out.
- If the extraction ratio is 1, that meansthe entire drug is cleared by the liver. If extraction ratio is 0, then no drug is cleared by hte liver.
T/F: A constant fraction of drug is always eliminated for EVERY half life
First order kinetics for most drugs
- Rate is proportional to amount of drug
- constant fraction of drug is always eliminated for EVERY half life.
Zero order kinetics (like phenytoin, aspirin, ethanol)
Amount of drug elimination remains constant throughout
Dosing regimen that should be used in a given situation is described by:
- Volume of distribution (Vd)
- Clearance (Cl)
Difference between Minimum Effective Concentration (MEC) required for a direct response and Minimum Toxic Concentration (MTC)
Drug therapy. Important things:
- What dose to maintain plasma conc. at steady state during therapy?
- How much time to reach steady state conc?
Rate of Administration=
- rate of elimination
- clearance x plasma conc.
represents dosing interval
Maintenance Dose (M)
- Dose needed to maintain the conc. within the therapeutic window when given repeatedly at a constant interval
- For IV infusion: Infusion rate=Clearance of drug x Steady-state plasma concentration
- For oral dosing: M=Clearance of drug x Steady-state plasma concn. x (dosing interval/F)
What is steady state plasma conc.?
When plasma conc. of drug is leveled off in a steady region.
Loading Dose (DL)
- dose of drug sufficient to produce plasma conc of drug that would fall within the therapeutic window after only one or two doses.
- IV DL= (target plasma conc.)x(volume of distribution)
- Oral dosing: [(target plasma conc.)x(volume of distribution)]/F
Four main types of receptors mediate the actions of endogenous molecules and drugs. What are they and give example of each
- Ligand gated ion channels (i.e. cholinergic nicotinic receptors, benzodiazapines--msec)
- G protein-coupled receptors (alpha and beta adrenoceptors--sec)
- Enzyme-linked receptors (i.e. insulin receptors--mins to hours)
- Intracellular receptors (steroid receptors--hours)
When epinephrine binds to alpha 1, it...
leads to smooth muscle contraction
When epinephrine binds to alpha 2, you get...
inhibition of NT release, depending on location
What is Kd?
- Kd is the dissociation constant of the DR complex.
- Kd is a measure of the affinity of the drug to the receptor. Affinity is the strength of binding and is inversely proportional to Kd. higher Kd, lower the affinity.
- Kd is the conc. at which 50% of receptors are bound/occupied
Dose response relationships (two approaches)
- graded DRC --in a single individual
- quantal DRC--in a group of individuals
Define ECmax and EC50
- ECmax--max response of the system to the drug (efficacy of the drug). Efficacy is the ability of drug to activate receptor to produce a maximal response.
- EC50--conc. of drug that produces 50% of the max response. It describes the potency of the drug
Examples of antagonism by receptor blockade
- competitive antagonist
- non-competitive antagonist
- Irreversible, or non-equilibrium antagonist
- Inverse agonist
Examples of antagonism by non-receptor blockade
- physiological antagonism
- chemical antagonism
- pharmacokinetic antagonism
Receptors that display constitutive activity as a result of over expression or as a result of mutation. They are active in the absence of an agonist.
Example of physiological antagnoism
- Two agonists acting by different mechanisms affect the same variable but in opposite directions
- i.e. Epinephrine: dilation of bronchial lumen
- Histamine: constriction of bronchial lumen
Therapeutic Index calculation
- Toxic dose (TD50)/effective dose (ED50)
- A measure of a drug's safety margin. Large value indicates wide margin between doses that are effective and doses that are toxic.
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