Pharmacology I

(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

Zantac

(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)

• Hydrocarbons
• Anesthestics
• Alcohols
• Lipids
• Many drugs

• Carbohydrates
• Proteins
• Ionized molecules

the pH at which the drug is half ionized.

Henderson-Hasselbach equation

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.

Chlorpromazine to melanin

thiopental

Anti-histamines

tetracycline

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])

4 L

10 L

28 L

42 L

• activation/detoxification
• biotransformation reactions: oxidation, reduction, and hydrolysis
• polar groups introduced, more water soluble, less lipophilic
• location: ER

Conjugation reactions catalyzed by transferases (i.e. glucoronyl, glutathione, sulfo-, specific amino acid transferases.  

• reactions most often abolish biological activity and add more polarity
• very water soluble

location: usually cytoplasm but DOMINANT REACTION GLUCORONIDATION occurs in ER

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.

• glucoronic acid
• glutathione
• acetyl coA
• sulfate
• amino acids

Conversion of an inactive drug to active drug by metabolism

• slow metabolizers of beta-adrenergic antagonists, neuroleptics, antidepressants and codeine.  
• Increased amphetamine toxicity can occur in patients with decreased CYP2D6 activity.

• EtOH induces CYPE1
• Barbiturates
• Phenytoin-anticonvulsant
• Carbamazepine-anticonvulsant
• Cigarettes
• Rifampicin

• Quinidine inhibits CYP2D6
• Isoniazid
• Chloramphenicol
• Erythroycin

• 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

first; the rate is proportional to the amount of drug. dA/dt=-kA

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.

Probenecid, an inhibitor of active secretion of organic ions, can block active loss of penicillin, causing increases in antibiotic level in plasma

• Glomerular Filtration (passive)
• Active secretion (proximal tubule--carrier mediated organic cations/anions are transported this way)
• Passive reabsorption (collecting duct)

125 mL/min

600 mL/min

4.5-8

Weak acids are RE-absorbed to the body at low pH.  You should increase pH with sodium bicarbonate to increase drug excretion.

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

• ionized
• water soluble

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.  
• 10-4)/10=0.6.  
• 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.

True

• Rate is proportional to amount of drug
• constant fraction of drug is always eliminated for EVERY half life.

Amount of drug elimination remains constant throughout

• Volume of distribution (Vd)
• Clearance (Cl)
• half-life
• bioavailability

Difference between Minimum Effective Concentration (MEC) required for a direct response and Minimum Toxic Concentration (MTC)

• What dose to maintain plasma conc. at steady state during therapy?
• How much time to reach steady state conc?

• rate of elimination
• clearance x plasma conc.

represents dosing interval

• 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)

When plasma conc. of drug is leveled off in a steady region.

• 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

• 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)

leads to smooth muscle contraction

inhibition of NT release, depending on location

• 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

• graded DRC --in a single individual
• quantal DRC--in a group of individuals

• 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

• competitive antagonist
• non-competitive antagonist
• Irreversible, or non-equilibrium antagonist
• Inverse agonist

• 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.

• 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

• 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.