describes how much and how fast the drug leaves its site of administration and is made available to the body fluids for disbribution

the primary photokinetic factor determining the length of time it takes a drug to produce its effects 

more rapid

faster 

Mechanisms of absorption

(4)

1. Diffusion

2. Filtration

3. Pinocytosis

4. Active Transport 

requires no energy; depends on conc. gradients; accounts for absorption of most drugs from the GI tract into circulation; small lipid-soluble, nonionized drugs readily difuse across cell membranes

carrier-mediated diffusion: e.g. vit. B12 

transfer of drug molecules against the conc gradient using metabolic energy (ATP)

(e.g. insulin, glucose) 

Factors Affecting Absorption

(4) 

1. route of administration

2. host factors

3. drug factors

4. bioavailability 

pH of stomach/intestine

presence/absence of food

presence of chelators (e.g. antacids, resins)

emptying time & GI motility (decrease w/ age, etc)

degree of thickness of skin (for topical) - avoid areas of blood exposure b/c will then go directly into blood 

drug form

degree of ionization

molecular size

concentration gradient 

special coating of additives are meant to delay absorption and protext drugs from being degraded in stomach (wait for diss. in alkaline env't)

liquid form of oral meds absorbed faster b/c no dissolution req'd (do this for quick relief)

some injectable & topical meds have subsatnce added to prolong absorption (e.g. nicotine patches) 

drug usually consists of two charged parts (neg/pos).  Ionization is separation of these particles in sol'n and drifting

pH of local env't directly influences drug absorption through its ability to ionize the drug 

nonionized drugs are lipid-____ and ____ across cell membranes

ionized drugs are lipid-____ and ____ across cell membranes 

soluble; readily diffuse

insoluble; nondiffusible 

rule of thumb:

acidic drugs tend to be ___ in acidic env'ts, hence faster rate of absorption in ____

basic drugs tend to be ___ in alkaline env'ts, hence better rate of absorption in ____ 

uncharged; stomach

uncharged; intestinal tract 

molecular weight must be <1,000 to cross membrane

(ex: big drugs are safe for pregnant women b/c they won't cross membrane to baby) 

percentage of drug available to produce a pharmacologic effect (how much of the drug that is administered reaches its site of action/target)

**this is how we compare drugs** 

via circulation

amount of space in the body a particular drug has to fill up in order to provide blood levels that are measurable and meaningful

Vd = amt of drug administered/conc. of drug in plasma

small Vd = drug stays in plasma & is not widely distributed

large Vd = drug widely found throuhgout the body 

Vd of water-soluble drugs ___ lipophilic drugs

Vd influences the ___ and ____ of drugs 

<

dosage; choice 

Circulation, CO, and blood supply to site of action

Obesity (body fat)

Edema

Protein binding

level of plasma protein albumin

blood-brain barrier

placental membranes 

Factor affecting distribution:

Circulation, CO, blood supply to site of action 

less CO, less active drug available

heart,liver,kidneys and brain receive the most CO; skin, bone, and adipose tissue receive lower amt, so, it is more difficult to deliver high conc. of drugs to these areas 

Factor affecting distribution:

Obesity (body fat) 

lipophilic drugs distribute into adipose tissue and tend to accumulate there (even to potentially toxic levels); less drug is available to produce an effect

fat is unsaturable (b/c so much of it)

lipophilic drugs are slowly released from the fat into blood stream so they have longer duration of action (so, longer duration of side effects) 

Factor affecting distribution:

Edema 

Factor affecting distribution:

protein binding 

not all drug molecules in plasma will reach target cells b/c many bind reversibly to plasma proteins, particularly albumin, to form drug-protein complexes

these are too big to cross capillary membranes, so drug is not available for distribution to body tissue; drug bound to proteins circulate in theplasma until released or displaced from the drug-protein complex

**only unbound/free drugs can reach their target cells 

protein ___ saturable

protein-bound drugs ___ bioavailable 

is (malnurished people need less amt of drug)

are not 

drugs can compete for protein binding sites and some agents have a greater affinity for these binding sites than other agents, so displace other drugs

**displaced meds can immediately reach high levels in the blood and produce adverse effects 

Factor affecting distribution:

level of plasma protein albumin 

less serum albumin, more active drug available

low albumin levels (infancy, hepatic disease) can affect "free drug conc" 

Factor affecting distribution:

blood-brain barrier 

very selective anatomical barrier that inhibits many chemicals from entering brain

protects brain from environmental insults

nature is not well understood; capillary beds that behave as epithelial barriers

drugs must be lipid-soluble, uncharged, small MW to pass 

Factor affecting distribution:

placental membranes 

placenta acts as simple lipoidal membrane and is not highly selective, so a ny drugs (prescriptions, OTC, herbal therapy) should be avoided

teratogenic effects of drugs important to consider 

detoxification, degradation, and removal from the body foreign, biologically active chemicals by:

1. increasing water-solubility for elimination in urine

2. inactivating chemicals

3. converting chemicals for elimination through gut (bile) 

hepatic microsomal enzyme;

P-450 

Factors affecting biotransformation/metabolism

(5) 

1.condition of the liver (since most drugs are detoxified by liver enzymes)

2.age (very young/old have altered metabolic capacity)

3. genetic (enzymes can be regulated by genetic factors; certain genetic disorders have been recognized in which pts lack specific met. enzymes)

4. hepatic insufficiency (impairs metabolism)

5. drug interactions 

Inducers (of P-450)

chemicals or drugs that decrease production of transforming enzymes --> will slow metabolism of other drugs, causing drug accumulation and increasing adverse effects

**DANGER = overdose; P-450 won't be metabolized 

First Pass Effect

(Presystemic Biotransformation) 

drugs absorbed from the small intestine are transported by portal circulation directly to the liver before being circulated ot the rest of the body

liver may biotransform much of the drug before it reaches systemic circulation

first pass effect inactivates drugs (neutralized/biotransformed)

important mechanism since a large # of oral drugs are rendered inactive by it, alternate routes of delivery that bypass the first-pass effect (e.g. sublingual, rectal) may need to be considered for these drugs 

Elimination/Excretion

which is the primary site of elimination? 

process by which drugs and their metabolites are removed from the body

kidney (liver also serves as site of elimination) 

most LMW, water soluble cpds are eliminated in urine (many drugs will be reabsorbed)

involves glomerular filtration and tubular secretion 

Renal Elimination is influenced by:

(3) 

1.rate of glomerular filtration (as vol. of urine increases, filtrate passes through the tubule more quickly and less time is available for reabs.)

2. urinary pH (the more acidic the urine, the more rapid elimination of basic drugs and vice versa; 5-8 pH of urine is normal)

3. competition for reabsorption (if a drug is actively secreted by the renal tubule, the admin. of a cpd that competes for the active transport mech. will reduce excretion) 

drugs and drug metabolites with a large MW are excreted by the biliary system

gradual elimination through the secretion and reabsorption processes is called enterohepatic recirculation

drug is not eliminated all at once; drugs present in the bile enter the small intestine where a portion is reabsorbed, returned to the liver and again secreted into the bile; continues until drug is eliminated (so admin. less dose and less frequently b/c stays in the system longer) 

reduction

creatinine clearance 

range of plasma drug levels between the MEC and the toxic concentration; when plasma levels are within the therapeutic range, there is enough drug present to produce therapeutic responses but not so much that toxicity results

**objective of drug dosing is to maintain plasma drug levels within the therapeutic range 

refers to a situation in which the amt of drug entering the system equals the amt being eliminated

steady state conc. may be reached faster by administering loading doses followed by regular maintenance doses 

highest plasma level of the drug (serum/blood toxicity right away)

draw 30 min after dose 

lowest plasma level of the drug (tissue toxicity; how much was deposited)

draw 30 min before next dose

**the does depends on this and the peak concentration 

most common description of a drug's duration of action; the time required by the body to metabolize and decrease the orignial plasma conc. of a  drug by half

indicates the time required to attain 50% of steady state, or a 50% decay from steady state after stopping drug

the greater the half-life, the longer it takes a med to be excreted 

dosing frequency

more

**so, half-life is NOT DEPENDENT ON THE DOSE 

it takes __-__ half-lives for a drug to reach steady-state conc. in the body.  Once steady state has been reached, any change upward or downward of the dose will require __-__ half-lives until a new steady state level is reached

Once a drug is stopped, it will take __-__half-lives before it is eliminated from the body 

4-5

4-5

4-5 

techniques for reducing fluctuations in  drug levels:

(2) 

1. administration of drugs by continuous infusion (i.e. insulin)

2. administration of drugs in frequent intervals 

two drugs with similar action sum their effects (1+1=2)

e.g. ETOH and sedatives cause increased sedation 

two drugs with different mechanisms of action produce greater effects (1+1=3)

e.g. codeine and aspirin together produce greatly increased pain relief 

one drug accelerates or slows the metabolism or excretion of another

(e.g. Coumadin and cimetidine affect metabolsim of many other drugs) 

effects of two drugs that cancel each other (1+1=0)

may  be due to competition for binding sites on cell membranes

basis for specific antidotes given to antagonize the toxic effects of another drug/chemical --> minimizing/eliminating an action that you know 

physical interaction of two drugs that interferes with the effects of at least one of the drugs

pharmacy or other resource should be consulted before mixing IV/syringe solutions

basic for administration of drugs to bind or inactivate in the GI tract another drug or chemical which may be toxic 

Food slows absorption of most drugs, but usually does not affect drug's action EXCEPT:

(5) 

determines receptor specificity; "lock & key" fit

chirality/stereoisomerism = common; >1/2 of all drugs are chiral molecules (i.e. existing as enantiomeric pairs)

in majority of cases, one of the enantiomers is ___ than its mirror imagine, reflecting ___ fit to receptor molecules

because enzymes are usually stereoselective, one drug enantiomer is ofen more susceptible than the other to _____ enzymes; thus, _____ of action may be different for each enantiomer. 

more potent; better

drug-metabolizing; duration 

Types of stereoisomers:

(2) 

Optical Isomers: have identical chemical and physical properties except: their effect on polarized light and their reazction with other chiral molecules; enantiomers are identical but not superimposable; distinguished by +/-, D/L, or S/R

Geometric Isomers: describes orientation of functional groups at end of molecule; no rotation possible; cis & trans isomers