JoJO

Study of actions, effects, and fate of drugs in body

• - drugs that are absorbed through GI system pass through liver first before going to the body
• - refers to how much active drug is left after some is de-activated in liver and sometimes in the stomach/intestines

Quantitative descriptions of the time course of drug and drug metabolite concentrations in plasma, tissues, or urine (drug fate or what the body does to the drug)

• - ratio of solubility in oil vs. water
• - A mean for expressing whether a drug is more lipid soluble or more water soluble ---> the higher the number, the more lipid soluble the molecule is

• study of drug effects and their mechanism of action
• the study of what the drugs do to you

• molecular mechanism of action
• may or may not be known and not observable

• desired therapeutic effect and teh undesired side effects (SE)
• usually know and observable

• route of administration thru the GI tract
• ex: Oral, sublingual, or rectal

plasma concentrations where the drug will give the desired response

more dangerous drug has a greater chance of having adverse SE

Less likely the drug is to kill somoene or have toxic SE

• route of drug administration by any other way except enteral.
• NOT necessarily injected only
• ex: IV, inhalation, intranasal, injections, patches, etc...

• where measurable response starts happening
• the lowest plasma concentration where you start to see desired effect
• Above this MEC is toxicity

• endothelial cells of CNS capillaries have tight junctions and no fenestrations
• lipid soluble drugs can diffuse across endothelial cells and basement membrane while water soluble drugs cannot readily diffuse across
• some drugs enter the CNS via active transport processes

• drug NOT bound to plasma binding proteins
• ex: Albumin

• hypothetical volume of fluid in which the drug is distributed
• Total amount of drug in body/plasma concentration

• doesn't need help getting across the barrier, has to be somewhat lipid soluble to do this
• it's the movement of a molecule down its gradient

from site of administration to plasma

Rate of drug dissolution, concentration gradient, blood flow, size of absorbing surface, lipid solubility, pH, drug charge and polarity, and condition of absorbing surface

• site of administration --> plasma --> interstitial space --> intracellular space
• will redistribute after time back to plasma after enough has gone back out of plasma to switch the concentration gradient

hepatic metabolism (phase I and II, biliary secretion), renal elimination, or throuh your breath, sweat, and tears

• Enterallly: Oral, sublingual, intravenous injection
• Parenterally

• many routes used because different drugs require different methods
• (can't swallow laughing gas or insulin), time course of action (if you
• need it quicker you won't use an oral adminstration), drug access (where
• you need the drug to go, inhale asthma meds), condition of patients
• (non-compliant is NOT good for daily oral)

• drug must first dissolve and be free in solution
• most drugs are absorobed in small intesttine more than stomach
• there is a large surface area to the small intestines and the drug must cross the epithelial cells and capillary walls

highly variable among pts, grastric/intestinal pH, gastric emptying time, presence/absence of food, or if durgs are co-administered with other drugs

Most used route, convenient, safe, drug recall is possible (by throwing up or grastric lavage) and usually INexpensive

• slowly absorbed - 30 min - 1 hour delay
• highly variable between pts
• some are inactivated by acids
• first-pass metabolism by liver happens
• requires conscious/cooperative pt
• GI irritation can occur

• warm and moit
• high blood flow
• absorption is rapid
• NO first-pass effect

Unpleasant taste

• NO barriers to absorption
• rapid onset
• subsequent control of drug concentration is possible
• large fluid volumes are possible

• High cost compared to oral admin
• difficult to administer (need trained personelle)
• can only be used in in-patients
• irreversible
• infection and embolism are possible

• lower blood flow in SQ region leads to slower drug absorption
• allows for sustained actions
• allows for injections of poorly water soluble drugs
• drawbacks --> uncomfortable, incovenient, potential for injury
• Sit as a "wad" in SQ slowly releasing drug over time

• fairly rapid absorption of WATER soluble drugs
• time course of absorption is dictated by water solubility of drug and blood flow to site
• allows for depot preparation where drug is leached out all over time and can provide drug over a month
• useful in non-compliant pts
• Painful and inconvenient

• Phospholipid bilayer --> hydrophobic barrier between two aqueous environments
• cell membranes do NOT have pores
• Drugs CANNOT filture thru membranes so they must diffuse thru the phospholipid bilayer

• absorption and penetration into cells is mainly by passive diffusion
• rate varies directly with concentration gradient

• concentration gradient
• drug size
• drug charge
• Drug solubility in water and in lipid
• blood flow
• condition and area of surface absorption

bigger diffuse less easily than smaller molecules

• drugs that are charged or higly polar are more soluble in water
• most drugs are weak acids or bases and exists in solution as both charged and uncharged forms
• if you increase the pH, you increase the unionized from so more can enter the cell

• repelled by hydrophobic barrier of cell membranes
• extent of passive diffusion for these drugs is limited and they are therefore poorly and slowly absorbed
• they are rapidly excreted in urine

• hydrophobic
• pass thru membranes more easily by passive diffusion
• more completely absorbed and slowly eliminated in urine

• major factor affecting concentration gradient of drugs throughout the body
• higher local blood flow maintains steeper concentration gradients and faster rates of drug movement from one compartment into another

• albumin is principal binding protein in plasma
• extent and affinity of drug-protein bindind differs widely
• these can affect the loading dose and other pharmacokinetic decisions and bound drugs can serve as a resevoir or a buffer for free drugs

displacement of drugs competing for binding sites on plasma proteins

• highly lipid soluble drugs become concentrated in fat cells and to a lesser extent, the brain
• drugs stored here will redistribute back to the plasma and the concentration gradients change

• Drug is highly lipid soluble
• it is given in IV
• target is high CO organ, such as the CNS

phenomenon of redistribution

• any chemical
• medically, any agent used in tx or prevention of dz, or prevention of pregancy

• drugs cause changes at molecular level by interacting with biological macromolecules
• drugs have molecular mechanism of action

actions and effect of drugs are dose-dependent

• Local
• Enteral
• Parenteral

• keratinous nature of skin severely limits absorption
• used to treate dermatological conditions
• Transdermal patches --> some drugs delivered thru skin patches
• Abdorption is SLOW and substained --> lipid soluble penetrate skin much more readily than water soluble drugs

• Epithelial cells --> because of tight junctions between cells, drug molecules must diffuse THRU these cells
• Capillary walls

• a suppository may be used when oral route is infeasible
• ie. in vomiting patient

used primarily for dx procedure

• Plasma compartment
• Extracellular fluid
• Total body water

drugs that are very large or that are extensively bound to plasma proteins cannot move thru endothelial fenestrations of capillaries and thus are trapped in plasma compartment

• drug may be small enough to pass thru endothelial slit junctions, but be very hydrophillic and thus incapable of diffusing into cells
• drugs such as this ahve a Vd that is the sum of plasma water and the interstitial spaces

• if a drug is small enough to cross into interstium and hydrophobic enough to readily diffuse thru plasma membrane and into intracellular space
• its Vd may approximate the total body water
• largest Vd

• drug molecules are constantly moving
• after a single dose of a drug has been completely absorbed and distributed ===> concentration of drug in plasma may fall below that of concentration in tissues ==> drug tend to move back out of tissue and into blood along its concentration gradient

• enzymatic conversion of parent drug into its metabolites
• metabolite may be larger or smaller than parent drug
• metabolite may be less active or more active than parent drug
• this process may or may not require energy

Liver

• Hepatic metabolism and biliary secretion
• Renal elimination
• Sweat, breath, tears, etc

• Major pathway for drug biotransformation
• combine sugar, amino acid, or other residue onto to drug ==> making it larger and more water soluble
• metabolites are too large to be freely filtered at glomerulus
• secreted into bile and eliminated with stool

• Conjugation reactions
• hydrolysis
• oxidation
• reduction

• many drugs and their metabolites are eliminated in urine
• This process involves glomerular filtration of plasma, may involve reabsorption and/or secretion in kidney tubules

• Concentration of free drug at its site of action is a fxn of:
• Absorption
• Distribution
• Biotransformation
• Excretion
• Involves passage of drugs across biological membranes

Important mechanism for passage of some drugs across special cells

• Renal tubules
• choroid plexus
• Hepatocytes

• Rate = kD
• D - drug concentration
• k - Rate constant of diffusion
• Rate is proportion to drug's concentration

• Ionized molecules
• Polar molecules

• nonpolar
• non-charged
• hydrophobic
• lipophilic

• Most drugs
• exist in solution simultanenously in ionized and non-ionized form
• Concentration of each form is determined by drug pKa and solution pH

• Strong acids and bases, b/c they are completely dissociated and ionized
• Weak electrolytes, b/c non-ionized form is highly polar and not much affected by pH

Total eq. plasma concentration of WA is HIGHER than intracellular concentration

Total plasma concentration is LOWER than intracellular concentration

• Is permanently charged
• highly water soluble
• very poorly absorbed
• will not readily cross blood-brain barrier
• rapidly excreted in urine if given IV

important for elimination of penicillins and related antibiotics, salicylates, indomethacin, sulfonamides

• potentially important for elimination of quarternary ganglionic blocking drugs
• certain neuromuscular blocking drugs

• Binding sites may have to be saturated with loading dose to achieve therapeutic concentration rapidly
• Resevoir fxn - elimination may be prolonged if there is significant binding
• Glomerular filtration and renal excretion are affected since bound drug is NOT filtered