Lecture 3 - Sept 23 Flashcards
ABCD skip
generally alpha constricts and beta dilates
Absorption
-once a drug gets in body, how does it get into bloodstream/circulation (across skin, mucous membranes, across GI wall)
-absorption is affected by:
-drug solubility, characteristic of the membrane to be crossed, size of drug molecule, affinity of the drug for other molecules
slide 5 absoprtion chart
absorption and passive dissuion
-most drugs cross membranes by passive diffusion (down concentration gradient) - the rate of absorption is proportional to the drug concentration
passive diffusion in absorption
- aqueous diffusion
-drug passes through aqueous pores in biomembranes - lipid diffusion
-if a drug is hydrophobic (lipophilic) and uncharged it dissolves in lipid membrane
factors affecting absorption
- drug solubility
-water soluble = charged/ionized, lipid soluble = uncharged/unionized
-drug ionization depends on if drug is acid or base and pH of solution - characteristics of membrane to be crossed
- size of drug
- affinity if drug
acids and bases
-acid = produces hydrogen (H+) when dissolved in water
-most acids in biological systems are weak acids
-base = produces a hydroxyl (OH) when dissovled in water
-bases are H+ acceptors
usually weak bases
pH scale
-pH measures H+ concentration
-pH is negative scale (low pH = lots of H+)
-pH is a log scale so difference of pH 5 and pH 6 is 10 times
drug solubility
-virtually all drugs are weak acids or bases
-only non-ionized (no charge) form of drugs is soluble in lipid membrane and can get across
-weak acids (HA) donate a proton (H+) to form an anion (A-), whereas weak bases (B) acccept a proton to from cations (HB+)
slide 11 weak acid and bases chart
slide 12
Ka formula and defintion
-Ka = tendency of the acid to dissocidate
Ka = [A-] [H+] / [HA]
Ka = [anion] [protons] / [undisociated acid]
Ka continued
-strong acid has a high Ka because it is almost all dissociated
-weak acid has a small Ka because it is almost all undisoccaited
Ka and pKa
-pKa = negative log of Ka
-the listed pKa for a substance represents the pH at which 50% of it is disscosciated and 50% is undiscciated (Ka =1)
-drug with a high Ka (strong acid) has a low pKa
-henderson hasselbalch equation
(pH = pKa + log [A-/HA]
-henderson hasselbalch equation (pH = pKa + log [A-/HA]
-this equation tells you how much of A- and HA you have at certain pH as long as you know pKa of a drug
-since pKa is a constant for each drug, the equation says the amount of ionised drug (A-) and lipophilic drug (HA) vaties with pH
will an acidic drug be absorbed in the stomach
-pH is low in stomach, ratio between A- and HA will be low = there will be lots of HA and little A-
-HA is non-ionized and lipophilic so it coild be easily absorbed into bloodstream from stomach
Drug solubility rules (acidic drugs)
- acidic drugs become more non-ionized at acidic pH
-an acid in an acidic solution will not ionize - acidic drugs become ionized at basic pH
-an acid in a basic solution will ionize
Drug solubulty rules: basic drugs
- basic drugs become more non-ionized at basic pH
-a base in a basic solution will not ionize - basic drugs become more ionized at acidic pH
-a base in an acid solution will ionize
hydrophilic = ionized
-hydrophilic = ionized molecule (charged)
-hydrophilc molecules dissolve in water
lipophilc = non-ionized
-lipophilic - nonionized molecules (not charged)
-lipophilic molecules pentreate membranes
slide 21-22 (vid explain in textbook?)
drug solubility summary
3 things to know if drug majority is lipophilic or hydrophilic:
- whether drug is an acid or bas
- the pKa of drug (pH at which # non-ionized molecules = # non-ionized molecules)
- the pH into which the drug is being placed
pKa = pH at which 50% ionized and 50% unionized
slide 24
slide 27-30 practice problems
ion trapping
-miconazole/monistat is a drug as antifungal in vaginal yeast infection
-the drug is a base that has a pka of 6.7
-in premenopausal women vaginal ph = 4.5
-drug will be ionized at 3.5-4.5 pH
-if it is ionized it cannot pentrate vainal wall and leave vaginal lumen
-ion trpaping = non-ionized drug enters are of different pH and becomes ionized and cannot leavve
slide 32
slide 33
charcateristics of membranes
Drug has to move across cell membranes:
-phospholipid bilayers → lipid like drugs dissolve in the lipid membrane
-aqueous pores exist in plasma membrane → they are usually too small for drugs
-some drugs use carrier proteins to circumvent the cell membrane (these carrier prtoeins carrry out active transport agaisnt conc gradient or facialtate passibe transport where no energy is required)
types of membranes
-mucous membranes (vaginal, oral, lung ex)
-cutaneous membrane (drugs given transdermally must travel across skin)
-drugs given IV must pass through capillary memrbane to leave the blood
size of drugs
-small mleucles pass through membranes easier than large ones
-vancomycin (antimicrobial) is too large to be absrobed in the gut
-given PO for GI issues, IV for systemic
stearic hindrance
-when some molecules are so complex in shaoe that they cannot be oriented in a way to pentrate the membrane
affinity for other molecules
-gastric destruction before absorption
-methicillin cannot be given PO because it is poorly absorbed and destroyed by stomach acid
-oral penicillins tend to bind to food so should be given 30 min before or 2 hours after meals
-if drug is not well absorbed then its bioavailability is low (amount of drug that arrives at target organ)
distribution
movement of drug from site of administration to site of action
(mostly dependent on blood)
water solubility and distribution
-water solubility = key to drugs solubilty in blood
-polar/charged molecules dissolve in blood –> rapid distribution
-acid drugs will be inozed in blood but dont pentrate tissue well
-nonpolar drugs like peniccilin, sex stroids, lipids need carrier protein or they cannot be distibuteed in bloodstream (these drugs are not active if not bound to carrier protein)
-albumin is the most important carrier protein that acidic drugs bind to
-drug interactins occur when 2 drugs compete for same carrier prtein
-ex warfarin.coumadin an anticouaglant competes with phenytoin an atiepileptic and ASA fight for albumin (giving any of these tgetehr increases plasma concetration)
concetration gradeint (factors influencing distribution)
-drug will move from high to low concentration
-initially drug flows from blood into organ but as blood levels fall the drug diffuses back into circulation
-tissues are exposeld to blood born drugs ar the rate of perfusion
-kidney and liver are well perfused to get most of the drug
-poorly perfused tissues like adipose get little drug
slide 40-41 on different capillary types
Blood brain barrier
-continuous capillaries, tight junctions, thick basal lamina
-only higjhly lipid soluble drugs can pas bbb (but not true in newborns as bbb is not established and have intracellular celfts)
-bilirubin can affect babys bbb more than adults
-loperamid/imodium is an opiod to treat diarrhea that causes opiate like symptos in baby but not adult
placental barrier
-maternal capillaries are fenestrated (so have membrane but there are few solutes that can pass the membrane and enter placenta)
-pinocytosis (cell drinking) carries maternal serum to the foetal compartment (aids in transfer of maternal antibody and all soluble materials across the placental barrier)
-placenta membrne is highly pemrable to lipids (ex diazepam levels can be higher in baby)
-placenta is realivtyly imperameable to charged, large bound to plasma protein drugs
generally if a drug can be absorbed orally then it can cross placenta
breast milk and drugs
-foetus is exposed to serum concentrations in utero
-during breastfeeding the newborn is only exposed to a drug in the milk and the drug is then diluted over the newborns volume (therefore dose to foetus during pregnancy is way larger than in pregnancy)
drug movement in breast milk
-drug enters milk from maternal plasma primarily bu diffusion
-drug passes from maternal plasma coparmtent through contrnous cappilaries then basilar membrane and out throufh apical membrane of alveolar cells in ducts
in first 2 weeks of breastfeeding there are large gaps between alveolar cells which allow IgA, maternal WBC and large proeins to pass easilt
impossible to predict drug delivery to newborn through milk
depends on lipid solubilty of drug, size, blood level in maternal ciruclation, protein binding, oral biolavailbity in infant, hallf life
RID relavent infant dose
=the amount of maternal dose received by infant (if RID is less than 10% then safe for breastfeeding)
Feeding Person’s Plasma Level:
-the feeding persons plasma level is the most important determinant of drug level in milk
-as the level of the medication in the feeding parents plasma begins its rise, the concentration in milk will increase (diffusion)
-any drug delivery system that delivers small amounts of drugs to maternal circulation (ex topical or inhalation) drugs are preferred
Protein Building and Lipophilicity:
The 2 most important determinants of rate of drug transfer to human milk are:
1. Degree of protein building
-most drugs bound to albumin in circulation; the free drug available for transfer to milk
-drugs that have high protein binding are found in lesser levels in milk
- lipid solubility
-extremely lipid soluble drugs pentetrat e milk in higher concentrations
-ex. loratadine/claritin is very lipid soluble and found in milk
-caffeine is very water soluble and doesnt penetrate milk well
M/P ratio
-M/P ratio = (Concentration of drug in milk) / (Concentration of drug in plasma)
-High M/P Ratio: If the M/P ratio is greater than 1, it indicates that the drug is more concentrated in breast milk than in plasma. This could mean that the baby is exposed to a higher level of the drug through breastfeeding.
-Low M/P Ratio: If the M/P ratio is less than 1, the drug is less concentrated in breast milk compared to plasma. This generally suggests a lower risk for the infant.
oral bioavailability
-once a drug is ingested by infant through milk it must be absorbed by infants GI tract
-oral bioavailanity is amount of drug that reaches circulation
molecular weight of drugs
-smaller the molecular weight of drug, the easier it pentrates into milk
-diffusion is fast for smaller molecules
-ethanol has small molecular weight so it rapidly enters milk, same with recreational drugs
pKa and human milk
-pKa of a drug is the pH at which the drug exists in equal amounts of charged and uncharged forms
-charged form of drug is hydrophilic and moves easily into blood
-uncharged form is lipophilic and moves easily through lipid membranes
-blood ph is 7.4 and milk is 7.2 so a chatged drug is less capable of transferring from milk back to parental plasma - drugs can become trapped in milk if they become uncharged (ion trapping so drug is held in milk and leaves slowly)
pka of blood and ph
-if oh is higher than pka the drug is moslty deprotonated
-if the ph is lower than pka the drug is mostly protonated
-blood ph 7.4, milk is 7.2
-baseic drugs with pka greater than 7 will be sequestered in more than basic drugs with lower pKa
-acidic drugs will ot be sequestered in milk becasue chnage from 7.4 to 7.2 will make more HA (lipid soluble)
-acidic drugs have lower M/P ratio
strategies to avoid drugs in human milk
-choose a drug safe for breastfeeding
-choose drug that deosnt readily pass into milk
-lowest dose for shortest time possible
-topical rather than oral when possible
-agents without active metabolites
-sometimes need to pump and dump
-discontinue nursing if drug is needed but not safe for baby
-avoid extended release drugs
slide 66 questions
drugs with extremely large Vd
diazepam/valium and digoxin have huge Vd
-either bind to tissues lightly or are highly lipophilic
-drugs with high Vd cross placenta and accumulate in placenta
-if drug crosses placenta this increases Vd
