Pharmacokinetics Flashcards
how were the elements believed to relate to disease
each element believed to correspond to a jumour in the body (cold, hot, dry and moist), healthresults when these are in balance if not led to diease
Wind: hot & moist = blood
Water: cold & moist = phlegm
Fire: Hot & dry = yellow bile
Earth: cold & dry = black bile
what was the origins of medicine in china based off of
excessive shade is associated with cold illnesses
excessive sunshine is associated hot illnesses
excessive wind is associated disorders of the extremities
excessive rain is associated abdominal disorders
excessive dark is associated disorders involving mental confusion
excessive light is associated disorders of the heart and mind
what is bloodletting?
- french physician routinely bled patients suffering from pneumonia and most recovered
- upon statistic analysis discovered that it increased mortality not decreased
*line of thinking was administered a treatment and they healed, but this ignored natural healing
how can you determine is a treatment works or if its natural healing
- can only know averages (how diseases behave on average, and how people respond to medicines on average)
- ust compare borups to avoid bias
why is absorption important, what must be considered
- Following administration, a drug must reach the systemic circulation
- drug must not be inactivated before reaching target tissue
- natural defense may limit the bioavailability
what is bioavailability?
- fraction of administered dose of the drug that reaches the systemic circulation
- can depend on route of administration, chemical form and various patient specific factors
Bioavailability = Quantity of drug reaching systemic circulation/ quantity of drug administered
must drugs are _____
weak acids or bases
- necessary bc must be able to pass through membranes and dissolve in stomach and blood
- if too acidic or basic wont be able to pass through mem
- if not acidic or basic at all it wont dissolve well so wont be carried efficiently thoguhout the body
cell membranes are permeable to ___
non-ionized (lipid solbule) molecules
how is ionization state of drug determined?
pH and pKa
pKa is the pH at which 50% of drug is ionized
pKa - pH = Log (prot/deprot)
will a weakly acidic drug with a pKa of 4.4 be better absorbed from the stomach or intestine
* want neutral, since drug is acidic want it protonated, acidic protonated when below pKa so abs in stomach
what is ion trapping
- drug accumulates on the side of the membrane where ionization is highest
- degree of ionization may differ on diff sides of the membrane (Ion trapping)
- generally, basic drugs accumulate in acidic fluids and acidic drugs accumulate in basic fluids
*tissue pH determines the degree of ionization
how are routes of administration chosen, what are the 2 main classifications
- suually according to transport molecules and other mechanisms that can be taken advanage of to aid with drug entry
- can be Enteral (oral) or Parenteral
- enteral is the simplest and parental does directly into systemic circualtion (not introduced in stomah or intestines)
what are other routes of administration other than enteral and parentral
- intraperitoneal injection (IP),
intradermal injection (ID),
intrathecal,
intrarectal (suppository)
inhalation.
what are the advantages and disadvantages or oral drugs
* drugs administered orally are carried by the portal system to the liver before entering systemic circualtion (first pass metabolism)
- liver enzymes may inactivate a fraction of ingested drug so dose must account
- drugs administered by other routes are not subject to first pass metabolism
advantages and disadvantages of subcutaneous injection (SC or SQ)
admin of a drug into a poorly vascularized adispose tissue
Advantage
- Suitable for solid pellets, insoluble suspensions, oily vehicles (“depot” formulations)
- easier than IV
- Abs slower than by IV or IM routes (can also be a disadvantage)
Disadvantage
- not for large volumes
- pain or necrosis with irritating drugs
- abs can be very slow
- infection possible at inj site
Advantages and disadvantages of intramuscular injection (IM)
*administration of a drug intoa well-vascularized intramuscular space
Advantages
- suitable for moderate volumes, oily vehicles (depot formulations)
- safer, easier than IV
Disadvantages
- local pain, swelling and infection possible
- avoid during anticoagulant treatment )extrensive hemorrhage/bruising may occur)
advantages and disadvantages of intravenous injection
- direct injection of a drug into systemic ciruclation
Advantages
- emergency use (rapid onset of activity)
- controlled drug delivery (continuous infusions)
- can deliver large volumes
Disadvantages
- higher risk of adverse effects (infection)
- often must innject slowly due to cardian toxicity risk
- not for oily or insoluble drugs
- requires mroe skill for administration
advantages and disadvantages for sublingual administration
- administration under the tongue. absorption occurs across roal mucosa and does not invovle the intestine
Advantage
- nof irst pass metabolism
Disadvantage
- patient must cooperate (not swallow drug)
- significant proportion of dose may be swallowed despite effrots not to
Advantages and disadvantages of topical administration
- applied to skin with intention of having it absorbed itno systemic circulation to produce effect elsewhere
advantage
- controlled release with prolonged duration of action (ex fentanyl patches)
- abs through damaged skin is enhanced (not always desireable)
Disadvantage
- slow onset of action
- excessive abs may occur if blood flow to skin is excessive (ex in animasl that sweat) and toxic conc may be achieved in systemic ciruclation
what is drug formulation
- refers to the physical form of a medication as well as its chemcial ingredients
- most inactive ingredients serve to balance pH, alter flavour, or produce desired physical form (aqueous solution, suspension, syrup, gel, solid etc.)
absorption vs distribution
- absorption is a prerequist for establishing adequate plasma drug levels
- distribution achieved by circulatory system and to a lesser degree the lymphatic system
- following abs into systemic it can reach target organ
*most of the drug does where it is not needed only a small fraction reaches receptor sites of the target organ
explain protal circulation and the first pass effect
- drugs admin PO are abs by the GI tract and then delivered via portal vein to the lvier
- liver metabolized the drug ebfore it reaches systemic circulation (first pass effect)
- drugs admin intravenously, transdermally or subcutaneously enter systemic circulation directly
what factors affect drug distribution
- physical cehmical properties
- anatomy and physiology of patients
- plasma protein binding
explain how physicochemical properties influence drug distribution
- degree of ionization
- size and molecualr weight
*influecnes the solublity
how does the anatomy and physiology of the patient influence drug distribution
- Tissue perfusion (brain, kidney, heart, liver recieve 20% of cardiac output)
- once drug enters the lood it distributes to entire blood volume in 1-2 min
- oranges with higher blood flow get more drug
- disease or trauma can reduce blood flow to an organ which changes results
- BBB
- Capillaries in the brain are much less permeable to some water-soluble substances due to the presence of glial cells
- Totally impermeable to plasma proteins
- Water soluble substances will enter CNS very slowly (systemic administration of these is useless if intended site of action is the CNS)
- Drugs with high lipid solubility and low protein binding cross BBB well
how does plasma protein binding effect drug distribution
- mainly albumin (many drugs bind readily to it)
- represents 50% of total plasma protein
protein-bound drug cannot enter tissues and cannot be eliminated via kidneys which results in inert reservoir of the drug
what is Volume of Distribution (Vd)
Drugs do not distribute equally to all tissues
- some remain almsot exclusively in the blood (7% of body volume)
- tohers dsitribute readily to other tissues
- Vd describes the extent to which a drug partitions between the plasma and tissue compartments
- represents the fluid volume requred to contain the total amount fo abs drug in bdoy at conc equiv to that in plasma at steady state
how id Vd calculated
Vd = amount of drug in body / plasma drug concentration
ex: a 57 kg patients (body volume = 1L/Kg BW) given a dose of 400 mg, the plasma conc is 100mg/L
Vd = 400mg / 100mg/L
- drug appears to ahve been dissolved in 4L of fluid
if some drug leaves the blood stream Vd will be ____ than 7% body volume
Vd will be larger
ex: 57 kg patient, dose = 400 mg plasma conc = 50mg/L
Vd = 8L
*this emans that 1/2 the dose remained in the blood stream and the other half has entered the tissue
**Blood is about 7% of body volume so 57 x 0.07 = 4L (so half is in the blood and half is in tissue)
ex a 57 kg patient given 400 mg of drug and plasma conc is 1mh/L
vd =400/1
vd = 400L (drug appears to have been dissolved in 400 L of fluid
- not possible, means that drug has distributed preferentually into tissues outside the blood steam maybe due to ion trapping, lipid solubility, irreversible bindind
ex: given 100 mg of drug IV to a 60 kg patient, drug conc in blood is 10mgL
Vd = 100mg / 10 mg/L
Vd = 10L
* 60 kg patient so 60 x 0.07 = 4.2
- just over half has distributed into toher tissues
Give 1,000 mg of furosemide IM to a 60kg patient
[drug] in plasma = 200 mg/L
Vd = 1000mg / 200mg/L
Vd = 5 mg/L
- patient has 4.2L of blood, almost all drug has remained in vasculature
500 mg given to 60 kg patient, [drug] = 8 mg/L
500/8 = 62.5L
- patient only ahve 4.2 L of blood so drug is distributed uniformly through body
10 mg digoxin given to 60 kg patient, [drug] in plasma is 0.02
10/0.02 = 500 L
- drug appears to have distributed to volume greater than the entire body (ion trapping, irreversible binding etc.
describe metabolism
- also called biotransoformation
- refers to a change in chemcial structure of an absorbed drug by enzyme catalyzed rxns fo parent drug to metabolite
what role to enzymes play in metabolism
- inactivate drugs and make easier to excrete
- why some drugs are administered as prodrugs
What is the major site of metabolism for xenobiotics
liver
- can also uccur in lungs, GI tract, kidneys and brain
what catalyzes biotransformation reactions?
- cellular enzymes located in endoplasmic reticulum (smooth ER), cytoplasm, mitochondria, nuclear or cell membrane and lysosomes
The metabolizing enzymes are present mainly in ____ which are ___ consisting of _____
- metabolizing enzymes are present mainly in microsomes which are vesicles consisting of membranes of ER
- thse contain membrane-bound P450 enzymes (mediate Phase I metabolism) and the cytosol which has cytoplasmic fluid and soluble Phase II enzymes.
what is phase 1
- enzymatic reactions: oxidation/reduction/hydrolysis
- oxidation is most common, add an oxygen or remove a hydrogen
- goal to make more polar metabolites to be excreted or go onto phase II
- makes it more reactive
what is phase II metabolism
- conjugation
- engogenous substances combine with the functional group derived from phase I reactions to produce a polar excretable product
- ex of conjugating substances = glucuronic acid, sulfate, glutathione, methyl groups, glycine, cysteine, methionine and acetic acid.
what enzyme does metabolism usually involve
- cytochrome P-450 (CYP) enzymes found in smooth ER
- heme containing proteins which maxamally abs light at 450 nm
- ex= carbon hydroxylation of pentobarbital, mitro reduction of chloramphenicol and hydrolysis of esterases for acetyl choline
- introduce or unmask -OH, -NH2, -SH
describe
- many drug metabolism rxns involve a system of hepatic P450 microsomal enzymes that oxidize drugs
- reaction is a series of oxidation/reduction steps in which iron moiety acts as an electron carrier to transfer electrons from NADPH to molecular oxygen
- reduced oxygen then transferred to drug resulitng in additional -PH on drug
- hydrophilicity and rate of excretion is inc
what are teh steps of P450 mechanism
- 6 steps
- drug complexes with oxidized CYP 450
- NADPH donates an electron to flavoprotein reductase, which reduces the P450-drug complex
- oxygen joins the complex and NADPH donates another electron creating activated oxygen-P450 complex
- ^ steps 3-4
- iron is oxidized witht he loss of water
- oxidized drug product is formed
what are the most common CYP 450s?
1A2, 2C9, 2C19, 2D6, and 3A4
- these acount for 95% of the oxidative metabolism of drugs
what are the types of phase II reactions
- Glucuronic acid conjugation: (UDP glucuronosyl transferase)
- very importnat, for large drugs (>500 MW) are excreted in bile (elim in feces)
- glucuronidases in gut bacteria can hydrolyze conjugate and free drug to be reabsorbed (enterohepati recirulation)
- individuals deficient in glucuronide synthesis are slow to metabolize certain drugs
- Sulphate conjugation (sulfotransferases)
- Phenols & alcohols conjugated to sulphate (SO4)
- acetaminophen , morphine
- Acetylation (N-acetyltransferases)
- occurs in drugs with -NH2 group conjugated to COCH3
- most sulfonamide antimicrobial dugs
- Glutathione conjugation (glutathione S-transferase)
- epoxides, arene oxides conjugated to GSH
- ex: some anticancer drugs (alkylating agents)
what factors affect drug metabolism
- Enzyme induction & inhibition
- Multidrug therapy
- Distribution
- Age
- Genetics
- Disease
describe renal excretion
- most common mechanism of drug elimination
- kidneys receive approx 25% of CO ensuring that they are continuously exposed to any drug in blood
- glomerular capillaries are highly porous and permeable: filtration of unbound drug is non saturable and non selctive
- rate of elimination depends on renal blood flow, glomerular filtration and drug binding to plasma protein
*inc bloof flow an filtration rate an dec plasma binding to inc elim
describe active tubular secretiona nd tubular reabsorption
- also eliminates drugs
- transporters in proximal tubules actively pump a minority of drug types into urine and active transporters in the distal tubules reabsorb some filtered drugs from provisional urine
describe drug filtration, secretion and reabsorption in the kidney
(1) filtered at the renal glomerulus, (2) secreted into the proximal tubule, (3) reabsorbed from the tubular lumen and transported back into the blood, and (4) excreted in the urine.
- relative balance of these rates determines the kinetics of drug elimination by the kidney
- enhancing blood flor, inc glomerular filtrationa and dec plasma protein bidning all cause a drug to be excreted more rapidly
*some drugs like penicillin are actively secreted into proximal tubule
describe biliary excretion
- small number of drugs excreted in bile then delivered to duodenum and removed in feces
- involves drugs not bound to plasma proteins and are metabolized by hepatocytes of liver
entrohepatic recylicing = bilary excretion combined with intestinal reabsorption
^ creates a reservoir of drugs in our body, and prolong the exposure of our body to the drug.
- drugs reabs are returned to liver via portal blood
why has charcoal been used for drug overdoses?
oral administration binds the drug and prevents its absorption from the intestine which will interrupt the cycle
If drug leaves blood stream to enter tissue Vd is ___ than 7% body volume
greater than 7%
If drug goes everywhere in the body what will be the value of Vd
