Absorption, Distribution, Metabolism, and Elimination Flashcards
What are the key kinetic principles?
- Absorption
- Distribution
- Metabolism
- Excretion/Elimination
What is absorption?
how a drug moves from its site of administration into the bloodstream
What is Distribution?
movement of the drug between blood and tissues
What is metabolism?
conversion of drugs into more hydrophilic metabolites
What is excretion/elimination?
removal of drugs and/or metabolites from the body
What features predict movement of drugs/metabolites?
- molecular size
- degree of ionization
- lipid solubility
- protein binding
To pass through lipid membranes, drugs must be…
non-ionized (uncharged)
To be water soluble, drugs need to be…
ionized (charged)
Most drugs we prescribe are ____ acids or _____ bases
weak acids or weak bases
Strong acids + water do what?
completely goes one way into H+ and conjugate base
Weak acids + water do what?
go both ways from H+ and conjugate base back to the weak acid
What happens with a weak acidic drug in an acidic pH?
non-ionized
protonated
What happens with a weak acidic drug in an basic pH?
ionized
deprotonated
What happens with a weak basic drug in an basic pH?
non-ionized
deprotonated
What happens with a weak basic drug in an acidic pH?
ionized
protonated
Acids are non-ionized (fat soluble) when…
protonated
Acids are ionized (water soluble) when…
deprotonated
Bases are non-ionized when…
deprotonated
Bases are ionized when…
protonated
What is the pKa?
the pH at which there are equal amounts of protonated and non-protonated
When pH=pKa…
protonated equals non-protonated
When pH < (less than) pKa…
protonated form predominates
When pH > (greater than) pKa…
non-protonated form predominates
What is the henderson-hasselbalch equation?
What is ion trapping?
because ionized molecules (drugs) cannot cross the membrane, this effectively traps them and enhance excretion
Acidic environments of abscesses will affect ionization state of…
local anesthetics
LA = basic, high pKa
Abscess = lower pH
— basic drug in an acidic pH the protonated and ionized form predominates
What is bioavailability (F)?
- fraction of drug that reaches the systemic circulation intact
What is the bioavailability of an IV drug?
100%
What is the hepatic extraction ratio?
fraction of drug in blood that is irreversibly removed during one pass through the liver
What is first pass clearance?
extent to which a drug is metabolized by the liver during its first pass in the portal blood through the liver to systemic circulation
Drugs with low hepatic extraction will have ____ first pass clearance
low
Drugs with high hepatic extraction will have ____ first pass clearance
high
First pass effect occurs due to metabolism by/in…
- gut bacteria
- intestinal brush border enzymes
- portal blood
- liver enzymes
Changes in hepatic enzymes _______ have significant effect on first pass clearance
won’t
changes in enzyme funciton will have a _______ effect on first pass effect
large
What are the advantages of enteral administration?
- most common route
- safest
- easiest
- most economical
What are the disadvantages of enteral administration?
- limited absorption
- emetogenic potential
- subject to first pass
- absorption may be affected by food or other drugs
- irregularities in absorption or propulsion
What is the enteral route of administration?
anything that hits the digestive tract before the blood stream
What is the parenteral route of administration?
everything else that is not enteral
What are the advantages of parenteral administration?
- not subject to first pass
- most rapid onset
- ability to titrate
- doesn’t require cooperation
What are the disadvantages of parenteral administration?
- greater patient discomfort
- requires additional training to administer
- concern for bacterial contamination
- injection-associated risks (extravasation, intra-arterial injection, limb loss)
For oral administraion, absorption is governed by…
- surface area for absorption
- blood flow to site of absorption
- dosage form administered
- ionization status
- concentration at site of absorption
What are the risks for oral administration?
enteric coating
— drugs destroyed by gastric secretions, low pH, or that cause gastric irritation
— risk of bezoar formation
— delayed release
What are the different types of parenteral routes?
- intravenous
- intramuscular
- subcutaneous
- intradermal
- inhalation
- intranasal
- intrathecal/epidural
- topical
- subgingival
What are the characteristics of intravenous route of administration?
● Immediate onset, Bypasses GI absorption
● Best for emergencies
100% bioavailability
What are the characteristics of intramuscular route of administration?
● Irritating drugs given this route
● Not as rapid response as IV
● Depot preparations (sustained release) ie., suspensions, ethylene glycol, peanut oil- all slow down absorption.
75-100% bioavailability
What are the characteristics of subcutaneous route of administration?
● Slower absorption than IV or IM
● Little risk of intravascular injection
● Examples: Insulin, Mechanical pumps, heparin (DVT prophylaxis)
75-100% bioavailability
What are the characteristics of intradermal route of administration?
- small amounts of drug
- tuberculosis skin test, local anesthetics
What are the characteristics of inhalation route of administration?
- almost as rapid as IV
- delievered directly to lung (good selectivity)
- gases, aerosols of solutions and powders (good for respiratory conditions)
5-100% bioavailability
What are the characteristics of intranasal route of administration?
- vasopressin for TX of diabetes, calcitonin (osteoporosis)
- method of drug abuse
5-100% bioavailability
What are the characteristics of intrathecal/epidural route of administration?
Subarachnoid space of spinal cord – into CSF (Lumbar puncture- Baclofen in MS, regional anesthetic in delivery, morphine drip)
What are the characteristics of topical route of administration?
avoids 50% of 1st pass metab
● When local effect is desired-but can provide systemic effects.
● Sublingual (100%), rectal (50%) bypasses liver- good bioavailability.
● Transdermal Controlled Release- Scopolamine, nitroglycerin, nicotine, fentanyl.
What are the characteristics of subgingival route of administration?
Perio specific uses: doxycycline (Atridox); minocycline (Arestin)
What is distribution dependent on?
- cardiac output
- capillary permeability
- blood flow
What is the distribution rate of the kidney/
360 mL/min/100gm
What is the distribution rate of the liver?
95 mL/min/100gm
What is the distribution rate of the heart?
70 mL/min/100gm
What is the distribution rate of the brain?
55 mL/min/100gm
What are the compartments for distribution?
- central (well perfused organs/tissues such as heart, blood, liver, brain, kidney)
- peripheral (less well perfused organs/tissues such as adipose, skeletal, muscle)
- special compartments (CSF, CNS, pericardial fluid, bronchial secretions, middle ear)
Where does distribution of drugs accumulate in tissues?
- organs
- muscles
- adipose
- bone
What can alter distribution?
- protein binding
- free vs bound
- competition
- disease impact
- drug levels
What effects distribution of drug in the CNS?
- blood brain barrier
- efflux transporters
- inflammatory processes
What is volume of distribution (VD)?
volume of fluid in which a drug would need to be dissolved to have the same concentration in plasma (doesn’t represent a “real” volume)
Drugs with a VD of < or equal to 5L are…
confined to plasma
Drugs with a VD of 5L-15L are…
distributed to extracellular fluid (RBC+plasma)
Drugs with a VD > or equal to 42L are…
distributed to all tissues in the body especially adipose
Increased VD (volume of distribution) has an ____________ likelihood tha drug is in the tissue
increased
Decreased VD (volume of distribution) has an ____________ likelihood that drug is confied to the circulatory system
increased
A drug must be _________ to be removed from the body
water-soluble
Lipid solubility is good for _________ but bad for ___________
- good for absorption and distribution
- bad for excretion
What does metabolism of drugs do?
- biotransformation
- converts drugs into polar metabolites
- lipophilic into hydrophilic
What does most of the metabolism of drugs?
liver (P-450 enzymes)
What is phase I of metabolism?
- catabolic
- exposes functional group on parent compound
- usually results in loss of pharmacologic actiity
- activation of prodrugs
What is the potential issue with genetic polymorphisms?
- people can be poor metabolizers or rapid metabolizers
- could lead to subtherapeutic effects or toxicity
What is phase II of metabolism?
- occurs after functional groups are exposed
- anabolic (adds water soluble molecules)
- much less inter-patient variability
- major reactions
What is excretion?
- removal of unchanged drug
- kidney, lung, feces (primary routes
- polar compounds > lipid compounds
What are the three processes of excretion in the kidney?
- glomerular filtration
- active tubular secretion
- passive tubular reabsorption
What types of drugs are excreted in the kidney?
- only unbound drugs
What type of drugs are reabsorbed in the kidney?
non-ionized weak acids and bases are passively reabsorbed
What in the kidney allows for trapping of ionized, acidic molecules and increases excretion?
alkaline urine
What is excreted out the lungs?
- primarily inhaled anesthesia or volatile liquid
Excretion through the lungs is affected by…
respiratory rate and blood flow
What is excreted through the feces?
- unabsorbed orally administered meds
- metabolites excreted in the bile
- un-reabsorbed metabolies secreted into the intestinal tract
Summary: Drugs have to cross lipid membranes and can do this by…
passive or active transport
Summary: What is the main factor that determiens the rate of passive transport?
lipid solubility
Summary: Only _____________ drugs can diffuse across lipid membranes
uncharged
Summary: Extensive protein binding can _____ drug elimination
slow
Summary: Drugs with ____ lipid solubility are not well absorbed form the gut
low
Summary: Gut absorption dpends on factors such as…
GI motility, GI pH, particle size, interaction with gut contents
Summary: ___________ is the fraction of dose that makes it to systemic circulation to elicit an effect
Bioavailability
Summary: unless they are protein bound most drugs are filtered through the…
glomerulus
Summary: phase I reactions are…
catabolic; involves oxidation, reduction, and hydrolysis
Summary: Phase II reactions are…
anabolic, conjugated, leaving inactive and polar product for excretion
