1 - Absorp --> Excrete Flashcards
integrated pharmacology: define
combining study methodology w/ drug development;
this is the first step in rational approach to drug therapy; incl:
- appropriate prescribed dose
- dose administered
- routes of admin
- conc. @ site of admin
- pharmacological effects
what factors determine amount of drug present at its active site at any given time?
“ME RAD”
- Metabolism (biotransformation)
- Excretion
- Route of drug admin
- Absorption
- Distribution
Which 3 factors depend on patient status
(that also determine the amount of drug present at its active site at any one time)?
MAE
- Metabolism
- Absorption
- Excretion
Which factors/parameters fall under “pharmacokinetics”?
- “ADME”
- Absorption
- Distribution
- Metabolism
- Excretion
pharmacoKINETICS: define
- the FATE of substances administered to living organism/
- how the body handles the drug
- FACTORS: “ADME”
pharmacoDYNAMICS: define
- interactions between drug and biological system
- pharmacological response (“what does the drug do re: outcomes?”)
- Outcomes:
- Clinical response = Toxicity or Efficacy
the outcomes/pharmacological effect of a drug would be referred to as what?
the pharmacoDYNAMICS of a drug
(i.e. clinical response = toxicity or efficacy)
what are the 2 overarching categories: routes of drug administration?
- ENTERAL = ORAL
- PARENTERAL = “NOT ORAL”
ENTERAL drug admin:
defiine, examples and key characteristics
- ORAL ADMIN
- Ex: Oral, Sublingual, Rectal
- KC:
- *MOST COMMON & relatively SAFE
- May cause GI irritation
- NOT GOOD FOR EMERGENCY
- Undergoes first pass metabolism
what is the most common type of drug admin? why?
oral admin (aka enteral)
it is common, relatively safe, and good for patient compliance
what is the benefit of sublingual versus traditional oral admin?
SUBLINGUAL (under the tongue) eliminated first pass biotransformation
first pass metabolism: define
aka first pass effect; or presystemic metabolism
phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced BEFORE it reaches systemic circulation
(therefore can limit the oral bioavailability of a drug –> limiting effectiveness of oral route)
examples of parenteral admin.
- respiratory (inhalation)
- injectible (IV, SC, IM)
- skin (topical, transdermal, inunction - rubbing an ointment or oil into the skin)
benefits of the following drug admin routes:
- rectal
- resp
- subQ
- IM
- IV
- Skin
- rectal –> 50% bypasses the liver
- resp –> inhalation for local or systemic effect
- subQ –> under the skin
- IM –> used for DEPOT effect
- IV –> directly into bloodstream, rapid onset, excellent in emergency, can be dangerous
- Skin –> topical or transdermal
which routes BYPASS the liver?
transdermal
subQ
IM
IV
INHALATION
RECTAL
key dosage forms?
- tablets - tablets, capsules, caplets
- liquid - aqueous, useful for pediatric formulations
- gaseous (e.g. nitrous oxide)
what is imperative to get from a patient before prescribing a drug?
A THOROUGH CASE HISTORY! you need to know every drug (prescribed or OTC or supplements) the patient is taking –>
important for many drug reactions
what does an idealized plasma concentration vs. time curve look like?
how does reality differ?
Looks like a gradual curve;
but SOME DRUGS CAUSE A SPIKE
4 types of drug absorption?
define each
- passive diffusion: *best possible result –> drug moves across membranes based on its lipid/water partition coefficient
- active transport: involves carrier proteins, saturable and utilize energy
- facilitated diffusion: carrier-mediates, w/ conc. gradient
- filtration: passive thru membrane pores
why is drug absorption important?
once a drug is administered, it MUST be absorbed thru biological membranes to produce a systemic effect
which type of drug absorption is saturable?
which is not saturable?
(passive vs. active)
ACTIVE is saturable; as it uses energy and runs out of ATP, can’t continue
PASSIVE IS NOT SATURABLE and the rate-absorption will increase as the concentration increases
Factors affecting PASSIVE DIFFUSION?
How do these affect diffusion?
-
CONCENTRATION
- INC. con –> FASTER absorption rate
-
LIPID-SOLUBILITY
- INC lipid solubility –> FASTER absorption rate
-
MOLECULAR WEIGHT
- DEC molecular weight –> FASTER absorption rate
-
SURFACE AREA
- INC molecular weight –> FASTER absorption rate
-
REGIONAL BLOOD FLOW
- INC regional BF –> FASTER absorption rate
how does increasing lipid solubility of a drug affect the absorption?
why?
THE MORE LIPID SOLUBLE –>the greater the rate of absorption
BECAUSE membranes are lipophilic/ hydrophobic
biochemistry of drugs?
(acid/base, ionization)
- many drugs are either WEAK ACIDS or WEAK BASES
- can exist in both IONIZED (charged) or NON-IONIZED (uncharged) forms
- non-ionized form is MORE LIPID SOLUBLE, and therefore crosses the membrane better
what factors determine the degree of ionization of a drug?
based on pH of the physiological compartment &
pKa of the drug
Henderson Hasselbach: WEAK ACID
a neutral molecule that can dissociate into an anion and hydrogen atom –>
*note: protonated form of weak acid is neutral, lipid-soluble form
henderson hasselbach: WEAK BASE
a neutral molecule that can form a cation (positively charged molecule) by combining w/ a proton
why will more aspirin absorb into the stomach rather than the small intestine?
since stomach is more acidic –> aspirin (weak base) is predominantly in HA (protonated) form and can pass through
factors affecting distribution?
- physicochemical properties
- cardiac output
- regional blood flow
- degree of plasma protein binding
- degree of tissue protein binding
- CNS and placenta (if it crosses or not)
when does displacement of class I drug occur?
when administered simultaneously with a class II drug
(class II displaces class I when administered together)
what effect does class I on have a class II drug?
class I drug will iNCREASE THE BIOAVAILABILITY OF A CLASS II drug
bioavailability: define
- subcategory of absorption
- the fraction of an administered dose of unchanged drug that reaches the systemic circulation (amount of drug administered that enters bloodstream unchanged)
general rules for oral absorption?
(acids/bases,
ionized molecules)
- acid/base
- weak ACIDS –> initial absorption in stomach; major portion in upper pt of sm intestine
- weak BASE –> absorbed in upper pt of small intestine
- ionization
- CHARGED molecules –> poorly absorbed
- NEUTRAL MOLECULES ARE READILY ABSORBED
what factors affect bioavailability?
- first pass metabolism
- solubility of drug
- chemical stability in the GI tract
redistribution: define
as drugs are NOT STATIC in the body, this is where the drug goes;
conc of drug will diminish over time
(drug is often stored in fat)
bioequivalence means two drugs have the same…
- same PEAK HEIGHT CONCENTRATION
- same TIME to peak height
- same AREA under blood conc curve
what factors determine INITIAL DISTRIBUTION PATTERN and EXTENT?
- physicochemical properties of drug
- ability of drug to pass thru membrane
- lipid solubility/pKa/molecular weight
- membrane carrier systems (present or absent?)
-
**cardiac output
- regional BF to various tissues and size of organs
- may accumulate less rapidly in skeletal musc. & slower in adipose tissue
- degree of plasma-protein binding –>
- facilitates absorption, but may reduce ability of drug to enter other tissues
- drugs may displace each other from binding sites –> adverse rxns
- degree of binding to tissue proteins
what other special considerations affect dist. pattern and extent?
- CNS –> drug may not cross BBB
- placenta-fetus
- milk-nursing infants
typical physiological volumes:
- plasma
- interstitial fluid
- intracellular fluid
- total body weight
- plasma: 4L
- interstitial fluid: 10L
- intracellular fluid: 28L
- total body weight: 42L
what are the possible termination pathways of drug action?
- redistribution
- elimination
- metabolism or (biotransformation)
- excretion
redistribution: define
- mvmt of drug AWAY FROM ACTIVE SITE –> other tissues to be stored
- factors affecting this:
- physicochem prop (e.g. more lipid soluble –> more redistribution)
- BF
metabolism: define
and OUTCOMES
- interaction of drug w/ biological system –> causing chemical change in drug (resulting in metabolite/metabolic product)
-
outcomes?
- inactive
- active
- more toxic
what is the purpose of drug metabolism?
the process makes drug LESS LIPID SOLUBLE/ MORE WATER SOLUBLE –> more READILY EXCRETED in aqueous excretions (urine)
(because MOST drugs are LIPID SOLUBLE, non-ionized @ physiological pH, and are partially bound to plasma proteins
what are the categories of metabolic reactions?
phase I (non-synthetic)
phase II (synthetic)
what is a phase I reaction?
(non-synthetic)
to convert parent drug –> more polar metabolite
if sufficiently polar/hydrophilic –> metabolites are excreted
(E.g. oxidation, reduction, hydrolysis(
what is a phase II reaction?
synthetic rxn
- adds group to substrate (conjugation)
- forms high-energy intermediates & transferases
- catalyzes coupling of endogenous substrate w/ drug/metabolite
- *MOST yield inactive products
- which type of metabolic rxn prepares drug for excretion?
- which type inactivates the drug?
- phase I
- phase II
where does metabolism occur?
- most ABSORPTION (after oral admin) from small intestine –> transported via portal system to liver
- most METABOLISM occurs in LIVER (first pass effect - where it may be partially metabolized)
what is the microsomal mixed function oxidase system?
microsomes: vesicles that from from lipophilic SER membranes being homogenized/fractionated;
mixed function oxidases: metabolic enzymes that remain assoc. w/ this fraction
enzymes require reducing agent (NADPH) and molecular oxygen –>
- NADPH-cytochrome p450 reductase
- *cytochrome p450 acts as terminal oxidase
cytochrome p450:
define and characteristics
- catalyze variety of chem ring and side chain hydroxylation –> changing molecules (mult. cytochrome forms exist w/ differing substrate specificity
- requires IRON (bc it’s a transition metal)
- ***Complexity of Cytochrome P450 system predominant and affects what we do; how we treat
- MUST know cytochrome metabolism
- everytime it goes thru the cycle, 1 CO is produced
examples of non-cytochome p450 mediated phase I rxns?
(oxidation can still occur by other means)
-
*XANTHINE oxidase –> which produces uric acid
- allopurinol, tx of chronic gout
- alcohol dehydrogenase: alcohol metabolism
factors influencing drug metabolism?
- BF and entry (rate) into liver
- enzyme inhibition and induction
- drug-drug interactions
- individual patient differences
- genetic factors (polymorphisms)
- diet and environment
- age and gender
enzyme induction: define
- some drugs (w/ repeat admin) can inc. rate of synthesis/reduce rate of degradation of p450 enzymes –> thereby“inducing” cytochrome p450 activity
- inc cytochrome p450 activity –> inc metabolism of some drugs
enzyme INHIBITION: define
- some drugs can COMPETE w/ another drug for same metabolic enzyme –> forming complex w/ and inactivating enzyme –> INHIBIT cytochrome p450 activity
- e.g. acute ethanol, cimetidine, disulfiram
which inducers affect the corresponding drug metabolism?
- phenobarbital
- rifampin
- chronic ethanol
- St. john’s wort
which INHIBITORS affect/reduce the corresponding drug metabolism?
- ethanol (Acute)
- cimetidine
- disulfiram
excretion: define
removal of drug/metabolites from the body –> external environment
*important in preventing/min. toxic effects of drugs
routes of excretion for drugs?
- volatile drugs: e.g. inhalational general anesthetics –> eliminated thru lungs/exhaled air
-
non-volatile drugs: e.g. water-soluble –> elim. by bodily excretions
- urine –> kidney/renal fxn
- bile –> gallbladder
how is drug excreted IF NOTHING ELSE HAPPENS TO IT AS IT PASSES THRU THE NEPHRON?
THEN the drug (water soluble, ionized) is excreted into the urine.
active tubular secretion: define
- a carrier mediated active transport process in the proximal tubule
- organic acids and bases may enter the nephron (separate systems for acids and bases).
- Drugs can compete with each other or endogenous compounds fortransport
active tubular reabsorption: define
an active transport process in the proximal tubule –> drugs may be reabsorbed back into the general circulation
passive reabsorption: define
- Process in the proximal and distal tubules in which a drug can re-enter the circulation by passive diffusion.
- Relatively lipid-soluble, non-ionized drugs will be reabsorbed instead of being excreted.
- By pharmacologically changing the pH of the tubular filtrate, it is possible to alter the excretion of a drug (this is referred to as ion-trapping).
biliary excretion: define
Drugs from the general circulation may enter the liver and be excreted into the bile. There are at least three different carrier-dependent systems, and competition can occur w/in each group:
- for organic acids,
- for organic bases, and
- for some steroids.
Drugs or their metabolites which have entered the gut via the bile may then be:
- directly excreted in the feces; OR
- undergoes enterohepatic recirculation
enterohepatic recirculation: define
drug or metabolite can re-enter the blood stream and prolong its half-life in the body.
zero order (elimination) kinetics: define
rate of elimination does not increase or decrease with changes in plasma concentration.
(e.g. ethanol)
FIRST ORDER kinetics: define
rate of removal is therefore proportional to their plasma concentration;
- a plasma half-life can be determined
- & conc of most drugs in the body is considerably less than that required to saturate the body’s eliminating capacity
factors altering rate of elimination?
- age
- environment
- disease
- gender
- drug-drug interactions
- individual variation
