Module A-2 Flashcards
Kinetic vs dynamic vs biophase figure
Figure relating pH and PKa
Pre-systemic elimination
Elimination by GI system before it can get to systemic circulation
-stomach acids hydrolyze drug
-enzymes from GI wall deactivate drug
-liver bio transforms drug before it reaches effect site
Properties impacting kinetics
-molecular size
-drug transporters
-degree ionization
-lipid solubility
Properties impacting kinetics
-molecular size
-drug transporters
-degree ionization
-lipid solubility
Key points of Oral
-Degree of ionization impacts absorption
-low bioavailability
-liver first pass
pKa
pH at which drug will be 50% ionized and non-ionized
Characteristics of non-ionized drugs
-lipid soluble
-hepatic metabolism
-no renal excretion
Characteristics of ionized drugs
-water soluble
-renal excretion
-do not cross lipid barriers
Bioavailability
Extent to which drug reaches effector site
-solubility (lipids vs aqueous)
-molecular weight
-pH
-pKa
-perfusion/blood flow to effector site
Ion trapping
Non-ionized drugs cross a lipid barrier and become ionized on the other side due to a change in pH and cannot cross back over-can quickly lead to toxicity
Two compartment model
Drug is first distributed to the vessel rich group (central compartment) and then redistributed to the the peripheral compartment or metabolized/excreted
Volume of distribution
Apparent volume in which drug has been distributed after it has been introduced
Variables:
-drug size
-carrier molecules
-disease states (burns, liver disease, pregnancy)
-solubility
Large Vd (>0.67 L/kg)
Widely distributed, likely lipophilic- think propofol
Small Vd (<0.4 L/kg)
Likely stays in plasma, highly hydrophilic, rocuronium
Oxidation
Loss of an electron
Reduction
Gain of an electron
Hydrolysis
Adding water to a compound to cleave it into acid and alcohol
Conjugation
Addition of a functional group to create more ionized compound at physiological pH
Phase 1 reactions
-increase polarity
-Primarily P450
-oxidation/reduction/hydrolysis
Phase 2 reactions
Conjugation- covalently links drug/metabolite with highly polar molecule to make water soluble and inactive
Glucuronidation & common drugs
Phase 2 reaction-addition of glucuronic acid
Propofol
Midazolam
Morphine
Other Phase 2 reaction examples
N-acetylation
Glutathione-S-transferases
Elimination half life
Time for plasma concentration to drop by half in elimination phase of plasma concentration curve
Context sensitive half time
Time to decrease by 50% from infusion that maintained a constant concentration (context is time of infusion)
Distribution half life
Amount of time to decrease by 50% in distribution phase of plasma concentration curve
First order kinetics
Drugs are eliminated at a constant fraction per unit time
Zero order kinetics
Drugs are eliminated at a constant AMOUNT per unit time
-commonly seen in overdose
Clearance
Volume of blood from which drug is completely eliminated per unit of time
-NOT amount of drug eliminated
Clearance=blood flow*extraction ratio
High Extraction ratio
> 0.7 Reliant on hepatic blood flow- considered high clearance drugs
Low extraction ratio
<0.3 Dependent on hepatic liver enzymes for extraction and changes in hepatic perfusion have no impact on
Ionization
Acid in acid
Non ionized
Ionization
Bases in bases
Non ionized
Ionization
Acids in base
Ionized
Ionization
Bases in acid
Ionized
Drug A is an acidic compound with pKa of 7.1. It is put in acidic environment of 6.0
7.1-6=1.1 therefore 99/1 percent
Acid in acid so 99% non-ionized
Drug B is an acid with pKa of 5, put in 7.4
2.4 so 99%
Ionized!!
Drug C is a base with pKa of 7.8, in 7.4
0.4 so 75/25
Base in more acidic environment so it is 75% ionized and 25% non-ionized
Other clearance factors…
Age- GFR declines, hepatic blood flow decreases, neonates have poor renal function
Gender- receptor sensitivity differences…
Liver disease- alters Vd
Absorption:
How a drug moves from its site of delivery into the bloodstream
Exponential Decay
The decay/decreases is proportional to the size of the quantity of interest
Plasma protein binding: three facts- name abundant types of
Albumin & alpha 1 acid glycoproteins are most abundant
Bound protein is NOT pharmacologically active
Unbound protein is available for receptor binding
Primary goal of metabolism/biotransformation
Make inactive & water soluble for excretion
Common enzyme in phase two reactions
Transferase
Conjugation adds a functional group (ie it transfers a functional group)
