Module A-2 Flashcards by Jackson Jones

Kinetic vs dynamic vs biophase figure

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Figure relating pH and PKa

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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

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Properties impacting kinetics

-molecular size
-drug transporters
-degree ionization
-lipid solubility

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Properties impacting kinetics

-molecular size
-drug transporters
-degree ionization
-lipid solubility

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Key points of Oral

-Degree of ionization impacts absorption
-low bioavailability
-liver first pass

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pKa

pH at which drug will be 50% ionized and non-ionized

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Characteristics of non-ionized drugs

-lipid soluble
-hepatic metabolism
-no renal excretion

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Characteristics of ionized drugs

-water soluble
-renal excretion
-do not cross lipid barriers

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Bioavailability

Extent to which drug reaches effector site
-solubility (lipids vs aqueous)
-molecular weight
-pH
-pKa
-perfusion/blood flow to effector site

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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

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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

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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

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Large Vd (>0.67 L/kg)

Widely distributed, likely lipophilic- think propofol

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Small Vd (<0.4 L/kg)

Likely stays in plasma, highly hydrophilic, rocuronium

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Oxidation

Loss of an electron

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Reduction

Gain of an electron

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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)