Pharmacokinetics: distribution and elimination Flashcards
Distribution of drug is achieved primarily thru the ________ circulation with minor contributions from the ________
Systemic, lymphatics
Once in the systemic circulation, a drug can
- Remain in vascular (blood) space
- Distribute to enter interstitial fluid
- Further distribute to enter intracellular fluid
Distribution of drug in the body is affected by
- Physiochemical properties of the drug
- Anatomy and Physiology of Patient: Tissue Perfusion
- Non-target Binding of Drug
Physiochemical properties of the drug that affects drug distribution
- Lipid solubility
- Size (molecular weight)
- Degree of ionization
Which tissues initially receive the drug distribution
vessel-rich tissues (liver, kidney, brain, heart) receive the greatest cardiac output and thus distribution of drug
Drug distribution to what tissues is slower
Distribution of drug to less well-perfused tissues (muscle, fat, skin, most
viscera) is slower, but accounts for most of the extravascular drug
Non target binding of drug refers to
Plasma protein binding and tissue binding
Plasma protein binding
Many drugs circulate in the blood bound to plasma
proteins; can show low to high affinity for proteins
-Cannot diffuse from vascular space to tissues
What binds drugs that are weak bases
α1-acid glycoproteins
Albumin
a major carrier for drugs that act as weak acids
Tissue binding
Many drugs accumulate in tissues at levels higher
than blood or interstitial fluid; can prolong drug action
-bind cellular proteins, phospholipids, etc that are not the target sites
The volume of distribution (Vd) describes
the extent to which a drug partitions between blood and tissue compartments
Volume of distribution equation
amount of drug in body (mg) / plasma drug concentration (ug/mL)
Drugs are eliminated (cleared) from the body either
-unchanged by the process of excretion or
-converted to metabolites by biotransformation
TRUE OR FALSE:
Although biotransformation (metabolism) and excretion are distinct processes, they have the same pharmocologic endpoint (reduction in circulating levels of active drug)
True
Rate of drug metabolism and excretion by an organ is generally limited
by
The rate of blood flow to the organ
“Kinetics of elimination of majority of drugs are first-order” meaning
constant fraction (%) of drug in blood (body) is eliminated per unit time
Units of clearance
(volume/unit time/kg body weight)
Clearance equation
Metabolism + Excretion / [Drug] plasma
What does the extraction ratio quantify
The extent to which an organ contributes to drug clearance
Extraction ratio equation
Extraction = [Drug]in - [Drug]out / [Drug]in
Do excretory organs eliminate polar (water soluble) or non-polar (lipid soluble) compounds more efficiently
Polar
What is the most important excretory organ
The kidney
Biliary tract excretion and reabsorption
-eliminated by feces
-reabsorption of excreted drug possible in small intestine –> enterohepatic recirculation of drug back to systemic circulation
Are drug s bound by plasma proteins easily filtered
No
Filtering of free (unbound) drug and metabolites
freely filtered at the glomerular capillaries (glomerulus); non-saturable and non-selective process
Renal excretion: Active drug secretion
Active drug secretion in proximal convoluted tubule adds drug to urine; is saturable, selective and inhibitable by other drugs
Renal excretion: reabsorption of drug
Reabsorption of drug back into blood from urine can be active in the distal
convoluted tubule but is mainly passive reabsorption of the nonionized form of the drug
Drug biotransformation or metabolism definition
change in the chemical structure of an absorbed drug within a living organism, usually by enzyme-catalyzed biochemical reactions
What is the main metabolizing organ
The liver
All orally administered drugs or other substances are first taken to
the liver
First pass effect
Where orally administered substances are first taken to the liver and extensively metabolized before reaching systemic circulation
What does the first pass effect do
- Reduces bioavailability of drug for target site
- Prevents some drugs from being given orally eg. lidocaine, many opioids (morphine, fentanyl)
Why is drug metabolism important
Enzymes play a pivotal role in metabolism by making drugs more excretable and terminating their action (inactivate)
Many _____________drugs must be metabolized to
more __________metabolites
lipid-soluble, water-soluble
Metabolism often results in _____ of the parent drug
inactivation
How are some drugs activated by metabolism
Administered as inactive “prodrugs”, gets converted into active metabolite
How many phases does drug metabolism occur in
2 phases
Phase I reaction of drug metabolism
Drugs are converted to more polar (hydrophilic) metabolites –> either excreted or –> undergo phase II reactions
Phase II reaction of drug metabolism
Substance from the diet is attached usually to the functional group derived from phase I reactions –> more polar, excretable product
What reactions are involved in phase I and II of drug metabolism
Phase I:(oxidation/reduction/
hydrolysis reactions)
Phase II: (conjugation reactions)
Characteristics of phase I reactions
-Processes usually involve one or more cytochrome P-450 (CYP) enzymes found in smooth ER
-Approximately 12 CYP450’s are known to be important for the metabolism of drugs; mainly the CYP2C, CYP2D, CYP3A subfamilies
Most common and least common phase I reactions
Most common: oxidation
Least common: Reduction and hydrolysis
What do phase I reactions do in terms of functional groups
Introduce or unmask
Oxidation in phase I reactions involves
Addition of oxygen or removal of hydrogen from drug
What percent of oxidative reactions involve CYP450 enzymes
95%
Characteristics of phase II reactions
Couple drug (or phase I metabolite) with substrates from diet to produce conjugates
Conjugates
Generally more polar, inactive and readily excretable
Types of phase II reactions (4)
1.Glucuronic acid conjugation (UDP
glucuronosyl transferase)
- conjugation of morphine, acetaminophen, salicylic acid, chloramphenicol, etc. to glucuronic acid
2.Sulphate conjugation (sulfotransferases)
-Phenols and alcohols conjugated to sulphate (SO4)
3.Acetylation (N-acetyltransferases)
-Occurs in drugs with -NH2 group conjugated to COCH3
4.Glutathione conjugation
(glutathione-S-transferases)
-Epoxides, arene oxides conjugated to glutathione (GSH)
Phase II: enterohepatic recirculation
Some phase II metabolites can be excreted into bile for elimination in feces, but glucuronidases in gut bacteria can hydrolyze the
conjugate off, and free the drug, which can be reabsorbed –> enterohepatic recirculation; prolongs drug elimination half life
Individuals deficient in glucuronide synthesis are slow to
Metabolism certain drugs
Examples of specific drugs involved in each phase II reaction
- Glucuronic acid conjugation
-conjugation of morphine, acetaminophen, salicylic acid, chloramphenicol, etc. to glucuronic acid
2.Sulphate conjugation
-acetaminophen, morphine
- Acetylation
-most sulfonamide antimicrobial drugs
4.Glutathione conjugation
-some anticancer drugs (alkylating agents)
Review metabolism summary
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