2- pharmacokinetics Flashcards
1
Q
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
A
PHARMACOKINETICS
2
Q
DISTRIBUTION
METABOLISM
A
Disposition
3
Q
METABOLISM
EXCRETION
A
Elimination
4
Q
LADMERT
A
Liberation
Absorption
Distribution
Metabolism
Excretion
Receptor
Toxicity
5
Q
central compartment
A
blood stream
6
Q
cannot exit the blood, diffuse to cell membrane, or bind to target receptor
A
protein bound drug
7
Q
-a constant for the drug that is estimated from the experimental data
-Any set of physical properties whose values determine the pharmacokinetic
characteristics or behavior of the drug
A
Pharmacokinetic parameter
8
Q
movement
A
kinetics
9
Q
-rate of movement, appearance/disappearance
-movement of the drug within the body
A
pharmacokinetics
10
Q
Semipermeable
Fluid Mosaic Model
A
cell membrane
11
Q
double layer of amphiphilic phospholipids with the hydrophilic heads in contact with aqueous solutions inside and outside the cell while the hydrophobic tail is inside the bilayer
A
lipid bilayer
12
Q
attached to the cell membrane, modulates function of integral proteins
A
peripheral proteins
13
Q
attached to membrane proteins (forming glycoproteins)
A
carbohydrates
14
Q
-spontaneous movement of molecules across a concentration gradient; no energy required
-simple diffusion
-facilitated diffusion
A
Diffusion/passive transport
15
Q
-transport of molecules against a concentration gradient; requires energy
-primary active transport
-secondary active transport
A
Active Transport
16
Q
Endocytosis
Exocytosis
Transcytosis
A
Vesicular Transport
17
Q
2 types of simple diffusion
no energy required
A
-transcellular
-paracellular
18
Q
Transcellular diffusion
A
through lipid bilayer
through channels
microvilli
19
Q
paracellular diffusion
A
-movement of molecules or ions between adjacent cells, passing through intercellular spaces rather than through the cell itself
-tight junction
20
Q
certain specific non-lipid soluble molecules or ions diffuse through
A
membrane channels
21
Q
other non-lipid soluble molecules or ions for which membrane channels are not present in the cell
A
cannot enter the cell
22
Q
lipid soluble molecules diffuse
A
directly through the plasma membrane
23
Q
most drugs that undergo transcellular diffusion through the lipid bilayer are
A
non-polar
hydrophobic/lipophilic
unionized
(LUNA)
24
Q
Carrier-mediated (carrier proteins)
Saturation may occur
e.g. glucose; vitamins B1, B2, and B12
A
Facilitated Diffusion
25
Carrier-mediated
Transport is accompanied by an energy-producing process
Active Transport
26
2 types of Carrier mediated active transport
-primary active transport
-secondary active transport
27
moves substances by using energy produced by ATP hydrolysis; pumps coupled to ATPase
Primary Active Transport
28
moves substances by using kinetic energy from the concentration gradient established by primary active transport
Secondary Active Transport
29
drugs that use active transport
-methyldopa
-levodopa
-methotrexate
-iron salts
-penicillin
-cephalosporins
-ACE inhibitors
-Renin inhibitors
30
downhill transport
from high to low
passive transport
31
uphill transport
from low to high
active transport
32
2 types of secondary active transport
symporter (same direction)
antiporter (opposite direction)
33
transport that involves vesicles
requires energy
vesicular transport
34
3 types of vesicular transport
endocytosis
exocytosis
transcytosis
35
transport process where a cell engulfs substances from its external environment by enclosing them in vesicles made from the plasma membrane
endocytosis
36
-transport process where cells expel substances by enclosing them in vesicles that fuse with the plasma membrane, releasing their contents outside the cell
-reverse of endocytosis
exocytosis
37
the material internalized by the membrane domain is transported through the cell
and secreted on the opposite side
Transcytosis
38
"Cell eating"
engulfment by the cell membrane of particles larger than 500 nm
e.g. polio and other vaccines
phagocytosis
39
"Cell drinking"
engulfment of small droplets of extracellular fluid by membrane vesicles
e.g. vitamins A, D, E, and K
Pinocytosis
40
-Selective molecule uptake
-receptors on their cell surfaces binding with ligands to form ligand-receptor
complexes on the cell surfaces
-the complexes cluster on the cell surface and then invaginate and break off from
the membrane to form coated vesicles
receptor mediated endocytosis
41
movement of solvent from a less concentrated solution to a more
concentrated solution through pores
Osmosis
42
movement of small molecules with the solvent during osmosis
e.g. water, sugars, urea
solvent drag
43
-oppositely charged molecules interact and form a neutral complex
-the neutral complex will then cross cell membranes by passive diffusion
e.g. quaternary ammonium compounds, sulfonic acids
ion-pair transport
44
-The process of movement of unchanged drug from the site of administration to
systemic circulation (central compartment)
-Considers the rate and extent of absorption
Absorption
45
Metabolism of drug before it
reaches the circulation
-via GI tract= oral/rectal
-drug is metabolized before it reaches the liver
-decreased unmetabolized drug to reach target site = decreased bioavailabilty
Intestinal – due to CYP450
enzymes (mainly CYP3A4)
first pass effect
46
main site of drug metabolism
liver/hepatic
47
-parameter to measure absorption
-A measure of the extent to which the drug reaches the systemic circulation
following administration by any route
-The fraction of drug reaching the systemic circulation following administration by
any route
bioavailability (F)
48
compares the amount of the active drug reaching the systemic circulation following extravascular administration with the amount of the same drug following intravenous administration
absolute bioavailability
49
compares the amount of the active drug reaching the systemic circulation following administration of a test formulation with the
amount of the same drug following administration from a reference
formulation; when there is no intravenous formulation
Relative bioavailability
50
comparison of bioavailability between generic drug and innovator drug
bioequivalence test
51
drug products that contain the same active drug substance in the same dosage form and are marketed by more than one
pharmaceutical manufacturer
multisource drug products
generic drug products
52
drug products marketed as new chemical entities
innovator drug products
53
no clinically significant difference in bioavailability
bioequivalent
54
bioavailability & bioequivalence test are conducted via
in vivo
in vitro
55
(by measuring the plasma drug concentration over time)
Area under the curve (AUC)
Peak concentration (Cmax)
Time of peak concentration (Tmax)
in vivo
56
Comparative dissolution
use dissolution apparatus
need a waiver
depends on the permeability & solubility of the drug
in vitro
57
the maximum concentration of drug in the
plasma
usually expressed in mcg/mL
peak plasma concentration (Cmax)
58
the time for a drug to reach peak plasma
concentration after administration
usually expressed in hours
useful in estimating the rate of absorption
time of peak concentration (Tmax)
59
the total integrated area under the plasma
drug concentration-time profile and expresses the total amount of drug that comes into the systemic circulation after administration
usually expressed in mcg-h/mL
-basis for bioavailability
area under the curve (AUC)
60
minimum concentration of drug in the plasma required to produce the therapeutic effect
Minimum Effective Concentration (MEC)
61
plasma drug concentration below MEC
subtherapeutic level
62
Minimum concentration of drug in the plasma
that produces adverse or unwanted effects
Minimum Toxic Concentration (MTC)
63
plasma drug concentration above MTC
aka maximum safe concentration (MSC)
toxic level
64
the time required for the drug to start
producing pharmacologic response
onset of action
65
the time period for which the plasma concentration of drug remains above MEC
duration of action
66
-absorption circumvented
-potentially immediate effects
-suitable for large volumes & irritating substances, or complex mixtures when diluted
-valuable for emergency
-permits titration of dosage
-usually required for high molecular weight protein & peptide drugs
-increased risk of adverse effects
-must inject solutions slowly as a rule
-not suitable for oily solutions or poorly soluble substances
intravenous
100% absorption
67
-prompt from aqueous solution
-slow & sustained from repository preparations
-suitable for some poorly soluble suspensions & for instillations of slow release implants
-not suitable for large volumes
-possible pain or necrosis from irritating substances
subcutaneous
75-100% absorption
68
-prompt from aqueous solution
-slow & sustained from repository preparations
-suitable for moderate volumes, oily vehicles, & some irritating substances
-precluded during anticoagulant therapy
-may interfere with interpretation with certain diagnosis tests (kinase test)
intramuscular
75-100% absorption
69
-variable, depends on many factors
(first pass effect)
-most convenient & economical, usually safer
-requires patient compliance
-bioavailability potentially erratic & incomplete
oral ingestion
70
Bioavailability is complete (F = 1.0).
Distribution is rapid.
Drug delivery is controlled and achieved with an accuracy and immediacy.
Irritating solutions can only be given via this route (IV infusion) because the
drug is diluted by the blood.
intravenous advantages
71
Unfavorable reactions can occur because high concentrations of drug may be
attained rapidly in plasma and tissues (IV bolus).
Once administered, there is often no retreat.
IV disadvantages
72
The rate of absorption via simple diffusion following SC injection is constant
and slow to provide a sustained effect.
Altering the period over which a drug is absorbed may be varied intentionally
(e.g. insulin for injection using particle size, protein complexation, and pH;
incorporation of a vasoconstrictor in the drug solution to retard absorption)
Subcutaneous advantages
73
Injection into a SC site can be done only with drugs that are not irritating to
tissue because severe pain and necrosis may occur.
SUBCUTANEOUS (SC) Disadvantages:
74
Advantages:
Drugs administered IM can be in aqueous solutions, which are absorbed
rapidly, or in specialized depot preparations (e.g. solution in oil; suspension in
depot vehicles), which are absorbed slowly.
INTRAMUSCULAR (IM)
75
Advantages:
A drug is injected directly into an artery to localize its effect in a particular tissue or organ.
Disadvantages:
Inadvertent administration can cause serious complications and requires careful management.
INTRA-ARTERIAL (IA)
76
Advantages:
Produces local and rapid effects of drugs on the meninges or cerebrospinal axis by injection into the spinal subarachnoid space, bypassing the BBB and blood- CSF barrier.
INTRATHECAL
77
Advantages:
Access to the circulation is rapid by this route because the lung’s surface area is large.
It achieves almost instantaneous absorption of a drug into the blood, avoidance
of hepatic first-pass loss, and in the case of pulmonary disease, local application of the drug at the desired site of action.
inhalational (by mouth, not nasal)
78
Advantages:
It achieves a local and direct effect.
skin
mucous membrane
eyes
ear
(drug not absorbed)
topical
79
Advantages:
This route is most often used for the sustained delivery of drugs.
Absorption through the skin can be enhanced by suspending the drug in an oily
vehicle and rubbing the resulting preparation into the skin.
Hydration of the skin with an occlusive dressing may be used to facilitate
absorption.
Disadvantages:
Toxic effects result from absorption through the skin of highly lipid-soluble
substances (e.g., a lipid-soluble insecticide in an organic solvent).
transdermal
skin
drug is absorbed
80
Advantages:
It is the safest and most common, convenient, and economical method of drug
administration.
Disadvantages:
It has limited drug absorption because of physicochemical factors of the drug
(e.g. solubility, permeability) and physiologic factors (e.g. GI enzymes, pH,
normal flora, surface area).
oral (PO)
81
Advantages:
Venous drainage from the mouth is to the superior vena cava, bypassing the
portal circulation (and first-pass metabolism).
-better absorption than oral
sublingual (SL)
82
Advantages:
Approximately 50% of the drug that is absorbed from the rectum will bypass the
liver (and hepatic first-pass metabolism).
The rectal route prevents destruction of the drug by intestinal enzymes or by
low pH in the stomach.
The rectal route is useful if the drug induces vomiting when given orally, if the
patient is already vomiting, or if the patient is unconscious.
Disadvantages:
Rectal absorption can be irregular and incomplete, and many drugs irritate of
the rectal mucosa.
RECTAL
83
factors affecting absorption
route
pH
surface area
84
pH in stomach
1-3.5
85
pH in small intestine
6-7.5
86
acidic (weak acid) drugs are absorbed
in the stomach,
87
basic (weak base) drugs are absorbed
in the small intestine,
88
drugs that pass through the lipid membrane
Lipophilic/hydrophobic
Unionized
Non-polar
89
The unionized form of an acid or basic drug, if sufficiently lipid soluble, is
absorbed but the ionized form is not.
90
The larger the fraction of drug is in the unionized form at a specific absorption
site,
the faster is the absorption
91
For drug compounds of MW >100, which are primarily transported by passive
diffusion, the process of absorption is governed by:
The dissociation constant of the drug.
The lipid solubility of the unionized drug.
The pH at the absorption site.
92
the higher the _________, the higher the extent & rate of absorption, regardless of pH
most drugs are absorbed in the small intestine, the small intestine has the largest ______ & also has gradually changing pH
surface area
93
-from central compartment/blood stream/systemic circulation to tissues
-movement of the drug into interstitial & intracellular fluids
-reversible transfer of drugs b/w compartments
-drugs distribute in different tissues & organs of the body
distribution
94
aka peripheral compartment
tissue compartment
95
the driving force in the concentration gradient b/w the blood & extravascular tissues
passive process
96
not a real physiologic or anatomic region but is considered a tissue or group of tissues that have similar blood flow and drug affinity.
compartment
97
the body is a single homogenous
compartment;
most drugs follow this model
one-compartment model
98
2 compartment
central and tissue compartment
99
the blood and highly perfused lean organs
such as heart, brain, liver, lung, and kidneys
2 compartment model
100
the slowly perfused tissues such as muscle,
skin, fat, and bone
tissue compartment / peripheral compartment
101
-parameter that measures distribution
-the measure of the apparent space in the body available to contain the drug
-refers to the fluid volume that would be required to contain all the drug
homogenously in the body at the same concentration measured in the blood
-reflects the extent to which it is present in extravascular tissues and not in the
plasma
volume of distribution (Vd)
102
low concentration of drug in the blood=
drug is in the tissues
increase in Vd
increase in distribution
103
Humans are 60% water.
ECF: 1/3 of total body water
Interstitial Fluid (80% of ECF)
Plasma (20% of ECF; 60% of blood)
ICF: 2/3 of total body water
FLUID COMPARTMENTS
IN THE BODY
104
Drugs with very large molecular weight or binds extensively to plasma proteins
are too large to move out through the endothelial slit junctions of the capillaries
and are effectively trapped within the
plasma compartment
105
Drugs with low molecular weight and are hydrophilic
can move through the endothelial slit junctions of the capillaries into the interstitial fluid
106
hydrophilic drugs cannot move across the lipid membranes of cells to enter
the water phase inside the cell and
remain outside the cells
107
Drugs with low molecular weight and are hydrophobic
can move into the interstitium through the slit junctions and
108
drugs that have a higher Vd have much higher concentrations in the
tissues (extracellular compartment) than in the plasma compartment
109
One dose or a series of doses given at the onset of therapy with the aim of
achieving the target concentration (within the therapeutic window) rapidly
Loading Dose
110
FACTORS AFFECTING DISTRIBUTION
Blood flow
Plasma protein binding
Tissue protein binding
Hydrophobicity/Lipophilicity
Physiologic barriers
111
volume of blood that circulates in the cardiovascular system and reaches different organs and tissues in the body per unit of time expressed in volume/time
total blood flow = mL/min (cardiac output at rest)
*general amount of blood pumped by the heart
blood flow
112
amount of xenobiotic that can be stored or distributed in a tissue depends on
the mass of tissue or the size of organ
tissue size
113
-influences not only the distribution of xenobiotics in the body, but also their pharmacologic and/or toxic response as well as their elimination
-also diminishes the response because only the free drug can bind to receptors
-most drugs, if not all, bind reversibly to
binding to plasma protein
114
major plasma proteins
Albumin- most abundant
a1-acid glycoprotein (orosomucoid)
lipoproteins
115
drugs cannot go to liver & kidney for elimination
protein bound drug (large in size)
116
acidic/weakly acidic compounds in ionized form with moderate or marked
lipophilicity
e.g., phenytoin, salicylates, phenylbutazone, disopyramide, and penicillins
albumin
117
ionized basic (cationic) compounds with moderate lipophilicity
e.g., propranolol, saquinavir, imipramine, quinidine, and lidocaine
a1-acid glycoprotein
118
neutral molecules and highly lipophilic
e.g., chlorpromazine
lipoproteins
119
because of its large molecular weight, does not permeate easily through the capillaries; thus, it remains mainly in the systemic
circulation
protein bound drug
120
drug with the same binding site compete for interaction results in
drug displacement
121
Is >95% protein-bound
Has a small volume of distribution (<0.15L/kg)
Shows a rapid onset of therapeutic or adverse events
the displaced drug
122
Has a high degree of affinity as the drug to be displaced
Competes for the same binding sites
The drug/protein concentration ratio is high (>0.10)
Shows a rapid and large increase in plasma drug concentration
the displacer drug
123
Drugs may accumulate as a result
of binding to lipids, proteins or nucleic acids in tissue cells.
124
Drugs accumulated in tissues leads to
higher concentrations of the drug in
tissues than in the extracellular fluids and blood.
125
When a drug has a high volume of distribution (Vd), it can accumulate in specific tissues and act as a reservoir, leading to
Prolonged drug effects (slow release from tissues back into plasma).
Potential local toxicity due to high drug concentrations in specific tissues
126
hydrophobic drugs
readily move across most biologic membranes
127
Hydrophilic drugs
do not readily penetrate cell membranes and must pass through the slit junctions.
128
most important/highly regulate or limit drug entry to the CNS
blood-brain-barrier BBB
129
form a solid envelope around the brain capillaries
astrocytes
130
nutrients are selectively transported from the blood to the brain through
specific receptors or transporters
131
lipophilic substances
diffuse passively
132
polar compounds (glucose, amino acids) are
transported actively
133
Not as effective as BBB
Many drugs with MW<1000 Da and moderate to high lipid-solubility cross the
barrier rapidly by simple diffusion (e.g. ethanol, sulfonamides, barbiturates,
gaseous anesthestics, some antibiotics)
Nutrients for fetal growth are transported by a carrier-mediated and energy-
requiring process (e.g. glucose, amino acids, minerals, some vitamins, purines,
pyrimidines)
placental barrier
134
Drugs are dangerous to the fetus particularly during:
(fetal organs develop): most drugs show teratogenic effects (e.g. thalidomide,
phenytoin, isotretinoin, testosterone, methotrexate)
Latter stages: drugs are known to affect physiologic functions (e.g. respiratory depression by morphine)
1st trimester
135
METABOLISM
aka biotransformation
The conversion of drugs into more hydrophilic metabolites for elimination and
termination of biological and pharmacological activity.
In general, biotransformation reactions generate more polar, inactive metabolites
that are readily excreted from the body.
However, in some cases, metabolites with potent biological activity or toxic
properties are generated.
Normally results in pharmacologic inactivation
Can result to pharmacologic activation (prodrugs) or change in pharmacologic
activity
Occasionally yields metabolites with equal activity
Rarely leads to toxicological activation
metabolism
136
Extrahepatic metabolism
Lungs
Kidneys
Intestine
Placenta
Adrenals
Skin
137
Different from the enzymes that metabolize food
2 categories:
microsomal
non-microsomal
138
-acts on lipophilic substrates or lipid soluble substrates
-Metabolize the majority of drugs
Microsomes are derived from the RER
Catalyze oxidation, reduction, hydrolysis and glucuronidation reactions
Important features:
The intact nature of lipoidal membrane-bound enzyme is essential for its
selectivity towards lipid-soluble substrates.
A number of lipid-soluble substrates can interact nonspecifically with the
microsomal enzymes.
The lipid-soluble substrate is metabolized into a water-soluble metabolite which
can be readily excreted.
microsomal enzymes
139
Include those that are present in soluble form in the cytoplasm and those
attached to the mitochondria but not to the RER
from cytosol=aqueous/polar/hydrophilic
Nonspecific enzymes that catalyze few oxidation and a number of reduction,
hydrolysis and conjugation reactions other than glucuronidation
Act on relatively water-soluble substrates
non microsomal enzyme
140
-oxidizes only 1 substrate
-only 1 oxygen atom is incorporated to the substrate
monooxygenases
141
oxidizes 2 substrates at the same time
mixed-function oxidases
142
represents a superfamily of heme containing enzymes with the potential to
catalyze dehydrogenation, hydroxylation, epoxidation, oxygenation, dealkylation,
and ring opening
CYTOCHROME P450 (CYP450)
143
a member of the oxidoreductase family of enzymes, is present
in high concentrations in the human liver and kidney; metabolism of alcohols
Alcohol Dehydrogenase
144
metabolize aldehydes to less reactive forms
Aldehyde Dehydrogenase
145
metabolism of purine bases and hypoxanthine to xanthine and
finally to uric acid
Xanthine Oxidase (XOD)
146
catalyze the hydrolysis of a large number of structurally diverse endogenous and exogenous esters, amides, thioesters, and carbamates in humans
Carboxylesterases (CES)
147
hydrolyze the peptide bonds of proteins and peptides
Peptidase (Protease/Proteinase)
148
The inactivation or detoxification pathways
Small polar endogenous compounds (e.g. glucuronic acid, sulfate, glycine, etc)
are covalently attached to either the unchanged drug or products of Phase I
metabolism to form highly water-soluble conjugates that are readily excretable
Enzymes involved are transferases
Capacity-limited
Glucuronidation
Sulfation
Methylation
Acetylation
Glutathione conjugation
Amino acid conjugation
PHASE II METABOLISM
Conjugation or synthetic reactions
149
Generally precede Phase II metabolism
A polar functional group (-OH, -COOH, -NH2, -SH) is introduced or unmasked (if
already present) on the otherwise lipid-soluble substrate
Products: primary metabolites
Include:
Oxidation
Reduction
Hydrolysis
PHASE I METABOLISM
Functionalization or asynthetic reactions
150
UDP Glucoronic Acid
UDP Glucoronosyltransferase
glucoronodation
151
acetyl-coa
n-acetyltransferase
acetylation
152
glutathione GSH
GSH-S-transferase
glutathione conjugation
153
glycine
acyl-coa glycinetransferase
glycine conjugation
154
phosphoadenosyl phosphosulfate PAPS
sulfotransferase
sulfation
155
S-Adenosylmethionine SAM
transmethylases
methylation
156
water
epoxide hydrolase
water conjugation
157
Increased drug metabolizing ability of the enzymes by drugs and other
substances
The agents that bring about such an effect: inducers
Most inducers are lipophilic with long elimination half lives
Mechanisms:
Increased enzyme synthesis
Decreased enzyme degradation
Enzyme stabilization
Enzyme activation
ENZYME INDUCTION
158
ENZYME INDUCTION
2 categories of inducers:
1- Phenobarbital type inducers – includes several drugs and pesticides
2- Polycyclic hydrocarbon type inducers – includes 3-methyl cholanthrene and
cigarette smoke
159
Auto-induction/self-induction:
carbamazepine, meprobamate, cyclophosphamide,
rifampicin
160
enzyme inducers:
Carbamazepine
Rifampicin
Alcohol (chronic intake)
Phenytoin
Griseofulvin
Phenobarbitone
Sulphonylureas (gliclasides)
161
A decrease in the drug metabolizing activity of an enzyme
Could be direct or indirect inhibition
Usually rapid and more important than enzyme induction
enzyme inhibition
162
result from interaction at the enzymatic site, the net outcome being a change in enzyme activity
direct inhibition
163
structurally similar compounds compete for the same site; reversible (e.g. methacholine inhibits metabolism of Ach for cholinesterase)
competitive inhibition
164
a structurally unrelated compound interacts with the enzyme at a different site from the drug being metabolized (e.g Pb, Hg, As,
organophosphates; isoniazid inhibits metabolism of phenytoin)
Noncompetitive inhibition
165
metabolic products compete with the substrate for the same enzyme
product inhibition
166
decrease in enzyme content
Decreased synthesis – ethionine, puromycin, actinomycin D
Increased degradation – CCl4, CS2, disulfiram
indirect inhibition
167
nutritional deficiency or hormonal imbalance
altered physiology
168
enzyme inhibitors
Metronidazole
Erythromycin
Disulfiram
Valproate
Isoniazid
Chlormphenicol
Ketoconazole
Grapefruit
Alcohol (acute intake)
169
FACTORS AFFECTING METABOLISM
Volume of Distribution
Ethnic Variations
Age
Diet
Disease States
170
metabolism is inversely related to
-volume of distribution
-drug elimination is dependent on the amount of drug delivered to the liver
-if the drug has a large Vd, most of the drug is in the extraplasmic space and is unavailable to the metabolizing organ
171
fat free diet
depresses CYP450 levels
-lipids are required to form microsomes
172
low protein diet
decreases metabolizing ability
173
high protein diet
increases metabolizing ability
174
acute alcoholism
decreases enzyme activity
175
chronic alcoholism
increases enzyme activity
176
liver disease
increased half life of drugs
177
kidney disease
glycine conjugation of salicylates, oxidation of vitamin D and hydrolysis of procaine decreases
178
congestive heart failure
myocardium infarction
decreased blood flow to the liver
decreased metabolism
179
diabetes
decreased UDPGA & glucuronidation
180
excretion
Removal of the drug from the body either as the unchanged drug or as a metabolite
The process whereby drugs and/or their metabolites are irreversibly transferred
from internal to external environment
Principal Organ: kidneys
Other Organs (nonrenal excretion): lungs, liver, intestine, saliva, sweat glands
181
renal excretion
Renally excreted drugs: water-soluble, nonvolatile, small in molecular size
(<500 Da)
Basic unit of the kidneys: nephron
182
NEPHRON
Glomerulus
Proximal tubule
Loop of Henle
Distal tubule
Collecting tubule and duct
183
Glomerular Filtration Rate (GFR)
volume of blood that is filtered per unit of time
Around 20% of renal blood flow
normal GFR: 125 mL/min or 7.5 L/h or 180 L/day
184
FACTORS AFFECTING RENAL
EXCRETION
Plasma drug concentration
Volume of distribution
pH and lipophilicity
Disease states
185
Clearance is directly proportional to ________ as more drug can be filtered from the blood into the urine.
plasma drug concentration
186
Clearance
______ is inversely related to volume of distribution
Drugs that are bound to plasma proteins cannot be filtered to the urine
Actively secreted drugs are less affected by protein binding
187
An acidic drug (e.g. penicillin) or a basic drug (e.g. gentamicin) which is polar in its
unionized form is
not reabsorbed passively regardless of extent of ionization in the urine; excretion is independent of pH and urine flow rate
188
rate of excretion is
the sum of filtration and secretion
189
Very weakly acidic, nonpolar drugs (pKa >8) such as phenytoin or very weakly
basic, nonpolar drugs (pKa<6) such as propoxyphene are mostly unionized in the
entire urine pH range and are therefore
extensively reabsorbed passively at all
urine pH values; rate of excretion is slow and independent of pH
190
A strongly acidic drug (pKa≤2) such as cromoglycic acid or a strongly basic drug
(pKa≥12) such as guanethidine is completely ionized at all urine pH values and
are therefore
not reabsorbed; rate of excretion is high and independent of pH
191
Acidic drugs with pKa 3-8 (e.g. NSAIDs) and basic drugs with pKa 6-12 (e.g. morphine analogs, tricyclic antidepressants) are affected by urine pH
excretion varies from negligible to almost complete
192
Drug overdose with a weakly acidic drug can be treated with
urinary alkalinization
193
Drug overdose with a weakly basic drug can be treated with
urinary acidification
194
DISEASE STATES: RENAL
IMPAIRMENT
Causes: hypertension, DM, hypovolemia, pyelonephritis, nephrotoxic agents (e.g.
aminoglycosides, phenacetin, Pb, Hg)
Renal Function (RF)
Can be determined by measuring the GFR
Inulin – exogenous; tedious
Creatinine – endogenous (product of muscle catabolism); widely used
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Creatinine clearance: involves
measurement of serum creatinine
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-synthesized in the liver, stored in the gall bladder, and secreted in the
duodenum with drug metabolites or unchanged drug.
-production and secretion is an active process.
-is important in the digestion and absorption of fats.
bile
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Almost 90% of the secreted bile acids
are reabsorbed from the intestine and
transported back to the liver for resecretion; the rest is excreted in the feces.
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Simple, absolute, and unambiguous
Could be zero-order or first-order elimination
Zero-order Elimination: rate of elimination is convenient because it is constant
First order Elimination: rate of elimination changes with respect to drug plasma
concentration; most drugs follow first-order elimination; expressed in terms of
clearance
RATE OF ELIMINATION
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-the factor that predicts the rate of elimination in relation to the drug
concentration
-considers the entire body as a drug-eliminating system from which many
elimination processes may occur
-represents the theoretical volume of blood which is totally cleared of drug per
unit time
*unit-volume/time
CLEARANCE (CL)
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=Loading Dose x F/AUC
clearance
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the time required to change the amount of drug in the body by one-half during
elimination
t1/2 = 0.693/k or
half-life (t1/2)
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-At this point, drug elimination will
equal the rate of drug availability.
-During each interdose interval, the
concentration of drug rises with
absorption and falls by elimination
-The target concentration should
be the:
Steady-State Concentration (Css)
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Drugs are administered in a series of repetitive doses or as a continuous infusion
to maintain a steady-state concentration of drug associated with the therapeutic
window
Dosing Rate =CL x Css / F
= Dosing Rate x Dosing Interval
maintenance dose
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