Pharmacokinetics Flashcards
What are pharmacokinetics what do they effect
what the body does to a drug,determine the onset, intensity, and duration of drug action
What are ADME
Absorption: First, absorption from the site of administration permits entry of the drug
(either directly or indirectly) into plasma.
Distribution: Second, the drug may reversibly leave the bloodstream and distribute
into the interstitial and intracellular fluids.
Metabolism: Third, the drug may be biotransformed through metabolism by the liver or
other tissues.
Elimination: Finally, the drug and its metabolites are eliminated from the body in urine,
bile, or feces
What does understanding ADME help us with
Clinicians can design optimal drug
regimens, including the route of administration, dose, frequency, and duration of
treatment. (Optimizing the treatment)
How is the route of administration determined
By the physical properties and therapeutic objects
What is the parenteral route
Parenteral= away from the GIT and it includes IV,IM,SC
What are the advantages for the oral route
Oral drugs are easily self-administered,
and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as
activated charcoal.
What are the disadvantages for the oral route
pathways involved in oral drug absorption are the most
complicated, and the low gastric pH inactivates some drugs, can’t be used while vomiting and diarrhea
How can we fight the low pH of the stomach
enteric-coated and extended-release preparations.
What are enteric coatings
chemical envelope that protects the drug from stomach acid,
delivering it instead to the less acidic intestine, where the coating dissolves and releases
the drug.
Give examples for E.C
omeprazole that is
acid labile, and for drugs that are irritating to the stomach, such as aspirin.
What are extended release coatings
have special coatings or
ingredients that control drug release, thereby allowing for slower absorption and
prolonged duration of action.
What are the abbreviations for extended release
ER, XR, XL, SR
What are the advantages for ER
can be dosed less frequently and may
improve patient compliance. In addition, ER formulations may maintain concentrations
within the therapeutic range over a longer duration, as opposed to immediate-release
dosage forms, which may result in larger peaks and troughs in plasma concentration
What are the other advantages for ER
advantageous for drugs with short half-lives. For example, the half-life
of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide
continuous pain relief. However, only two doses are needed when extended-release
tablets are used.
Study the two tables, slide 6-7 from the notes
يلا يا قدع
What is absorption
transfer of a drug from the site of administration to the bloodstream.
What does the rate of absorption depends on
on the environment where the drug is
absorbed, chemical characteristics of the drug, and the route of administration
What are the mechanisms of absorption
Passive, facilitated,active, endocytosis
What is passive diffusion
the drug moves from an
area of high concentration to one of lower concentration. Passive diffusion does not
involve a carrier, is not saturable, and shows low structural specificity
How can the drugs penetrate the cell wall
Water-soluble drugs penetrate the cell
membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move
across most biologic membranes due to solubility in the membrane lipid bilayers.
What is facilitated diffusion
entering the cell through specialized transmembrane carrier proteins that
facilitate the passage of large molecules.
Does facilitated diffusion need ATP, does it get saturated
It does not require energy, can be
saturated, and may be inhibited by compounds that compete for the carrier.
What is active transport
involves specific carrier proteins that span the membrane.
However, active transport is energy dependent
What is endocytosis
used to transport drugs of exceptionally large size across the
cell membrane.Vitamin B is transported across the gut wall by
endocytosis,
But exocytosis is the reverse of
endocytosis. Many cells use exocytosis to secrete substances out of the cell whereas certain neurotransmitters (for example, norepinephrine) are stored
in intracellular vesicles in the nerve terminal and released by exocytosis.
How does the pH effect the absorption
A drug passes through membranes more readily if it is uncharged , therefore weak acids drugs are better in acidic conditions while weak bases are better in basic conditions
How does the blood flow affect absorption
The intestines receive much more blood flow than does the stomach, so absorption from
the intestine is favored over the stomach.
How does the surface area affects absorption
With a surface rich in brush borders containing microvilli, the intestine has a surface area
about 1000-fold that of the stomach, making absorption of the drug across the intestine
more efficient.
Why is the drug not absorbed well during severe diarrhea
Because the drug drug moves through the GI tract very quickly
Why is the drug slowly absorbed after a meal
The presence of food in the
stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a
meal is generally absorbed more slowly
What is p-glycoprotein
transmembrane transporter protein responsible for transporting
various molecules, including drugs, across cell membranes
Where can we find p-glycoprotein
the liver, kidneys, placenta, intestines, and brain
capillaries,
Does it increases or decreases absorption and why
P-glycoprotein reduces drug
absorption. If “pumps” drugs out of cells.
P-glycoprotein is associated with multidrug resistance
Yes
What is bioavailability
the rate and extent to which an administered drug reaches the systemic
circulation.
How do we determine bioavailability
comparing plasma levels of a drug after a particular
route of administration (for example, oral administration) with levels achieved by IV
administration.
What determines/influence bioavailability
First pass,solubility, chemical instability, nature of the drug formulation
What is first pass hepatic metabolism
If the drug is rapidly metabolized in the liver or gut
wall during this initial passage (it enters the portal circulation before entering
the systemic circulation), the amount of unchanged drug entering the systemic
circulation is decreased.
How do we combat first pass hepatic metabolism
Drugs
with high first-pass metabolism should be given in doses sufficient to ensure that enough
active drug reaches the desired site of action.
Give an example for a drug that goes under first pass hepatic metabolism
more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence,
it is primarily administered via the sublingual, transdermal, or intravenous route.]
How does chemical instability effect bioavailability
Some drugs, such as penicillin G, are unstable in the pH of gastric contents. Others, such
as insulin, are destroyed in the GI tract by degradative enzymes
How does the nature of the drug formulation effects the bioavailability
particle size, salt form, crystal polymorphism, enteric coatings, and the
presence of excipients can influence the ease of
dissolution and, therefore, alter the rate of absorption.
What is bioequivalence
Two drug formulations are bioequivalent if they show comparable bioavailability and
similar times to achieve peak blood concentrations
What are therapeutic equivalence
they are pharmaceutically equivalent with similar clinical and safety profiles.
Remember
therapeutic
equivalence requires that drug products are bioequivalent and pharmaceutically
equivalent.
What is drug distribution?
the process by which a drug reversibly leaves the bloodstream and
enters the extracellular fluid and tissues.
What does drug distribution depends on?
Blood flow, capillary permeability, binding to the plasma proteins, lipophilicity
How does the blood flow effects distribution
It explains the short or long duration of the drugs, علاقة طردية
What organs get more blood flow than others
“vessel-rich organs” (brain, liver, and kidney)
Is the blood flow In the skeletal, adipose, skin and viscera higher or lower
Lower
What determines the capillary permeability?
by capillary structure and by the chemical nature of
the drug.
How can the capillaries vary in the structure
the fraction of the basement membrane
exposed by slit junctions between endothelial cells.
What’s the difference between brain capillaries and liver ones
the liver and spleen, a significant
portion of the basement membrane is exposed due to large, discontinuous capillaries
through which large plasma proteins can pass. In the brain, the capillary
structure is continuous, and there are no slit junctions
How can the drug enter the brain
drugs must pass through the endothelial cells of the CNS ( highly lipophilic and unionised) capillaries or undergo active
transport.
How does the reversible drug binding to the protein effect the diffusion
It slows down the diffusion giving the drug a prolonged effect
Which plasma proteins is the major drug binding protein
lipids, proteins,
or nucleic acids such as albumin
Can drug binding to the protein act as a reservoir
Yes, since it’s reversible it will slowly re-release the drug
Why do drugs accumulate in the tissues
Drugs may accumulate because of binding to lipids, proteins,
or nucleic acids. Drugs may also undergo active transport into tissues
What’s the effect of the conc of the drug binding to proteins and extracellular fluids compared to the tissuees
The conc will be lowered in the blood
How do lipophilicity effect drugs
Lipophilicity increases the penetration of the cell membrane therefore it increases the distribution
What is the volume of distribution VD
defined as the fluid volume that is required to
contain the entire drug in the body at the same concentration measured in the plasma
Describe the drug distribution in the plasma compartment
Has a low VD (4L/70-kg)
High molecular weight
Very high protein binding
Trapped within the vascular compartment because it can’t go through the slit junction
Examples heparin
Describe the drug distribution in the extracellular fluid
Low molecular weight
Hydrophilic
Can pass through slit junctions of the endothelial tissues
14L/70kg
Example amino glycosides
Describe the the drug distribution in the total body water
Low molecular weight
Lipophilic
Can move through the slit junction and cell membrane
42L/70kg
Example Ethanol
What are the major routes of drug elimination
Hepatic, biliary, urinary
They reduce the drug conc in the blood
Why can’t the kidney efficiently excrete lipophilic drugs
readily cross cell membranes
and are reabsorbed in the distal convoluted tubules
How can we help the liver to excrete lipophilic drugs
lipid-soluble agents are
first metabolized into more polar (hydrophilic) substances in the liver via two general
sets of reactions, called phase I and phase II
What is phase 1 metabolism
convert lipophilic drugs into more polar molecules by introducing or
unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually
involve reduction, oxidation, or hydrolysis. Phase I metabolism may increase, decrease, or
have no effect on pharmacologic activity.
What effects the p450
Genetic variation, inducer drugs , inhibitor drugs
How does genetic variation effects the p450
Variations in P450 activity may alter drug efficacy and the risk of adverse events, example some individuals obtain no benefit
from the opioid analgesic codeine, because they lack the CYP2D6 enzyme that activates
the drug.
Give another example on genetic variation
clopidogrel ( a pro drug) carries a warning that patients who are CYP2C19 “poor
metabolizers” have a diminished antiplatelet effect when taking this drug and an
alternative medication should be considered
What are cyp inducers
Certain drugs (for example, phenobarbital, rifampin, and carbamazepine) are
capable of inducing CYP isozymes. This results in increased biotransformation of drugs
and can lead to significant decreases in plasma concentrations of drugs metabolized by
these CYP isozymes, often with concurrent loss of pharmacologic effect
Name the problem with using rifampin for TB and HIV patients
significantly decreases the plasma
concentrations of human immunodeficiency virus (HIV) protease inhibitors, thereby
diminishing the ability to suppress HIV replication.
What are the cyp inhibitors
Inhibition of drug metabolism can lead to significant increases in plasma drug
concentration and resultant adverse effects or drug toxicity
Name same examples for cyp inhibitors
Numerous drugs inhibit one or more of the
CYP-dependent biotransformation pathways of warfarin. For example, omeprazole is a
potent inhibitor of three CYP isozymes involved in warfarin metabolism
Name some natural substances that acts as inhibitors
Grapefruit juice, inhibits cyp3a4 and can be toxic with, nifedipine, clathromycin, simvastatin
What is phase 2 metabolism
This phase consists of conjugation reaction.A subsequent conjugation reaction with an endogenous
substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in
polar, usually more water-soluble compounds that are often therapeutically inactive
Talk about the drug clearance through the kidney
Drugs must be sufficiently polar to be eliminated from the body,Removal of drugs from
the body occurs via a number of routes; the most important is elimination through the
kidney into the urine.
What happens during glomerular filtration
Drugs enter the kidney through renal arteries.Free drug (not bound to albumin) flows through the capillary slits into the
Bowman space as part of the glomerular filtrate.Lipid solubility and pH do not influence the passage of drugs into the glomerular
filtrate. However, variations in GFR and protein binding of drugs do affect this process.
What happens in the proximal tubular secretion
Secretion primarily occurs in the proximal tubules by two energyrequiring active transport systems: one for anions and one for cations.Each of
these transport systems shows low specificity and can transport many compounds. Thus,
competition between drugs for these carriers can occur within each transport system.
What happens during distal tubular reabsorption
As a drug moves toward the distal convoluted tubule, its concentration increases and
exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the
nephric lumen, back into the systemic circulation
How can we increase the clearance through distal tubular reabsorption
Manipulating the urine pH
to increase the fraction of ionized drug in the lumen may be done to minimize the
amount of back diffusion and increase the clearance of an undesirable drug
What is ion trapping
weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak
bases may be increased by acidification of the urine example, over dose by phenobarbital
Name some other routes for clearance
the intestines, bile, lungs, and breast milk
How can drugs be cleared through the skin, bile and milk
Drugs that are not absorbed after oral administration or drugs that are secreted
directly into the intestines or into bile are excreted in the feces.
The lungs are primarily
involved in the elimination of anesthetic gases.
Elimination of
drugs in breast milk may expose the breast-feeding infant to medications and/or
metabolites being taken by the mother and is a potential source of undesirable side
effects to the infant.
What is the total body clearance
is the sum of all clearances from the drugmetabolizing and drug-eliminating organs
What is half life
The time required to clear 50% of the drug
Name some clinical situations resulting in changes in drug half life
1) diminished renal or hepatic blood flow, for example, in cardiogenic shock, heart failure,
or hemorrhage;
2) decreased ability to extract drug from plasma, for example, in renal
disease
3) decreased metabolism, for example, when a concomitant drug inhibits
metabolism or in hepatic insufficiency, as with cirrhosis
How can we decrease the half life of the drug
1 increasing hepatic blood flow
2 decrease protein binding
3 increase metabolism
Good job
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