Pharmacokinetics, drug interactions Flashcards
________ - produces pharmacological action
free drug
drug bound to plasma protein is most likely ________
inactive
Displacement of a drug from plasma protein binding generaly causes ….
no change in its overall effect or adverse effects
Most drug is extravascular, so a change in free plasma drug concentration caused by displacement from plasma protein binding would be ______
minimal
Most drug is intravascular, so a change in free plasma drug concentration caused by displacement from plasma protein binding would have _________
significant effects
After absorption a drug is …
distributed to various body compartments
Distribution
the REVERSIBLE movement of a drug between body compartments
Factors that affect distribution from the general circulation to other tissue compartments are:
(4) ICBP
Ionization
Capillary permeability
Blood Flow
Plasma protein binding
Capillary Permeability:
In the _____, ______, and ______, the capillaries are very leaky.
kidney, liver and spleen
Capillary Permeability:
what do drugs doregardless of whether they are poorly lipid soluble, charged, or polar?
drugs leave the capillaries regardless
Blood Brain Barrier
Brain capillaries have __________
tight junctions
Blood-Brain Barrier
Only __________ drugs diffuse across brain capillaries
(unless other drugs are actively transported across)
lipophilic drugs
__________ exist between endothelial cells in the brain capillary
tight junction
Blood Brain Barrier
Clinical implication:
The degree to which drugs penetrate the ____ should be known to treat diseases of the nervous system properly.
brain
Blood Brain Barrier
Clinical implication:
The amine _______ (to treat Parkinson’s disease), has to be administered in the form of its precursor because it can’t cross the blood-brain barrier.
Dopamine
Dopamine’s precursor can be used to treat what disease of the central nervous system?
Parkinson’s disease
What is the precursor of dopamine? Why can’t it cross the Blood brain barrier?
L-dopa
because its metabolized by enzyems in the BBB
Blood Brain Barrier
Clinical implication:
The Blood brain barrier does not work properly in ares of ______ or _____
infection or injury
Blood Brain Barrier
Clinical implication:
______ of the brain develop new blood vessels and capillaries that have NO tight junctions.
Tumors
Blood Brain Barrier
Clinical implication:
substances such as _____________________ penetrate normal brain tissue very slowly, but they enter tumor tissue easily to help in diagnosis.
radioactive iodine-labeled albumin
Blood flow:
The tissue that receives more ______ receives more _____.
drug, blood
Blood flow:
____, _____, _____ receive more blood flow than
skeletal muscle. Whereas fat and _____ receive little blood flow.
Brain, liver, kidneys
skin
Total Body Water = ___% of body weight ~ ___ L.
___ of TBW in intracellular fluid space ~ ___ L.
___ of TBW in extracellular fluid space ~ ___ L.
___ of extracellular fluid is intravasuclar (i.e. plasma)
Adult blood volume ~ ___ L.
60% , 42L
2/3 , 28L
1/3 , 12L
1/3
5L
When we administer a drug, it distributes into many compartments - aka _________
volume of distribution (Vd)
______ - can be defined as a theoretical or apparent volume in which the total amount of administered drug should be uniformly distributed to account for its plasma or blood concentration.
Volume of distribution.
What is the formula for Volume of distribution (Vd) ?
Vd = dose administered / Plasma concentration
A high Vd indicates…..
that most of the drug is in the extravascular compartment (eg. amiodarone)
Volume of distibution - clinical significance
If the plasma concentration of a drug is high (eg due to high plasma protein binding) its Vd will be ___
low
Volume of distibution - clinical significance
A low Vd indicates taht…
most of the drug is in the vascular compartment (eg. bound to plasma proteins, a drug such as warfarin).
Redistribution of Drugs
Initially - what happens to organs like the brain and kidney when a drug is intravenously administered?
the brain and kidney receive greater percent or fraction of cardiac output and majority of the intravenously administered drug.
show profound drug effect.
Redistribution of Drugs
Initially - What happens to organs such as adipose tissue and skin after intravenous administration of drug?
organs like the adipose tissue and skin receive much less blood flow and very little drug.
Redistribution of Drugs
After time - what happens to adipose tissue after drug administration?
adipose tissue accumulate drug due to high storage capacity.
Redistribution of Drugs
While adipose tissue accumulates drug due to storage capacity , what happens to plasma concentration of the drug?
it falls
Redistribution of Drugs
As the drug is redistrubuted to major storage tissues, What happens to organs such as the brain and kidney?
drug is quickly removed from organs lke the brain and kidney to equilibriate with low plasma concentration
drug effect quickly wears off in brain and kidney
***EG. I.V. thiopental to induce anesthesia.
Redistribution of Drugs
Parenteral anesthetics such as ___________ (a lipid barbiturate drug) are used to induce anaesthesia.
intravenous thiopental
Redistribution of Drugs
Induction from anaesthesia is ______ (fast or slow)
Recovery from anaesthesia is ______ (fast or slow)
a ______ (higher/lower) concentration is given to take advantage of _______
If we use the regular concentration of thiopental what will happen?
fast or rapid
fast or rapid
lower , redistribution
then anesthesia and recovery will be prolonged over many hours, there will be little redistribution.
Biotransformation (Drug Metabolism)
The main purpose of drug metabiolsim is…
chemical modification of drugs by enzymes, to make them MORE POLAR (less lipid soluble) , and therefore readily excretable by the kidneys.
Biotransformation (Drug Metabolism)
Drug metabolizing enzymes are present in:
*L
*G
*L
K
S
B
B
The liver
Gastrointestinal Wall
Lungs
Kidneys
Skin
Blood
Brain
Biotransformation (Drug Metabolism)
Certain drugs do not reach their site of action because of ___________.
EG. a drug can be destroyed by digestive enzymes.
What would be useful in such cases?
pharmacokinetic obstacles
Their precursors, known as prodrugs, may be useful in such cases.
Biotransformation (Drug Metabolism)
____ are inactive when administered. What can cause them to be converted to active form?
Prodrugs
After metabolism they are converted to active form
Biotransformation (Drug Metabolism)
Examples of Prodrugs:
_______________ - omeprazole, Iansoprazole are prodrugs.
What are they used for?
Proton - pump inhibitors
reduce stomach acid secretion.
Biotransformation (Drug Metabolism)
Examples of prodrugs:
what are 2 examples of proton-pump inhibitors?
What prodrug is convereted into Active compound dopamine to treat parkinson’s disease?
omeprazole, iansoprazole
Levo-dopa or L-dopa
Two-Phase Biotransformation
Phase I _________ reactions
Phase 2 ______ reactions
Functionalization
conjugation
Two-Phase Biotransformation
Oxidation, reduction, and hydrolytic reactions have what effect on the drug?
What Phase of biotransformation is this?
makes the drug more polar but not necessarily inactive
Phase I functionalization reaction
Two-Phase Biotransformation
Phase I includes what types of reactions?
oxidation, reduction and hydrolytic reactions
Two-Phase Biotransformation
Conjugation to polar groups: glucuronidiation, sulfation, acetylation has what effect on the drug?
What phase of biotransformation is this?
must of these result in drug inactivation
Phase II conjugation reactions
Two-Phase Biotransformation
Phase I Enzymes:
Microsomal cytochrome ___ belongs to what family of enzymes?
- they transfer electrons from ______ to an oxygen molecule and thus ______ drugs. (mostly hydroxylations, and dealkylations).
P450 , monooxygenase family of enzymes.
NADPH, oxidize
Two-Phase Biotransformation
Phase I Enzymes:
Microsomal cytochrome P450:
these enzymes act on structurally unrelated drugs which means they are ….
they are located in the ________ of the cell.
they require _____ and ___
Metabolize the ____ (shortest, widest) range of drugs
In most cases these reactions _____ (activate or inactivate) the drug.
not very substrate specific
endoplasmic reticulum
NADPH O2
widest
inactivate
Two-Phase Biotransformation
Phase I Enzymes:
Over ___ % of drug oxidation by cytochrome enzymes can be attributed to 6 main CYPs:
What are they?
ACCDEA
90%
CYP1A2
CYP2C19
CYP2C9
CYP2D6
CYP2E1
CYP3A4
Two-Phase Biotransformation
Phase I Enzymes:
_____ is the primary enzyme for metabolism of about _____ of all drugs and is inhibited or induced by many drugs.
This can cause ___________
CYP3A4
Half or 50%
can cause drug-drug interactions (DDI)
Two-Phase Biotransformation
Phase I Enzymes:
What are the top 3 relative proportions of drugs metabolized by CYPs:
CYP3A4 - largest 50%
CYP2D6 ~ 18%
CYP2C9 ~ 18%
Factors affecting drug biotransformation:
What are the 2 factors of biotransformation?
enzyme induction and inhibition
Two-Phase Biotransformation
Drugs (including herbals) and other substances (foods) can _____ or ____ the expression of some metabolizing enzymes, especially the ________ enzymes.
This can possible cause the creationg of more enzyme.
stimulate or inhibit
cytochorome P450 enzymes.
Two-Phase Biotransformation
Significance of Phase I drug metabolizing enzymes:
Induction or inhibition of phase I enzymes (CYT P450) can cause ____________ when two or more drugs that are metabolized by the same ____ are given.
______ is the primary enzyme for metabolism of about half of all drugs and is inhibited or induced by many drugs and is involved in many drug drug interactions.
drug-drug interactions DDI
enzyme
CTP3A4
Two-Phase Biotransformation
Induction of enzyme and drug interactions:
Inducers cause … _________________.
What can cause treatment failure?
Examples include:
R
B
*S
expression of more CYP enzymes and faster elimination of substrate drugs.
Lower than expected drug levels can cause treatment failure
Rifampin (antibiotic)
Barbiturates
*St John Wort (herbal antidepressant)
Two-Phase Biotransformation
Inhibitors can … ________________.
Higher than expected drug levels can cause ______.
Examples:
*G
*C
E
I
inhibit the activity of CYP enzymes and reduce elimination of substrate drugs.
drug toxicity
*Grapefruit juice
*Cimetridine (stomach acid inhibitor)
Erythromycin (antibiotic)
Itraconazole (antifungal)
Two-Phase Biotransformation
What is CYP Polymorphism?
The most common P450 polymorphism in Caucasians is ______ expression.
around 10% of Cucasians lack expression of this enyzme.
around 5% of ____ lack expression of this enzyme.
Genetic variations in the population - mutations are foundi n some drug metabolizing enyzmes in some people.
CYP2D6
Africans
_____ is almost ineffective as an analgesic in some patients. This drug must be metabolized by ______ to morphine for analgesic effect.
Codeine
CYP2D6
Two-Phase Biotransformation:
Phase II reactions:
In these reactions a chemical group such as
GA
S
G
AA
A
are added to the drug.
Glucuronic Acid
Sulfate
Glutathione
amino acids
acetate
Two-Phase Biotransformation:
Phase II reactions:
The conjugated drug is ___________ and in most cases inactive.
The conjugated drug is ______ (rapidly/slowly) excreted.
Enzymes for Phase II reactions are mostly located where?
highly polar
rapidly
cell cytosol
Two-Phase Biotransformation:
Phase II reactions: (clinical significance)
___% of Americans and
__-__% of Eurpoeans have reduced expression of ______ enzyme.
What does this enzyme do?
50%
60-70%
Acetylating enzyme (N-acetyl transferase or NAT - “slow acetylators”)
they slowly metabolize drugs such as Isoniazid (antituberculosis drug), procainamide (anti-arrythmic drug) and caffine.
Drug interactions can be easily avoided in most cases
T or F?
True
Drug interactions are defined as a situation in which…
What are the 3 possible outcomes?
a substance affects the activity of a drug.
- Increased effect, toxicity
- Decreased effect, treatment failure
- New effect. (rare)
Drug interactions cause up to ___% of hospital admissions.
>__% use > 1 drug/week
>__% use > 5 different drugs/week
12% use > __ different drugs/week
2.8%
90%
40%
10
Which sex takes more drugs, men or women? In particular, what type of drugs do they take?
women
psychoactive, arthritis drugs
Drug use is greatest among what 3 groups of people?
F
H
N
frail elderly
Hospital patients
nursing home residents
- typically a nursing home resident is given 7-8 drugs on a regular basis.
The interaction between two drugs is called - _____
between a drug and a food item is called - ______
between a drug and herbs is called - ______
drug-drug interactions (DDI)
Drug-food interactions
Drug-herb interactions
Types of Drug-Drug Interactions:
____________ - two drugs affecting the same system (effect on the organism) e.g Two sedative drugs will produce more sedation.
Pharmacodynamic Interaction
Types of Drug-Drug Interactions:
__________ - One drug changes the absorpion, distribution, metabolism, excretion (ADME) of another.
Pharmacokinetic Interaction
What changes in a pharmacokinetic interaction?
ADME
absorption
distribution
metabolism
excretion
Drug-Drug Interaction - Examples:
Absorption:
Antacids reduce absorption of _______ (antibiotic)
calcium supplements reduce absorption of _______ (hormone)
tetracycline
thyroxine
Drug-Drug Interaction - Examples:
Distribution:
Competition for plasma protein binding by ________ (N-SAIDs) and ______ (anticoagulant).
Is Plasma protein binding specific or non specific?
non steroidal anti-inflammatory drugs (N-SAIDS)
warfarin (anticoagulant)
nonspecific
Drug-Drug Interaction - Examples:
Excretion:
_______ reduces exretion of penicillin by competition for the ____________.
Which of the 2 drugs is used to treat Gout by reducing reabsorption of uric acid?
Probenecid
kidney tubule transport system
Probenecid
Drug-Drug Interaction - Examples:
Metabolism:
Two drugs metabolized by the same enzyme can compete for the enzyme. (eg. _______)
CYP3A4
Drug-Drug Interaction - Examples:
What is the most common reason for drug-drug interactions?
Metabolism - one drug affecting the metabolism of another drug.
What drug is very notorious in terms of drug-drug interactions (DDIs)?
Warfarin
What are the five major mechanisms and examples of drug interactions with warfarin?
P
Ga
Gu
Wm
I
Altered platelet function
Direct gastrointestinal injury
Altered gut vitamin K synthesis
Altered warfarin metabolism
Interference with Vitamin K cycle
Warfarin DDI:
an example of :
altered platelet function is…
Direct gastrointestinal injury is…
Altered gut vitamin K synthesis is…
Altered warfarin metabolism is…
Interference with vitamin K cycle is…
acetylsalicylic acid, clopidogrel
nonsteroidal anti-inflammatory drugs
antibiotics
co-trimoxazole, metronidazole, fluconazole, amiodarone
acetaminophen
NSAIDs and warfarin interaction
An NSAID greatly increases risk of warfarin ______ because of multiple interactions:
Toxicity
NSAIDs and warfarin interaction
4 reactions that increase the risk of warfarin toxicity due to NSAIDs:
- Protein bound warfarin is ______ by NSAID - what does this cause?
- Nsaids_________________ (anticlotting action) that adds to anticoagulant action of warfarin
- Some NSAIDs prevent ______________________ by competition for the metabolizing enzyme. This causes what?
- NSAIDs directly cause gastric injury and warfarin _____________.
- displaced, increase in free plasma warfarin and causes toxicity
- supress platelet function
- metabolism of warfarin , increase in plasma warfarin and toxicity
- can cause gastric bleeding.
What are the 4 reactions that result from Warfarin NSAIDs interactions?
protein bound warfarin is displaced and increase free warfarin and toxicity
NSAIDs supress platelet function increasing the anticoagulant function of warfarin
Some NSAIDs prevent metabolism of warfarin by competition for the metabolizing enzyme - which increases warfarin and toxicity
NSAIDs directly cause gastric injury and warfarin can cause gastric bleeding.
Drug metabolism Interactions
When should the possibility of drug interactions resulting from metabolism be considered?
when a patient is taking 2 or more drugs
Drug metabolism interactions:
When should interactions with food items or herbal medicines be considered?
When a patient is taking a single drug metabolized by Cytochrome P450 enzymes
Drug metabolism Interactions
When should genetic variation of metabolizing enzymes be considered?
in cases of drug toxicity or treatment failure.
DDI Summary:
What out for DDIs in:
1.
2.
4.
the elderly
receiving more than 2 drugs
receiving warfarin, NSAIDs, antiplatelets, statins, thyroxine, statins, thyroxine
New signs/ symptoms after starting a new drug - investigate for DDI or ADR(adverse drug reaction)
ADR stands for?
adverse drug reaction
P-glycoprotein is a(n) _________.
What does it do?
Whats it’s specificity ?
Where is it located?
efflux pump (in to out)
uses energy (ATP) it removes compounds from inside to the outside .
has a broad substrate specificity for drugs - digoxin, quinidine, and others.
Many sites (luminal surfaces) :
- colon, small intestines
- kidney tubules
- brain
- liver- bile canaliculi
- Placenta
- cancer tissue (lots located here)
digoxin does what?
increases contraction and can lead to heart failure. Very toxic
P-glycoprotein expression is increased or incduced by what 2 drugs?
It is inhibited by what 4 types of drugs?
St. John’s Wort, Rifampin
verapamil, quinidine, macrolide antibiotics (erythromyacin) , antifungals
P-glycoprotein in the blood brain barrier do what?
What mechanism is used?
protects the central nervous system (CNS) from a variety of structurally diverse compounds .
done through its efflux mechanisms
P-glycoprotein plays a clinical role in drug resistance to ____________.
P-glycoprotein is over expressed in ________.
after exposure to anticancer agents , and it pumps out the _____________.
cancer chemotherapeutic agents
tumor cells (eg. actue myelogenous leukemia)
anticancer drugs
drugs such as calcium channel blockers, __________ and _________ inhibit P-glycoprotein and may be useful to reverse resistance .
phenothiazines and cyclosporin A
Enterohepatic recirculation
Entero —> ______
Hepatic —> ______
a compound is conjugated in the _____, excreted in the ______, deconjugated in the _______ (by bacterial enzymes) and is reabsorbed into the circulation.
Gi Tract
Hepatic
liver, bile, intestine
What phenomenon prolongs the duration of action (half-life) of a drug?
Enterohepatic recirculation
Enteroheatic Recycling :
Bile acids are conjugated in the ____ to ______ and ____ and excreted in the intestine where they are ________.
What percent of bile salts are reabsorbed and used in cholesterol synthesis?
liver, taurine, glycine, deconjugated
95%
If we give a bile acid biding resin such as __________ or _________ we interrupt the enteropeatic recycling of bile salts and does what to cholesterol synthesis and plasma levels?
cholestyramine or metamucil
reduce cholesterol synthesis and plasma levels.
Entero-Hepatic Recirculation - clinical significance
Oral contraceptive failure when ___________.
____________ is excreted via bile duct and is eliminated by bacteria in the intestines producing _____. This interrupts enterohepatic cycling.
antibiotic is taken.
Estrogen glucuronide , Estrogen.
An ______ such as rifampin also induced ____ enzymes that metabolize the contraceptive hormones and thus reduces their effectiveness.
antibiotic
CYP enzymes
_______ is the volume of blood from which a drug is irreversibly removed per unit of time.
Whats the units?
Clearance
ml / min (/kg)
What are clearance values useful for ?
Rate of administration (maintenance dose) = ________
Whole body (systemic) clearance of a drug is…..
calculate maintenance dose of drug.
i.e. the dose that will allow us to maintain as steady-state concentration of a drug in the plasma
Rate of Elimination.
sum of clearance of that drug by all organs. (liver, kidney, lungs ect.)
Systemic clearance = clearanceliver + clearancekidney …
Renal Clearance:
______ is a passive process. The kidney does not filter what kind of drug?
What kind of drug is filtered at the glomerulus?
Filtration
protein bound drugs aren’t filtered
free drug is filtered
Renal Clearance
Some drugs:
_______ (low pKa) and _______ (high pKa) are secreted where?
Is this process active or passive?
strong acids
strong bases
mainly secreted in the proximal tubule.
Active process with separate transporters for anions and cations.
Renal Clearance:
Unless the drug is _______, some of it is going to be reabsorbed.
very polar
Renal clearance:
What is the net removal formula?
Filtration of free drug takes place where?
Where does secretion and reabsorption take place?
Net removal = filtered + secreted - reabsorbed
Glomerular capillaries
Vessels surrouning the tubules.
What 3 processes in the kidney help remove drugs from the body?
Filtration
Secretion
Reabsorption.
Drug Elimination Kinetics
Most drugs are eliminated according to a _______________.
A _____________ of drug is eliminated per unit of time.
Rate of elimination is proportional to what?
Blood concentration declines in a(n) ________ over time ie decreases at a rate that is proportional to its current value.
First order rate process
Constant fraction
proportional to the plasma concentration
exponential fashion.
Define First -order rate of elimination.
When 40 molecules of drug is distributed evenly throughout 5 compartments, how many molecules will reach the enzyme in the liver after equilibrium?
a constant fraction of drug is eliminated per unit of time.
40 x 1/5th = 8 molecules in the liver
Zero-order Elimination
Define Zero-order:
a constant amount of drug is eliminated per unit of time because that is the maxiumum rate of elimination when the pathway for elimination is saturated.
Zero-Order Elimination
this metabolic mechanism for most d rugs will be saturated when?
are the doses for this rate process commonly used in therapeutics?
at very high concentrations
No
Zero-order Elimination
The metabolic capacity for very few drugs becomes saturated at concentrations within the _________:
What are some examples?
therapeutic range
eg. phenyton, asperin (acetylsalicylic acid -ASA) , carbamazepine, ethanol
Half-life and its clinical significance
Define Half-life:
Half life applies to drugs that are eliminated by what processing rate?
For practical purposed it takes about _ half-lives for more than 90% of a drug to be effectively eliminated from the body.
the time required for the blood(or plasma) concentration of a drug to be reduced by 50%
first order rate of elimination
5
Half-life and its clinical significance
What is required for a drug to achieve steady-state concentrations in the plasma?
Steady concentration is defined as?
Example Q: If the half-life of a drug is 20 hours, then it will reach steady concentrations after what amount of time?
a fixed dose given at fixed intervals, its takes 5 half-lives for that drug to reach steady-state concentrations in the plasma.
where high elimination rate equals the administration rate.
5x20 = 100 hours.
Time to steady-state or elimination is indpendent of ______.
Time required to reach steady state depends on ________ rate.
How many half lives are requried to reach 97% of steady state?
How many half lives are required to eliminate 97% of drug?
dosage
elimination rate
5
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