Pharmacokinetics, drug interactions Flashcards by Cody Nelson

________ - produces pharmacological action

free drug

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drug bound to plasma protein is most likely ________

inactive

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Displacement of a drug from plasma protein binding generaly causes ….

no change in its overall effect or adverse effects

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Most drug is extravascular, so a change in free plasma drug concentration caused by displacement from plasma protein binding would be ______

minimal

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Most drug is intravascular, so a change in free plasma drug concentration caused by displacement from plasma protein binding would have _________

significant effects

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After absorption a drug is …

distributed to various body compartments

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Distribution

the REVERSIBLE movement of a drug between body compartments

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Factors that affect distribution from the general circulation to other tissue compartments are:

(4) ICBP

Ionization

Capillary permeability

Blood Flow

Plasma protein binding

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Capillary Permeability:

In the _____, ______, and ______, the capillaries are very leaky.

kidney, liver and spleen

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Capillary Permeability:

what do drugs doregardless of whether they are poorly lipid soluble, charged, or polar?

drugs leave the capillaries regardless

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Blood Brain Barrier

Brain capillaries have __________

tight junctions

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Blood-Brain Barrier

Only __________ drugs diffuse across brain capillaries

(unless other drugs are actively transported across)

lipophilic drugs

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__________ exist between endothelial cells in the brain capillary

tight junction

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Blood Brain Barrier

Clinical implication:

The degree to which drugs penetrate the ____ should be known to treat diseases of the nervous system properly.

brain

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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

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Dopamine’s precursor can be used to treat what disease of the central nervous system?

Parkinson’s disease

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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

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Blood Brain Barrier

Clinical implication:

The Blood brain barrier does not work properly in ares of ______ or _____

infection or injury

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Blood Brain Barrier

Clinical implication:

______ of the brain develop new blood vessels and capillaries that have NO tight junctions.

Tumors

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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

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Blood flow:

The tissue that receives more ______ receives more _____.

drug, blood

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Blood flow:

____, _____, _____ receive more blood flow than

skeletal muscle. Whereas fat and _____ receive little blood flow.

Brain, liver, kidneys

skin

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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

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When we administer a drug, it distributes into many compartments - aka _________

volume of distribution (Vd)

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\_\_\_\_\_\_ - 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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: ## Footnote 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: ## Footnote 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. 1. Increased effect, toxicity 2. Decreased effect, treatment failure 3. 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: 1. Protein bound warfarin is ______ by NSAID - what does this cause? 2. Nsaids\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ (anticlotting action) that adds to anticoagulant action of warfarin 3. Some NSAIDs prevent ______________________ by competition for the metabolizing enzyme. This causes what? 4. NSAIDs directly cause gastric injury and warfarin \_\_\_\_\_\_\_\_\_\_\_\_\_.

1. displaced, increase in free plasma warfarin and causes toxicity 2. supress platelet function 3. metabolism of warfarin , increase in plasma warfarin and toxicity 4. 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. 3. 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) : 1. colon, small intestines 2. kidney tubules 3. brain 4. liver- bile canaliculi 5. Placenta 6. 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 = clearance_liver+ clearance_kidney ...

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 5