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What is pharmacokinetics?
The study of drub movement throughout the body.
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Why do we study pharmacokinetics?
To determine the best dose and dosing interval for a patient, to determine the most advantageous route of administration of a drug for the patent and to make adjustments to dosage based on the patients ability to eliminate the drug from their body.
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What are the three phases of pharmacokinetics?
Absorption, Distribution and Elimination
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What is absorption?
How the drug gets in the body. The movement of a drug from its site of administration to the blood stream.
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What is distribution?
How the drug gets around the body.
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What is elimination?
How the drug gets out of the body by metabolism and/or excretion.
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What is the main barrier to absorption of a drug in the body?
Cellular membranes made of lipid molecules
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What are the three characteristics that allow a drug to cross cellular membranes?
They must be lipid soluble, they must mimic an endogenous agent that is normally transported across the cellular membrane (like levadopa) or they must be small enough to fit through the pores of the membrane (MW < 200, lithium is only one).
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What are the characteristics of a lipid soluble drug?
They are nonpolar, have few or no OH groups or charged nitrogen atoms. Drugs with benzene rings are usually very lipid soluble.
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What condition must a weak acid or weak base meet to cross the membrane?
They must be non-ionized.
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What four factors affect absorption of a drug?
- 1. Rate of dissolution
- 2. Surface area contact of the molecules of the drug and the membrane to be crossed.
- 3. Lipid solubility
- 4. Likelihood that it will be ionized after absorption
- How do drugs administered intramuscularly enter the blood stream?
- Through fenestrations in the capillary walls.
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What is a good route to administer drugs that are not in solution?
Intra-muscular (IM)
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What is a good route to administer drugs in solution, suspension or emulsion?
Subcutaneous (SQ)
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Why is absorption slower in SQ than in IM?
Because the subcutaneous space is poorly vascularized.
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What are some factors that influence absorption of drugs by oral administration?
Solubility, pH, food, enteric coatings, transit time, interaction with other drugs, and gastric emptying time.
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Where is a topical drug administered?
At its site of action.
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Where is the concentration of a topical drug greatest?
At its site of action. The process of absorption and distribution dilutes the drug.
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Where is the site of action for a transdermal drug?
Systemic via the bloodstream.
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What are the solubility characteristics of a transdermal drug and why?
Must be lipid soluble to get through the skin and into the bloodstream. It must enter the bloodstream at therapeutic levels.
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How do inhaled drugs get into the blood stream and work systemically?
They must cross the pulmonary epithelium and enter the pulmonary capillaries. From their they are transported systemically by the bloodstream.
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What is bioavailability?
The fraction of an orally administered drug that reaches systemic circulation.
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What are two components of bioavailability?
Absorption and first pass metabolism.
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What is first pass metabolism?
The amount of drug that is metabolized in the liver before it enters systemic circulation.
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When is a drug considered eliminated?
When the drug molecules are changed through metabolism.
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When is a drug considered orally inactive?
When all the molecules of a drug have been destroyed by first pass metabolism.
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Can charged (ionized) drugs leave circulation? Why?
Yes, they cannot pass through the membrane of the endothelium, but they can leave through the fenestrations in capillaries.
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Why is it important for drugs to be able to leave the circulation and enter tissues?
Drugs must be able to get to peripheral tissues where the receptors might be.
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Under what circumstances can a drug not leave circulation and reach peripheral tissues?
If the drug is bound to albumin plasma protein) it will not leave circulation or be eliminated.
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What are three reasons the blood-brain barrier is harder to cross than other epithelium?
- 1. Capillaries are not fenestrated in the brain.
- 2. Basement membrane is continuous in brain capillaries
- 3. Astrocytic foot processes cover the exterior surface of capillaries
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What kinds of drugs can cross the blood-brain barrier?
Lipid soluble or drugs that have transporters.
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Name two types of drugs that have difficulty crossing the placental barrier.
Charged drugs and protein drugs (insulin and cytokines)
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What are three ways you can treat a fetus by treating a mother?
- 1. Supplemental oxygen
- 2. Antibiotics
- 3. Steroids (lung development)
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What are two kinds of drugs that can cause harm to fetus?
- 1. teratogens (cause birth defects)
- 2. opioids and other respiratory depressors
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What categories of drugs will definitely harm the fetus?
Category X
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What categories of drugs show good evidence that they will not harm the fetus?
Category A
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What are the drugs categories for which there is less evidence one way or another whether they will harm the fetus?
- Categories B, C and D
- What are the enzymes that work on drugs in the liver collectively known as?
- Cytochrome P450 enzymes or microsomal enzymes
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What is conjugation?
The process by which a polar group is attached to the drug molecule rendering it less lipid soluble and more likely to be excreted in urine.
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What are three molecular groups that are used in conjugation?
Acetate, hydroxyl and glucuronide
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What are four byproducts/effects of metabolism? Give an example of each.
- 1. Inactivation - procaine to PABA
- 2. Increased effectivness. – codeine is transformed into morphine
- 3. Activation of a prodrug – Prazepam to desmethyldiazepam
- 4. Drug toxicity – acetominophen, when taken in too high a quantity triggers another kind of metabolism which renders the metabolite toxic. Liver toxicity due to acetominophen is the leading cause of liver failure in the US
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What is the main difference between an active and inactive metabolite?
Active metabolite continues the action of the drug. Inactive metabolites halt action of the drug after enough molecules are metabolized.
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What are two ways to test for liver function and which is better?
Testing for an elevation of liver enzymes and testing for plasma proteins. Although an elevation in liver enzymes is an indication of dying liver cells, it does not represent the number of live livers cells. Since plasma proteins are synthesized in the liver, a low level of plasma proteins (like albumin) would be a good indicator of liver disease.
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What is one situation in which one drug would interfere with the metabolism of another drug?
If the drug inhibits the action of the cytochrome P450 enzymes.
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Should the dose of a drug with hepatic metabolism be increased or decreased in the case of liver disease and why?
The dose of the drug should be decreased, because if there is liver disease, the drug will not be fully metabolized and it may enter the bloodstream at toxic levels.
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What is an inducer?
A drug that speeds up hepatic metabolism causeing less to be available systemically.
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What is the indication when creatinine clearance is low?
- Low creatinine clearance indicates that renal function is poor, leading to a slower than normal elimination/excretion of a drug.
- What is enterohepatic circulation?
- When drugs end up in bile and are reabsorbed into the intestines ending up back in the bloodstream.
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Why is it important to know the level of drugs in the plasma?
Because the concentration of the drug in the plasma and the concentration of drug at the site of action are directly related. The more in the plasma the more will be at the site of action.
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Is the concentration of drug in the plasma the same as the concentration at the receptor?
No. It just tells us what concentration is reaching the receptors.
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What is half-life?
The time it takes for half of a drug to be eliminated.
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How is half-life measured?
Using plasma concentration levels. In one half life, the plasma level will decrease by ½.
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What is the relationship between half-life and rate of elimination?
Half-life determines the rate of elimination. The more drug present, the faster it is eliminated.
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How many half-lives does it take to almost completely eliminate a drug from the body?
4 – 5. Five half-lives eliminates 96% of a drug.
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What is an example of a drug without a half-life and what does this mean about its metabolism?
Alcohol. This means that alcohol is absorbed at a constant rate no matter how much is present.
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What are five factors that influence half-life of a drug?
- 1. Heredity
- 2. Hepatic disease
- 3. Renal disease
- 4. Concurrent therapy with a drug that induces metabolism
- 5. Concurrent therapy with a drug that inhibits metabolism
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What happens to half-life of a drug it is given concurrently with another drug that induces metabolism?
Half-life decreases
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What happens to half-life of a drug if it is given concurrently with another drug that inhibits metabolism?
Half-life increases
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What is the effect on half-life when a person has renal disease?
When a person has renal disease, renal excretion slows down and half-life increases for drugs that are eliminated by renal excretion.
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What is the effect on half-life when a person has hepatic disease?
When a person has hepatic disease metabolism is inhibited and half-life increases for drugs that are eliminated by hepatic metabolism.
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What adjustments to dose will be made for someone who has decreased metabolism?
The dose will be decreased so that toxic levels will not remain in the body.
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What adjustments to dose will be made for someone who has increased metabolism?
The dose will be increased to maintain therapeutic levels.
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What is steady state?
The point at which the dose of a drug is equal to the amount of drug eliminated during the dosing interval.
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What is a good solution to a drug dose that peaks into the toxic range and troughs into the ineffective range?
Decrease the dosing interval maintaining the same dose. This will shorten the peaks/troughs while maintaining the same mean plasma concentration of the drug.
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What route of administration is good for drugs that have extremely short half-lives?
Continous IV infusion.
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What route of administration is good for drugs where a steady plasma rate is very important?
Continous IV infusion
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What is a loading dose?
A large dose given at the beginning of therapy.
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What is the purpose of loading dose?
It helps in reaching a therapeutic dose more quickly.
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