Pharmacokinetics lecture Flashcards
5/31/19
Pharmacokinetics
Foucsed on how drugs are handled in the body from the time they enter to elimination
4 main processes of pharmacokinetic events
1) absorption - entrance of drug into blood stream
2) distribution - moving from blood stream into tissues of body
3) metabolism - physical and chemical alterations that a substance undergoes in the body
4) excretion - eliminating waste products of drug metabolism
Plasma drug concentration time curve (time response curve)
For most drugs, there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma, therefore the plasma drug conc. can be determined to theorize the impact it is having at its site of action (which typically cannot be measured)
Onset of action
T0 to T1, btwn administration and time effect begins at the MEC
Duration of action
T1 to T3, lengh of time to which the drug is above the MEC
Time to peak
T0 to T2, time for peak action of the drug
Drug absorption is bypassed by drugs that are administered via…
…directly in the blood stream
Drug characteristics that make it easier to be absorbed
- More lipid soluble
- More nonpolar
Common sites of absorption of drugs
1) mucosa of stomach, mouth, small intestine, or rectum
2) Blood vessels in muscles or subcutaneous tissues
3) dermal layer
Lipid bilayer
Impermeable to water and other non lipid soluble substances, may allow passage of small molecules through channels or transporters
Most common mechanism of drug absorption
passive diffusion
Fick’s law
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Facilitated transport
Passive process to carry drug molecules passively down a conc. gradient facilitated through a carrier molecule
Active transport
Requires ATP and carrier molecules to move a drug from a low to high conc area in an active process
Endocytosis
Minor method by which some drugs are transported into cells
Route of drug administration
Determine rate and efficiency of absorption, depend on the physical and chemical properties of the drug, intended site of action, and desired onset
Oral administration
Used whenever possible, safest and most convenient route, onset of action is 30-60 min, most absorption occurs in small intestine, drug enters liver and can be metabolized
First pass effect
Occurs when a drug is largely metabolized by the liver before reaching systemic circulation, often requires administration of higher dose as a result
Sublingual administration
Used whenever rapid effects are needed, absorption directly through oral mucosa into blood stream, few minute onset of action, avoids first pass
Rectal administration
Often used when a localized effect is needed or another route is not feasible (unconscious or vomiting), onset is 15-30 min, retention varies by patient
Disadvantages of alimentary administration
Rate of absorption varies, can be a problem if small range in blood levels separates desired therapeutic and toxic effects, patient compliance is not ensured, first pass effect
Parenteral administration
Sterile injection of a drug such as intraveonous, subcutaneous, intramuscular, etc
Intravenous administration
Bypasses absorption barrier, onset in several minutes, insoluble drugs cannot be delivered via IV
Subcutaneous administration
Often done for drugs inactivated by stomach, action is several minutes
Intramuscular administration
Onset of several minutes, provide sustained drug injection over period of time
Advantages of parenteral administration
More rapid response time, dose can be more accurately delivered, feasible when alimentary path not possible, large volumes can be administrated
Disadvantages of parenteral administration
Rapid absorption can lead to adverse effects, sterile formulation and aseptic technique. local irritation at site of injection, not suitable for insoluble substances
Topical administration
Most oitments, gels, creams are applied to skin, eye or ear for local effects with onset of 1 hour, systemic absorption is relatively minimal
Transdermal drug deliver systems
Provide continuous drug delivery (nicotine patches, birth controls)
Inhalation administration
Lungs have large surface for absorption with onset within 1 min, effects can be local or systemic
Intranasal administration
DRug absorption can cause either local or systemic effects
Vaginal administration
Local effects with onset of 15 minutes
Most drugs are ______ acids or _____ bases
Weak, weak
Weak acids are more likely to be absorbed where and why?
In the stomach, because it has a very low pH
Weak bases are more likely to be absorbed where and why?
The duodenum because it has a neutral pH 5-7
Drugs that affect the pH of the intestine can have an impact on…
…other drugs that need to be absorbed
Presence or absence of food in stomach
- Food in stomach tends to slow absorption due to slower emptying of stomach
- Some foods may interact with drugs, preventing or greatly reducing absorption
- Some medications can be irritating to the stomach but buffered by food
Drug formulation (solubility)
- Tablets and capsules require time for dissolution to occur
- Liquid generally absorbed faster
- Smaller size of drug particle, faster rate of dissolution and absorption
Decreased intestinal motility can result in…
…prolonged contact of drug with mucosa and therefore increased absorption
Bioavailibility
Amount of drug dose that reaches the systemic circulation ex) if 100mg administered and 50mg reaches blood stream, 50% bioavailable
Determination of bioavailability
Comparing plasma levels of drug after particular route of administration compared to levels achieved by injection, which has a bioavailibility of 100%
Bioavailability determination
- physical and chemical characteristics of the drug
- formulation
Bioequivalence
Indicates that a drug in two or more similar dosage forms reaches the general circulation at the same relative rate to the same relative extent
A rated drug
FDA has named the generic drug as therapeutically equivalent to the brand name drug
B rated drug
FDA has named the generic drug has bioequivanlent problems to the brand name drug
AB rated drug
FDA has named the genric drug has bioequivlanet problems to the brand name drug that has been resolved by evidence and study to be therapeutically equivalent
Therapeutic interchange
Different drugs that have the same pharmacological and or therapeutic effects
example of therapeutic interchange
Ibuprofen (motrin) and naproxen (aleve)
Factors that determine how much drug reaches any one organ or area
- physical or chemical characteristics of drug
- cardiac output
- plasma protein binding
- blood flow to tissues
- Presence of specific tissue barriers
Volume of distribution
Ratio of total drug in the body to the concentration of the drug in the plasma
If Vd=42L, if Vd=5.5L
Drug is evenly distributed, drug is conc. in plasma
If Vd>42L
Drug is sequestered in a depot, usually adipose tissue
Plasma protein binding
Several different proteins in plasma can have drugs reversibly bind to them, ratio of bound/unbound varies on a drug by drug basis, bound drugs are pharmacologically inactive, protein binding drugs have a long duration of action, some drugs can displace others that bind protein
Can disease states affect amount of protein binding?
yee
Sites of drug storage
- Adipose tissue (lipid soluble drugs)
- Bone (tetracycline will bind calcium permanently)
- Muscle
- organs
Drug elimination chemical alterations
Made inactive and more polar to improve ability to remove through kidney
Importance of inactivation of drugs to allow for renal secretion
Without, it would take years to remove from the body
Prodrugs
Compounds pharmacologically inactive as administered then undergoes conversion into active form while in the body
Sites of metabolism of drugs
Primarily in the liver
Phase 1 (nonsynthetic) metabolism
Function to increase polarity of drug molecule, a site for phase 2 metabolism as well, involves oxidation, reduction, and hydrolysis
Phase 2 (synthetic) metabolism
Coupling of a drug or its metabolite with endogenous substrate to conjugate it and increase greatly the polarity and enhance secretion
Oxidation, reduction, hydrolysis
Types of phase 1 metabolism, oxidation is most common
Metabolic induction
When some drugs are taken repeatedly, they stimulate the drug microsomal meetabolizing syndrome, increasing the amount of enzymes and faster rate of drug metabolism, duration of action is decreased for all drugs metabolized by cytochrome P-450, formulates tolerance
Metabolic inhibition
Some drugs inhibit rather than induce production of microsomal enzymes, excess drug may accumulate in the body and the dose requirement may need to be reduced to avoid toxicity
Liver function and drug metabolism
Can see compromised drug metabolism abilities, newborns and fetuses lack microsomal enzyme system
Renal excretion
Primary method of drug excretion, drug filtered through glomerulus, some are reabsorbed, but the more polar they are the less likely they are to be resorbed
GI excretion
Certain drugs can enter the intestines by the way of the biliary tract, after being released in the intestines, can be absorbed into the blood again
1st order kinetics
For most drugs is proportional to the plasma concentration, conc. of drug diminishes logarithmically with time
zero order kinetics
Occurs when drug elimination does not change with time
2 compartment model
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Clearance
Volume of plasma cleared of drug per unit time (ml/hr)
2 major sites of clearance
1) liver (metabolic clearance)
2) kidneys (renal clearance)
Goal of dosing interval
To dose within time frame so that drug levels remain in therapeutic range repeatedly for however long desired result is required
Delayed release purpose
To create a dosing interval that gives a steady state concentration in the therapeutic zone
Additive character of clearance
Dividing rate of elimination at each organ by conc. of drug presented to it yields the respective clearance of that organ, which can all summate to total clearance by the body
If mechanisms of elimination become saturated….
…Then first order kinetics no longer is method of drug removal, zero order kinetics is
Importance of plasma drug levels
Because it is impractical to measure a drug conc. at the site of action, there is a direct correlation btwn therapeutic or toxic dosages and amount of drug present in plasma.
Minimum effective conc.
The lowest plasma drug levels for which therepeutic effects will occur - to be beneficial drug conc. must be at or above this value
Toxic conc.
The plasma drug levels for which toxic effects will occur - to be beneficial drug conc. must be below this value
Therepeutic range
Space between minimum effective conc. and toxic conc. that a drug can produce a therapeutic response
Width of therapeutic range can vary. Why is this a problem?
A small therapeutic range dictates the ease at which a drug can be administered safely or not
Plateau drug levels
When the amount of drug entering the body in the therepeutic range equals the rate at which it is being removed from the body
Cpss max
Peak level of a dosing interval
Cpss min
Trough level of a dosing interval
Cpss avg
Avg concentration level achieved between the peak and trough of dosing interval
Time required to achieve steady state is not based on _________, but rather requires ______
dosage size, 4-5 half lives to reach
Continuous infusion
Drug administration technique that keeps plasma levels nearly constant
Reducing dosage size and increasing frequency
Drug administration technique deccreases the fluctuation between dosages
Age impact on drug metabolism
- Fetus and premature infants lack drug metabolizing enzymes
- Children can metabolize drugs more quickly than adults
- elderly things fall apart
Sex/race impact on drug metabolism
-Sex/race differences have been observed in some cases on ability to metabolize drugs
