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Adv Pharm > Chapter 4: Pharmacokinetics, Pharmacodynamics Drug Interactions > Flashcards

Chapter 4: Pharmacokinetics, Pharmacodynamics Drug Interactions Flashcards

1
Q

pharmakinetics

A

Pharmacokinetics is the study of drug movement throughout the body
Pharmacokinetics also includes drug metabolism (biotransformation) and drug excretion
Passage of drugs across membranes
Action of body on the drug *

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2
Q

Pharmacodynamics

A

The study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced
The study of what drugs do to the body and how they do it
action of drug on the body*

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3
Q

pharmacokinetics: absorption

A

movement of drug from site of administration into the blood

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4
Q

pharmacokinetics: distributions

A

movement of the drug form the blood to the interstitial spaces, tissues and body cells (site of action)

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5
Q

pharmacokinetics: metabolism

A

biotransformation, enzymatic mediated alternation of the drug structures
most often takes place in the liver
hepatic micrsomal enzyme system 450 sysem

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6
Q

pharmacokinetics: excretion

A

movement of drugs and their metabolites out of the body
both metabolism and excretion together

Defined as the removal of drugs from the body
Drugs and their metabolites can exit the body through urine, sweat, saliva, breast milk, or expired air

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7
Q

passage of drugs across membranes

A

channels and pores -only smallest of componds (K, Na) can pass thru channels and pores
transport systems (p-glycoprotein) -selective, depeonds on structure of drug
direct penetration of the membranes (mot common, like dissolves like -cell membranes are primarily lipids, to penetrate drugs must be lipid solable)

For most drugs, movement throughout the body is dependent on the drug’s ability to penetrate membranes directly
Most drugs are too large to pass through channels or pores
Most drugs lack transport systems to help them cross all of the membranes that separate them from their sites of action, metabolism, and excretion

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8
Q

p-glycoprotein

A

P-glycoprotein: Transmembrane protein that transports a wide variety of drugs out of cells
Liver: Transports drugs into the bile for elimination
Kidney: Pumps drugs into the urine for excretion
Placenta: Transports drugs back into the maternal blood
Brain: Pumps drugs into the blood to limit drugs’ access to the brain

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9
Q

Polar molecules

A

No net charge, uneven distribution of a charge (pos and neg charges within the molcule tend to congregate separate. Ex. Water.

Polar dissolves in polar solvents

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10
Q

Ions

A

moleculs that have a net electrical charge
can only cross membrane if very small compound, most mst be nonionizd to cross membrane

most drugs are either weak organic acids or weak organic bases, which can exist in charged and uncharged form -electrical charge depends on the pH of surrounding medium.

Quaternary ammonium compounds
Molecules that contain at least one atom of nitrogen and carry a positive charge at all times

pH-dependent ionization
Acid is a proton donor: Tends to ionize in basic (alkaline) media. acid is best absorbed in acdic environment ex gastric acid.
Base is a proton acceptor: Tends to ionize in acidic media

Ion trapping (pH partitioning)
drgs tend to go to the side that favors their ionization
Acidic drugs accumulate on the alkaline side
Basic drugs accumulate on the acidic side

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11
Q

absorption

A

Movement of a drug from its site of administration into the blood
The rate of absorption determines how soon effects will begin
The amount of absorption helps determine how intense the effects will be

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12
Q

factors affecting drug absorption

A

Rate of dissolution

Surface area
Lager = more absorption

Blood flow
More flow = more absorption

Lipid solubility
Lipid solvable absorbed quickly bc they can cross lipid cell membrane

pH partitioning
Greater absorption with differences bc the pH of plasma and pH at site of administration such that the drug has greater tendency to be ionized in the plasma

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13
Q

IV admin

A

Barriers to absorption: none
Absorption pattern: instant
Advantages: rapid onset, reach peak levels
Disadvantages: irreversible, must be water soluble

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14
Q

IM admin

A

Barriers to absorption: cap walls are easy to pass, blood flow to tissue is important
Absorption pattern: rapid with water soluble, slow with poorly soluble drugs
Advantages: good way to admin poorly soluble drug, allows for depot prep
Disadvantages: discomfort and potential for injury

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15
Q

SQ admin

A

No significant barriers to absorption
Similar to IM

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16
Q

oral admin

A

Barriers to absorption: the epithelial lining of the GI tract so y need to have adequate cellar structure there to facilitate absorption
Absorption pattern: slower and chance for variability
Drug movement after absorption: allow absorption to take place, also first pass effect (oral meds have to go to liver for biotransformation)
Advantages: easy admin, potentially reversible
Disadvantages: inactivation from gastric acid and digestive enzymes, availability of the drug depends on the first pass in the liver

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17
Q

pharm preps for oral admin

A

Tablets
Take time to dissolve

Enteric-coated preparations
Coating over tablet that takes time to dissolve
Pass thru gastric and absorbed in small int

Sustained-release preparations
Developed so med is all dissolved and absorbed at the same time
Bits of release as time passes

Liquids
More dissolved than tablet

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18
Q

additional routes of admin

A

Topical
Gels absorbed quickly
The more liquid the base, the faster the absorption
Lotions absorpted more quickly than creams and creams absorbed more quickly than oint

Transdermal
patches

Inhaled

Rectal

Vaginal

Direct injection to a specific site—for example, heart, joints, nerves, central nervous system

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19
Q

3 factors distribution is determined by

A

BF to tissues
exiting the vasclar system
entering cells

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20
Q

distribution: BF to tissues

A

Drugs are carried by the blood to tissues and organs of the body

Blood flow determines the rate of delivery

Abscesses and tumors
Low regional blood flow affects therapy
Pus-filled pockets rather than internal blood vessels
Solid tumors have a limited blood supply

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21
Q

distribution: exiting the vasclar system

A

Typical capillary beds
Drugs pass between capillary cells rather than through them
lipid solable can pass thru cells

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22
Q

blood-brain barrier

A

Capillaries of the central nervous system have tight junctions that prevent free diffusion

Drugs must be able to pass through the cells of the capillary wall

Only drugs that are lipid soluble or that have a transport system can cross the blood-brain barrier to a significant degree

not fully developed at birth -more sensitive to CNS drugs, can delvelop quickly

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23
Q

placental drug transfer

A

Membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs
Movement is determined in the same way as it is for other membranes

Risks with drug transfer
Birth defects: Mental retardation, gross malformations, low birth weight
Mother’s use of habitual opioids: Birth of drug-dependent baby

ionized, highly polar, protein bound drugs, and drugs that are substrates for the GP transporter excluded

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24
Q

distribution: protein binding

A

Drugs can form reversible bonds with various proteins

Plasma albumin is the most abundant and important protein -% of drg molecules bound depends on the strength of the attraction beteen albumin and drug
Large molecule that always remains in the bloodstream
Affects drug distribution

ex. warfarin and albumin have a strong attraction ~99% of drug is bond. Gentamicin has weak attracion to albmin, only ~ 10% is bound.

can cause drug interactions. drugs compete for binding sites on albmin. drugs become free form and increase intensity of bodys response to drug, can be toxic

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25
Q

distribution: entering cells

A

Some drugs must enter cells to reach the site of action

Most drugs must enter cells to undergo metabolism and excretion

Many drugs produce their effects by binding with receptors on the external surface of the cell membrane
These do not need to cross the cell membrane to act

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26
Q

hepatic drug-metablizing enzymes

A

Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, which is also known as the P450 system
Metabolism does not always result in a smaller molecule

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27
Q

therapuetic consequences of drug metabolism

A

Accelerated renal drug excretion

Drug inactivation

Increased therapeutic action
Ex. Codeine turns into morphine

Activation of prodrugs
Compound that is inactive when administrated, then is metabolized into active fom
Advantage if drug can’t cross BBB

Increased or decreased toxicity
Conversion of tylenol produces hepatotoxic metabolte

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28
Q

special considerations in drug metabolism

A

Age
Infants liver is not fully active until 1y
Old decrease in metabolism

Induction or inhibition of drug-metabolizing enzymes
Drugs that are p450 substrates
Inducers increased metabolism by stimulating enzyme synthesis -> decrease active drug
Inhibiters decrease metabolism -> increase in active drug

First-pass effect
rapid hepatic inactivation of certain oral drugs. when drugs are absorbed thru GI tract, they go to the liver via hepatic portal vein before systemic circ, drug could be inactivated on first pass thru liver -no therapuetic effect. give drug parentally to prevent this.

Nutritional status
Cofactors need to metabolism

Competition among drugs
Decreases rate at which one or both metablized
Drugs can accumulate -> toxic

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29
Q

enterohepatic recirculation

A

Repeating cycle in which drug is transported
From the liver into the duodenum (via the bile duct)
Back to the liver via the portal blood

Limited to drugs that have undergone glucuronidation (converts lipid soluable drugs to water soluable forms by binding to glucronic acid)
Glucuronide can be removed in duodenum, allowing for transport back across the intestinal wall into blood
allows drug to stay in body longer

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30
Q

Renal routes of drug excretion

A

Glomerular filtration
Small drugs are pushed out thru cap wall to tubular urine. Drugs bound to albumin are too big to pass thru urine, so stay in blood

Passive tubular reabsorption
[ ] of drug is lower in blood than tubule. This [ ] gradient is a driving force to move drugs from tubules back into blood
Lipid soluable drugs readily cross membrane -> passive reabsorption back into blood.
Nonlipid soluable remain in urine and excreted.

Active tubular secretion
Active transport system that pumps drugs from blood to urine

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31
Q

nonrenal route of drug excretion

A

Breast milk

Other nonrenal routes of excretion
Bile - drugs that do not undergo Enterohepatic recirculation excrete thru feces
Lungs (especially anesthesia)
Sweat/saliva (small amounts)

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32
Q

time course of drug responses

A

Plasma drug levels
Single-dose time course
Drug half-life
Drug levels produced with repeated doses

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33
Q

plasma drug levels: clinical sigificance

A

providers monitor PDL to regulate drug responses.
drug responses rt drug [ ] at site of action (near impossible)
direct corrlation between therapuetic and toxic responses and the amount of drug present in the plasma

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34
Q

plasma drug levels: 2 plasma drug levels defined

A

Minimum effective concentration MEC
Plasma drug level below which therapeutics effects will not occur
To be effective drug must be above this level

Toxic concentration
Levels of drugs too high
See toxic effects

35
Q

plasma drug levels: therapuetic range

A

The objective of drug dosing is to maintain plasma drug levels within the therapeutic range

How wide this is is a determinant of the safety level of a drug
Narrow is unsafe

36
Q

single-dose time course

A

The duration of effects is determined largely by the combination of metabolism and excretion
For drug levels above the minimum effective dose, the therapeutic response will be maintained
Drug levels rise with aborption and decrease with metabolism

37
Q

half-life

A

Defined as the time required for the amount of drug in the body to decrease by 50%
Percentage, not a specific amount
Determines the dosing interval

38
Q

half-life ex.

A

caffeine: 3-5hr
zithromax: 68 hr
warfarin: 20-60 hr, ~40 hr average

39
Q

time to reach plateau for a drug

A

~4 half life
as long as dosage remmains constant, the time reqiured to reach plateau is independent of dosage size

40
Q

time for drug to be removed from body if dosage stops

A

4-5 half lives

41
Q

drug levels produced with repeated doses

A

Process by which plateau drug levels are achieved
peak is the highest level of drug, trough is the lowest level
Techniques for reducing fluctuations in drug levels -IV administration continuous infusion, depot preparation -releases drug slow and steady, reduce both the size of each dose and the dosing interval (keep the total daily dose constant)
Loading doses -large doses to quickly get levels up
maintenence dose -plateau maintained by smaller doses
Decline from plateau ~4-5 half life

42
Q

pharmacodynamics: dose-response relationships

A

Relationship between the size of an administered dose and the intensity of the response produced

Determines the following:
The minimum amount of drug to be used
The maximum response a drug can elicit
How much to increase the dosage to produce the desired increase in response

As the dosage increases, the response becomes progressively larger

Treatment is tailored by increasing or decreasing the dosage until the desired intensity of response is achieved

Three phases occur

43
Q

two characteristic properties of drugs are revealed in dose-response curves

A

maximal efficacy and relative potency

44
Q

maximal efficacy

A

The largest effect that a drug can produce (height of the curve)
Match the intensity of the response with the patient’s need
Very high maximal efficacy is not always more desirable

45
Q

relative potency

A

The amount of drug that must be given to elicit an effect
Rarely an important characteristic of the drug
Can be important if a lack of potency forces inconveniently large doses
Implies nothing about maximal efficacy; refers to dosage needed to produce effects

46
Q

receptor

A

A receptor is any functional macromolecule in a cell to which a drug binds to produce its effects (generally proteins)

Technically, receptors can include enzymes, ribosomes, and tubulin

The term receptor is generally reserved to refer to the body’s own receptors for hormones, neurotransmitters, and other regulatory molecules

47
Q

Receptor binding

A

The binding of a drug to its receptor is usually reversible

Receptor activity is regulated by endogenous compounds

When a drug binds to a receptor, it will mimic or block the action of the endogenous regulatory molecules and increase or decrease the rate of physiologic activity normally controlled by that receptor -drugs cant make the body do anything it doesnt already do. Drugs only work because a mechanism in the body is in place

Drugs can compete for receptor binding

48
Q

important proprties of receptors

A

Receptors are normal points of control of physiologic processes

Under physiologic conditions, receptor function is regulated by molecules supplied by the body

Drugs can only mimic or block the body’s own regulatory molecules

Drugs cannot give cells new functions

Drugs produce their therapeutic effects by helping the body use its preexisting capabilities

In theory, it should be possible to synthesize drugs that can alter the rate of any biologic process for which receptors exist

49
Q

4 primary receptor families

A

Cell membrane–embedded enzymes

Ligand-gated ion channels

G protein–coupled receptor systems

Transcription factors

50
Q

receptor and selectivity of drug action

A

The more selective a drug is, the fewer side effects it will produce

Receptors make selectivity possible

Each type of receptor participates in the regulation of just a few processes

Lock-and-key mechanism

Does not guarantee safety

Body has receptors for each of the following:
Neurotransmitters
Hormones
All other molecules in the body used to regulate physiologic processes

51
Q

simple occupancy therapy

A

Cannot explain different maximal efficacies of drugs
Intensity of the drug response is proportional to the number of receptors occupied by that drug
Max response is when all receptors occupied

52
Q

modifed occupancy theory

A

Affinity -Strength of the attraction between drug and receptor

Intrinsic activity
Ability of the drug to activate a receptor upon binding
High = high ME of med
Low = low ME of med

53
Q

drug-receptor interactions

A

Agonists

Antagonists
Noncompetitive
Competitive

Partial agonists

54
Q

agonists

A

Agonists are molecules that activate receptors

Endogenous regulators are considered agonists

Agonists have both affinity and high intrinsic activity

Dobutamine mimics norepinephrine at cardiac receptors

Agonists can make processes go “faster” or “slower”

55
Q

antagonists

A

Produce their effects by preventing receptor activation by endogenous regulatory molecules and drugs

Affinity but no intrinsic activity

No effects of their own on receptor function

If there is no agonist present, an antagonist will have no observable effect

Ex. antihistamines –bind to histamine receptors and prevent activation
Ex. Naloxone blocks opioid receptors

56
Q

noncompetitive antagonists

A

Bind irreversibly to receptors
Reduce the maximal response that an agonist can elicit (fewer available receptors)
Impact not permanent (cells are constantly breaking down “old” receptors and synthesizing new ones)
Example: Omeprazole

57
Q

comptitive antagonists

A

Compete with agonists for receptor binding

Bind reversibly to receptors

Equal affinity: Receptor occupied by whichever agent is present in the highest concentration

58
Q

partial agonists

A

These are agonists that have only moderate intrinsic activity

The maximal effect that a partial agonist can produce is less than that of a full agonist

These can act as antagonists as well as agonists

59
Q

regulation of receptor sensitivity

A

receptors are dynamic cell components

The number of receptors on the cell surface and the sensitivity to agonists can change in response to:

Continuous activation
Desensitization//refractory/down regulation
Cell less responsive
Destruction of receptor

Continuous inhibition
Hypersensitivity
Increase receptors

Continuous exposure to agonist
Desensitized or refractory
Downregulation

Continuous exposure to an antagonist
Hypersensitive

60
Q

drug responses that do not involve receptors

A

Simple physical or chemical interactions with other small molecules
Examples of receptorless drugs:
Antacids, antiseptics, saline laxatives, and chelating agents

61
Q

interpatient variability in drug responses

A

The dose required to produce a therapeutic response can vary substantially among patients

Measurement of interpatient variability

The ED50
Dose that produces a response in 50% of the population

62
Q

Clinical implications of interpatient variability

A

The initial dose of a drug is necessarily an approximation

Subsequent doses must be “fine-tuned” based on the patient’s response

ED50 in a patient may need to be increased or decreased after the patient response is evaluated

63
Q

therapuetic index

A

Measure of a drug’s safety

Ratio of the drug’s LD50 (average lethal dose to 50% of the animals treated) to its ED50

The larger/higher the therapeutic index, the safer the drug

The smaller/lower the therapeutic index, the less safe the drug

64
Q

drug-drug interactions

A

Interactions can occur whenever a patient takes more than one drug

Interactions can be intended/desired and/or unintended/undesired

Patients frequently take more than one drug
Multiple drugs to treat one disorder
Multiple disorders requiring different drugs
Over-the-counter medications, caffeine, nicotine, alcohol, and so on

65
Q

consequences of drug-drug interactions

A

Intensification of effects
Increased therapeutic effects -Sulbactam + ampicillin
Increased adverse effects -Aspirin + warfarin

Reduction of effects
Reduced therapeutic effects -Propranolol + albuterol
Reduced adverse effects -Naloxone to treat heroin overdose

Creation of a unique response -Alcohol + disulfiram

66
Q

basic mechanisms of drug-drug interactions

A

Drugs can interact through four basic mechanisms:
Direct chemical or physical interaction
Pharmacokinetic interaction
Pharmacodynamic interaction
Combined toxicity

67
Q

direct or physical interaction

A

Never combine drugs in the same container without establishing compatibility

Most common in intravenous solution
Precipitate: Do not administer

68
Q

drug-drug interaction: pharmacokinetic interactions

A

Altered absorption
Altered distribution
Altered metabolism
Altered renal excretion

69
Q

drug-drug interactions: altered absorption

A

Elevated gastric pH
Laxatives
Drugs that depress peristalsis
Drugs that induce vomiting
Adsorbent drugs
Drugs that reduce regional blood flow

70
Q

Drug-drug interactions: altered distribution

A

Competition for protein binding
Alteration of extracellular pH

71
Q

drug-drug interactions: altered metabolism

A

Most important and most complex mechanism in which drugs interact

Cytochrome P450 (CYP) group of enzymes
Inducing agents: Phenobarbital -Increase rate of metabolism two- to threefold over 7 to 10 days
Resolve over 7 to 10 days after withdrawal
Inhibition of CYP isoenzymes -Usually undesired

72
Q

interactions that involve PGP

A

Transmembrane protein that transports a wide variety of drugs out of cells

Reduced or increased PGP
Intestinal epithelium: Affects absorption
Placenta: Affects drug export from placental cells to maternal blood
Blood-brain barrier: Affects drug export from the cells of brain capillaries into the blood
Liver: Affects drug export from liver into bile
Kidney tubules: Affects drug export from renal tubular cells into the urine

73
Q

Drug-drug inteactions: altered renal excretion

A

Drugs can alter:
Filtration
Reabsorption
Active secretion

74
Q

Pharmacodynamic interactions

A

At the same receptor -Almost always inhibitory (antagonist/agonist)
At separate sites -May be potentiative (morphine and diazepam)
OR
Inhibitory (hydrochlorothiazide and spironolactone)

75
Q

Drug-drug interactions: combined toxicity

A

Drugs with overlapping toxicities should not be used together

76
Q

Clinical significance of drug-drug interactions

A

Drug interactions have the potential to significantly affect the outcome of therapy
Responses may be increased or reduced
The risk for serious drug interaction is directly proportionate to the number of drugs a patient is taking
Interactions are especially important for drugs with low therapeutic indices
Many interactions are yet to be identified

77
Q

Min ADR drug-drug interactions

A

Minimize the number of drugs a patient receives
Take a thorough drug history
Be aware of the possibility of illicit drug use
Adjust the dosage when metabolizing inducers are added or deleted
Adjust the timing of administration to minimize interference with absorption
Monitor the patient for early signs of toxicity
Be especially vigilant when a patient is taking a drug with a low therapeutic index

78
Q

Max dose of tylenol

A

Max changed from 4000mg to 3000mg
~50 million people use tylenol per day

79
Q

Drug-food interactions: drug absorption

A

Decreased absorption
Rate
Extent of absorption (occasionally) -Milk and tetracycline, fiber and digoxin

Increased absorption
High-calorie meal and saquinavir -Without food, not enough is absorbed

80
Q

Drug-food interactions: drug metabolism

A

The grapefruit juice effect (not occurring with other citrus fruits or juices)
Inhibits the metabolism of certain drugs
Raises the drugs’ blood levels -Increase in felodipine, Others: Lovastatin, cyclosporine, midazolam, and so on

81
Q

Drug-food interactions: drug toxicity

A

Monoamine oxidase inhibitors (MAOIs) and tyramine-containing foods
Theophylline and caffeine
Potassium-sparing diuretics and salt substitutes
Aluminum-containing antacids and citrus beverages

82
Q

Drug-food interactions: drug action

A

Warfarin and foods rich in vitamin K

83
Q

Drugfood interactions: timiing of drug administration

A

Some drugs are better tolerated on an empty stomach
Others should be taken with food, especially for nausea

84
Q

Drug-herb interaction

A

Conventional drugs can interact with herbal preparations

Interactions with herbal medicines are just as likely as they are with prescription medications

Reliable information about drug-herb interactions is lacking

Example of known interaction:
St. John’s wort induces drug-metabolizing enzymes and reduces the blood levels of many drugs

Grapefruit juice inhibit metabolism of drugs and increase levels 450 system cyp3a4 -Inhibit for about 3 days after last dink

Adv Pharm (76 decks)

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