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Unit 1 Flashcards

1
Q

define pharmacology

A

study of interactions of drugs (chem subs) with biological systems

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2
Q

define pharmacotherapy

A 
"dosage regimen"
involves section of the right drug in the right dose to interact with the right drug target to produce the desired therapeutic effects:
-prevention
-diagnosis
-treatment
-cure
of a particular disease
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3
Q

pharmacokinetic and pharmacodynamic principles

A

allow the determination of the relationship between the dose of the drug given the patient, the plasma concentration (Cp) that results from the dose, and the clinical effects that will result from that plasma conc

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4
Q

drug effects and plasma conc

A

therapeutic or toxic, they’re directly related to each other for most drugs in clinical use

graphs of Cp vs time determine drug pharmacokinetics

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5
Q

MEC

A

minimum effective conc

can be determined for both the desired (therapeutic) response and any adverse responses

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6
Q

single or first dose administration concepts

A
  • onset of effect: time to reach MEC
  • duration of action: time above MEC
  • therapeutic window (AKA therapeutic index): difference in Cp between the desired and adverse response MEC
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7
Q

goal of pharmacotherapy

A

when multiple doses are administered to reach and maintain plasma con’s at steady state within the therapeutic window to produce the desired response with a minimum of toxicity

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8
Q

multiple or maintenance dose administration concepts

A
  • steady state: condition exists when the rate of drug administration (rate IN) equals the rate of drug elimination (rate OUT)
  • time to steady state: attained in 4-5 half-lives when maintenance doses are administered at constant interval
  • steady state conc: average Cp after steady state achieved
  • fluctutations in steady state Cp: related the number of half-lives in the dosing interval (time between doses)
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9
Q

dosage regimen (for multiple dose administrations)

A

key element in pharmacotherapeutics
designed to ensure that the desired steady state drug level (Cp ss (avg)) is maintained within the therapeutic window by balancing the rate of drug elimination with the prescribed rate of drug administration

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10
Q

4 things to select for with dosage regimen:

A 
contents of a prescription:
select drug and dose
select route of administration 
select dosage frequency 
select duration
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11
Q

pharmacodynamics- mech of action

A

what the drug does to the body

enables identification of drug target and therapeutic category

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12
Q

drug target

A

commonly a membrane or intracellular receptor, an enzyme in a critical biosynthetic pathway, or a membrane transport protein

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13
Q

drug actions

A

enhance or block the normal physiology of the various organ systems, depending on pathophysiology
NO unique actions

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14
Q

physiology vs pathophysiology vs pharmacology

A

student learns physiology to identify potential target for drug action
pathophysiology- determine how the target should be manipulated (enhanced or blocked)
pharmacology- select appropriate drug to induce manipulation

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15
Q

pharmacokinetics: what the body does to the drug

A

info regarding drug absorption, distribution, and elimination that is necessary for designing dosage regimens

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16
Q

absorption and distribution affects route of:

A

administration

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17
Q

bioavailability

F

A

how much of the dose of the drug will reach its target in the body

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18
Q

time to peak effect

TMax or Cmax

A

how fast does the drug reach its target

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19
Q

volume of distribution

Vd

A

what dose (mg) to obtain desired plasma conc Cp- mg/L

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20
Q

absorption

A

passage of drug from the site of drug administration (AKA route of administration) into blood

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21
Q

distribution

A

movement of the drug from the bloodstream to the tissues, where it can access targets for both therapeutic and side effects of the drug

includes considerations of drug-protein binding, passage across blood-brain barrier or placenta, and selective accumulation affecting drug efficacy or toxicity (lungs, bone, ear, kidney/urine, saliva, breast milk)

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22
Q

route of administration

A

site of application of the drug into or on the patient

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23
Q

systemic vs topical effects from drug administration

A

systemic- absorbed into bloodstream and distribute to sites of action in body

topical- mostly remain at site of application for local action

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24
Q

elimination affects:

A

frequency of administration

-how long the drug will stay at its target in the body (duration of action) (half life)

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25
Q

major organs of elimination

A

Liver- metabolism

Kidney- excretion via urine

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26
Q

rate of elimination

A

half life

determines length of time the drug will remain in the bloodstream to exert its clinical effects

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27
Q

adverse rxn

A

predictable from mech of action

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28
Q

2 type of dose

A

loading dose LD

maintenance dose MD

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29
Q

dose equation

maintenance dose equation

A 
dose = Cp x Vd or 
Cp = dose / Vd

MD / tau = Cpmax x CL
In = Out

Tau= dosing interval
CL= clearance
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30
Q

pharmacokinetics of elimination- half life

A

allows quick rule of thumb estimates of:

time for elimination of drug from plasma
time to reach steady state plasma drug levels following multiple doses
fluctuations in plasma levels between doses

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31
Q

drug effect vs plasma level

A

direct correlation

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32
Q

routes of absorption

A

local routes: site of action receptors

  • inhalation
  • dermal
  • aural, nasal, throat, vaginal, ocular/conjunctival
systemic: absorbed through tissue reservoirs or liver
oral
rectal
IV
transdermal
sublingual
buccal
inhalation
subcutaneous
intramuscular
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33
Q

4 factors influencing drug membrane passage

A

molec size (can be affected by binding plasma proteins; smaller crosses better)

lipid solubility (set by oil:water partition coef; increasing increases membrane passage)

degree of ionization (affected by tissue pH, influences lipid solubility; unionized = greater crossing)

conc gradient (created at site of admin)

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34
Q

drug permeation across cell membrane routes

A

passive diffusion- water soluble drugs through aqueous channels

passive diffusion- lipid soluble drugs via hydrophobic bonding with membrane lipids

active transport and facilitated diffusion- via membrane carrier molecs (p-glycoproteins)

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35
Q

most common mech for drug passage across a membrane

A

lipid diffusion through membrane itself

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36
Q

graph of Cp vs Time

A

determines 4 pharmacokinetics parameters-
absorption, distribution, metabolism, elimination

area under curve shows extent of absorption

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37
Q

bioavailability F

A

F = AUC(oral) / AUC (IV)

-Expressed as % of IV dose reaching plasma by the oral route
-used for dosage adjustments when route is changed
F = 100% for IV, no absorption step is involved

other routes of systemic drug action: Intramuscular, subcutaneous, sublingual, inhalation
-F usually approaches ~100% (~75% -

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38
Q

bioavailability F

oral administration

A

F varies 0-100% depending on:
survival of drug in GI environ (acidity, digestive enzymes)
ability to cross GI membranes (small, uncharged, lipid soluble cross best)
efficiency of drug metabolism (GI/liver)
–first pass effect requires you to up the dose for same drug conc

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39
Q

first pass effect

A

wide drug and interpatient variation
needing to pass through liver (and its metabolic processes) to get to the plasma

oral--> 
intestine --> 
hepatic portal vein --> 
liver biotransformation (metabolism) --> 
systemic circulation
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40
Q

ways to bypass 1st pass effect

A

IV administration
rectal dose (alcohol enema)
sublingual/buccal

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41
Q

ex first pass effect is best described as:

A

hepatic or gastric metabolism of a drug prior to entry into the systemic circulation

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42
Q

estimate rate of absorption

A

Tmax and Cpmax

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43
Q

rate of absorption from the oral route

A

for clinically useful drug levels Rate of absorption Rabs is at least 10x greater than Rate elim

Drug formation can be a factor in rate of absorption

  • increased for liquid preps or rapidly disintegrating tablets (vs standard tablets)
  • decreased with enteric coated products or sustained release preps (time to peak slowed and Cpmax blunted– bioavailability UNAFFECTED)
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44
Q

rate of absorption from parenteral routes

A

rate of onset of effected determined primarily by route rather than individual drug characteristics for soluble formulations

IV = 
inhalation > 
intramuscular > 
subcutaneous > 
oral

insoluble formulations/suspensions are designed to slow rate of absorption and extend duration of action

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45
Q

determining equivalency of drug products

A

major equivalency test- required by FDA for generics is bioequivalency

generic drug product is bioequivalent to brand name drug product if:
-rate of absorption AND extent of absorption (AUC- bioavailability) of active drug in generic formulation is within set limits

bioequivalent = therapeutic equivalents

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46
Q

general factors affecting drug absorption

A

drug solubility in aqueous environ

  • formulation must have hydrophilicity to dissolve
  • molec must be lipophilic to cross lipid membranes

rate of dissolution

  • solid for oral dosage formulation
  • suspended particles for parenteral formulation

conc of drug at site of admin (gradient)

circ at site of absorption (disease or exercise effects)

area of absorbing surface (stomach vs intestine vs lungs)

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47
Q

routes of drug elimination

A

urine
feces
breast/sweat glands- milk, sweat
expired air

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48
Q

ex type of drug with greatest oral viability:

A

large hydrophobic drugs, yet soluble in aqueous solutions

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49
Q

oral route absorption

A

relatively slow onset of action; variable bioavailability

absorption from GI tract primarily via lipid diffusion; favored with less ionization BUT most drugs absorbed best from SI due to large SA

increase GI motility increases rate of absorption; reaches SI faster
-food slows absorption by delaying gastric emptying; potential for drug-food interactions

  • take on full stomach to protect stomach
  • take on empty stomach to protect drug
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50
Q

stomach and SI absorption

A

better extent of absorption in stomach
better rate of absorption in SI

dissolution delayed until reaching the more basic pH of SI

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51
Q

pros and cons of controlled-release preparations

A

advantages:
decrease number of daily doses
maintain drug affect overnight
eliminate toxic peaks or sub therapeutic troughs

cons-
interpatient variations with Cp
dosage form failure

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52
Q

IV drug administration

A

most rapid onset of action (100% bioavailability)

most direct route of admin

  • no membrane passage factors
  • accuracy-immediacy of drug delivery exceeds all routes

-used for drugs with narrow therapeutic index

bypass absorption barriers- increased infection potential

most hazardous route- can reach toxic levels rapidly and reversal of effect often difficulty

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53
Q

intramuscular route

A

rapid onset (5-10 min) and approaching 100% bioavailability

absorption may be erratic and incomplete if drug solubility in soon is limited (ex. diazepam)

depot forms in oil or suspensions exhibit slower, more sustained absorption (hours-days)
-onset delayed as release or dissolution step must occur before moles is absorbed

ex. contraceptives, anti-inflammatory glucocorticoids

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54
Q

subcutaneous route

A

often utilized for slower, constant rate of absorption
bioavailability near IV ~100%

absorption altered by varying particle size, pH, protein complexation, vasoconstrictor, pellet implantation

drugs must be non-irritating
injection vol more limited than IM route

ex. insulin preparations

  • injection of soln provides relatively rapid onset of action
  • injection of suspension slows onset- increases duration
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55
Q

sublingual-buccal route

A

onset of action within minutes
high bioavailability
-drains into Superior Vena Cava, so no first-pass effect

useful if drug is lipid soluble and potent (

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56
Q

rectal suppository or solution route

A

non-rapid onset and variable bioavailability- generally greater than oral

useful if vomiting, unconscious, post-GI surgery, presence of GI irritation, or uncooperative patient

patient acceptance is not high

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57
Q

transdermal patch

A

application to skin for treatment of SYSTEMIC conditions

prolonged drug levels to provide extended duration of action
hours-week

first pass metabolism is avoided

  • increased bioavailability
  • plus reduced potential for adverse rug rxns (ADRs) related to hepatic actions

ex. contraceptives, nitroglycerin, fentanyl, clonidine

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58
Q

patient in ER with drug overdose

best route of administration of antidote?

A

intravenous

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59
Q

which route of drug administration has the most rapid onset of action?

A

inhalational

but also intravenous

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60
Q

inhalation route for local effects

A

molecs in suspension (aerosol/microparticles)
applied at site of action in lungs
designed to maximize local actions

effects depend on particle size

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61
Q

dermal local route

A

application via skin or mucous membranes for treatment of local conditions (inflammation, infection)

generally minimal systemic absorption

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62
Q

bioavailability summary

A

100% IV

75-100% IM, SC, SL, inhalation, transdermal
tissue environ is non-destructive

0-100% oral; variable due to GI and 1st pass metabolic effect

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63
Q

speed of onset of drug effect summary

time to peak effect

A

most rapid (sec-min): inhalational, IV

intermediate (5-15 min): sublingual, IM, SC, buccal

slower (15-30 min): oral

slowest (hours): transdermal, oral (enteric coated and sustained release), depot forms of IM and SC

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64
Q

duration of action summary

time above MEC

A

special drug formulations:
delay drug molec release
slow drug absorption from some routes
extend duration of action (independent of t1/2)

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65
Q

charged drug molecs and BBB

A

permanently charged molecs cannot cross blood brain barrier

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66
Q

physiologic factors influencing drug distribution

A

sites requiring drugs to pass through cells, not between (whether there are gap junctions)

pH of fluids in compartments

lipid solubility of non-ionized form

drug binding to plasma proteins (only free drug is diffusible)

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67
Q

tissues with tight junctions

A

limit movement of certain drugs (large, protein bound, ionized, high water solubility)

GI mucosa- negligible absorption (have to go through cells)

Blood brain barrier and placenta- limited distribution

renal tubules- reduced absorption back into blood and increased urinary excretion

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68
Q

true about blood brain barrier

A

drugs can cross BBB through specific transporters

lipid soluble drugs readily cross the BBB

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69
Q

weak acids vs weak bases

A

weak acid -COOH
most readily cross when in an acidic environ (pH RCOO- + H+

weak base -NH3+
R-NH3+ R-NH2 + H+
most readily cross when in basic environ (pH > pKa)

non-ionized forms are more readily absorbed
ionized forms are “trapped”

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70
Q

pKa

A

the pH where the amount of an unprotonated substance = amount of protonated substance

when pH = pKa
HA = A-
BH+ = B

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71
Q

Henderson Hasselbach Equation

A

pH - pKa = log (non-protonated/ protonated)

10^ (pH - pKa) = (unprotonated / protonated)

allows determination of % ionized
allows predictions of pH at which majority of drug will be ionized and whether absorption or trapping is favored

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72
Q

ex. aspirin is weak acid with pKa of 5.4. What % of a given dose will be in the ionized form (water-soluble) at plasm pH of 7.4?

A

about 99%

10^ (7.4-5.4) = 100/1

5.4 to 7.4 means 100 fold change

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73
Q

ex Hydrochlorothiazide is a weakly acidic drug with pKa of 6.5. If administered orally, at which of the following sites of absorption will the drug be able to most readily pass through the membrane?

mouth pH 7.0
stomach pH 2.5
duodenum pH 6.1
jejunum pH 8.0
Ileum pH 7.0
A

want pH to be less than pKa to become -COOH uncharged

leaves stomach and duodenum

stomach is best answer- drug will cross membrane best where most of it will be unionized; better EXTENT of drug absorption

SI (due to SA) changes RATE of absorption, not extent

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74
Q

ion trapping

A

total conc of drug is greater on one side of lipid barrier where extent of ionization is greater

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75
Q

clinical significance of ion trapping

A

alteration of urinary pH to trap weak acids or bases and hasten renal excretion (plasma has buffering capacity)

-alkalinization of urine can trap weak acid aspirin in overdose situations

greater potential to concentrate basic drugs (like opioids) in more acidic breast milk

forensic pathology- weak base toxins are found concentrated in the acidic contents

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76
Q

effect of protein binding on drug disposition

A

only free drug is diffusible, so protein binding:

  • reduces conc of active, free drug
  • hinders metabolic degradation and reduces excretion (dec elimination and incr half life)
  • decreases Vd
  • decreases ability to enter CNS through BBB

but- protein-binding rarely of clinical concern unless changes occur after therapy has been started

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77
Q

protein-binding displacement interactions

A

administration of 2nd drug displaces 1st drug from binding sites, increasing free levels of 1st drug
-often small and transient increase as free drug distributes to tissues and subject to metabolism and excretion

very unlikely to be of clinical consequence unless:
displaced has narrow therapeutic index
displacing drug is started in high doses
Vd of displaced drug is small
response to drug occurs more rapidly than redistribution

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78
Q

ex effects of increasing the binding of a drug to plasma proteins

A

decreases plasma conc of active drug
dec elimination of drug by liver metabolism and kidney excretion
inc dose needed to achieve therapeutic effectiveness
inc possibility of adverse interactions with other drugs that bind plasm proteins

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79
Q

rate of distibution

A

most drugs absorbed into and eliminated from a central plasma compartment

rate of distribution seldom of clinical consequence
-slow distribution out of plasma can led to “bolus” toxicity for drugs given IV

80
Q

extent of distribution

A

Vd in L/kg
size of compartment necessary to account for total drug in body if present at same conc in body as Cp

is an apparent vol that represents the relationship between dose of a drug and the resulting Cp

we’re ok not knowing conc of drug in tissues because response of drug is proportional to Cp

81
Q

determination of Vd

A

single dose of drug (Ab) is administered IV and Cp at time 0 (C0) is determined and Vd is calculated

Vd= amount of drug in body (Ab) / Cp

82
Q

ex. bolus or slug effect is most likely to be seen when drugs are administered via:

A

IV

83
Q

Cp vs Vd relationship

A

inverse relationship

the more of the dose that remains in the plasma, the less the Vd

84
Q

vol of compartment vs Vd for drugs

A

plasma/blood 3-5 L
drugs highly bound to plasma proteins:
Heparin 4 L, Warfarin 10 L

EC water 12-15 L
drugs highly water soluble that don’t enter cells:
ibuprofen 11 L, Gentamicin (22 L)

Total body water 42 L
drugs that freely enter cells (small molecs): Lithium 46 L, ethanol 42 L

other compartments > 50 L
drugs highly lipid soluble sequestered at tissue sites:
amitriptyline 1050 L, Fluoxetine 2450 L

85
Q

ex new drug is in phase 1 testing and has Vd of 3-5 L in a 70 kg patient. Vd value most consistent with:

A

drug is highly bound to plasma proteins

could also be highly lipid soluble and use a lipoprotein

86
Q

clinical use of Vd

A 
Vd will vary between patients depending on:
body size (based on weight)
composition (fat vs lean; more fat = lower Vd)
changes in protein binding
determine loading dose
determine effect on Cp
87
Q

general characteristics of drug metabolism

A

lipid soluble compounds converted to more water-soluble (more polar) compass to be more readily excreted

liver is primary organ of drug metabolism
lung 30%
kidney 8%
intestine 6%
skin 1%
placenta 5%
88
Q

most common outcome of drug metabolism:

A

> 95%

inactivating-detoxifying process forming rapidly excreted and pharmacologically inactive metabolites

89
Q

less commonly seen outcome for drug metabolism:

A

morphine

inactive prodrug to active drug

toxic metabolite

90
Q

ex drug metabolism usually results in a product that is:

A

less likely to distribute intracellularly

more water soluble than parent drug

91
Q

phase 1 vs phase 2 rxn types

A

Phase 1:
oxidations
-hydrolysis
-reductions

Phase 2:
conjugations

92
Q

phase 1 vs phase 2 enzymes

A

1: CYP450
esterases-amidases
reductases

2: transferases

93
Q

phase 1 vs phase 2 genetic polymorphism

A

1: significant
2: significant

94
Q

phase 1 vs phase 2 induce-inhibit

A

1: significant
2: possible- less

95
Q

phase 1 vs phase 2 development patterns

A

1: variable
2: variable

96
Q

phase 1 vs phase 2 age changes

A

1: decrease in 1/3
2: minimal (want to use this with older patients)

97
Q

phase 1 vs phase 2 satiability:

A

1: minimal
2: substantial

98
Q

phase 1 biotransformations

A

renders the molec more water soluble

drug metabolite can then undergo conjugation in a phase 2 rxn

rxns incl: oxidation, reduction, hydrolysis

99
Q

phase 2 biotransformations

A

conjugations
endogenous substrate combines with:
-pre-existing or metabolically inserted func group (via phase 1 rxn) on the drug
-substrates are high-E and in limited supply; increased likelihood of depletion; zero order kinetics

forms highly polar (water soluble) conjugate that is readily excreted via urine

phase 2 rxn may rarely precede phase 1 runs

rxns include: glucouronidation, acetylation, glutathione/glycine/sulfate conjugation

100
Q

ex drugs metabolized by CYP 460 enzyme they:

A

require molec O2
generally highly lipid soluble
usually become more highly oxidized
metabolized in smooth ER

101
Q

phase 1 genetic polymorphisms

A

exist; variations in activity of certain drug metabolizing enzymes among patients

amplichip test: to detect polymorphisms in CYP2D6/2C19

classified at extremes: ultra-rapid (UM) or poor metabolizers (PM)

clinical significance depends on whether drug metabolism is detoxifying or activating

102
Q

genetic polymorphisms with detoxifying and activating rxns

A

detoxifying rxns:

PM: CYP2D6 increased antipsychotic drug toxicity

UM: CYP2D6 nonresponse to antidepressants

Activating rxns:

PM: CYP2C19 dec efficacy of PPIs for PUD

PM: CYP2D6 insufficient analgesia with codeine

UM: CYP2D6 codeine intoxication due to rapid metabolism to morphine

103
Q

ex old female underwent total hip arthroplasty
post-procedure pain adequately managed with morphine; discharged with tylenol #3 prescription (acetaminophen-codeine). within 24 hrs pain became intolerable. Which CYP450 genetic polymorphism is most likely she didn’t respond to codeine analgesia?

A

poor metabolizer for CYP2D6

104
Q

phase 2 conjugations- general

A

drug or drug metabolite is coupled/conjugated to highly energetic endogenous reactant provided by a coenzyme

limited supply of reactants renders phase 2 rxns more easily saturable (zero order elimination kinetics) than phase 1

operative enzymes known as transferases

product most often highly water soluble and readily excreted (exception N-acetylation)

105
Q

ex a phase 2 drug metabolism rxn:

A

will be less likely to decline in activity with aging than phase 1
rxns

more likely to reach saturation Vmax
not dependent on O2 and NADPH as cofactors
doesn’t have to be preceded by phase 1 rxn

106
Q

ex local anesthetics such as lidocaine or bupivacaine are metabolized in the liver by:

A

amidases

107
Q

ex what phase 2 rxn makes phase 1 metabolites readily excretable in urine?

A

sulfation and glucouronidation

108
Q

enzyme induction of drug metabolism

A

increase in activity in response to certain compds

observed with > 300 different compds (inducers):
cigarette and marijuana smoke
air pollutants
industrial chemicals
DDT
numerous drugs

most is known about induction of CYP450 enzymes, but some forms of phase 2 enzymes (UGT) are also inducible

109
Q

mech of induction

A

mainly due to increased synthesis of enzyme protein, but decreased turnover also occurs

generally requires 48-72 hours to see onset of effect

110
Q

inhibition of drug metabolism

A

occurs with many drug metabolizing enzymes
-phase 1 more prone than phase 2

variety of mechanisms:
inhibit enzyme synthesis
inhibitor can be competitive substrate
allosteric inhibitor
formation of a metabolite
-destroys enzyme
-forms tight complex inhibiting further activity
111
Q

metabolic drug-drug interactions

A

most occur via effects on CYP450 sys; inhibitors and inducers of specific P450 isozymes are known

effects most obvious when drugs are given orally via 1st pass effect

112
Q

metabolic inducers vs inhibitors

A

inducers- increase metabolic rate

inhibitors- decrease

clinical effect is dependent on whether metabolic rxn is:
inactivating (detoxifying; most common 95%)
activating

113
Q

therapeutic consequences of induction

A

maximal effects of enzyme induction usually seen in 7-10 days; require similar time to dissipate

induction by one agent may increase clearance of other drugs

114
Q

production of pharmacokinetic tolerance:

A

induction by a drug of its own metabolism: phenobarbital-carbamazepine

115
Q

clinical implications (of resulting drug interactions) of induction

A

reduced therapeutic effect if inactivation rxn is accel

increased toxicity if activation rxn in accel

increased toxicity if toxic metabolite is produced

116
Q

drug-drug interactions

oral contraceptives plus rifampin

A

rate in = rate out

drug dose / freq = Cp x CL

rate in unchanged = Cp x (increased CL due to Rifampin), which means lower Cp for Oral contraceptive and possible unplanned pregnancy

117
Q

therapeutic consequences of inhibition

A

inhibition of metabolism can occur as soon as sufficient hepatic conc is reached (generally within hours)

time to effect on steady state Cp is dependent on inhibited drug’s half life

inhibition by 2nd drug of 1st drug metabolism gives dec CL of 1st drug gives higher Cp gives inc toxicity

if an activating metabolic rxn (less common) is inhibited, then reduction in therapeutic effect

118
Q

drug-drug interaction

lipitor plus erythromycin

A

rate in = rate out
lipitor / frequency = Cp x CL

rate in unchanged = Cp x (dec CL due to Erythromycin),, so inc Cp for Lipitor and inc risk for myopathy

119
Q

clinically relevant inducers and inhibitors

A 
inducers:
PP CREST
phenobarbital
phenytoin
carbamazepine
rifampin
*ethanol
*St. John's Wort
*Tobacco Smoke (not nicotine)
inhibitors:
FACE HOG
fluoxetine (other SSRIs)
azalea antifungals
*cimetidine
erythromycin/clarithromycin
HIV protease inhibitors
*omeprazole
*grapefruit juice

*available without prescription

120
Q

zero order kinetics

A

amount of drug eliminated per unit time is constant

most often due to saturation of hepatic metabolic processes (esp phase 2 conjugations)

seen with a few drugs at therapeutic doses and many at toxic doses

saturation unlikely to occur with renal excretory process, but maybe the liver

121
Q

biological factors influencing drug metabolism

A

diet and nutritional factors- little known about role in humans

sex- some evidence for differences

age-
perinatal: some enzyme sys’s are not well developed at birth
neonatal: variable dev patterns
old age: decrease in phase 1 CYP450 with aging (1/3 of patients)

genetic factors- inter individual and interethnic differences

disease states

122
Q

renal clearance mech

A 
filtered drug from glomerulus
pH dependent passive reabsorption 
active secretion (back to ureters)

trapping drug in urine increases its elimination

urine 1mL/min

123
Q

ex alkalinization of urine by giving bicarbonate is used to treat patients with pentobarbital (weak acid) overdose. What best describes the rationale for alkalinization of urine here?

A

to reduce tubular reabsorption (back into blood) of pentobarbital

124
Q

biliary-fecal excretion

A

blood and drug go through liver
excretion via bile and bile duct into intestines to be excreted via feces

enzymes can interfere and cause enterohepatic recycling

125
Q

ex the addition of glucuronic acid to a drug molec:

A

increases its water solubility

usually leads to inactivation of the drug

126
Q

excretion into breast milk

A

most drugs do cross into breast milk, but usually at low levels

resulting infant plasma level for most drugs is substantially below therapeutic level

desynchronize breastfeeding and peak milk-drug conc’s

  • breastfeed at end of dosing interval
  • administer drug immediately after nursing
  • administer a dos prior to infant’s longest sleep time
  • shorter nursing periods (fat (and drug) content of milk increases during feeding period)
127
Q

pulmonary route of excretion

A

gases, alcohols, and volatile substances (simple diffusion)
parent drug is usually cleared without metabolism
rate for highly soluble gases dependent on respiratory rate
rate for poorly soluble gases (N2O) depends on blood flow

128
Q

sweat excretion

A

responsible for certain skin reactions to ingested drugs

129
Q

saliva excretion

A

accounts for dug “taste” noted after IV administration

if drug excreted in saliva is then swallowed, same fate as oral administration

130
Q

hair excretion

A

responsible for cancer chemotherapy-induced hair loss

note- drug assays can be performed on samples from all routes of excretion

131
Q

ex regarding termination of drug action:

A

hepatic metabolism and renal excretion are the 2 most important mech’s involved

132
Q

ex the best-documented and quantitatively the most clinically important mech by which drug-drug interactions occur is via:

A

inhibition or induction of the metabolism of the drug

also interference with renal tubular secretion of the drug

133
Q

first order kinetics

A

rate of elimination is proportional to the conc of the Cp

-rate of elimination is fastest when you have the most- half lives

most clinically utilized drugs are eliminated by 1st order kinetics when given in therapeutic doses

biological processes for drug elimination are 1st order processes

134
Q

graph of drug elimination

A

Cp vs time
-steeper sloper means greater elim rate

ln Cp vs time

  • straight slope; Ke (elim rate)
  • y-intercept is ln Cp 0
135
Q

half life

A

characteristic of first order kinetics

constant fraction of drug is eliminated per time and is independent of the total amount present

time required to eliminate half of drug t 1/2 = 0.693/ke

  • time for drug to be eliminated= 4-5 half lives
  • time to reach steady state when drugs are administered continuously- 4-5 half lives (use loading dose when you can’t wait 4-5 half lives)
  • degree of fluctuations in Cp between doses (number of half lives in dosing interval Tau / t1/2)
136
Q

ex if Cp of a drug declines with first order kinetics, it means:

A

the half life is the same regardless of Cp

the rate of elimination is constantly changing as the Cp changes

137
Q

clearance

A

L/hr or mL/min

CL = Vd x ke

theoretical def: Vd which is completely cleared of drug in a given period of time by combined tissue processes such as kidney and livery and others

proportionality constant that makes Cp at steady state equal to the ke

MD/tau = CL x Cp (ss)

clearances from each organ are additive

138
Q

ex half life of a drug is dependent on:

A

clearance (inverse)

Vd (direct)

139
Q

hepatic clearance

A

varies with blood flow to liver

-for high extraction drug- changes will have major influence on CL
low extraction’s do not

140
Q

renal clearance

A

varies as kidney func varies (serum creatinine –> CrCL used as an estimate of GFR)

changes in renal func will alter renally eliminated drug CL

necessitates dose changes to prevent drug accumulation “renal dosing”

141
Q

summary- calc pharmacokinetic parameters from ln Cp vs time graph

ke
Cp0
t1/2
Vd
F
A

ke: from slope of beta elimination phase

Cp0- from extrapolation of line to time 0

t1/2- from 0.693/ke

Vd- from dose/ Cp(at a time)

from Cp vs time:
F from AUC

142
Q

effect of dose on Cp ss

A

time to reach steady state plateau is related to the half life of a drug; independent of drug dosage

increasing maintenance dose will not reach steady state sooner, but will cause Cp ss to be higher when ss is reached

143
Q

use of loading dose

A

to attain desired steady state Cp sooner, give an LD then follow with normal maintenance dose schedule

LD = Cp x Vd

*have potential to create bolus effect

144
Q

ex erythromycin is an antibacterial agent with a half life of 6 hrs. the prescribed dosage regimen is 500 mg every 6 hrs. how long will it take to reach steady state using this regimen?

what is the fold-fluctuation in Cp between doses?

A

T 1/2 = 6 hrs
4 or 5 x 6 hrs = 24-30 hrs

fluctuation between doses:
2^x, where x = number of half lives in the dosing interval
2^1, so 2 fold

145
Q

ex if the dosage regimen for erythromycin is changed from 500 to 1000 mg every 12 hours, one will observe that:

what will the new fold-fluctuations be?

A

MD 500 mg
tau 6 hrs

MD 1000 mg
tau 12 hrs

fluctuations in Cp will be increased (2^1 vs 2^2)

fold-fluctuations:
2^2 or 4-fold

146
Q

effect of dosing interval on Cp ss fluctuation

A

more half lives (NOT more hours) in a dosage interval means greater fluctuation

amount of fluctuation in Cp that can be tolerated for any drug is determined by its “therapeutic index”

Fluctuations in Cp can be blunted by slowing absorption via controlled-extended release preps

147
Q

ex which drug dosage regimen would result in least amount of fluctuation in the Cp drug level during the dosing interval?

A

lowest ratio of tau: half life

ex. drug t1/2= 12 hrs dosed every 6 hrs

2^ 1/2

148
Q

agonist
stereoisomer
antagonist

A

agonist- l-isoproterenol
full activity
mimic- same manner as endogenous ligands
(ex NTs and hormones)

stereoisomer- d-isoproterenol
less activity

antagonist- propanolol
no activity
block- unable to generate characteristic response
**an antagonist has NO effect in the absence of the agonist for the receptor
-extent of effect of antagonist depends on level of “normal tone” mediated by agonists in that tissue

149
Q

dose response curves

A

increasing doses of drug and measuring the specified response to each dose
-resulting curve is hyperbola

curve is relatively linear at low doses (therapeutic range)- response usually increases in direct proportion to dose

curve levels off at high drug doses- limit to the increase in response that can be achieved by increasing the drug dose
-at high enough dose, all receptors are occupied and no further increase in response can be obtained

150
Q

ED50

potency

A

concentration EC50 or dose ED50 required to produce 50% of the individual drug Emax

depends on:
affinity Kd of receptors for binding the drug

determines: dose to produce a given effect
- more potent the drug, the less needed for a given effect
- EC50 values used to compare potencies of different drugs

151
Q

Emax

efficacy

A

maximal effect or power or maximal efficacy

limit of dose-response relationship on response

indicates relationship between receptor binding and ability to initiate response

efficacy most important determinant of clinical utility

potency simply determines what dose will achieve the desired level of response

152
Q

ex from this equation E/Emax = D / (ED50 + D), ED50 best tells you

eqn in general shows you:

A

the potency of the drug

there is a limit to the increases in response that can be achieved by increasing the dose

153
Q

full vs partial agonists

A

full- occupy receptor and produce full or max response

partial- occupy same receptor but produce less than max response
-less efficacious, 100% receptor occupancy, so decreased response

potency and efficacy can vary independently

154
Q

agonists and dose response curve

A

x axis- log drug dose

  • displays potency (ED50)
  • smaller dose = more potent

y-axis- response

  • displays Efficacy (Emax)
  • bigger response = more efficacious
155
Q

ex if 30 mg of detorolac produces the same analgesic response as 200 mg of ibuprofen, which is true?

A

ketorolac is more potent than ibuprofen

156
Q

ex in the presence of buprenorphine, a higher concentration of morphine is required to elicit full pain relief. Buprenorphine by itself has a smaller analgesic effect than does morphine, even when given at the highest dose. Which of the following is correct regarding these medications?

A

morphine is a full agonist and buprenorphine is a partial agonist

morphine is more efficacious than buprenorphine

157
Q

ex In the presence of naloxone, a higher concentration of morphine is required to elicit full pain relief. Naloxone by itself has no effect. Which of the following is correct regarding these agents?

A

naloxone is a competitive antagonist

158
Q

classification of antagonists

A

blocks SAME receptor:
Active site (always competitive)
or
noncompetitive (active site or allosteric site)

Non receptor antagonists:

  • chem antagonist- no receptor involved
  • physiological antagonist- acts on different receptor
159
Q

pharmacologic competitive antagonists

A

binds same receptor
does not elicit response
prevents agonist response
reversible nature; allows block to be overcome by agonist conc (surmountable)

EC50 increases (potency decreases) 
Emax unchanged
--shift curve to right
160
Q

noncompetitive antagonists-

A
  • irreversible (or reversible?)
  • antagonism cannot be surmounted by increasing agonist conc; func receptors have been “removed” from the sys; less receptors to contribute to the response regardless of agonist conc

EC50 minimally affected
Emax reduced
–shifts curve down

161
Q

ex a reversible competitive antagonist

A

causes the EC50 of an agonist to increase

162
Q

ex an irreversible competitive antagonist

A

irreversible competitive AKA non-competitive

has no effect on the potency of an agonist
causes the Emax of an agonist to decrease

163
Q

physiologic antagonist

A

activates or blocks a distinct receptor that mediates a physiologic response opposite to agonist

164
Q

chemical antagonists

A

does NOT involve receptor binding

acts via modification or sequestration of agonist

165
Q

ex Symptoms of allergic rhinitis include nasal congestion (vasodilation) and runny nose (edema) caused by histamine’s interaction with H1 receptors on vascular smooth muscle. Loratadine is a treatment of choice, working via a competitive blockade of histamine H1 receptors on blood vessels. The role of loratadine in the treatment of allergic rhinitis is best described as:

A

pharmacologic antagonism

166
Q

maintaining Cp in therapeutic window achieved by:

A

proper design of dosing regimen

167
Q

quantal dose response curve

A

dose vs % individuals responding

plot of data provides population response

such curves can provide info on drug safety by comparing therapeutic responses to toxic responses (historically death)

168
Q

ex regarding measures of drug toxicity:

A

quantal dose-response curves can provide info on relative drug potency

169
Q 
adverse reactions-
extension effects
side effects
idiosyncratic reactions
drug allergy
A

extension- arise from therapeutic effect; dose related and predictable (mechanism based)

side- unrelated to therapeutic goal; predictable, dose-dependent

  • same drug-target interaction different organ or sys
  • unrelated pharmacodynamically to therapeutic action

idiosyncratic reactions-
genetically determined abnormal response to drug; unpredictable

drug allergy- immunologic; unpredictable; dose independent

170
Q

pharmacokinetic drug drug interactions can result in:

A

elevated drug conc’s- leading to toxicity
-via reduced elimination rates (most common) or protein-bound drug displacement (rare)

or

decrease in Cp- sub therapeutic levels
-via more rapid drug elimination (common) or decreased drug absorption

occur when 2nd drug changes Cp of 1st drug
-if still in therapeutic range- not clinically significant

171
Q

patient categories at high risk for interactions:

A

elderly
patients in high risk clinical situations:
-dependent on drug treatment
-acute illness
-unstable disease
patients with renal/hepatic disease
patients with multiple prescribing physicians

172
Q

pharmacokinetic interactions absorption ex

tetracycline plus antacids-milk

A

rate in = rate out

drug dose / freq = Cp x CL
tetracycline / (lower abs from antacid/milk) = (lower Cp for tetracycline so unresolved infection) x unchanged CL

173
Q

pharmacokinetic interactions absorption ex

alcohol plus food

A

rate in = rate out

alcohol / (reduced abs speed from food) = (reduced peak Cp from alcohol, so delay and reduction in inebriation) x unchanged CL

174
Q

pharmacokinetic interactions- distribution

A

blood flow-
drug indued decrease in cardiac output, so decreased hepatic blood flow so dec hepatic CL so incr Cp

protein binding- displacement drug drug interactions
-displacement of 1st drug from protein by 2nd drug results in increased levels of unbound-free 1st drug

175
Q

pharmacokinetic interactions- metabolism

A

Well-documented, qualitatively and clinically most significant

Involve changes in metabolic elimination rate, can be:

Increased by inducers, leads to reduced and possibly subtherapeutic Cp levels

Decreased by inhibitors leads to increased possibly toxic Cp levels

Most interactions occur via effects on CYP450 enzymes

176
Q

pharmacokinetic interactions- excretion and kidney opportunities

A 
renal excretion-
glomerular filtration (f[GFR])
tubular secretion (fixed capacity)
tubular resorption (pH effect) back to blood
177
Q

circumvent or prevent drug-drug interactions

A

modification of dosing schedules to compensate for anticipated DDI
selection of alt non-interacting drug in same therapeutic class
document all patient drug use
vigilance with narrow TI drugs
caution in high risk clinical sit’s
consider DDI if clinic course unexpectedly deteriorates

178
Q

single most important determinant of poisoning outcomes

A

provision of good supportive care

179
Q

toxicokinetic strategies

A

prevent- decrease toxin abs; decrease rate in

inhibit toxication- prevent toxic conversion

enhancement of metabolism- detox of toxic species

increase elimination- increase rate out

antidotes-
antagonism of toxin action at target; limited utility-
300,000 potential poisons but only 20-30 specific antidotes

180
Q

ex for majority of poisoning cases, the mainstay of treatment will be:

A

support of vital function

181
Q

prevention of absorption methods

A

emesis: empties stomach contents rapidly (syrup of Ipecac)

gastric lavage- wash stomach w/ saline; removal via NG tube

chemical absorption- activated charcoal (binds drug; limits abs)

osmotic cathartics- Mg Citrate or Sulfate

182
Q

ex which poisoning interventions acts primarily via increasing the elimination of the toxin?

A

alkalinization of the urine with sodium bicarbonate

administration of a heavy metal ion chelator

183
Q

enhance elimination methods

A

inhibition of toxication- methanol and ethylene glycol (minimally toxic until metabolized)

enhance detoxication- speed up metabolism (acetaminophen)
–acetaminophen overdose- saturates Phase 2 pathways; leads to liver damage
====treat with N-acetylcysteine

hemodialysis

manipulate urine pH

184
Q

ex A homeless middle-aged male patient His breath smells like formaldehyde and he is acidotic. Which of the following is the most likely cause of this patient’s intoxicated state?

how do you treat this?

A

methanol; leads to formaldehyde and formic acid production; leads to severe acidosis and retinal damage

(vs ethylene glycol- oxalic acid; nephrotoxicity)

treat- with ethanol or fomepizole

185
Q

ex which poisoning intervention acts via inhibiting toxication?

A

ethanol
and
fomepizole

186
Q

ex identify the enzyme responsible for producing the hepatic metabolite of acetaminophen

A

CYP2E1

187
Q

FDA’s role in drug regulation

A
  • placement in Rx vs OTC categories
  • evaluation process for determining safety and efficacy of new drugs
  • removal of dietary supplements deemed unsafe
  • equivalency of brand name vs generic drug products
188
Q

4 categories of drugs

A

prescription (eval; prescript; low abuse pot)

controlled sub (eval; prescript; abuse pot)

OTC (eval; no abuse pot)
dietary supplements (not eval)

dietary supplement

4 categories distinguished by:

evaluation of drug efficacy and safety

availability by prescription or OTC purchase

potential for abuse leading to dependence

189
Q

drug vs dietary supplement

A

drug: therapeutic agent intended to diagnose, treat, cure, or prevent a disease
- known molec entities
- manufacturers must demonstrate proof of efficacy and safety before marketing

dietary supplement- product intended to supplement the diet; not represented as food

  • incl vitamins, minerals, AA’s, herbs
  • DSHEA Act of 1994- allows sale to public without prior evidence of safety or efficacy

health claims on label must contain:“This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease”.

190
Q

evaluation of drug efficacy and safety

A 
drug dev and approval process- 
in vitro studies
animal testing
clinical testing
-Phase 1 is it safe (20-100 patients)
-Phase 2 does it work (100-300) 
-Phase 3 does it work double blind (1000-3000)
New Drug Application around year 8-9
marketing; patent expires 20 yrs after NDA
191
Q

ex true statements regarding regulation of pharmacologically active chemicals in the US

A

extensive testing on animals must be performed before being tested in humans

192
Q

FDA equivalency category for generic drugs

A

formulation has pharmaceutical equivalence

molecs have bioequivalence

effect has therapeutic equivalence
(expensive and time consuming- not required by FDA for generic drugs)

-assumed that bioequivalent drugs will be therapeutically equivalent

193
Q

pharmaceutical alternatives

A

same therapeutic moiety
different salts, esters, or complexes of that moiety
different dosage forms (capsules vs tablets) or strengths (200 vs 250 mg)

immediate release products not equivalent to extended-release products with same active ingredient

194
Q

1994 Dietary Supplement Health and Education Act

A

drug vs supplement classified based on intended use
if sold in US prior to 1994- not required to be reviewed by FDA for safety; presumed to be safe
-post 94- manufacturers must provide “reasonable” evidence that the produce is safe for humans (not safe and effective; but aren’t permitted to market unsafe or ineffective products; burden of proof on FDA before it’s removed from market)

bottom line- FDA has minimal regulatory control over sale and distribution of dietary supplements

supplement- vitamin, minerals, AAs, herbal meds
first 3: know molec entity imparting activity; safe dosage ranges
-info not known for majority of herbal substances

195
Q

claims for dietary supplements
health
structure/function

A

health claim- describes effect substance has on reducing risk or preventing disease

  • requires FDA authorization
  • ex Ca may reduce risk of osteoporosis

structure/func claim- describes role of substance intended to maintain the structure/function of body

  • no requirement from FDA
  • cannot mention specific disease
  • must include the infamous disclaimer on label
  • ex Ca may help maintain bone health
196
Q

Controlled substances

5 schedules

A

DEA oversees manufacturing/distribution
requires DEA number

5 schedules based on:
medical usefulness
abuse potential
potenial for dependence

1- may not be prescribed
2-4 (CO =2-5) require a prescription

2’s must be in handwriting; NO refills

3,4(5)- may be telephoned; refills ok (5x/6mo)

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