PHARM... Flashcards
1
Q
what is pharmacodynamics?
A
effect of drug on the body
2
Q
small differerences in structure produce __________ changes in activity and toxicity.
A
dramatic changes
3
Q
How does a drug produce its effect?
A
interacting w/a macromolecule within or expressed at the surface of a cell - the receptor.
4
Q
What is an agonist?
A
a drug that activates molecular, biochemical, physiological events associated with that interaction
5
Q
What does a receptor do?
A
Recognition (confers selectivity; receptor must recognize drug and drug must fit well in receptor site to activate)
Signal transduction (trasnmits signal to cell)
6
Q
Do drugs initiate new cellular functions?
A
NO.
they only increase or decrease cell function
7
Q
What imparts selectivity in drug binding?
A
RECOGNITION
(the drugs binds one or a small # of receptor types)
8
Q
What imparts specificity of drug action?
A
tissue localization of different recepter types
(the drug exerts a distinctive influence on the body - only effect specific places)
9
Q
What is pharmacology?
A
study of substances that interact with living systems through chemical processes
10
Q
What are the majority of drug receptors?
A
they’re proteins, which include enzymes, transporters, ion channels, structural proteins, and regulatory proteins.
11
Q
Do most drugs bind to receptors covalently?
A
no, most drugs interact through weak forces.
12
Q
4 ways transduction mechanisms act:
A
1) directly alter the function of the receptor (e.g. an ion channel or enzyme)
2) generate a “2nd” messenger (e.g. cyclic AMP) which in turn alters cellular function
3) involve changes in gene transcription due to interaction of an activated receptor complex with DNA.
4) direct effects on RNA or DNA are also possible when nucleic acids act as the drug receptor.
13
Q
Transduction Mechanisms
G Protein-coupled Receptor Signaling
A
Drug binds to G-protein
Most common drug receptor group
GPCRs regulate “2nd messengers” such as cAMP, cGMP, Ca2+, diacylglycerol (DAG), and inositol trisphosphate (IP3).
14
Q
What is the best known of the Transduction Mechanisms?
A
Ion Channels
ligands bind, allows ions to follow electrochemical grandients…can lead to depolarization…
channels regulated by membrane potential - channel substrates include Na+, Cl-, Ca2+, K+
15
Q
Which of the Transduction Mechanisms involves dimerization upon binding?
A
Receptors as Enzymes/ligand binding
think insulin/cytokines etc - express catalytic activity.
Many are kinases
Intrinsic enzyme activity phosphorylates diverse effector proteins
16
Q
Which of the Transduction Mechanisms is the only floating one?
A
The ones regulating nuclear transcription.
the others are all in membrane. These float around in cytoplasm with a chaperone
17
Q
What are the attributes of receptor-mediated processes
A
A. Highly compartmentalized; confers drug specificity
B. Self-limiting (most; excepting intracellular hormone receptors); potential basis for drug tolerance [doesn’t keep going - turns off]
C. Organized into opposing systems; another potential basis for drug tolerance as well as possible drug-drug interactions.
D. Create opportunities for signal amplification (characteristic of G-protein)
E. Operate through a relatively small number of 2nd messenger systems; another potential basis for drug-drug interactions (essentially an expansion of attribute C). # of receptors greatly outnumber secondary signals - has to do with control
18
Q
Do all drugs interact with receptors?
A
No!
- some interact with small molecules or ions (chelators)
- some act by physicochemical mechanisms (may move water in/out of certain systems, change pH, act as anesthesia…)
- some target rapidly dividing cells (e.g., chemotherapeutic agents)
19
Q
What are cell cycle-specific drugs?
A
toxic to cells that are dividing or preparing to divide
some = structural analogs of certain compounds that act by interfereing w/DNA/RNA synthesis
others bind to DNA and cause strand breaks
others target cellular machinery needed for cell division
20
Q
What are cell cycle-nonspecific drugs?
A
toxic to cells cycling OR resting (G0)
many damage/bind to DNA, interfering with normal cell function
21
Q
What is the Occupancy Theory?
A
Drug + Receptor Drug Receptor Complex -> Effect
It assumes that effect is proportional to receptor occupancy and that interaction is monovalent (one receptor binds one ligand).
22
Q
Why do you use log dose line in dose-response curves?
A
So it’s easier to get EC50
23
Q
What is response to a drug proportional to?
A
RECEPTOR OCCUPANCY
24
Q
What is affinity?
A
ability to complex w/receptor.
characterized as 1/KD
25
The greater the affinity, the ________ the drug concentration required to produce an effect
LOWER
26
what is potency?
relative position of dose-response curve (it's comparative, and high potency does not necessarily make a drug better)
27
What is efficacy?
the ability of a drug-receptor complex to produce a response
also known as *intrinsic activity*
28
What is the difference between a full agonist and a partial agonist?
**Full Agonist (X)**
Maximal response
Has full efficacy (alpha=1)
**Partial Agonist (Z)**
Produces less than maximal response
Has partial efficacy (1\>alpha\>0)
29
What is the difference between a
pure antagonist
a competitive antagonist
and a
non-competitive antagonist?
**pure antagonist:**
has afinity for receptor
inhibits action of agonist
has no efficacy (alpha = 0)
**competitive antagonist:**
- reversible
- agonist dose-response curve will shift to RIGHT in presence of compet. antagonist
- apparent affinity of agonist is reduced
- slope does not change
- maxmal response can be produced
**non-competitive antagonist:**
- irreversible (permanent interaction with receptor)
- apparent affinity changes little if at allll
- slope reduced
- maximal resopnse reduced
- apparent # of receptors decrease (you can't rescue the response)
30
What is physiological antagonism?
totally different type - using 1 drug to deal with the effects of another; not to do with receptors like others.
invovles interactions among regulatroy pathways mediated by different receptors
a drug that impacts 1 pathway is used to "antagonize" (counteract) an effect caused by a **different pathway**
31
What is a partial agonist?
efficacy - 1\>alpha\>0
in presence of full agonist, it may act as an antagonist
**there are different levels of effect - it is quite common, but something that occupancy theory does not explain**
32
What is the other case where occupancy theory is not relevant?
**Inverse Agonist**
add drug, get LESS effect
add antagonist to it, and it becomes unresponsive to everything
33
There has been step-wise sophistication in models - 2-state theory led to 3-state theory led to 4-state theory...
how do people think about all this mess now?
every receptor in environment that strongly impacts it; there are allowsteric sites on the receptor that modify the receptor's response to ligands and drugs.
34
What's with 'spare receptors'?
**Occupancy of a small percentage of receptors often elicits a maximal response.** In this case the system behaves as if it has “spare” receptors (i.e., more than it “needs”). **Under these circumstances the EC50 and KD values will be differen**t (perhaps substantially so) - *a clear violation of simple occupancy theory.*
## Footnote
you can max out the system with 5% occupancy or something - it is the secondary messengers limiting the responses, not the receptors
35
What is the Quantal Dose Effect?
what is ED50?
- responses are all or none
- the curve shows the population response to a drug
- **Can** be used to **find** the median effective dose** (ED50)** is the dose required to produce the response in 50% of the population.
**-can't use this to find KD or max efficacy**
- can get potency from looking at curve
- individual response = hyperractive if repsond to dose \<
36
what is tolerance?
form of hyporeactivity induced by repeated administration
37
what is a form of hyporeactivity induced rapidly after only a few doses?
tachyphylaxis
38
What is LD50?
drug concentration that will kill half your patients
39
what is ED50
drug concentration that will be effective in 50% of patients
40
what is the therapeutic index?
TI = LD50/ED50
measure of relative safety
41
What is CSF?
certain safety factor (a difficult to calculate conservative measure of safety)
CSF = LD1/ED99
LD1 (dose producing death in 1% of population)
ED99 (dose producing therapeutic response in 99% of population)
(larger the TI or CSF the better...there is no minimum, because sometimes you have to use drugs with small #s - like Chemo etc)
42
are certain molecules always agonists or always antagonists?
could be agonst at 1 receptor, partial agonist at another receptor, and an antagonist at a different receptor.
The “predominant” activity at any given time may be highly dependent on dose due to differences in affinity (i.e., KD values) for the different receptors with which the drug interacts.
43
what's with side effects?
relates to drug activities at different receptor types (implies imperfect selectivity)
since the "main effect" is highly dependent on dosage, high dose levels may “unmask” undesired side effects that are not evident at lower dosages. Alternatively, dose may be adjusted by the clinician to emphasize a particular pharmacological effect
44
What is pharmacokinetics?
what the body does with a drug
response to a drug is a function of its concentration at the receptor site
45
What order of kinetics does pharmacokinetics follow?
1st order
46
What controls the concentration of a free drug and the duration of its action?
ADME
Absorption extent and rate
Distribution
Metabolism (extent and rate of biotransformation)
Excretion
47
What is MEC?
minimum effective concentration - any plasma concentration above this level will produce an effect
48
what mechanism of drug transfer is this?
- electrochemical gradient = driving force
- no energy required (moves down that electrochem or concentration gradient)
- net movement across membrane at equilibrium = 0
- does not saturate
- not inhibitied by structurally similar analogs
- rate of movement described by Fick equation:
Flux = DAK(Cout-Cin)/(change in X)
This is **Passive DIffusion**
a. (Cout - Cin) = concentration gradient
b. D = diffusion constant of drug within the membrane (inversely proportional to size)
c. K = membrane:partition coefficient (measure of relative lipid solubility, hydrophobicity)
d. A = surface area of membrane
e. ∆X = thickness of membrane
f. DKA/∆X = permeability constant (P)
g. Equilibrium of highly lipid soluble drug may occur on first passage through an organ
49
What is the one thing flux is inversely proportional to in passive diffusion?
Flux is proportional to the
diffusion constant (D)
concentration gradient (Cout-Cin)
membrane surface area (A)
relative lipid solubility (K)
**inversely proportional to the thickness of the membrane (change in X)**
50
What is the effect of ionization?
weak acid exists in plasma in equilibrium - but A- anion can't cross the membrane
weak base B can cross, the catation BH+ can't cross
**cations/anions basically never cross**
results in ion trapping
51
What is ionic trapping?
At equilibrium **net movement** = 0 because it is **determined by concentrations of the neutral form**, but the total concentration of drug (neutral and charged) on either side of membrane may be different.
pKA = pH at equilibrium...the [base] may be equal on each side, but one side may have a million cations of that base and the other may have none
52
Weak acids get trapped in relatively __________ environments
weak bases get trapped in relatively ___________ environments
weak acids trapped by relatively BASIC environments; weak bases trapped by relatively ACIDIC environments.
Has therapeutic implications for the renal excretion of drugs - increasing urinary pH enhances the renal excretion of a weak acid while lowering the urinary pH enhances the excretion of a weak base
53
70% of drugs in current use are weak (acids/bases)??
weak BASES
54
name 2 bulk flow mechanisms
Filtration (movement of fluid through aqueous channels - limiting factor = channel size)
Endocytosis (active bulk flow thru membrane; engulfs volume of fluid; may be selective or nonselective)
55
carrier mediated mechanisms: which is which?
*movement down electrochemical gradient*
*movment against electrochemical gradient
requires energy*
Facilitated Diffusion
1. Transport of large, water-soluble molecules, including both ionized and nonionized molecules, e.g. glucose and amino acids
2. Movement DOWN a concentration gradient
3. Carrier mediated
Active Transport
1. Transport of large, water soluble molecules, and both ionized and nonionized molecules, e.g. secretion of organic acids and bases by renal proximal tubule and by liver into bile
2. Movement UP a concentration gradient
3. Carrier mediated
4. Requires energy; can distinguish primary (ATP hydrolysis) and secondary (coupled to another compound’s electrochemical gradient) mechanisms
BOTH
selective & inhibited by similar chemicals
saturate at high substrate concentrations
56
what is the ABC superfamily?
**A**TP-**b**inding **c**assette superfamily
## Footnote
Active transporters (primary mechanism)
Usually move substances out of cells.
Over expression of MDR1 and other ABC transporters by tumor cells may confer resistance to chemotherapeutic agents.
57
What is the SLC superfamily?
SLC (solute carrier) superfamily
## Footnote
Includes facilitated transporters and active transporters that work through a secondary mechanism
May move substances into or out of cells (equally capable of flipping either way, but net flux is determined by concentration gradient)
major role in nervous system...
58
What do the ABC and SLC families have in common?
## Footnote
a. Are pharmacodynamically important as target molecules;
b. Are pharmacokinetically important in modulating uptake and excretion from the body
c. May work in concert to move compounds into and out of cells
d. May work in concert with biotransformation enzymes to facilitate drug elimination
e. Can account for many drug toxicities, inherited drug susceptibilities, and **drug-drug interactions**
59
How are most drugs absorbed?
passive diffusion
60
what is the difference between enteral and parenteral routes of drug administration?
enteral = via intestines
parenteral = outside the intestines
61
How different routes compare for absorption speed?
IM \> SC \> Oral
62
What is the preferred route and why?
Why not always use it?
Oral:
i. Easiest to self administer
ii. Cheapest dosage form to manufacture
iii. Safest dosage form to administer (time for take-backs if something is wrong)
iv. Good patient compliance
I. some drugs get destroyed by GI tract
II. goes from intestines to hepatic vein to liver - 1st pass metabolism: sometimes impossible to get into general circulation
III. rate of uptake is highly variable - many things change it
63
What is bioavailability?
a measure of the fraction of an administered dose of a drug that is absorbed into the systemic circulation
Formulation can alter bioavailability; includes such factors as disintegration rate, dissolution rate, solubility of preparation, particle size, and coatings
Oral bioavailability = AUCoral/AUCiv
where AUC = area under the plasma concentration-time curve
64
Lipinski's Rule of 5,
- not \>5 H-bond donors
- not \>10 H-bond acceptors
- molecular mass \< 500
- octanonl:water partition coefficietn (log basis) \<5
Do drugs possessing these attributes have good or poor bioavailability?
GOOD bioavailability; if something violates 1 or more of these rules, it shows poor bioavailability.
**_these describe a relatively small, moderately lipophilic molecule_**
65
Other routes of administration:
sublingual
rectal route
IV
sublingual (under tongue; can avoid 1st pass metabolism)
rectal route (can somewhat avoid 1st pass metabolism)
IV: dose/timing controlled perfectly...but once injected, it is what it is and you can't take it back
66
What is the important form of a drug and what factors affect distribution?
FREE form is what gets distributed, and factors affecting distribution:
* 1. Relative tissue perfusion rates*
- higher rates -\> faster equilibrium
- kidney lung liver, brain (when not stopped by blood-brain barrier) have high rates; bone/fat waaaay slow; muscle = intermediate
* 2. Plasma protein binding*
- bound drugs don't cross membranes
- pharmacologically intert (don't interact with a receptor), but may act as a "reservoir"
- albumin binds many weak acids
- alpha1-acid glycoprotein binds many weak bases
* 3. Partitioning between plasma and tissues*
- pH and ion trapping
- Tissue protein binding
- lipid solubility
67
NOTES ON PERFUSION RATES:
a function of relative tissue perfusion rates: if a tissue is perfused rapidly, drug will diffuse rapidly
when dealing w/neutral compounds, there is competition between tissue and plasma
Drug partitions into tissue based on relative affinity for tissue versus that in plasma.
ex.) those that are lipophillic will partition between tissue and plasma based on relative lipid concentration in that tissue and plasma.
68
What are the specialized barriers to distribution?
**Blood-brain barrier:**
- “Tight” endothelium + glial cells (won't just move through - get excluded)
- May be very important clinically for conditions that involve the CNS (drugs that simply can't reach brain)
• Does not apply to lipophilic substances (cross easily)
**Placental Barrier:**
if there is a barrier there, not very importent - assume the baby will get whatever drug you're giving the mother
69
Apparent Volume of Distribution:
VD = critical concept
**it's the volume in which the drug *appears* to be distributed, at equilibrium**
Basically, it's the
mass of drug / concentration of drug in plasma at any point in time after equilibrium has been achieved.
VD is “apparent” and does not necessarily correspond to any “real” volume
Reflects the relative affinity of drug for the whole body and the plasma itself
*Essentially represents the body as a big bag of plasma into which drugs are diluted. * *The VD is the volume of plasma that would be required to contain all of the drug in the body given the measured concentration in plasma. *
70
How to interprete apparent value:
normalize to body weight
allows you to compare it to plasma volume, extracellular fluid volume, total body water, etc
71
If something causes a drug to distrubte OUT of plasma and INTO tissue, will it increase or decrease VD?
● Things that cause a drug to distribute out of plasma and into tissue **increase** VD while *things that cause a drug to remain in plasma tend to decrease VD*
EXTREMELY high VD values means drug has completely moved out of plasma and into tissue
- Normalized values (L/kg) may vary considerably for the same drug in different individuals due to differences in relative lipid content, water content, etc., depending on the behavior of that particular drug
72
What terminates Drug Action?
- **storage** (redistribution)
- **excretion** (as unchanged "parent")
- **Biotransformation** (basically gone thru metabolism)
73
What are the 2 phases of redistribution?
1st distributes to tissues with HIGH perfusion rates
2nd distributes to tissues with LOW perfusion rates
(If something in low perfused tissue has high affinity for drug, eventually the chemical will move out of plasma and into those low perfused tissues)
74
What are the 3 things that determine drug elimination in urine?
- Filtration (thru "leaky capilary bed" - glomerulus) If not bound to something like albumin or AGP, it will go straight through filtration. Only free, unbound drug or metabolite in plasma is filtered)
- Reabsorption (reclaim water; concentration of drug in remaining water goes up. This sets us a concentration gradient: if drug can diffuse, it will want to diffuse out of kidney back to plasma, via passive diffusion/facilitated transport.
- Active Secretion (done via active transport: all over kidney tubule: recognize things in plasma and pump them into urine)
75
What is ClR?
**Renal Clearnance**
**the volume of plasma (L) cleared by the kidneys per hour**
Renal clearance defined as volume of plasma entirely cleared of drug or metabolite /unit of time by the kidney
Where:
CU = Concentration of drug in urine (mg/L)
VU = Volume of urine formed/unit time (L/h)
CP = Concentration of drug in plasma (mg/L)
ClR = Renal clearance (L/h)
76
What is the relationship between ClR (renal clearance) and GFR (glomerular filtration rate) for drugs that are Filtered?
Filtered and Reabsorbed?
Filtered and Secreted?
* Filtered Only*
* *ClR = GFR** = 125 ml/min (avg. adult)
*Filtered & Reabsorbed*
**ClR \< GFR**
(many drugs filtered, but then reabsorbed - so renal clearance is less than 125 ml/min)
*Filtered & Secreted*
**ClR \> GFRz**
(some blood that goes to kidney isn't actually filtered, but can still provide chemicals to be taken out in urine. therefore more is cleared than goes thru glomerulus)
\*note: this is standard measurement of patient kidney function
77
What does Biliary Excretion involve?
May require metabolism
**Facilitated** (blood -\> hepatocyte) **and** **active** (hepatocyte -\> bile) **transport** of anions, cations, some neutral compounds
**Enterohepatic circulation** (taking compound and conjugating it wih endogenous molecule, increasing molecular weight and turning it into an ion so it can be pumped into bile and then to GI tract...can then be cleaved off to GI, where is is available to be reabsorbed AGAIN.)
78
What is respiratory excretion for?
for gases and volatile agents such as alcohol
Other excretory sites - sweat, tears, saliva, milk
79
Biotransformation:
**transforming compounds to make them more hydrophillic**
1. Many drugs are lipid soluble and nonpolar, including the neutral form of weak acids and bases.
2. Most of these compounds are transformed by enzymes in the liver and elsewhere
3. Biotransformation usually results in a metabolite more polar than the parent compound and therefore more easily eliminated
4. Biotransformation may produce an inactive or active metabolite
5. May be required to activate a drug (from a prodrug); examples include codeine-to-morphine, prednisone-to-prednisolone, many others
80
What do the phase I reactions of Biotransformation do?
Add or expose functional group
(e.g., OH, NH2, SH)
Oxidation most common reaction
Metabolites generally more polar
Metabolites may be active or inactive
81
What do the Phase II reactions of biotransformation do?
Synthetic reactions (covalent type rxs)
Glucuronidation most common reaction
Metabolites generally a lot more polar
Inactivation usually results
82
What is the most important organ of biotransformation?
LIVER
Gets stuff from diet before they reach the general circulation. So can ID and eliminate anything it doesn't want.
83
Other important tissues in biotransformation:
GI tract
Kidney
Lungs
Skin
Plasma
tend to possess different complement of metabolizing enzymes: if the lungs have an enzyme that specifically transforms a certain drug, the lungs will be the most important organ for that particular drug.
84
What is the CYP system?
Cytochrome P450 System
localized to smooth endoplasmic reticulum
responsible for Phase I metabolism of many drugs
diff. CYP enzymes possess diff. substrate specificity
rates differ among individuals (cocentrations of CYP protein; forms of CYP expressed - one of the major reasons there are dfferences in drug clearence between individuals)
85
Monoamine & Diamine Oxidases
metabolize biogenic amines
(norepinephrine, seretonin, etc - terminate effects of neurotransmitters. this is a major target for anti-depressants (allow those biogenic amines to stick around longer))
86
Phase II - conjugation reactions
Glucuronidation
acetylation
sulfate conjugation
methylation
glutathione conjugation
glucuronidation - Microsomal conjugation reactions - adding big clunky charge (enzymes for this largerly in SER right along with CYPs)
others take place in cytoplasm:
acetylation - masks functional group; eliminating drug activity
- any of these could be major pathway for a specific drug
87
*Inhibitors of biotransformation: *
**microsomal drug oxidation**
**nonmicrosomal Drug Oxidation**
micro:
1. A common mechanism of inhibition involves competition between two or more drugs for same enzyme.
2. Grapefruit juice inhibits P450 - cimetidine and ketoconazole - diminishing ability to clear certain drugs (not competitive, but binding somewhere else)
nonmicro:
1. Disulfiram (Antabuse) inhibits aldehyde dehydrogenase
2. Iproniazid, originally developed to treat TB - found to be an antidepressant! inhibits monoamine oxidase
88
What happens when drugs induce expression of P450?
They induce their own clearance - many drugs do this.
This gives an apparent drug tolerance: requires more drugs for same effect. (because of enhanced clearance)
89
What other factors that alter biotransformation?
genetics
diet
environment (heavy smoking, industrial exposure induce metabolism)
age (lower rate in babies, reduced rate in elderly)
pregnancy (increased metabolism and renal clearance means increased drug clearance)
90
What is Pharmacogenomics?
| (or pharmacogenetics)
* Study of genetic differences among individuals and how these differences give rise to differences in response to drugs
* One component of an approach commonly referred to as “personalized” medicine
91
How is the free plasma drug concentration determined?
by
rate of absorption
volume of distribution (VD)
rate of elimination
92
Which happens when?
all 3 happen at once
picture shows a single oral dose: different things dominate at different times
93
Difference between zero order kinetics and first order kinetics?
First Order is shown below.
Zero order kinetics
Rate is constant (e.g., 10 µg/hr)
see this in alcohol clearence - these enzymes saturate easily, so get linear decline
ex. shown below
First order kinetics
*Rate changes with and is proportional to drug concentration*
Constant fraction of drug absorbed or eliminated per unit time
Rate proportional to concentration
- More common
* *-passive diffusion and distribution in blood inherantly 1st order**
94
KNOW THIS ONE!!!
log-transform previous data set,
now see 3 phases:
k1 - distribution phase (out of plasma into tissues...concentratioin in plasma declines precipitately..get equilibrium between tissue/plasma in a couple hours)
k2- Elimination phase (clearing plasma drug)
good approx. for many drugs: ignore K1 phase,
VD=X/C0
this is foundational experiment
Vd = apparent volume of distribution
X = total amount of drug adminstered
C0 = concentration of drug at t0 (time 0)
ke : 1/time is the elimination rate constant
95
what is the 1st order elimination slope?
slope = -(ke/2.3)
96
What is 1st order half life?
t1/2 = 0.693/ke
if elimnation rate goes down, the time the drug is in the body goes down too
97
What is the equation for whole-body clearance?
Cl = clearance rate *(volume of plasma you would ahve to clear of drug in a unit of time to account for observed elimination from the body)*
Vd = distribution
ke = Cl/VD
ke will be changed by changes in clearance or distribution
98
how is drug half-life related to clearnance and distribution?
the drug half-life is proportional to VD
and inversely proportional to Cl
t 1/2 = 0.693 (Vd/Cl)
99
What are the 2 methods of patient dosing?
continuous infusion
periodic administration of a fixed dose
100
What is the plateau principal?
continuous infusion, eventually plateaus....
note if just stop infusion, concentration declines quickly
Also Note: get 93% of the approach to steady state in 4 hafl lives. Takes same amount of time to eliminate 90% of the drugs
101
what is the equation for max concentration?
**Xmax=** Ki/ke= KI(t1/2/0.693) = **1.44 KI t1/2 **
max amount in body is proportional to infusion rate (Ki) and half life
102
How does ke affect plateau level?
how fast you come to steady state is a funciton of how fast you clear the compound (eliminate)
103
How does steady state cncentration relate to infusion reate and clearance?
**Css=Ki/Cl**
**steady state concentration (mg/L) = infusion rate (mg/hr) divided by clearance (L/hr)**
thus, there is there is one and only one dosing rate that will produce the desired steady state concentration for a given clearance rate.
104
departures?
shown = continuous infusion (red)
and 2 period oral dose: same dose, but given every 4 hours or every 8 hours. (blue and green, respectively)
The departure amount is the only thing changing here.
if at any pt. the cocnetration goes below MEC, patient isn't getting any help; could also swing up into toxicity level
105
What is the maintenance dose?
**Maintenance dose**
```
_**Maintenance Dose =
Dosing Rate (amount/hr) x Dosing Interval (hr)/f**_
```
where f = bioavailability [must account for fact that \<100% of drug will be absorbed)
i. Dose of a drug that will produce the desired therapeutic level at plateau (steady state)
ii. It is equal to the amount of drug, at plateau, that must be administered at each dosing interval to replace the amount of drug lost during the preceding interval
106
what is the loading dose?
The administration of a loading dose may be required, which will produce the desired steady state level rapidly
**Loading Dose = CSS(VD)/f**
After administering the loading dose, a maintenance dosage regimen is initiated to maintain the drug at the desired CSS.
107
What is TDM?
therapeutic drug monitoring
## Footnote
Refers to patient-specific monitoring of serum drug levels and optimization of the dosing regimen as a means of tailoring treatment to the individual
When required (one or more of the following):
- Drugs with a narrow TI
- Poor correlation between administered dose and observed effects
- Large individual differences in CL
- A toxicity profile that is difficult to recognize clinically before serious damage occurs
108
Which drugs are commonly monitored in TDM?
Drugs that are commonly monitored include:
Aminoglycoside antibiotics (e.g., gentamicin)
Antiepileptics (e.g., phenytoin)
Cardioactive agents (e.g., digoxin, lidocaine)
Theophylline, lithium, methotrexate, cyclosporine
109
How does TDM work?
Population kinetic parameters appropriate to a patient’s age, gender, weight, etc., are used in along with knowledge of a compound’s kinetic behavior (e.g., principle route of elimination) and routine measures of organ function (e.g., creatinine clearance) to design a dosing protocol (i.e., the same approach used for other drugs).
Measured drug concentrations are then used to monitor the patient and, if necessary, develop patient-specific kinetic parameters for use in adjusting the dosing regimen.
110
What are the possible results of an overdose?
unmasking of a different effect
usually results in an extreme manifestation of the drug's usual pharmacological action
111
What is another adverse drug effect"
* *• Drug-drug interactions; recall various mechanisms**
- One drug impacts the CL or VD of a second
- Two drugs operate on the same or opposing signaling pathways
- Physiological antagonism
112
What are the 3 types of adverse drug rxns that occur only in susceptible patients, usually with a genetic basis.
* Intolerance; a lower dose threshold for the drug’s normal action. May have CL or VD basis.
* Allergic reactions; effect unrelated to normal pharmacological action. Typically requires prior exposure which elicits an immune response.
* Idiosyncratic reactions; effect unrelated to normal pharmacological action. Mechanism often unclear although some are probably immune responses
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Is the clearance model the only one?
No, there are other approaches, such as the non-compartmental analysis
