APEX: PharmacoKinetics Flashcards
1
Q
What is the loading dose?
A
The amount of a drug that must be administered to quickly achieve a therapeutic plasma concentration.
2
Q
The Vd describes what relationship?
A
Relationship between a drug’s plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body
3
Q
What are the 2 things that Vd assumes?
A
The drug distributes instantaneously (Full equilibration occurs at t=0)
The drug is not subject to biotransformation or elimination before it fully distributes.
4
Q
Vd is a calculated
A
Value and it is something we can directly measures.
5
Q
Vd formula
A
Vd = amount of drug/ desired plasma concentration
6
Q
Concentration is a measure of
A
amount per volume
7
Q
Total body water is
A
42L
8
Q
Total body water divisions
A
Extracellular 14
Intracellullar 28
9
Q
Extracellular volume division
A
Plasma volume 4L
Interstitial fluid 10L
10
Q
A drug with a Vd that exceed total body water
A
> 0.6L/kg or >42L ) is asssumed to be lipophillic.
11
Q
Lipophillic drug distributes into the
A
Total body water as well as into fat.
12
Q
Meaning of lipophilic drugs as far as plasma concentration:
A
Higher dose to achieve a given plasma concentration. Propofol has a very large Vd
13
Q
A drug with a VD less than TBW is assumed to be
A
Hydrophillic.
14
Q
Hydrophillic drugs does not distribute into _____Therefore_____
A
FAT therefore requires a lower dose to achieve a given plasma concentration.
15
Q
Example of hydrophillic drugs
A
NMB are restricted to the ECF and have a comparatively small Vd
16
Q
Vd is affected by what drugs characteristics
A
Molecular size
Ionization
Protein binding
patient characteristics(pregnancy and burns)
17
Q
The higher the Vd
A
the higher the loading dose must be given to achieve the predetermined plasma concentration.
18
Q
For an IV mediation, bioavailability equals one since it is
A
injected directly into the bloodstream.
19
Q
Dose that achieves a given plasma concentration is
A
Dependent on the route of administration.
20
Q
Clearance is directly proportional to
A
Blood flow to clearing organ
Extraction ratio
21
Q
What is clearance?
A
volume of plasma that is cleared of drug per unit of time
22
Q
Clearance relationship to blood flow?
A
Clearance is directional proportional to blood flow to the clearing organ, extraction ratio, and drug dose.
23
Q
Clearance relationship to drug concentration?
A
CL is inversely proportional to half life and drug concentration on the central compartment.
24
Q
Cl is directly proportional to (BED)
A
Blood flow to clearing organ
Extraction ratio
Drug dose
25
What is clearance Cl is inversely proportional to
Half life
| Drug concentration in the central compartment.
26
The most important clearing organs are
liver
kidney
Organ independent (Hoffman elimination and ester hydrolysis in the plasma)
27
To maintain a steady state concentration in the plasma,
the infusion rate or dosing interval must equal the rate of clearance by metabolism and elimination.
28
What is vital when calculating a continuous infusion or determining a dosing interval?
Clearance.
29
SS Rate of administration =
rate of elimination
30
What is the definition of steady state
When the amount of drug entering the body is equivalent to the amount of drug being eliminated from the body.
31
Steady state means that there is a
Stable plasma concentration.
32
Each of the compartment has_______When there is steady state.
Equillibrate , although the amount of total drug may be different in different compartments.
33
Steady state is achieved after _____ half times
five.
34
The steepest portion of the curve represents? What phase is that?
Redistribution from the plasma to the tissues. THIS IS CALLED THE ALPHA PHASE
35
The less steep portion of the curve represents
Elimination from the plasma. This is called the BETA PHASE
36
Mnemonic to remember curve dose response
D up E dow
37
The plasma concentration curve graphically depics the
Biphasic decrease of a drug's plasma concentration following a rapid IV bolus.
38
When we give a rapid bolus , the drug follows it
concentraton gradient fromthe central compartment (plasma) to the peripheral compartments (the tissues)
39
As a general rule, the more lipophillic:
the larger the Vd, and the steeper the slope.
40
As soon as a drug enters the plasma part of it
Redistributes based on the concentration gradient between the plasma and the tissues.
41
At the same time, some of the drugs in the plasma is
undergoing elimination
42
As concentration in the plasma continues to decline as a result of continued elimination, the concentration gradient
reverses and drug redistributes from the peripheral compartment and re-enters the central compartment.
43
The flatter slope (beta phase) represents
Drug elimination from the central compartment.
44
The alpha portion of the curve represents
Distribution called also T1/2 alpha
45
The beta portion of the curve represents
Elimination called also T1/2Beta
46
Rate constants communicate
The speed at which a reaction occurs (how fast molecules move between compartments)
47
K12 is the
rate constant for drug transfer from central to peripheral compartment
48
K21 is the
Rate constant for drug transfer from peripheral to central compartment
49
Ke is the
Rate constant for drug elimination from body
50
The 3 compartment model has multiples
```
VD
tissue concentration
Rate constants
half lives
clearances.
```
51
Elimination half life is the
time requires for a drug's plasma concentration to decline by 50 percent.
52
After four half lives have elapsed, the patient's serum will contain
6.25 % of the original dose.
53
Elimination half-LIFE is t
the time it takes for 50% of the drug to be removed from the body after a rapid IV injection
54
Elimination half-TIME is
time it takes for 50% of drugs to be removed from the plasma during the elimination phase.
55
When the rate of a drug removal from the plasma is not the same as the rate of drug removal from the body,
the elimination half life and half times will be different.
56
By convention, we say that a drug has been cleared from the body when
96.9% of the dose has been eliminated from the plasma. This occurs after 5 half times.
57
The half time measures a
Constant fraction and not a constant amount. (meaning it takes the same period of time for the plasma concentration of a drug to fall from 200 mg/L to 100mg/L as it does for the same drug to fall from 50mg to 25mg/L
58
Context sensitive half time takes what into account
The duration of the drug administration
59
Contect sensitive half time is the
Time required for the plasma concentration to decline by 50% after the infusion is stopped.
60
The context sensitive half time for a fentanyl infusion increases as function of
how long it was infused.
61
Explain the context sensitive half time for a fentanyl infusion
A longer infusion had more time to fill up the peripheral compartment, therefore more fentanyl has to be eliminated and will have a longer elimination half time.
62
Context sensitve half time of 3 opiods that are longer
Fentanyl
alfentanil
sufentanil
63
Context sensitve halft time of 1 opioids that is metabolized differently
Remifentanil. Even though it is highly lipophillic, it is quickly metabolized by plasma esterases
64
Context sensitive half time from highest to lowest
```
FASR
Fentanyl
Alfentanil
Sufentanil
Remifentanil
```
65
If you put a strong acid or a strong base in water what will happen?
Will ionize completely
66
If you If you put a weak acid or a weak base in water what will happen?
A fraction of it will ionized, and the remaining fraction will be unionized.
67
Describes the process where a molecure gains a positive or negative charge
Ionization
68
How does ionization affects a molecule?
affects molecule's ability to diffuse through lipid membranes.
69
The amount of ionization dependent on 2 main things
pH of the solution
| The pKa of a drug. (dissociation constant)
70
What happens the pka = pH
50% of the drug will be ionized and 50% will be unionized.
71
Small changes in pH can have a profound impact on
the degree of ionization (more pronounce if the pKA and pH ave very close, and less if pKa is very far from the ph)
72
Explain solubility of ionized molecule with water and lipid?
Hydrophillic
| Lipophobic
73
Explain solubility of unionized molecule with water and lipid?
Hydrophobil
| lipophillic
74
Explain pharmacologic effect of ionized molecule? inactive vs active
Not active
75
Explain pharmacologic effect of unionized molecule? inactive vs active
ACtive
76
Explain Hepatic biotransformation of ionized molecule?
Less likely
77
Explain Hepatic biotransformation of unionized molecule?
more likely
78
Explain diffuses accross the lipid bilayer of ionized molecule? IONIZED
BBB
GI tract
Placenta
No
No
No
79
Explain diffuses accross the lipid bilayer of ionized molecule? UNIONIZED
BBB
GI tract
Placenta
Yes
Yes
Yes
80
Acidic drug in a basic PH (ionized vs unionized)
Ionized
81
Acidic drugs wants to accept/donate protons
Donate
82
Basic drugs wants to accept/donate protons
accepts
83
The acidic drugs happily donates its protons and will become
Ionized.
84
An acidic drug will be highly _______ in an acidic ph
UNIONIZED
85
The acidic drugs wants to donate protons and the acidic solution
Wants to also donate protons. Since there are no protons acceptors, the acidic drugs retains its proton and will remain unionized.
86
A base in an acidic solution will be highly
Ionized
87
The basic drugs wants to accepts protons and the basic solution
Wants to do the same. Since there are no proton donors, the basic drugs will remain unprotonated, and will remain unionized.
88
Drugs are usually prepared as a
salt that dissociated in solution
89
A weak acid is paired with a
Positive ion Cations (sodium, calcium, magnesium)
90
Sodium thiopental is an example of weak acid or weak base?
Weak acid.
91
With weak acid name that is first is the
Cation
92
A weak base is paried with a
Negative ion such as chloride or sulfate
93
Lidocaine hydrochloride is an examples of weak acid or weak base
Weak base.
94
Which circumstance creates the strongest gradient for passage of LA from the mother to the fetus?
Maternal alkalosis
| Fetal acidosis
95
Explain ion trapping of LA in the fetus.
Maternal alkalosis : Increases the unionized fraction in the maternal circulation; more LA is available to diffuse accross the placenta.
Fetal acidosis: Increases the ionized fraction inside the fetus. this prevents the LA from crossing the placenta (back to the mother, thus trapping inside the fetus)
96
Fraction of a drug that will freely diffuse across the cell membrane? after what happens?
Unionized fraction. It will ionize according to its pKa and the pH of the solution on this side of the membrane. therefore the drug concentration as well as the degree of ionization will be different on each side.
97
How to calculate free fraction of protein bound drugs.
If a drug is usually 98% bound by plasma protein and the bound fraction is reduced to 96% , the free fraction wil increase by ?
New value - old value / old value x 100
4-2/2 x 100 = 100%
98
Plasma proteins are synthesized by the
liver.
99
Plasma protieins are
too large to pass through the cell membrane and therefore remain confined to the circulation.
100
The drug and plasma protein form this type of bond
weak bond such as an ionic, hydrogen or van de waarls bondd
101
Can a drug bound to plasma protein bind to a receptor?
no
102
Only this type of drug form can affect the body
released from the protein.
103
What is the most plentiful plasma protein?
Albumin
104
What is the primary determinant of plasma oncotic pressure?
albumin
105
What is the half life of albumin?
3 weeks
106
Albumin can serve as a measurement of
protein synthesis
107
Albumin reflect chronic or acute changes?
Chronic but not acute changes.
108
ALbumin carries + or - change
negative
109
Albumin binds primarily to ____drugs , however it also binds to
Acidic: neutral and basic drugs.
110
2 Proteins that binds to basic drugs
Alpha 1 acid glycoprotein
| Beta globulin
111
Conditions that decreases albumin
```
Liver disease
Renal disease
old age
Malnutrition
Pregnancy
```
112
5 Conditions that increase Alpha 1 acid glycoprotein
| CROMS
```
Chronic pain
RA
Old age
MI
Surgical stress
```
113
Conditions that Decreased alpha 1 acid glycoprotein
Neonates
| pregnancy
114
Alterations in plasma protein binding can theoritically affect
Drugs therapeutic effect.
115
Changes in protein binding can result from 2 things
Decreased plasma protein
| Competition for binding sites on the protein
116
Decreased plasma protein mediated by those 3 things
```
Reduced synthetic function (Liver disease , malnutrition)
Increased protein excretion (renal disease)
Altered distribution (3rd trimester of pregnancy)
```
117
How does pregnancy decrease plasma protein?
There is altered distribution
118
How does renal disease decrease plasma protein?
Increased protein excretion
119
How does reduced synthetic function decrease plasma protein?
Liver disease and malnutrition
120
Steady state between the bound and the unbound fractions will be re-established after
5 half lives have elapsed.
121
Relationship of Vd and plasma protein binding
Inversely related
122
2 things that can displace drugs from protein binding site.
Bilirubin and thyroxine.
123
Kinetic model describes the process that metabolizs a constant amount of drugs per unit time/
Zero order kinetic
124
Constant fraction of the drug is metabolized per unit time
First order kinetic.
125
For the majority of drugs the rate of metabolism is dependent on what 2 factors
1. Concentration of site of metabolism (influenced by blood flow)
2. Intrinsic rate of the metabolic process. influenced by genetics, enzyme induction, enzyme inhibition
126
Situation where there is more drug than enzyme
Zero order kinetic. , biotransformation process becomes saturated.
127
In zero order kinetic what happens
Not enough enzyme is available to metabolize all the drug that is delivered to it. The enzyme will metabolize a constant AMOUNT PER UNIT OF TIME>
128
First order kinetics: the enzyme will
metabolized a constant fraction per unit time.
129
Can first order convert to zero order?
Yes it is possible for a drug that follows first order kinetics to change to zero order kinetics if the enzymatic pathway becomes saturated.
130
Drug metabolism is divided in 3 phases :
Phase I
Phase II
Phase III
131
Phase I of drug metabolims is
Modification mediated by Oxidation, reduction , hydrolysis
132
Phase II of drug metabolism is
Conjugation
133
Phase III of drug metabolism is
Excretion
134
The enzymatic process of altering the chemical structure of a molecule?
metabolism or biotransformation.
135
Primary organ of metabolims?
Liver
136
The hepatic microsomal enzymes of the p450 system are generally confined to the
Smooth Endoplasmic reticulum
137
Another site of primary metabolism other than liver
plasma.
138
Key reactions in plasma related to metabolism
Hoffman elimination
139
Hoffman elimination are depended on 2 factors
pH
| temperature.
140
Hydrolysis reaction are catalyzed by
Non-specific esterases
| Pseudocholinesterase.
141
The primary role of metabolism is to
Change a lipid soluble, pharmacologically active compound into a water soluble , pharmacologically inactive byproduct.
142
With metabolims, by creating molecules with greater water solubility _______Ionization and _____Vd
Increases Ionization and decreases their vd.
143
Increase ionization and decrease vd faciliate
delivery to the kidneys for elimination.
144
Also able to eliminate products
GI tract.
145
If the body was unable to change a lipid soluble into a water soluble byproducet, the lipid soluble drug would be
continuously reabsorbed by the renal tubules into the pericapillary fluid and returned to the plasma. Drug would remain in the body for a very long time.
146
Sometimes body converts an inactive molecuel into a pharmacologically active molecule called
PRODRUG
147
Fospropofol is a
Prodrug that is metabolized by ALKALINE PHOSPHATASE to its active metabolite PROPOFOL
148
Fospropofol metablized by
Alkaline phosphatase
149
Phase one reactions results in
small molecular changes that increase the polarity of a molecule to prepare it for a phase 2 reaction.
150
Most phase I biotransformation are carried by the
P450 system.
151
Oxidation work by
Adds an oxygen molecule to a compound.
152
Reduction work by
Add electron to a compound
153
Hydrolysis work by
Add water to a compound to split it apart
154
Phase 2 reactions do what
conjugates an endogenous, highly polar, water soluble substrate to the molecule. this results in a soluble, biologically inactive molecule ready for excretions.
155
Common substrate for phase II conjugation reactions:
```
Glucuronic acid
Glycine
Acetic acid
Sulfuric acid
Methyl group
```
156
Do all drugs require phase I or Phase II?
Some drugs do not require preparation by phase I reactions, and may proceed directly to phase II reactions.
157
What is ENTERO HEPATIC CIRCULATION?
Some conjugated compound are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation. (BIS)
158
Example of drugs that UNDERGOES enterohepatic circulation?
Diazepam.
159
Phase 3 which is elimination involves? present where?
ATP dependent carrier proteins that transport drugs across cell membranes. These kidney, liver, GIT
160
3 drugs that under perfusion dependent hepatic elimination ?
Propofol
Fentanyl
Lidocaine
161
2 drugs that undergo capacity dependent hepatic elimination ?
Diazepam
| Rocuronium
162
Hepatic clearance is the product of
Liver blood flow - how much is delivered to liver
| Hepatic extraction ratio - how much is removed by liver
163
The extraction ration is a measure of how
how much drugs is delivered to clearing organ vs how much is removed by that organ
164
Extraction ratio=
Arterial concentration - venous concentration/ arterial concentration.
165
Extraction ratio of 1 means that
100% of the drug delivered to the clearing organ is removed.
166
Extraction ratio of 0.5 means that
50% of the drug delivered to the clearing organ is removed.
167
Flow limited elimination is defined by an ER
>0.7
168
For a drug with HIGH HEPATIC RATIO >0.7 clearance id dependent on
LIVER BLOOD FLOW
169
High hepatic ratio defined as
ER > 0.7
170
For high hepatic ration drugs, hepatic blood flow
Greatly exceed enzymatic activity, so alteration in hepatic enzymes has little effect.
171
For High ER drugs increase liver blood flow leads to_____Clearnce
increase
172
ER relationship to Clearance
Directly proportional.
173
There are 2 types of clearance as far as ER
Flow limited
| Capacity limited
174
Drugs with low ER undergo
Capacity limited elimination
175
Low hepatic extraction ratio defined as
ER < 0.3
176
For low hepatic extraction ratio, clearance depends on
ability of the liver to extract drug from the blood.
177
Low ER and changes in hepatic enzyme activity
Changes in hepatic enzyme activity or protein binding have a profound impact on clearance of these drugs.
178
Alteration in liver blood flow minimally affect clearance with
drugs with LOW ER because only a small amount of drug is removed per unit time.
179
Changes in the liver's intrinsic ability to remove drug from the blood is influenced by
the amount of enzyme present.
180
Enzyme induction effect on clearance
Increase clearance.
181
Enzyme inhibition effect on clearance
Decrease clearance
182
When administered orally , high ER drugs are subject to what?
First pass metabolism. After the drug is absorbed from the GIT, it is delivered to the portal circulation, where a portion of it is metabolized before the drug can reach the biophase. The oral dose must be adjusted to compensate this effect. This explain discrepancies between oral and IV dose regimens.
183
Drugs not affected by liver blood flow or hepatic enzyme activity?
Remifentanil
184
Low hepatic ER Drugs
```
Rocuronium
Diazepam
Lorazepma
Methadone
Thiopental
Theophilline
Phenytoin.
```
185
High ER drugs : to get questions right not necessarily all the class mentioned
```
CCBs
BBs
opioids
LAs
Narcan
```
186
Codeine is biotransformed to its active metabolite
Morphine CYP 2D6
187
Which drugs inhibits codeine metabolims?
Prozac
188
Quinidine and SSRIs on CYP2D6
Inhibit Cyp2D6
189
Poor choices for patients taking Quinidine and SSRIs?
Codeine , oxycodone, hydrocodone because they will not be effectively metabolized to morphine and will fail to provide adequate pain relief.
190
What is the most important mechanism of drugs biotransformation in the body?
P450 system
191
Other name for P450
Mixed function oxidase system
| Monooxygenases
192
P450 enzymes are located where
Smooth ER of the Hepatocyte.
193
P450 also located in extrahepatic tissue such as
lung, kidenys, skin, adrenal gland, GIT
194
What contribute to variations in enzyme efficiency from person to person?
Genetic polymorphisms
195
What is the most important cytochrome P450 enzymes?
CYP 3A4 Metabolizing 50% drugs that we administer
196
What is the OTHER important cytochrome P450 enzymes?
CYP2D6
197
A unique feature of the P450 system is that
Exogenous chemicals can influence the expression of these enzymes
198
An enzyme inducer stimulates
synthesis of additional enzyme.
199
How does enzyme induction affect clearance and half time?
Increases drug clearance
| Reduced T1/2
200
An enzyme inhibitor
Competes for binding site on an enzyme. Few binding sites available
201
How does enzyme induction affect clearance and half time?
Decrease drug clearance
| Increase T1/2
202
Examples of Enzymes inducers (RPPCSC)
```
Rifampin
Phenytoin
Phenobarbital (barbiturates)
Carbamezepine
Smoking tobacco
Consuming alcohol
```
203
How does enzyme induction affect the dose, plasma level and clearance?
Dose increase may be required.
Plasma level decreased
Clearance increase.
204
How does enzyme inhibition affect the dose, plasma level and clearance?
Dose decrease may be required
Plasma level increased
Clearance decrease
205
Examples of Enzyme inhibitors (CAGEKOI)
```
Cimetidine
Amiodarone
Grapefruit Juice
Erythromycin
Ketoconazole
Omeprazole
Isoniazid
```
206
Inducers of CYP2D6
Disulfiram
207
Inhibitors of CYP2D6
SSRIs
Isoniazid
Quinidine
208
CYP1A2 substrate
Theophilline *small therapeutic index
209
CYP2D6 substrate
Codeine
Oxycodone
Hydrocodone
210
CYP1A2 inducers
Tobacco
Cannabis
Ethanol
211
CYP1A2 inhibitors
Erythromycin
| Ciprofloxacin
212
Organic anion transporters are present in the
Proximal Convoluted tubule, they actively secrete anions into the urine.
213
Key function of kidney is the
Elimination of metabolic waste into the urine
214
Drugs fate is determined by its
Polarity and the pH of the glomerular fluid
215
Hydrophillic drugs will be excreted
unchanged
216
Lipophillic drugs and excretion
Must undergo biotransformation reactions to increase their water solubility before they can be excreted by the kidneys.
217
Lipophillic drugs that HAVE NOT undergone biotransformation , will be
reabsorbed into the peritubular fluid by diffusion.
218
There are 2 processes that deliver drug to the urine
Glomerular filtration
| Organic ion transporters.
219
Glomerular filtration : drugs that are not bound to plasma proteins
Will be freely filtered by the glomerulus
220
Glomerular filtration : drugs that are HIGHLY bound to plasma proteins
resistant to glomerular filtration, only the free fraction will be filtered.
221
Organic anion and cation transporters; Transport proteins located in the proximal renal tubules actively
Secrete organic acids, and bases into the urine.
222
Organic anion transporters (OAT)
Furosemide
Thiazide diuretics
PCN
223
Organic cation transporters (OCT)
Morphine
Meperidine
Dopamine
224
Urine ph Influence what
Whether drugs are excreted in urine or reabsorbed into the peritubular capillaries,.
225
Like dissolves
like
226
AAA
Acidic drugs are better Absrobed in an ACIDIC MEDIUM
227
BBB
Basic drugs are Better absorbed in a BASIC medium
228
2 things that can acidify the urine? how does this help?
Ammonium chloride
Cranberry juice
Helps eliminate basic drugs.
229
2 things that can alkalize the urine? how does this help?
Sodium bicarbonate
Acetazolamide
helps eliminated acidic drugs
230
Enzymatic drug metabolism in the plasma tends to occur via one of three pathways?
Pseudocholinesterase
Nonspecific esterase
Alkaline Phosphatase
231
Drugs metabolize via pseudocholinesterase:
Succinylcholine, COCAINE (+hepatic)
| Ester LAs
232
Drugs metabolize via Nonspecific esterase
```
REEAh
Remifentanil
Esmolol
Etomidate
Atracurium (+hoffman)
```
233
Drugs metabolize by alkaline phosphatase
Fospropofol
234
Hoffman elimination takes place where?
Plasma.
235
Drugs by both hoffman + nonspecific esterases
Atracurium
236
Drugs that undergo hoffman elimination benzoisoquinoliium
Cisatracurium
237
Causes the opposite effect to that of a full agonists and example?
Inverse agonist
| Propranolol
238
Occupies the receptor binding site and prevents agonist from binding to it , does not tell the cell to do anything? Example?
ANTAGONIST
| Cisatracurium
239
Is only capable of partially turning on a cellular response
PARTIAL AGONIST
| Nalbuphine
240
Can maximally turn on a specific cellular response?
AGONIST
| Propofol
241
Pharmacological effect of 2 drugs given at the same time will be greater than the sum of their individual effects
1+1 = 3
Synergism
242
Pharmacological effect of 2 drugs given at the same time are added to each other 1+1 =2
Addition
243
Simultaenous administration of one drug cancels out the effect of a second drug 1+1 =
0
244
Major flaw of the context sensitive half time
It only illustrates the time it takes for the concentration to decline by 50% in the central compartment. Meaning it does not necessarily predict the time to wake-up after an infusion is stopped.
245
Enantiomeric drugs supplied as racemic mixtures:
Ketamie
Ephedrine
Desflurane
246
Biotransformation of morphine to
Morphine-6-Glucuronide
247
Biotransformation of morphine to Morphine-6-Glucuronide is an example of
Conjugation
248
3 drugs that exhibit ZERO order (LINEAR) kinetics
```
WE PATH
Warfarin
Ethanol
Phenytoin
Aspirin
Theophylline
Heparin
```
249
Drug must likely to cause theophilline toxicity?
Erythromycin
