F4-THERAPEUTIC DRUG MONITORING Flashcards
(308 cards)
1
Q
Which specimens are used in therapeutic drug monitoring
A
Serum + Plasma + Whole blood
2
Q
What is the purpose of therapeutic drug monitoring
A
Ensure drug dosage produces maximal therapeutic benefit + Identify if drug is above or below therapeutic range
3
Q
Minimum and maximum drug concentrations needed for desired therapeutic effect
A
therapeutic range
4
Q
How is standard dosage determined
A
Derived from observations in healthy population
5
Q
What is involved in the quantitative evaluation of circulating drug concentration
A
Measuring the amount of drugs present in the circulation
6
Q
Which common indication for therapeutic drug monitoring involves patient non-compliance
A
Identifying non-compliance
7
Q
Which common indication for therapeutic drug monitoring prevents toxic effects
A
Preventing the consequences of overdosing
8
Q
Which common indication for therapeutic drug monitoring prevents ineffective treatment
A
Preventing the consequences of underdosing
9
Q
What happens when a drug is overdosed
A
Toxicity occurs
10
Q
What happens when a drug is underdosed
A
Drug is no longer effective
11
Q
Which principle states that only the dose separates a drug from a poison
A
Paracelsus’ principle
12
Q
Which type of drug requires therapeutic drug monitoring for maximizing therapeutic effect
A
Drugs with a narrow dose range
13
Q
Which clinical scenario requires therapeutic drug monitoring for optimizing dosing regimen
A
Drug–drug interactions + Changes in patient’s physiologic state
14
Q
Which patient population benefits from therapeutic drug monitoring for regimen design
A
Patients not under monotherapy
15
Q
Which factors influence the circulating concentration of an orally administered drug
A
Rate of absorption + Rate of distribution + Will drug produce desired biologic response + Rate of metabolism + Rate of elimination
16
Q
Which key factors affect circulating drug concentration
A
Route of administration + Rate of absorption + Distribution of drug within body + Rate of elimination
17
Q
Location within the body where the drug exerts its therapeutic effect
A
site of action
18
Q
Which route of administration offers the most direct drug delivery to the site of action
A
Intravenous administration
19
Q
Unchanged fraction of the administered dose entering systemic circulation and reaching site of action
A
bioavailability
20
Q
Which routes of drug administration are commonly used
A
Intravenous + Intramuscular + Subcutaneous + Transcutaneous + Suppository + Oral + Inhalation
21
Q
Transfer of a drug from its site of administration into the bloodstream is
A
absorption
22
Q
Which factors affect absorption of orally administered drugs
A
Dissociation from administered form + Solubility in gastrointestinal fluids + Diffusion across gastrointestinal membranes + Intestinal motility + pH + Inflammation + Food + Other drugs + Age + Pregnancy + Pathologic conditions
23
Q
Which drugs are absorbed more rapidly
A
Liquid medications
24
Q
Which process allows most drugs to gain access to the body
A
Passive diffusion
25
Where are weak acids efficiently absorbed
Stomach
26
Where are weak bases efficiently absorbed
Intestine
27
Process by which a drug reversibly leaves the bloodstream and enters extracellular and intracellular spaces
drug distribution
28
Which property largely determines drug distribution
Lipid solubility
29
Which drugs easily traverse cellular membranes
Hydrophobic drugs
30
What is volume of distribution
Describes the distribution characteristics of the drug
31
Which drugs have a large volume of distribution
Hydrophobic drugs
32
Which drugs have a small volume of distribution
Ionized or plasma-bound drugs
33
Which fraction of drug can interact with the site of action
Free (unbound) fraction
34
Which factors can change serum-binding proteins
Inflammation + Malignancies + Pregnancy + Hepatic disease + Nephrotic syndrome + Malnutrition + Acid–base disturbances
35
What is the main binding protein for drugs in serum
Albumin
36
Which organ is the major site of drug metabolism
Liver
37
Which system is involved in drug metabolism
Hepatic mixed-function oxidase system
38
Circulating drug from GI tract routed through liver before entering general circulation
first-pass metabolism
39
Which factors influence liver metabolism
Genetics + Fatty or cirrhotic liver
40
Natural exogenous substances foreign to life
xenobiotics
41
Which enzymes are involved in drug metabolism
Phase I and phase II enzymes
42
What do phase I reactions produce
Reactive intermediates
43
What do phase II reactions produce
Water-soluble substances
44
Which functional groups are involved in phase II reactions
Glutathione + Glycine + Phosphate + Sulfate
45
What happens when the mixed-function oxidase system is induced
Accelerated clearance and shorter half-life
46
Which disease states can slow drug clearance
Hepatic disease
47
Which processes eliminate drugs
Hepatic metabolism + Renal filtration
48
Which fraction of drug is subject to glomerular filtration and renal secretion
Plasma free fraction
49
What happens to serum half-life and concentration if glomerular filtration rate decreases
Serum half-life and concentration increase
50
Activity of a drug in the body as influenced by absorption
pharmacokinetics
51
How does pharmacokinetics assist in drug therapy
Establishing or modifying dosage regimen
52
Which specimens are preferred for therapeutic drug monitoring
Serum + Plasma
53
Which methods are used for drug measurement in therapeutic drug monitoring
Chromatography + Immunoassays
54
Which chromatographic method is considered the gold standard
GC-MS
55
Which chromatographic methods are also used
HP-LC + TLC
56
Which assay uses antibodies reactive to the drug
Immunoassays
57
When should trough concentrations be drawn
Right before the next dose
58
When should peak concentrations be drawn
1 hour after an orally administered dose
59
Study of how a person’s genes affect their response to medications
pharmacogenomics
60
What is the long-term goal of pharmacogenomics
Help doctors select the best drug and dosage for each patient
61
Which categories of patients are identified in pharmacogenomics
Responders + Non-responders
62
Which genetic polymorphisms affect drug metabolism
Cytochrome P450 gene family
63
Which enzymes are associated with genetic variations in drug metabolism
CYP2D6 + CYP2C9 + CYP3A4
ytochrome P450 2D6, Cytochrome P450 2C9, and Cytochrome P450 3A4
64
How does identifying genetic abnormalities help in prescribing drugs
Allows accurate drug and dose selection
65
What dose adjustment is made for slow metabolizers
Lower doses
66
What dose adjustment is made for fast metabolizers
Higher doses
67
Which class of drugs includes digoxin and quinidine
Cardioactive drugs
68
Which drug treats cardiac arrhythmias and congestive heart failure
Digoxin
69
Which cardiac condition is treated by digoxin when the heart muscle is weakened
Congestive heart failure
70
What is the mechanism of action of digoxin
Inhibits membrane Na-K-ATPase
71
What are the intracellular effects of digoxin in cardiac myocytes
Decrease intracellular potassium + Increase intracellular calcium
72
Which factors influence absorption of orally administered digoxin
Dietary factors + GIT motility + Drug formulation
73
What percentage of digoxin is protein bound in circulation
About 25 percent
74
Where is the free form of digoxin sequestered
Muscle cells
75
What is the route of administration for digoxin
Oral
76
What is the average half-life of digoxin in adults
38 hours
77
How is digoxin eliminated
Renal filtration of plasma unbound form + Hepatic metabolism
78
What is the therapeutic range for digoxin
0.5 to 2.0 mg/ml
79
When does serum digoxin level peak after oral dose
2 to 3 hours
80
Which drug treats cardiac arrhythmias and is extracted from Cinchona bark
Quinidine
81
What are the most common formulations of quinidine
Quinidine sulfate + Quinidine gluconate
82
What percentage of quinidine is bound to serum proteins
70 to 80 percent
83
What is the route of administration for quinidine
Oral
84
What is the half-life of quinidine
6 to 8 hours
85
How is quinidine eliminated
Hepatic metabolism
86
Does barbiturate use affect quinidine metabolism
Yes induces hepatic metabolism
87
What is the therapeutic range for quinidine
2.3 to 5.0 µg/mL
88
When does peak serum concentration of quinidine sulfate occur
2 hours after administration
89
When does peak serum concentration of quinidine gluconate occur
4 to 5 hours after administration
90
Which levels are monitored for quinidine
Trough levels
91
Which drug is the hepatic metabolite of procainamide
N-acetylprocainamide
92
What percentage of absorbed procainamide is bound to plasma proteins
About 20 percent
93
What is the route of administration for procainamide
Oral
94
What is the half-life of procainamide
4 hours
95
How is procainamide eliminated
Renal filtration + Hepatic metabolism
96
What is the therapeutic range for procainamide
4 to 10 µg/mL
97
What is the therapeutic range for NAPA
12 to 18 µg/mL
98
When does peak plasma concentration of procainamide occur
About 1 hour post dosing
99
Which drug is commonly used as a quinidine substitute
Disopyramide
100
What is the route of administration for disopyramide
Oral
101
What is the half-life of disopyramide
About 7 hours
102
How is disopyramide eliminated
Renal filtration + Hepatic metabolism
103
What is the therapeutic range for disopyramide
3.0 to 7.5 µg/mL
104
When does peak serum concentration of disopyramide occur
1 to 2 hours
105
Which class of drugs includes gentamicin, tobramycin, amikacin, kanamycin
Aminoglycosides
106
What type of infections are treated by aminoglycosides
Gram-negative bacteria + Some gram-positive bacteria
107
What is the mechanism of action of aminoglycosides
Inhibits bacterial protein synthesis
108
What are the toxicities of aminoglycosides
Nephrotoxicity + Ototoxicity
109
Which organ is affected by aminoglycoside nephrotoxicity
Kidneys
110
What is the effect of aminoglycoside nephrotoxicity on the kidneys
Impairs proximal tubules + Leads to electrolyte imbalance + Causes proteinuria
111
What is the effect of aminoglycoside ototoxicity
Destruction of inner ear
112
What are the routes of administration for aminoglycosides
Intravenous + Intramuscular
113
What is the half-life of aminoglycosides
2 to 3 hours
114
How are aminoglycosides eliminated
Renal filtration
115
What is the trough therapeutic range for gentamicin and tobramycin
Less than 2 µg/mL
116
What is the peak therapeutic range for gentamicin and tobramycin
3 to 12 µg/mL
117
What is the trough therapeutic range for amikacin
Less than 8 µg/mL
118
What is the peak therapeutic range for amikacin
20 to 35 µg/mL
119
When does peak concentration of aminoglycosides occur after administration
1 to 2 hours
120
Which drug is a glycopeptide antibiotic effective against gram-positive cocci and bacilli
Vancomycin
121
What percentage of vancomycin is protein bound
About 55 percent
122
What are the toxic side effects of vancomycin
Red man syndrome + Nephrotoxicity + Ototoxicity
123
What is red man syndrome
Hypersensitivity reaction due to rapid infusion of vancomycin
124
What are the symptoms of red man syndrome
Pruritic erythematous rash in face + Neck + Upper torso
125
What is the route of administration for vancomycin
Intravenous
126
What is the half-life of vancomycin
4 to 6 hours
127
How is vancomycin eliminated
Renal filtration
128
What is the therapeutic range for vancomycin
5 to 10 µg/mL
129
When does peak concentration of vancomycin occur after dosing
1 hour
130
Which vancomycin levels are monitored
Trough levels
131
Which class of drugs includes phenobarbital and phenytoin
Antiepileptic drugs
132
Which drug is a slow-acting barbiturate that controls several types of seizures
Phenobarbital
133
What percentage of circulating phenobarbital is protein bound
50 percent
134
Which toxicities are associated with phenobarbital
Drowsiness + Fatigue + Depression + Reduced mental capacity
135
What is the route of administration for phenobarbital
Oral
136
What is the half-life of phenobarbital
70 to 100 hours
137
How is phenobarbital eliminated
Hepatic metabolism via MFO system
138
What is the therapeutic range for phenobarbital
10 to 20 µg/mL
139
When does peak serum concentration of phenobarbital occur after oral dose
About 10 hours
140
Which levels are measured for phenobarbital
Trough levels
141
Which drug is an inactive proform of phenobarbital
Primidone
142
Which active form is primidone converted to after absorption
Phenobarbital
143
Which type of seizures is primidone used to control
Grand mal seizures refractory to other antiepileptic drugs
144
What is the route of administration for primidone
Oral
145
What is the half-life of primidone
8 hours
146
How is primidone eliminated
Hepatic metabolism
147
What is the therapeutic range for primidone
5.0 to 12.0 µg/mL
148
When should specimens be drawn for monitoring primidone and phenobarbital
Just before the next dose
149
Which drugs need to be measured to assess total potential phenobarbital in circulation
Primidone + Phenobarbital
150
Which drug is commonly used for seizure disorders
Phenytoin
151
What is another use for phenytoin
Short-term prophylactic agent in brain injury
152
What percentage of phenytoin is protein bound
87 to 97 percent
153
Which toxicities are associated with phenytoin
Seizures + Hirsutism + Gingival hyperplasia + Vitamin D deficiency + Folate deficiency
154
Which injectable preform of phenytoin is converted to phenytoin in about 75 minutes
Fosphenytoin
155
What is the route of administration for phenytoin
Oral
156
What is the half-life of phenytoin
6 to 24 hours
157
How is phenytoin eliminated
Hepatic metabolism
158
What is the therapeutic range for bound phenytoin
10 to 20 μg/mL
159
What is the therapeutic range for free phenytoin
1 to 2 μg/mL
160
When do peak concentrations of phenytoin occur
3 to 12 hours post dose
161
Which drug is used as monotherapy for petit mal or absence seizures
Valproic acid
162
What percentage of circulating valproic acid is protein bound
93 percent
163
Which toxicities are associated with valproic acid
Nausea + Lethargy + Weight gain + Pancreatitis + Hyperammonemia + Hallucinations
164
What is the route of administration for valproic acid
Oral
165
What is the half-life of valproic acid
11 to 17 hours
166
How is valproic acid eliminated
Hepatic metabolism
167
Which drug may induce valproic acid metabolism
Other antiepileptic drugs
168
Which drug inhibits valproic acid metabolism
Felbamate
169
What is the therapeutic range for valproic acid
50 to 120 µg/mL
170
Which fraction of valproic acid should be measured in TDM
Free fraction
171
Which drug is effective in various seizure disorders but less frequently used due to toxicity
Carbamazepine
172
Which toxicities are associated with carbamazepine
Hematologic dyscrasias + Aplastic anemia
173
What percentage of carbamazepine is protein bound
70 to 80 percent
174
What is the route of administration for carbamazepine
Oral
175
What is the half-life of carbamazepine
10 to 20 hours
176
How is carbamazepine eliminated
Hepatic metabolism
177
What is the therapeutic range for carbamazepine
4 to 12 µg/mL
178
When do peak concentrations of carbamazepine occur
4 to 8 hours after dosing
179
Which drug is used for controlling petit mal (absence) seizures
Ethosuximide
180
What is the route of administration for ethosuximide
Oral
181
What is the half-life of ethosuximide
40 to 60 hours
182
How is ethosuximide eliminated
Hepatic metabolism + Renal filtration
183
What percentage of ethosuximide is eliminated by renal filtration
20 percent
184
What is the therapeutic range for ethosuximide
40 to 100 µg/mL
185
When do peak concentrations of ethosuximide occur
2 to 4 hours after dosing
186
Which drugs are considered second-generation antiepileptic drugs
Felbamate + Gabapentin + Lamotrigine + Levetiracetam + Oxcarbazepine + Tiagabine + Topiramate + Zonisamide
187
Which drug is used in severe epilepsies such as Lennox-Gastaut syndrome in children and refractory epilepsy in adults
Felbamate
188
Which syndrome in children is treated with felbamate
Lennox-Gastaut syndrome
189
What is another name for Lennox-Gastaut syndrome in children
Childhood epileptic encephalopathy
190
Which types of seizures and condition are seen in Lennox-Gastaut syndrome
Multiple seizure types + Mental retardation
191
Which type of epilepsy in adults is treated with felbamate
Refractory epilepsy + Drug resistant epilepsy
192
When is felbamate considered for adults
When an adult fails to be seizure free after adequate administration of 2 antiepileptic drugs
193
What percentage of felbamate is protein bound
30 percent
194
Which drugs induce felbamate metabolism
Phenobarbital + Primidone + Phenytoin + Carbamazepine
195
What is the route of administration for felbamate
Oral
196
What is the half-life of felbamate
14 to 22 hours
197
How is felbamate eliminated
Renal and hepatic metabolism
198
What is the therapeutic range for felbamate
30 to 60 µg/mL
199
Which drug may be indicated as monotherapy or adjunct therapy for complex partial seizures with or without generalized seizures
Gabapentin
200
What is the most common type of seizure in adults
Complex partial seizures
201
How long do complex partial seizures typically last
1 to 2 minutes
202
Which part of the brain is affected by complex partial seizures
One part
203
What are the symptoms of complex partial seizures
Inability to control movement or talk + Memory loss
204
What is the route of administration for gabapentin
Oral
205
What is the half-life of gabapentin
5 to 9 hours
206
How is gabapentin eliminated
Unchanged by the kidneys
207
Does gabapentin bind to serum proteins or undergo hepatic metabolism
No
208
What is the therapeutic range for gabapentin
12 to 20 µg/mL
209
Which drug is used in patients with partial and generalized seizures
Lamotrigine
210
What is the difference between partial and generalized seizures
Partial: impulse in small part of brain + Generalized: impulse from entire brain
211
What percentage of lamotrigine is protein bound
55 percent
212
Which drugs induce lamotrigine metabolism
Phenobarbital + Primidone + Phenytoin + Carbamazepine
213
Which drug inhibits lamotrigine metabolism
Valproic acid
214
What is the route of administration for lamotrigine
Oral
215
What is the half-life of lamotrigine
15 to 30 hours
216
How does valproic acid affect lamotrigine half-life
Increases to 60 hours
217
How is lamotrigine eliminated
Hepatic metabolism via MFO system
218
What is the therapeutic range for lamotrigine
2.5 to 15 µg/mL
219
Which drug is used in partial and generalized seizures and does not bind to serum proteins
Levetiracetam
220
What is the route of administration for levetiracetam
Oral
221
What is the half-life of levetiracetam
6 to 8 hours
222
What is the therapeutic range for levetiracetam
8 to 26 µg/mL
223
Which drug is a prodrug metabolized to licarzepine
Oxcarbazepine
224
Which types of seizures is oxcarbazepine used for
Partial seizures + Generalized tonic-clonic seizures
225
What are the components of tonic-clonic seizures
Tonic: stiffening of muscles + Clonic: jerking movements
226
What is the old term for tonic-clonic seizures
Grand mal
227
What percentage of oxcarbazepine is protein bound
40 percent
228
What is the route of administration for oxcarbazepine
Oral
229
What is the half-life of oxcarbazepine
8 to 10 hours
230
How is oxcarbazepine eliminated
Hepatic metabolism
231
Which drugs induce oxcarbazepine metabolism
Phenytoin + Phenobarbital
232
How much do enzyme inducers decrease oxcarbazepine blood concentration
20 to 40 percent
233
What is the therapeutic range for oxcarbazepine
12 to 35 µg/mL
234
Which drug is used in treating partial seizures and is highly protein bound
Tiagabine
235
What percentage of tiagabine is protein bound
96 percent
236
What are the toxicities of tiagabine
Confusion + Difficulty speaking clearly + Mild sedation + Paresthesia in extremities
237
What is paresthesia
Tingling sensation in the fingers
238
What is the route of administration for tiagabine
Oral
239
What is the half-life of tiagabine
4 to 13 hours
240
How is tiagabine eliminated
Hepatic metabolism via MFO pathway
241
What is the therapeutic range for tiagabine
20 to 100 ng/mL
242
Which drug is used in partial and generalized seizures and is minimally protein bound
Topiramate
243
What percentage of topiramate is protein bound
15 percent
244
What are the toxicities of topiramate
Change of taste + Pins and needles sensation in extremities
245
What is the route of administration for topiramate
Oral
246
What is the half-life of topiramate
20 to 30 hours
247
How is topiramate eliminated
Renal filtration + Hepatic metabolism
248
Which drug is used in partial and generalized seizures and is bound to erythrocytes
Zonisamide
249
What percentage of zonisamide is protein bound to erythrocytes
60 percent
250
What is the half-life of zonisamide in monotherapy
50 to 70 hours
251
What is the half-life of zonisamide when coadministered with other AEDs
25 to 35 hours
252
What is the route of administration for zonisamide
Oral
253
How is zonisamide eliminated
Hepatic metabolism + Renal filtration
254
What is the therapeutic range for zonisamide
10 to 38 µg/mL
255
Which drug is used to treat bipolar disorder
Lithium
256
Which mood disorder is characterized by depressed and manic states
Bipolar disorder
257
Which symptoms are seen in the depressed state of bipolar disorder
Hopelessness + Suicidal thoughts
258
Which symptoms are seen in the manic state of bipolar disorder
Elation + Irritability + Potential dangerous behavior
259
Does lithium bind to proteins
No
260
What are the symptoms of lithium toxicity at 1.5 to 2 mmol/L
Apathy + Lethargy + Speech difficulties + Muscle weakness
261
What are the symptoms of lithium toxicity above 2 mmol/L
Muscle rigidity + Seizures + Possible coma
262
Which methods are commonly used to measure lithium
ISE + FEP + AAS
263
What is the route of administration for lithium
Oral
264
How is lithium eliminated
Renal filtration
265
What is the therapeutic range for lithium
0.5 to 1.2 mmol/L
266
Which class of drugs is used to treat Class of drugs used to treat
depression, insomnia, extreme apathy, loss of
libido
Tricyclic
Antidepressants
(TCAs)
267
Which drugs are examples of tricyclic antidepressants
Imipramine + Amitriptyline + Doxepin
268
Which drugs are metabolites of tricyclic antidepressants
Desipramine + Nortriptyline
269
What are the toxicities of tricyclic antidepressants
Drowsiness + Constipation + Blurred vision + Memory loss + Seizures + Cardiac arrhythmia + Unconsciousness
270
What percentage of tricyclic antidepressants is protein bound
85 to 95 percent
271
What is the route of administration for tricyclic antidepressants
Oral
272
What is the therapeutic range for tricyclic antidepressants
100 to 300 ng/mL
273
Which drug is an atypical antipsychotic used to treat schizophrenia
Clozapine
274
What is the therapeutic range for clozapine
350 to 420 ng/mL
275
Which drug treats schizophrenia, acute manic
episodes, &recurrence of
bipolar disorders
Olanzapine
276
What is the therapeutic range for olanzapine
20 to 50 ng/mL
277
Which drug is used to prevent rejection of allogenic organ transplants
Cyclosporine
278
What are the toxicities of cyclosporine
Renal tubular dysfunction + Glomerular dysfunction
279
What is the route of administration for cyclosporine
Oral
280
What is the absorption rate of cyclosporine
5 to 50 percent
281
How is cyclosporine eliminated
Hepatic metabolism
282
Which specimen is preferred for cyclosporine monitoring
Whole blood
283
Which drug is 100 times more potent than cyclosporine
Tacrolimus
284
What is the main toxicity of tacrolimus
Nephrotoxicity
285
In which condition are elevated tacrolimus levels seen
Cholestasis
286
What is the route of administration for tacrolimus
Oral
287
How is tacrolimus eliminated
Hepatic metabolism
288
Which drug is an antifungal agent with immunosuppressive activity
Sirolimus
289
For which transplant patients is sirolimus FDA approved
Kidney transplant
290
What are the toxicities of sirolimus
Thrombocytopenia + Anemia + Leukopenia + Infections + Hyperlipidemia
291
Which substances does sirolimus bind to more highly
Lipoproteins
292
What is the half-life of sirolimus
62 hours
293
What is the therapeutic range for sirolimus
4 to 12 µg/L
294
Which specimen is preferred for sirolimus monitoring
Whole blood
295
Which drug is a prodrug rapidly converted to its active form mycophenolic acid
Mycophenolate mofetil
296
What is the mechanism of action of mycophenolic acid
Lymphocyte proliferation inhibitor
297
Which patients is mycophenolic acid most commonly used with
Renal transplant patients
298
Which drugs is mycophenolic acid commonly used with
Cyclosporine + Tacrolimus
299
What percentage of mycophenolic acid is protein bound
95 percent
300
What is the therapeutic range for mycophenolic acid
1.0 to 3.5 µg/mL
301
Which specimen is preferred for mycophenolic acid monitoring
Plasma
302
Which drug is used as high-dose methotrexate for anti-cancer therapy
Methotrexate
303
Which agent is used as a rescue with high-dose methotrexate
Leucovorin
304
What is the source of folic acid for cell DNA synthesis
Leucovorin
305
Which cells divide more rapidly than normal cells
Neoplastic cells
306
What is the mechanism of action of methotrexate
Inhibits DNA synthesis by depleting folic acid
307
Which cells are affected by methotrexate
All cells
308
What are the effects of methotrexate on healthy cells
Decreased WBC + Decreased RBC + Decreased platelet synthesis + Hair loss + Mouth sores + Liver damage + Lung damage + Nerve damage + Kidney damage
