Exam 2 Flashcards
1
Q
Active Ingredient in Asprin
A
Salicylate
2
Q
Aspirin Main Function
A
Anti fever
Pain Relief
3
Q
Other Names for NSAIDS
A
Non steroidal anti inflammatory drugs
Non opioid analgesics
4
Q
Main Target or NSAIDS
A
Prostaglandin synthesis
We cannot inhibit prostaglandin receptors, so we inhibit their synthesis
5
Q
Prostacyclin Function
A
Main vasodilator
6
Q
Thromboxane Function
A
Leukocyte modulation
Inflammation
7
Q
NSAIDS Inhibit The Enzyme
A
Cyclooxygenase, or COX
8
Q
COX 1 Expression
A
Constitutively expressed in most tissues
9
Q
COX 1 Action in Platelets
A
Increases platelet aggregation through thromboxanes
10
Q
COX 2 Expression
A
Inducible
11
Q
COX 2 Function
A
Inflammatory response to specific injury in specific tissues
12
Q
NSAID Selectivity for COX 1 and COX 2
A
Tenfold selectivity for COX 1
13
Q
Aspirin Processing
A
Rapidly hydrolysis and deacytylated to salicylic acid
14
Q
Salicylate COX Inhibitory Properties
A
Reversible and competitive
15
Q
Typical Aspirin Pill Mass
A
325mg OR 500mg for extra strength
16
Q
Drug Drug Interactions of Aspirin
A
Warfarin
Methotrexate
Sulfonamides
17
Q
Mechanism of Drug Drug Interactions of Aspirin
A
Plasma protein binding
18
Q
Pharmacokinetics of Low Dose Aspirin
A
Metabolized by glucuronide liver conjugation
Excreted by the kidneys
First order and saturable kinetics
19
Q
Pharmacokinetics of High Dose Aspirin
A
Excreted by kidneys UNMETABOLIZED
Organic Anion Transporters OAT
Zero Order Kinetics
Half life increases with increasing dose
20
Q
Half Lives of Aspirin
A
2 hr for low does
10 to 12 hrs for mid dose
12 to 15 hrs for high dose
21
Q
Aspirin Dose for Pain Relief
A
650 to 1000mg every 4 hrs
DOES NOT TAKE DOWN INFLAMMATION
22
Q
Aspirin Mechanism of Fever Reduction
A
Inhibits prostaglandins in hypothalamus to return thermo regulatory set point to normal
23
Q
Aspirin Dose for Anti inflammation
A
1000mg
24
Q
Aspirin Mechanism of Anti thrombosis
A
IRREVERSIBLE acetylation of COX in platelets, leads to inhibition of clot for the life of that platelet
25
Tissue Most Susceptible to Aspirin Anti thrombosis
The gut, because aspirin activation happens in the gut
26
Aspirin Dose for Thrombosis Prevention
75 to 81mg per day
27
This formulation of aspirin is better for anti thrombosis
Plain, rather than enteric coating
28
Main Adverse Effects and Contraindication of Aspirin
Bleeding
Use with extreme caution in patients with clotting deficiency
29
Aspirin does this to GI cancer risk
Reduces it
30
Most Common Aspirin Side Effect
GI Irritation
GI Bleeding
31
Function of Enteric Coating
Prevents tablet from dissolving in stomach
Drug is then released in the intestines
32
Aspirin Safety In Pregnancy
Avoid in 3rd Trimester, may prematurely close ductus arteriosus
33
Symptoms of Mild Salicylate Toxicity
Mild is 2 to 3 Tablets Per Day
Ringing in ears
Dizziness
Headache
Confusion
Deafness
Drowsiness
Thirst
34
Lethal Salicylate Dose
About 80 to 150%mg
35
Salicylate Overdose Mechanism
Central vasomotor
36
Propionic Acid Derivative NSAIDS
Ibuprofen and Naproxen
37
Propionic Acid Derivative NSAID Actions
Analgesic, antipyretic, and anti inflammatory
Similar to aspirin but less toxic
RESVERSIBLE and COMPETATIVE
38
Propionic Acid Derivative NSAID Mechanism
Totally REVERSIBLE and COMPETITIVE COX Inhibition
Different from aspirin, which shows irreversible COX inhibition in the platelets
39
Recommended Ibuprofen Dose for Analgesia and Fever Reduction
200mg every 4 to 6 hours
40
Recommended Ibuprofen Dose for Antiinflammation
400mg every 4 to 6 hours
41
Max Daily Ibuprofen Dose
3200mg
42
Naproxen Distinction From Ibuprofen
Longer half life
43
Albumin Binding of Ibuprofen and Naproxen
98% bound
44
Dosage of Ibuprofen and Aspirin Taken Together
Take either 8hrs before or 30 minutes after taking aspirin
45
Acetic Acid Derivative Drugs
Indomethacin
46
Indomethacin Dosage
25mg every 4 to 6 hours
47
Indomethacin Usage
Severe inflammation from things like RA
48
Indomethacin Main Side Effect
TERRIBLE HEADACHE along with other central symptoms
49
Selective COX2 Inhibitor
Celecoxib
50
Celecoxib Usages
Chronic pain like OA and RA
51
Celecoxib Metabolism
CYP 2C9 Phase I
52
Celecoxib Drug Interactions
Inhibits CYP 2D9 inhibition in some patients, which inhibits metabolism of SSRIs, tricyclics, and anti arrhythmia drugs
53
Celecoxib Most Common Side Effect
Edema
Increased Risk of MI
SOME GI Issues
54
Celecoxib Contraindications
Pregnancy
Sulfa Drug Allergy
55
Acetaminophen Drug Class
Non opioid analgesic
NOT AN NSAID
Does not get rid of inflammation
56
Acetaminophen Action
UNKNOWN
57
Acetaminophen Metabolism
Conjugation
Action by CYP 2E1
This is both phase 1 and phase 2 metabolism
58
Why Take Acetaminophen and not Aspirin
Way safer than aspirin
No risk of Reye Syndrome
59
Acetaminophen Most Common Severe Side Effects
Liver damage in long term usage, which can be exacerbated by alcohol
60
Mechanism of Acetaminophen Overdose
First Fraction Phase 2 glucuronidated and excreted in urine
Second Fraction Phase 2 sulfated and excreted in urine
Third Fraction phase 1 metabolized into NAPQI
In health individuals NAPQI is broken down by glutathione
Glutathione depletion in unhealthy people causes toxic NAPQI buildup
61
N acetyl cysteine Mechanism
Replenished glutathione to break down NAPQI
62
Rational For Combination Therapy
Usually requires less dose of each drug
Different drugs can manage different aspects of the same disease
63
Two Broad Categories of RA Drugs
Traditional Disease Modifying Antirheumatics
Biologic Response Modifiers
64
Are Drugs Necessary to Treat RA?
ABSOLUTELY!
65
Pitfalls of NSAID and Steroid Therapy in RA
Kills inflammation but does not stop the tissue damage
66
Hallmarks of Traditional DMARDS
Small Molecule
Usually Oral
Broadly immunotoxic
67
Hallmarks of Biologic Therapies
Proteins
Must be injected
Very specific immune suppression
TARGET INDIVIDUAL SPECIFIC SIGNALING MOLECULES
68
Use of Steroids in RA
Used as a ‘“bridge” therapy
Metabolic side effects and toxicity prevent long term use
69
Traditional DMARDS
Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide
Minocycline
70
First Line Typical DMARD
Methotrexate
71
Methotrexate Administration
Usually oral
Once Per Week, the drug becomes hepatotoxic if used more frequently
72
Methotrexate Cell Biology
Folic acid analog
Enters thru folic acid transporters but polyglutamation traps it inside cell
Effective Half-life larger than plasma half life
73
Methotrexate Mechanism 1
Acts as an antifolate to inhibit dihydrofolate to block the synthesis of purines and pyrimidines
74
Methotrexate Mechanism 2
Inhibits AICAR Transformylase
This inhibits general purine synthesis
Increases adenosine outside the cell
75
Methotrexate Mechanism 3
Inhibits thymidylate synthetase
This reduces thymidine synthesis
76
Methotrexate Elimination
By the kidneys
77
Methotrexate Contraindications
Liver Failure
Pregnancy
Nursing
78
Hydroxychloroquine Pharmacokinetics
Oral
Taken daily
Slow onset and long half life
STORED IN SKIN
79
Hydroxychloroquine Adverse Effects
Retinal Damage
Skin Damage
Hypoglycemia in Diabetes
80
Hydroxychloroquine Mechanism
Unknown but something to do with altering cellular pH
81
Sulfasalazine Drug Class
Salicylate
82
Sulfasalazine Pharmacokinetics
Oral and taken daily
Metabolized in gut prior to absorption
Broken down into salicylate and sulfapyridine
83
RA Triple Therapy
Start With Weekly Methotrexate
Then add daily hydroxychloroquine and Sulfasalazine
84
Leflunomide Mechanisms
Inhibits Dihydroorotate dehydrogenase which inhibits pyrimidine synthesis
Overall inhibits T Cells and antibody production by B Cells
85
Leflunomide Pharmacokinetics
Oral daily
Is a product
Long half-life due to enters hepatic recirculation
86
Adverse Effects of Leflunomide
STRONGLY TETRATOGENIC
Absolutely contraindicated before and during pregnancy
Cholestyramine Washout Prior to Stopping Birth Control
Must be negative twice at least two weeks apart
87
Minocycline Mechanism
Inhibits metallo proteinases including collagenase
Decreases collagen degradation in RA
88
Minocycline Side Effects
Dizziness
Hyperpigmentation
89
Biologics General Mechanism
Targets Individual Specific Mediators Early in Inflammation
Block antibody production and release
Blocks signaling molecules
90
General Biologic Side Effects
Increased Risk of Infection
Blood Dyscrasias
Increased Risk of Cancer
GI Issues
91
Anti TNF Drug Mechanism
Inhibits TNFa Receptors
92
Etanercept Specific Mechanism
Free circulating p75 subunit of the TNFa receptors that binds up TNFa before they can bind to a cell
93
Etanercept Pharmacokinetics
Injected SubQ Weekly
Shortest Duration of all anti TNF agents
94
Etanercept Main Adverse Effects
PML
Lymphomas
95
Infliximab Mechanism
Binds TNF similar to etanercept but NOT part of the TNF receptor
96
Infliximab Pharmacokinetics and Use
IV Every 4 to 8 weeks after loading dose
ALWAYS COMBINE WITH OTHER TRADITIONAL DMARDS
97
Infliximab Side Effects
Similar to Etanercept
Can also cause hypotension so NO USE IN HEART FAILURE
98
Adalimumab and Golimumab Mechanism
Anti TNF monoclonal antibodies like Infliximab
Fully human protein
99
Adalimumab and Golimumab Use
Injected subQ
Twice per month for adalimumab
One monthly for Golimumab, which can also be IV
100
Abatacept Mechanism
CTLA 4 Analogue that block the CD28 receptor on T Cells and blocks their activation
BLOCKS OVERACTIVE T CELLS
101
Abatacept Pharmacokinetics and Use
Peptide injected subQ weekly or given IV monthly
Only for moderate to severe RA NOT RESPONSIVE TO OTHER DMARDS
102
Abatacept Precautions
Serious infection
Pulmonary issues
DO NOT COMBINE WITH TNF INHIBITORS
103
Rituximab Mechanism
Anti CD20 antibody, so a B Cell inhibitor
104
Rituximab Pharmacokinetic and Use
IV with 2 injections 2 weeks apart, then not again for at least 6 months
Use in combination with methotrexate
105
Selective Toxicity
The ability of a drug to injure target cells without injury to the host
106
Minimal Inhibitor Concentration or MIC
Lowest concentration of an agent that prevents visible bacterial growth on an agar plate or test tube
107
Minimum Bactericidal Concentration
Lowest concentration of a substance that actually kills bacterial cells and doesn’t just suppress growth
108
General Mechanism of Selective Toxicity
Differences between bacterial and host cells structure, ie bacteria have cell walls but human cells do not
109
Antibiotic Spectrum
Defines the range of organisms an antibiotic is effective against
110
Bacteriostatic
Suppressing cell proliferation but does not cause cell death and relies on the immune system to ultimately clear the infection
111
Bactericidal
Directly causes cell death
A drug is considered bactericidal only if the MBC is no more than 4X higher than its MIC
112
Post Antibiotic Effect
Delay in growth of bacteria after removal of antibiotic
Often determines frequency of dosage
113
Three Types of Antibiotics
Time dependent
Peak Concentration Dependent
Area Under the Curve of a Concentration vs. Time Graph Dependent
114
Value of the Area Under a Concentration vs. Time Graph
Total dose given over the entire time of administration
115
Innate Antibiotic Resistance
Antibiotic was never active due to structural and physiological properties of certain bacteria
116
Acquired Resistance
Loss of formerly active antibiotic by vertical or horizontal gene transfer
117
Vertical Gene Transfer Aquired Resistance
A random mutation makes the next generations of bacteria resistant
118
Horizontal Gene Transfer Acquired Resistance
Bacteria transfer genes thru plasmids that code for things that render antibiotics ineffective
119
Four Mechanisms of Acquired Resistance
Inactivation by bacterial drug metabolizing enzymes, sometimes induced by initial doses of antibiotic
Decreased uptake or efflux transporters
Reduced binding affinity due to mutations in amino acid sequences of target site proteins
Bypass or Overcome blockade of a target metabolic process or pathway
120
Are newer antibiotics more effective than older antibiotics
NO!
Newer antibiotics are developed to overcome resistance and not for broad efficaciousness
121
Oral Bioavailability of Most Antibiotics
POOR due to hydrophilicity of most antibiotics
122
These places are difficult for antibiotics to reach
Bone
Eye
Pulmonary epithelium
Abscessed tissues
Biofilms
123
IV Route is Preferred in These Patient
Critically Ill Patients with Bacterial Meningitis or Endocarditis
Patients with Nausea and Vomiting
124
Procalcitonin
Biomarker of infection now used to determine duration of antibiotic treatment
125
This value is correlated but not directly related to antibiotic efficacy
Blood Levels
Blood levels of drug may not be the same as drug levels at the site of infection, but we still use blood levels to determine antibiotic dosage and simply correlate that to antibiotic properties
126
Breakpoint
Drug concentrations at which bacteria are susceptible to antibiotic therapy
127
Antibiotic Clearance
Primarily through the kidneys
MUST consider kidney health with most antibiotics
128
Consider Kidney Function in these Antibiotic Classes
Aminoglycosides
Glyco and Lipo peptides
Beta lactams
Sulfonamides
129
Consider Liver Function in these Antibiotic Classes
Lincosamides
Macrolides
Tetracyclines
Nitroimidazoles
130
Options for Patients with Reduced Renal Function
Decreased the dose
Switch to a drug not cleared by the kidneys
131
Combination Therapy is Necessary in These Infections
TB
H. pylori
132
These Broad Antibiotic Classes Interfere With One Another if Given Concomitantly
Bacteriostatic and bactericidal
133
Aminoglycosides In Pregnancy
Ototoxicity and nephrotoxicity
134
Tetracyclines in Pregnancy
Bone growth suppression and tooth staining
135
Sulfonamides in Pregnancy
Kernicterus
136
Folate Antagonists in Pregnancy
Maternal folic acid deficiency causes neural tube defects
137
Fluoroquinolones in Pregnancy
Toxic to developing cartilage
138
Drug Permiability in Gram Negative Bacteria
Hydrophilic drugs can cross the outer membrane via passive transport thru PORINS
139
Drug Permeability in Gram Negative Organisms
Antibiotics readily cross the THICK peptidoglycan wall by diffusion to effect targets OUTSIDE the plasma membrane
These infections are often easier to treat
140
Atypical Bacteria
Chlamydia
Mycoplasma
Rickettsia
Legionella
All have NO CELL WALL AT ALL
141
Beta Lactam Drug Subclasses
Penicillins
Cephalosporins
Carbapenems
Monobactams
142
Beta Lactam General Mechanism
Bind and inhibits penicillin binding proteins, which then inhibits cross linking peptidoglycan polymers so interferes with cell wall construction
143
Beta Lactam Time Dependence
Bactericidal and time dependent
Most effective during log growth phase of bacteria
144
Inhibition of Penicillin Binding Proteins Triggers This Final Step
Activated autolysins which lead to cell lysis
145
Cell Wall Inhibitor Drug Classes
Beta Lactams
Non Beta Lactams
146
Mechanisms of Beta Lactam Resistance
Innate inability for drug to pass through porins
Acquired mutations of penicillin binding proteins
Inactivation of Drug Through Beta Lactamase Expression
147
Beta Lactamase Heterogeneity
Inducible Chromosomal
Transferable Plasmid
Narrow
Broad
148
Standard Penicillins
Penicillin G
Penicillin V
149
Standard Penicillin Activity
G+ Cocci and Bacilli
Most Anaerobes
Less G- Cocci
150
Standard Penicillin Inactivity
Strains that produce beta lactamase
All G- Bacilli
NOT VERY EFFECTIVE AGAINST G- INFECTIONS
151
Standard Penicillins Usage
Pen G unstable in stomach acid so given IV
Pen V stable in acid so given orally
152
Antistaph Penicillins Prototype Drug
Nafcillin
153
Anti Staph Penicillin Mechanism
Bulky R groups prevent action of beta lactamase
154
Anti Staph Penicillin Activity
PEN G resistant methicillin susceptible staph and strep, and THAT’S IT
155
Amoxicillin Activity
Standard penicillins
Some G- bacilli
156
Mechanism of Amoxicillin Activity Against G- Bacilli
Charged amino group enables transfer thru outer porins
157
Aminopenicillins
Amoxicillin
158
Extended spectrum Aminopenicillins
Piperacillin tazobactam
159
Piperacillin tazobactam Activity
Many more G- strains than standard aminopenicillins
ANTIPSEUDOMONAL
160
Piperacillin tazobactam Mechanism
Improved transport thru porins and gives high affinity for G- penicillin binding proteins
161
Tazobactam Mechanism
Beta lactamase inhibitors
162
Penicillins Pharmacokinetics
Poorly absorbed orally
Short half life
Given frequently multiple times per day or by continuous IV infusion
163
Penicillin G Benzathine
Given IM once per week to continuously slowly release penicillin G
Keeps blood levels low but still effective
164
Penicillins Metabolism
Excreted UNCHANGED in the urine
Excreted by active renal secretion
165
Maculopapular Penicillin Rash
Non allergic rash that happens 3 to 14 days after penicillin usage, especially with EBV coinfection
DOES NOT IMPACT THERAPY
More associated with the amino penicillins
166
True Penicillin Allergy Mechanism
Ig E Mediated urticarial rash sometimes with fever, vasculitis, anaphylaxis
167
Structural Difference Between Penicillins and Cephalosporins
Six Membered ring fuzed to beta lactam ring with an R group on either side of the rings
168
Cephalosporins Generational Pattern
Starts with good G+ coverage and increases G- coverage and resistance to beta lactamase as the generation increases
169
First Generation Cephalosporins
Cefazolin
Similar spectrum to anti staph penicillins with more G- coverage
Used mainly for surgical site infection prophylaxis
170
Second Generation Cephalosporins
Cefoxitin
Not really used much any more
171
Third Generation Cephalosporins
Ceftriaxone
Higher G- activity but less G+ activity
Penetrate BBB to enter CNS well
Drug resistance mediated thru extended spectrum beta lactamase
172
Fourth Generation Cephalosporins
Cefepime
Used for empiric treatment of hospital acquired infections
173
Fifth Generation Cephalosporins
Ceftaroline
Only beta lactam active against MRSA
174
Cephalosporins Pharmacokinetics
Same as penicillins
175
Carbapenems
Imipenem cilastatin
176
Cilastatin Function
Protects imipenem from breakdown by host kidney enzymes
177
Carbapenems Activity
Great G- coverage with good G+ coverage
Charged so can penetrate porins
Highly resistant to beta lactamase
178
Carbapenems Pharmacokinetics
Given parenterally
Eliminated thru the kidneys
179
Monobactams
Aztreonam
180
Monobactams Activity
Only active against G- aerobes
Good for patients with SEVERE penicillin allergies
181
Monobactams Pharmacokinetics
Given IV or IM or BY INHALATION
Good for pseudomonal infections in CF patients
182
Glycopeptides
Vancomycin
183
Glycopeptides Mechanism
Inhibits cell wall synthesis by preventing polymerization of cell wall precursors through binding of Ala D Ala terminus
184
Vancomycin Activity
ONLY G+ aerobes and anaerobes
Molecule too big to fit thru porins
185
Vancomycin Resistant Mechanism
Altered cell wall amino acid sequence from Ala D Ala to Ala D Lactate
186
Vancomycin Pharmacokinetics
Minimal oral absorption and short half life
Excreted unchanged by the kidneys
187
Vancomycin Adverse Reactions
Permanent ototoxicity
Reversible nephrotoxicity
Flushing reaction
188
Phosphoenolpyruvate Analog
Fosfomycin
189
Fosfomycin Action
Works INSIDE the bacteria to inhibit the enzyme that converts NAG to NAM, so interrupts synthesis of cell wall precursors
190
How does fosfomycin enter the bacterial cell?
A transporter that only exists in bacteria
191
Fosfomycin Activity
Used only in UTIs
192
Protein Synthesis Inhibitor Drug Classes
Aminoglycosides
Tetracyclines
Macrolides
Lincosamides
Oxizolidinones
193
Protein Synthesis Inhibitor General Mechanism of Action
Bind to 30S or 50S subunit of bacterial ribosomes
194
General Effect of Inhibition of Bacterial Ribosomal Function
Bacteriostatic, except for Aminoglycosides
195
Mechanism of Aminoglycoside Bactericidal Effect
Cause miscoding of mRNA
EXCEPTION to protein synthesis inhibitor Bacteriostatic rule
196
Aminoglycoside Bacterial Binding Site
30S subunit
197
Aminoglycosides
Gentamicin
198
Aminoglycoside Structural Effects
Positive charge makes it unable to cross membrane
MUST USE TRANSPORTERS
199
Gentamicin Activity
Most active against aerobic G- bacilli
Also active against mycobacteria and protozoal parasites
200
Gentamicin Mechanism of Action
Binds to cell wall LPS
Gets through the cell wall with porins
Collects between the cell wall and cell membrane
Gets through the membrane with O2 dependent transport
201
Gentamicin Post antibiotic effect
Residual activity for several hours after plasma levels fall below MIC
202
Gentamicin Pharmacokinetics
Not absorbed by the GI tract
Do not penetrate lungs or eyes
Short half life
Excreted through the kidneys
MUST CHECK BLOOD LEVELS as drug is not stored in the adipose at all
203
Gentamicin Resistance
Drug inactivation by bacterial kinase and acetyltransferase
204
Gentamicin Adverse Effects
Reversible Nephrotoxicity
Irreversible Ototoxicity
205
Gentamicin Dose Pattern to Avoid Toxicity
One large dose instead of multiple small doses
Works due to LONG post antibiotic effect
206
Tetracyclines
Doxycycline
207
Doxycycline Binding Site
Binds to 30S subunit
208
Doxycycline Mechanism of Action
Active transport into bacteria using a transporter not found in mammal cells
Blocks the A site of mRNA ribosomal complex so tRNA cannot land there
209
Doxycycline Activity
BROAD SPECTRUM
Atypical Bacteria
Rickettsia and Lyme
Protozoans like Malaria
210
Doxycycline Resistance
Increased drug efflux
Expression of ribosomal proteins that interfere with tetracycline binding to the A site
211
Doxycycline Pharmacokinetics
Activity correlates with AUC/MIC
Orally effective
Chelates with cations which prevents absorption
Major biliary excretion with some renal excretion
212
Tetracyclines Adverse Effects
GI Upset
Photosensitivity
Accumulates in bones and teeth
Accumulates in breastmilk
Avoid in pregnancy, nursing, and children under 8, EXCEPT DOXYCYCLINE
213
Macrolides
Azithromycin
Clarithromycin
214
Macrolides Naming Tool
A “thro” before the “mycin”
215
Azithromycin Binding Site
Between P site and A site of 50S subunit
216
Azithromycin Mechanism of Action
Inhibits protein translocation in a growing peptide chain at the ribosome
217
Azithromycin Activity
Broad
218
Azithromycin Low Level Resistance
Efflux transporters for G+ cocci
219
Azithromycin High Level Resistance
Plasmid encoded methylation of 50S subunit
This is MULTI DRUG RESISTANCE
220
Azithromycin Pharmacokinetics
Well absorbed orally
Excreted in Feces
METABOLIZED BY CYP3A4
221
Azithromycin Adverse Effects
Long Q T
222
Lincosamides
Clindamycin
223
Clindamycin Mechanism of Action
Binds to 50S subunit
Blocks peptide bond formation
Bacteriostatic
224
Clindamycin Activity
G+ cocci and anaerobes
DOES NOT WORK AGAINST G-
225
Clindamycin Resistance
50S Subunit MLSb Binding Site Mutation
226
Clindamycin Pharmacokinetics
Orally well absorbed
Penetrates well into bone and abscesses
227
Clindamycin Adverse Reactions
C diff colitis
228
Oxazolidinones
Linezolid
229
Linezolid Mechanism
Bind to 23S rRNA of 50S subunit which blocks formation of initiation complex
230
Linezolid Activity
G+ aerobes
MRSA
DOES NOT WORK AGAINST G-
231
Linezolid Pharmacokinetics
Orally well absorbed and distributed
Activity of AUC/MIC
Long post antibiotic effect against MRSA
232
Linezolid Adverse Effects
Myelosuppression so check blood levels
Peripheral and optic neuropathy
Lactic Acidosis
Serotonin Syndrome
233
Nucleic Acid Synthesis Inhibitors
Fluoroquinolones
Antifolates
Nitroimidazole
234
Antifolates
Cyclic Lipopeptides
Polymyxin
235
Fluorquinolones
Anything with “floxacin”
Ciprofloxacin
236
Fluoroquinolone Mechanism
Inhibit G- DNA gyrase and G+ topoisomerase
Overall bactericidal
237
Fluoroquinolone Activity
BROAD
Most effective against aerobic G- bacilli
238
Fluoroquinolone Resistance
High usage
Altered gyrase affinity
Increased efflux
Qnr proteins that protect gyrase
239
Fluoroquinolone Pharmacokinetics
Oral and parental
Peak/MIC activity
Oral absorption reduced by divalent cations like Ca2+
240
Fluoroquinolone Adverse Effects
Tendon rupture
CNS Issues
Peripheral Neuropathy
Long QT
Photosensitivity
Neuromuscular Blockade
241
Nitroimidazole
Metronidazole
242
Nitroimidazole Mechanism
Bactericidal PRODRUG converted to active form by ANAEROBIC enzyme
Active form causes free radical DNA breakage
243
Nitroimidazole Activity
Prototype drug against ANAEROBES
244
Nitroimidazole Resistance
Uncommon
245
Nitroimidazole Pharmacokinetics
Excellent oral bioavailability
peak/MIC dependent
246
Nitroimidazole Adverse Reactions
Headache
GI Issues
Benign Discolored Urine
Possibly Carcinogenic
Reversible Peripheral Neuropathy
Disulfiram like Reaction With Alcohol
247
Difference Between Bacterial and Human Folate
Bacteria synthesize folic acid from pteridine, PABA, and glutamate
Humans take it whole from diet
248
This Blocks the Reaction Between Pteridine and PABA in Bacteria
Sulfonamides
249
This Blocks the Coversion from Dihydrofolate to Tetrahydrofolate in Bacteria and Humans
Trimethoprim
250
Sulfonamides
Sulfamethoxazole
251
Sulfonamides Mechanism of Action
Structural analogue of PABA
Inhibits the first step of bacterial folate synthesis
Used on its own is Bacteriostatic
252
Sulfonamide Resistance
Increased PABA to overcome inhibition
Mutation of dihydropteroate synthase active site
253
Sulfonamide Adverse Reaction
Kernicterus in Neonates
Hypersensitivity Rash and Stevens Johnson Syndrome
Hemolytic Anemia in G6PD Deficiency People
254
Bacterial DHF Inhibitors
Trimethoprim
255
Trimethoprim Mechanism
Inhibits bacterial DHFR that converts dihydrofolate to tetrahydrofolate
When used with sulfonamides is BACTERICIDAL
256
Trimethoprim Resistance
Increased synthesis of DHFR to overcome inhibition
DHFR mutated for reduced binding affinity
257
Trimethoprim Adverse Reaction
Folate deficiency and bone marrow suppression in folate deficient patients
Hyperkalemia
258
TMP SMX Activity
Broad range of G+ and G- bacteria
Opportunistic fungal pathogens
259
Sulfamethoxazole Concomitant With Trimethoprim
TMP SMX
260
Cyclic Lipopeptides
Daptomycin
261
Daptomycin Mechanism
Diffuses thru cell wall
Lipid tail pokes a hole in the bacterial cell membrane
Bactericidal
262
Daptomycin Activity
ONLY G+ activity
Cannot penetrate G- outer membrane
263
Daptomycin Resistance
Minimal
264
Daptomycin Pharmacokinetics
AUC/MIC Dependent
Only give IV
Distributes to the vascular space only
Cleared by the kidneys
265
Daptomycin Adverse Effects
Myopathy
Eosinophilic Pneumonia
266
Polymyxins
Colistin
267
Polymixin Mechanism
Binds to outer membrane LPS and phospholipid of outer membrane of G- bacteria
Detergent like effect that disrupts outer and inner membrane
268
Polymixin Resistance
Rare by increasing due to mutation in gene that modifies LPS to reduce binding affinity
269
Polymixin Pharmacokinetics
Peak/MIC dependent
Colistin sulfate for topic and oral use NOT ABSORBED
Colistimethate prodrug for IV, inhalation, or intrathecal use
270
Polymixin Adverse Reactions
Nephrotoxicity
Neurotoxicity
271
Anti TB Drugs
Isoniazid Pyridoxine
Rifampin
Ethambutol
Pyrazinamide
272
General Mechanisms of TB Intrinsic Resistance
1. Complex Cell Wall
2. Efflux Transporters
3. Intracellular Location
4. Slow proliferation rate and dormancy
273
Layers of Unique Mycobacterium Cell Coating
Outer Lipid
Mycolic Acid
Arabinogalactan
274
Does multidrug TB therapy broaden the spectrum of activity?
NO! Adding more drugs makes therapy more specific
275
Drug Resistant TB Definition
Usually defined by resistant to Isoniazid and Rifampin
276
Isoniazid General Mechanism
Inhibits mycolic acid synthesis
277
Isoniazid Specific Mechanism
1. Prodrug passively diffuses across cell coating
2. Converted to active free radical drug by peroxidase
3. Free radical inhibits mycolic acid synthesis enzyme
278
Isoniazid Activity
Bactericidal to active bacilli
Bacteriostatic to quiescent bacilli
279
Isoniazid Resistance
Mutation or deletion of katG gene
280
Isoniazid Metabolism
Acetylated and N Acetyl Isoniazid is excreted by the kidneys
Half life is 1 hour in rapid acetylators and 3 hours in slow acetylators
281
Isoniazid Adverse Reactions
Peripheral Neuropathy Due to B6 Deficiency
Mild Hepatotoxicity
Drug Induced Hepatitis
282
Rifampin General Mechanism
Inhibits mycobacterial DNA dependent RNA polymerase
Bactericidal
283
Rifampin Specific Mechanism
Binds to B subunit of RNA polymerase to inhibit transcription
DOES NOT BIND TO MAMMALIAN RNA POLYMERASE
284
Rifampin Activity
Combination therapy with isoniazid for active TB
Alternative to isoniazid as a monotherapy for latent TB but RISK OF RESISTANCE
Mycobacterium avium
Broad spectrum antibiotic
285
Rifampin Adverse Effects
Hepatotoxicity due to cholestatic jaundice
Discolored urine
Strong inducers of CYP isoforms due to lipid solubility
286
Ethambutol General Mechanism of Action
Disrupts cell wall assembly thru disrupting arabinose
287
Ethambutol Specific Mechanism
Inhibits arabinosyl transferase
Bacteriostatic
288
Ethambutol Resistance
EmbAB Mutation
289
Ethambutol Activity
Combination therapy for active TB
Mycobacterium avium
290
Ethambutol Adverse Effects
Optic Neuritis leading to red green color blindness
291
Pyrazinamide Specific Mechanism
Prodrug converted to POA
Bacteriostatic
292
Pyrazinamide Activity
Combination therapy for active TB
293
Pyrazinamide Adverse Effects
Hepatotoxicity
Hyperuricemia leading to gout
294
Six Categories of Antifungals
Nucleic Acid Synthesis Inhibitors
Fungal Membrane Stability Inhibitor
Squalene Epoxidase Inhibitors
Sterol Demethylase Inhibitors
Mitotic Inhibitors
Cell Wall Inhibitors
295
Nucleic Acid Synthesis Inhibitors
Flucytosine
296
Fungal Membrane Stability Inhibitors
Amphotericin B
297
Squalene Epoxidase Inhibitors
Terbinafine
298
Sterol Demethylase Inhibitors
Fluconazole
299
Mitotic Inhibitors
Griseofulvin
300
Cell Wall Inhibitors
Caspofungin
301
Primary General Target of Antifungal Therapy
Ergosterol biosynthesis
302
Similarity Between Fungal and Human Metabolism
Fungi also use CYP enzymes, but to build cell membrane components
303
Fungal Cell Wall Components
Chitin, Beta D Glucans, and Glycoproteins
304
Amphotericin B General Mechanism of Action
Disrupts ergosterol at the membrane to create pores
305
Amphotericin B Administration
Poor oral absorption
Must be given IV
306
Nystatin Administration
Oral swish and swallow to treat oral and esophageal thrush
307
Amphotericin B Usage
Broad spectrum agent for systemic fungal infection
Initial therapy used to decrease fungal burden, then replaced by safer drugs
308
Amphotericin B IV Adverse Reaction
Infusion related cytokine storm
Renal toxicity to afferent arteriols
Renal toxicity to proximal tubular cell injury leading to hypokalemia
Anemia due to injured kidneys producing insufficient erythropoietin
309
Flucytosine General Mechanism of Action
Inhibits DNA and RNA Synthesis
310
Flucytosine Specific Mechanism of Action
Actively transported into fungal cells with fungal specific cytosine permease
Converted to 5 fluorouracil by cytosine deaminase
5 Fluorouracil Converted to 5 FdUMP
5 FdUMP Inhibits Thymidylate Synthase
Overall Fungistatic
311
Can Flucytosine Be Used Alone?
NO! Cells quickly develop resistance
Use with amphotericin B
312
Flucytosine Pharmacokinetics
Orally absorbed and well destributed
313
Flucytosine Adverse Reactions
Direct myelosuppression
Hepatotoxicity
314
Griseofulvin Usage
Older drug so used rarely
Used now in kids with ringworm
315
Griseofulvin Unique Mechanism of Action
Accumulates in keratin of live skin cells
When cells die and fungi eat them, the fungi get poisoned
Because of this it works VERY SLOWLY
316
Griseofulvin Cellular Mechanism
Binds tubulin to disrupt the mitotic spindle
317
Griseofulvin Adverse Reactions
Headache
Photosensitive skin
318
Terbinafine Mechanism of Action
Inhibits squalene epoxidase
Squalene cannot be converted to lanosterol
319
Terbinafine Administration
Topic or oral
Oral for fungal toenails
320
Terbinafine Adverse Reactions
Dermal irritation
Disturbance of taste
Rare Hepatotoxicity
321
Fluconazole Mechanism of Action
Blocks conversion of lanosterol to ergosterol by inhibiting 14a Sterol Demethylase
322
Fluconazole Usage
Usually given orally
Maintenance therapy for systemic fungal infections
Vaginal Yeast Infections
323
Fluconazole Adverse Reactions
Drug interactions because of inhibition of human CYP
324
Caspofungin Mechanism of Action
Disrupts final assembly of FUNGAL CELL WALL
Fungicidal
325
Caspofungin Pharmacokinetics
Given IV
Cleared by liver
326
Caspofungin Usage
Systemic yeast infections
327
Antiprotozoal Drugs
Chloroquine
Artemether
Primaquine
Metronidazole
Paromomycin
328
Most Common Most Severe Most Acute Malaria
Falciparum
328
Antihelmenthic Drugs
Albenzadole
Ivermectin
329
Milder Recurrent Form of Malaria
Vivax, or relapsing malaria, that remains dormant in the liver
330
Prophylactic Malaria Drugs
Chloroquine
Primaquine
331
Drugs of Active or Latent Malaria
Artemether
Chloroquine
Primaquine
332
Blood Stage Clinical Cure Antimalarials
Chloroquine
Artemisinins like Artemether
333
Liver Stage Radical Cure Antimalarials
Primaquine
334
Prophylactic Antimalarial Properties
Orally Effective
Long Half Life
Low Toxicity
335
Chloroquine Mechanism of Action
Ion trapped in parasitic food vacuole and infected red blood cells
Inhibits parasitic digestion of hemoglobin
336
Chloroquine Resistance
Mutated efflux transporter called PfCRT
337
Chloroquine Activity
Clinical cure and prophylaxis
Ineffective against most strains of P. falciparum in Africa, Asia, and South America
338
Chloroquine Adverse Reactions
Well tolerated at prophylactic low doses
Pruritis, headache, GI Issues, and cardiac toxicity in high doses
339
Artemether Mechanism of Action
Unclear, maybe toxic free radicals
340
Artimether Activity
First line oral treatment for resistant falciparum malaria
Short half life makes it not useful for prophylaxis
Always given with lumefantrine to prevent resistance development
341
Artimether Adverse Reactions
Mostly Unclear
Potential Neurotoxicity
342
Primaquine Unique Property
Only liver stage antimalarial
343
Primaquine Mechanism of Action
Unknown
344
Primaquine Activity
Use with Chloroquine for Radical Cure
Terminal prophylaxis for vivax and ovale
Primary prophylaxis in all species
345
Primaquine Adverse Reactions
Hemolytic Anemia in G6P Deficiency
Contraindicated in Pregnancy
346
Other Common Protozoal Infections
Trichomoniasis
Giardiasis
Amebiasis
Cryptosporidiosis
347
Two Types of GI Antiprotozoal Agents
Systemic Absorbed
Luminal Unabsorbed
348
Systemic Antiprotozoals
Metronidazole
349
Metronidazole Antiprotozoal Activity
Systemic amebiasis given in combination with a luminal drug
350
Metronidazole Antiprotozoal Mechanism of Action
Prodrug converted to DNA damaging metabolite
351
Luminal Antiprotozoal Agents
Paromomycin
352
Paromomycin Mechanism of Action
Like all aminoglycosides binds to the 30S subunit
353
Paromomycin Activity
Alone for asymptomatic amebiasis
Combination for amebic colitis or dysentery
354
Paromomycin Adverse Reactions
GI Distress
355
Albendazole Mechanism of Action
Inhibits polymerization of parasitic B Tubulin which prevents formation of microtubules
Paralyzes helminths
356
Albendazole Activity
Enterobiasis infections
Cestode and roundworm infection
357
Albendazole Adverse Reactions
Teratogenic
Liver toxicity long term
Bone marrow suppression long term
358
Ivermectin General Mechanism of Action
Tonic muscle paralysis of parasites
359
Ivermectin Specific Mechanism of Action
Glutamate gated Cl- channel activation
Membrane hyperpolarizes
360
Ivermectin Mechanism of Specificity
P glycoprotein efflux transporter keeps the drug out of the mammalian CNS
361
Ivermectin Activity
Broad spectrum against nematodes and arthropods
362
Ivermectin Adverse Reactions
Host immune reaction to dying parasites
Teratogenic
