Transcript Pharmacology Jeopardy Part 1

Pharmacology
Jeopardy
Block 2 - Part I
Peter O. Beaumont, M.Sc. (Pharm)
St. Vinnie’s Fall 2000
Antibiotics
It is thought that a
cell Tx with
penicillin may have
to produce these in
order to be
bactericidal
What are…
Autolysins
– This is part of the reasoning why
you should not mix tetracyclines
with cell wall synthesis inhibitors
The estimated rate
of resistance of
S. aureus to
penicillin G
What is…
90%
– You should always be cognizant of
this when prescribing antibiotics
for Staph infections
This ‘prophylactic’
acronym reminds
you what drugs to
use for many staph
infections
What is…
CONDoM
– recall, all the penicillins with ‘ox’ in
them can be taken orally.
– Naficillin, can be oral, but abs is
variable
– Methicilin is definitely not oral
For P. aeruginosa,
choose one of
these penicillins
What are…
Mezlocillin
Carbenicillin
Azlocillin
Ticarcillin
Piperacillin
This penicillin is
cleared by the kidney,
but spends time in
the bile, making it
useful against this
‘fishy’ organism
What is…
Ampicillin &
Salmonella (Carrier
state)
This aminopenicillin
is not affected by
food when taken
orally
What is…
Amoxicillin
Penicillin G does not
penetrate well into
these 3 organs
What are…
The eye, prostate
and meninges
(uninflammed)
The only penicillin to
be used in patients
with Renal Failure
What is…
Naficillin
– It is the only one cleared mainly be
the liver
Match the beta-lactam ADR
neutropenia
hepatitis
nephritis
allergic rash in
Mono
Naficillin
Oxacillin
Methicillin
Ampicillin
Fever chills, rigors
and arthralgia due
to release of
spirochete toxins
What is…
The Herxheimer
Reaction
– Occurs with most spirochetes, and
is independent of the antibiotic
used
While 1st-Gen Cephs
are known for their
activity for G-pos,
organisms they are
still active against
these G-negs...
What is…
• Proteus mirabilis
• Enterobacter
• E. coli
• Klebsiella pneumoia
• Mloraxlla catarrhalis
These drugs have in
common the side
effect of
hypoprothombinemia
and a disulfiram-like
reaction
What are…
Cefoperazone,
Moxolactam and
Cefomandole
– 3rd, 3rd and 2nd gen agents
The main difference
between 3rd and
4th-Gen cephs..,
What is…
more resistance to
beta-lactamase
– Especially chromosomal lactamase
produced by Enterobacter
Type of
superinfection
likely in 3rd-Gen
cephs
What is…
Gram-positive
organisms
– recall, as you move from 1st to 3rd
Gen, there is more G-neg activity
and less G-pos activity
Don’t ask me why,
but this common
lab test may
become positive
with the use of
cephalosporins
What is…
Urine test for
glucose
– Apparently, this is for all classes of
cephs.
The First Gen Cephs
Parenteral
Oral
Cefazolin (Ancef™)
Cephalexin (Keflex™)
Cephalothin
Cephapirin
Cephradine
Cefadroxil
Cephadrine
Radical Zoltan lothes rox-star pirsonalities who
drive lexuses
The spectrum of this
class of betalactams is just like
the
aminoglycosides
What are…
Monobactams
– Active against G-negs
– No activity against G-pos or
anaerobes
– Aztreonam is the only drug in the
class
This beta-lactam has
the broadest
spectrum of all and
greatest resistance
to lactamase
What is…
Imipenem
– Think Omni-potent imipenem
– Cilastin makes it resistant to
dihydropeptidase in the kidney
The only iv drug
studied that is
limited solely to
G-pos organisms
What is…
Vancomycin
– iv for Tx of MRSA (usually with an
aminoglycoside)
– po for Tx of C.difficile
– one exception is G-neg
Flavobacterium - but I don’t think
we studied it
This antibiotic works
only in the
periplasmic space
What is…
Bacitracin
– Interferes with cycling of the lipid
transporter Bactoprenol
– too toxic for systemic use
– G-pos organisms only
Inhibits the
conversion of L-ala
to D-ala
What is…
Cycloserine
– Inhibits alanine racemase
– almost exclusively used as 2nd
line Tx for TB due to toxicity
– “Psycho-serine”
Sulfas used in
bowel-prep, based
on the absorption
profile
What are…
Phthalylsulfathiazole
Succinylsulfathizole
and Sulfaquanine
– Neomycin is also effective in this
regard
Acidity in the urine
causes
precipitation of this
drug class
What are…
Sulfa drugs
Mechanisms of
resistance to sulfa
drugs...
What are…
• decreased affinity for
dihydropteroate synthase
• overproductoin of PABA
• increased acetylation
– Plasmid mediate
The crossing of
unconjugated
bilirubin into the
CNS in newborns
What is…
kernicterus
– Occurs in sulfonamides and other
drugs that are normally highly
bound to albumin in adults
This drug is supposed
to release
formaldehyde as part
of its mechanism of
action
What is…
methanamine
mandelate
– forms insoluble complex with
sulfas
– not active against Proteus due to
urea splitting activity - pH must be
below 5.5
With this drug... your
patient might say,
“Thanks Doc, I don’t
have to pee so often,
but it sure comes out
funny looking”
What is…
phenazopyridine
– urinary anaesthetic
– produces red-orange urine
– no antibacterial effect on its own
The common ADR of
Trimethoprim,
pyrimethamine, and
sulfas
What is…
dose-dependent
bone marrow
depression due to
lack of folate
The enzymes
inhibited by sulfa
drugs,
pyrimethamine,
Trimethoprim and
Methotrexate
What are…
Dihydropteroate
synthase, parasitic,
bacterial and
mammalian DHFR,
respectively
At therapeutic,
bacteriostatic
concentrations, the
degree of toxicity in
Fast acetylators
What is…
potentially more
– fast acetylators have fewer incidences
of immune mediated ADRs (SJS, SLE,
etc.)
– acetylation blocks antibacterial activity,
but not the other toxicities. To achieve
Tx levels, you need more drug in these
patients!
DOC in AIDS PCP
What is…
Sulfmethoxazole Trimethoprim
– Also effective in acute
toxoplasmosis, and malaria but
pyrimethamine might be better if
that is all you are treating
These drugs block
relaxation of
positively
supercoiled DNA
What are…
Fluoroquinolones
– effective in UTI caused by MDR
Psuedomonas
– Concentrations higher in prostate,
kidney, bile and stool
This drug is only
good for UTI and
specifically not
pseudomonas or
proteus
What is…
Nitrofurantoin
– No systemic activity
– bacteria reduce the agent to
reactive intermediate, but require
pH below 5.5
Bacteriostatic drug
working at the 30S
subunit
What is…
tetracyclines
– Aminoglycosides also work at the
30S subunit, but they are
bacteriostatic
The only important
cause of atypical
CAP, not covered
by tetracyclines
What is…
Legionella
– Tetracyclines are active against
Mycoplasma & Chlamydia
– Also includes: G-pos, G-neg, and
Spirochetes
Two agents used to
Tx SIADH
What are…
demeclocycline and
+
Li
– Impt ADR of demeclocycline is
photosensitivity
Renal tubular
acidosis,
aminoaciduria,
glycosuria,
proteinuria,
polydipsia
What is…
Fanconi Syndrome
– impt ADR from ingesting
OUTDATED (expired) tetracyclines
The two main
antibiotics used in
the Tx of Acne
What are…
Tetracyclines and
Clindamycin
– Tretinoin (Accutane™) is used too,
but it is not an antibiotic, it is a
retinoid
– Some macrolides and sulfas are
also used occasionally
Broad spectrum,
bacteriostatic agent
working at the 50S
subunit
What is…
Chloramphenicol
– Inhibits peptidyl transferase
– Macrolides also work at the 50S,
but according to Dr. Reddy they
are not broad spectrum
– Bacteroides are highly susceptible
Impt dose-related
ADR of
Chloramphenicol
seen in all age
groups
What is…
Bone Marrow
Suppression
– Aplastic anaemia is idiosyncratic
– Grey-baby syndrome is only in
newborns
Generally, a
substitute for Pen
G (in allergy), and a
DOC for atypical
CAP
What is…
Erythromycin
–I
Chief reason for
discontinuance of
erythromycin
What is…
Gastrointestinal
intolerance
– Direct stimulation of gastric
motility.This is a significant problem,
albeit with minimal morbidity
– incidence of liver tox is increased in
pregnancy
Increased acid stability,
less GIT upset and
activity agasinst Mavium, leprae & T.gondii
What is…
Clarithromycin
– also has a longer T1/2 than
erythromycin
– Azithromycin adds an even longer
T1/2, permitting once-daily dosing
Same mechanism of
action as the
macrolides, but an
entirely different
structure
What is…
Clindamycin
– Main indication is severe
Bacteroides infection
– high incidence of resistance in C.
difficile --> Pseudomembranous
colitis
– Supplanted Erythro in prophylaxis
of endocarditis peri-operatively
Interferes with 30S
ribosome and
causes misreading
of mRNA
What are…
Aminoglycosides
– Main clinical indication in Tx
aerobic, G-neg organisms
(PPEEKS)
– No activity in anaerobes
– Synergy with cell-wall agents
Aminoglycoside
without activity for
G-neg rods
What is…
Streptomycin
– Ancient Drug for ancient bug
– Plague, TB and tularemia
Aminoglycoside
used as 2nd line Tx
in Pen resistant
gonorrhea
What is…
Spectinomycin
– Use a ‘speculum’ before you Rx
spectinomycin
– Not ototoxic or nephrotoxic like
other aminoglycosides
Indicated in pre-op
bowel prep and
hepatic coma
What is…
Neomycin
– Sterilizes the bowel, eliminating
bacterial source of ammonia in
liver - which exacerbates liver
failure
Use this
aminoglycoside for
parasite infection
What is…
Paromycin
– Too toxic for systemic use
– Given po as a luminal amebicidial
agent
– crypto, visceral leish, and cestodes
The other major side
effect everyone
forgets about with
aminoglycosides
What is…
NMJ blockade
– curare-like, reversible with
neostigmine and Ca gluconate
Topical agents with
G-neg activity, that
interact with
membrane
phospholipids
What are…
polymixins
– commonly used in ophthalmic and
otic preparations
– combined with Bacitracin to cover
G-pos or neomycin for additional
G-neg
Antifungals
These 2 drugs….
Are antifungals that both
have efficacy against
cryptococus
neoformans meningitis
and are given p.o.
What are…
Flucytosine and
Fluconazole
– if you said Amphotericin B,
remember, it is only given iv!
The amphipathic
nature of these
polyene drugs….
Allow them to create
pores in fungal
membranes
What are…
Amphotericin B and
Nystatin
– both of these agents bind to
ergosterol and are amphipathic (a
hydophobic side and a hydrophilic
side) - wanna guess where amphoteracin got
its name?
These 4 drugs….
All affect
microtubule
formation as part of
their mechanism of
action
What are…
Colchicine
Griseofulvin
Vincristine
Albendazole (et al)
Better take this drug
with a Big Mac,
fries and a shake,
but not your
sleeping aids
What is…
Griseofulvin
– absorption increased by fat, and
decreased by barbiturates
Drug A inhibits the
absorption of B, but
B inhibits the
metabolism of A.
Hint: ulcers and
fungi
What are…
A: Cimetidine
B: Ketoconazole
– ketoconazole requires and acid
environment for absorption and
competes for CYP3A4 with
cimetidine
These drugs….
Provide induction
and maintenance
Tx of Cryptococus
neoformans,
respectively
What are…
Amphotericin B and
fluconazole
This drug….
Is used for topical
Tx of Candida, but
not dermatophytes
What is…
Nystatin
– only miconazole, clotrimazole and
econazole affect dermatophytes
topically
– Giseofulvin gets, them, but does
so systemically
This antifungal….
Plus the right
bacteria, will
depress your bone
marrow
What is…
Flucytosine
– Some intestinal bacteria will
deaminate 5-fluorocytosine to 5fluorouracil, an effective
antineoplastic agent in mammalian
cells
CANCER
CHEMOTHERAPY
If a drug killed
99.99% of all cells
in a 100g tumour;
this many cells
would remain
What is…
7
10
– A 100 g tumour = ~1011 cells, there
fore, you would lose 4-orders of
magnitude
An effective route of
admin for
mechlorethamine,
but not
cyclophosphamide
What is…
intra-arterial
– Cyclophosphamide requires
metabolic activation
By definition, these
antineoplastics
work best in the
M-phase of the cell
cycle
What are…
Vinca Alkaloids and
paclitaxel
– Both affect microtubule assembly
and hence the mitotic spindle
Decreasing order of
toxicity of the 3
main alkylating
agents in the
handout
What are…
mechlorethamine >
cyclophosphamide
> chlorambucil
– Chlorambucil is safe enough to be
used as an immunosuppressant
This metabolite of
Cyclophosphamide
is toxic to the
bladder
What is…
acrolein
– Causes hemorrhagic cystitis and is
Tx with sulfhydryl agents like
MESNA (2-mercapotethane sulfate)
– Considered most useful alkylating
agent
This class of
alkylating agents
have better efficacy
in CNS tumours
What are…
Nitrosoureas
– Carmustine (BCNU) and Lomustine
(CCNU) are more lipophilic than
the other agents
This alkylating agent
is said to have
efficacy in
suppressing bone
marrow prior to
transplant
What is…
Busulfan
If in doubt, the
limiting toxicity of
any anti-CA agent
is:
What is…
Bone Marrow
Suppression
– However, there are some very
notable exceptions to follow…..
An important result
of mass destruction
of CA cells.
Hint: think DNA
breakdown
products
What is…
Hyperuricemia
– release of purines from damaged
cells leads to increases in uric acid
after metabolism by xanthine
oxidase
This agent acts like
an alkylating agent,
but is structurally
dissimilar.
What is…
Cisplatin or
Carboplatin
The limiting toxicity
of cisplatin, which
is reduced by IV
fluids and mannitol
What is…
nephrotoxicity
– ototoxicity and peripheral
neuropathy are not affected
By decreasing protein
binding, this happens
quicker in Caroplatin
and hence returns the
limiting toxicity back
to bone marrow
What is…
renal elimination
– Carboplatin is used in many
patients who cannot tolerate the
nephrotoxicity of cisplatin
These 4 agents are
by definition Sphase specific
What are…
5-FU, Methotrexate,
mercaptopurine &
Ara-C
– These agents are either
antimetabolites, or interfere with
purine or pyrimadine synthesis
Inhibition of this
enzyme leads to
lack of dTMP and
reduced
components for
purine synthesis
What is…
DHFR
This drugs inhibits
the previous
enzyme
What is…
Methotrexate
This agent is
regarded by many
as having the
broadest anticancer
spectrum
What is…
Doxorubicin
– Daunorubicin is only used against
leukemias
Mechanisms of
action of
Doxorubicin
What are…
Intercalatoin of DNA,
effects on Topo II,
toxic free radical
– Partly cell-cycle specific, partly not
– H. Baer packet says not
This agent,
combined with
etoposide and
cisplatin is effective
in Testicular CA
What is…
Bleomycin
– Significant lung toxicity
Dose-limiting
toxicity of
doxorubicin
What is…
cardiomyopathy
– Dose-related, occurs beyond
(cummulative) 500mg/m2
Mechanism of the
podophyllotoxins
What is…
inhibit Topo II
– Cause DNA strand breaks
– work in late 2-G2
– Etoposide & Teniposide
GASTROINTESTINAL
PHARMCOLOGY
The general Tx
regimen for
established H.pylori
mediated PUD
What is…
PPI or H2 or bismuth
+
Metrondazole & 2nd
Antibiotic
selectively binds the
ulcer AND may
have antibacterial
effects
What is…
Bismuth
– ADR: black mouth and stool,
salicylism
This H2 receptor
antagonist
prototype drug
affects the
metabolism of
many other drugs
What is…
Cimetidine
– Competatively inhibits P450
– Cause estrogenic effects
The difference in
efficacy among the
newer H2
antagonist
What is…
Essentially none
– Longer lasting, few SE, more $$
The active
metabolite of this
class of “antacids”
irreversibly inhibits
the H/K ATPase
What are…
proton pump
inhibitors
– Omeprazole and lansoprazole
– effect remains until new pump is
synthesised
– Generally well tolerated
analogue
2
What is…
misoprostol
3 effects of
misoprostol
What are…
inhibit acid
secretion, stimulate
bicarb secretion,
increase mucus
secretion
Major
contraindication for
misoprostol
What is…
pregnancy
– pro-abortificant actions
This agent
preferentially binds
the ulcer base to
protect it
What is…
Sucralfate
– absorbs acid, pepsin and bile
Common ingredient
of Nytol,
Dramamine and
Dimetap
What is…
Dimenhydrinate
– 1st Generation H1 blockers
– block both H1 and ACH receptors
to produce anti-emtic effect
One of the original
“truth serums”,
now used as a
patch to prevent
sea sickness
What is…
Scopolamine
– Primary action is Anti-cholinergic
effect on CTZ zone
– major SE of sedation
– Benztropine (Cogentin) and
cyclizine are congeners
These agents should
be “high” on your
list of adjuncts in
Cancer Tx
What are…
Cannabinoids
– Dronabinol and nabilone
(derivatives of
tetrahydrocannabinol)
– You can figure out the SE
Predictable SE of
Prochlorperazine &
promethazine
(Compazine and Phergan for
you clinicians out there)
What is…
Parkinsonism
– Upsets the DA - ACh balancein the
basal ganglia
Treatment of the SE
of above with this,
actually enhances
the anti-emetic
effect!
What is…
Diphenhydramine
– Additional anti-ACh effect restores
the ratio in the BG
– benztropine may also be
commonly used
Anti-serotonin agent
with good efficacy
in N&V associated
with Chemo and
Rad
What is…
Ondansetron
– blocks the 5-HT3 receptor (which is
the only ion channel of the HT
receptor group)
Amazing combo of
CNS anti-emetic
and gut promotility
make this agent
very useful
What is…
Metoclopromide
– Anti-DA and anti-5-HT3 in CNS
– muscarinic agonist in the GIT
SE of the above
agent… based on
mechanism of
action
What is…
Also causes
Parkinsonism
– Specific effect mentioned in class
is occulogyral crisis
Medical reason for
not using mineral
oil laxatives
What is…
fat soluble vit
dificiency and lipid
pneumonitis if
aspirated
Social reason to not
use mineral oil
laxatives
What is…
They leak out you
bum!
Mech of Act of Exlax, etc.
What is…
irritant to
Auerbach’s plexus
in the colon
– phenolphthalein turns stools pink remember CHEM 101?
– May cause post-use constipation
These agents have a
positive effect on
the G.I. Ward, that
is a SE on the
orthopedics ward
What are…
Opiods
– Diphenoxylate is a weak analogue
of meperidine (Demerol)
– direct action on the ENS: fewer
propulsive waves
This agent is
commonly added to
anti-diarrhea opiod
preparations
What is…
Atropine
– unpleasant CNS SE limit addictive
potential of diphenoxylate
This anti-diarrheal
requires no
addition of atropine
What is…
Loperamide
– Does not cross the BBB in
significant amounts
Class of agents
used to decrease
GIT tone and
motility
What are…
Anti-cholinergics
– Dicyclomine mentioned in the
notes
– Reportedly, has less anti-ACh side
effects than atropine
END of Part I