First Sem Pharma Notes
First Sem Pharma Notes
First Sem Pharma Notes
lonired : hydrophilic
LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
- Usually, but not always, due to metabolism of the
drug in the gut, portal blood or the liver
- Oral route = slowest absorption because of first-
pass effect
- Rectal (suppository) = partially avoid first-pass
effect
- All other routes avoid first pass effect and are
absorbed faster.
1.2 Absorption of Drugs
A. Routes of Administration
Sample Question:
- the amount absorbed into the systemic circulation
A 60-year-old patient with severe cancer pain is given 10
divided by the amount of drug administered
constitutes “bioavailability” mg of morphine by mouth. The plasma concentration is
found to be only 30% of that found after intravenous
administration of the same dose. Which of the following
terms describes the process by which the amount of
active drug in the body is reduced after administration
✗ 1st pass eat
but before entering the systemic circulation?
(A) Excretion
(B) First-order elimination
(C) First-pass effect
(D) Metabolism
(E) Pharmacokinetics
✗ 1st pay
unit B. Blood Flow
skin
= systemic A. Determinants of Distribution
eaut 1. Size of the organ – determine concentration gradient
between blood and organ.
First- Pass Effect
2. Blood flow – determine the “rate of uptake” of the
- Term given to “elimination of a drug before it enters drug; highly perfused tissues (brain, heart, kidneys and
the systemic circulation “ splanchnic organs) achieve higher tissue concentrations
sooner than poorly perfused tissues (fat, bone)
Cheer up future doctor!!!!
LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
3. Solubility – influences the concentration of the drug
in the extracellular fluid surrounding the blood vessels;
if drug is very soluble in the cells, the concentration in
the perivascular space will be lower and diffusion from
the vessel into extravascular space will be facilitated;
organs that have high lipid content dissolve a high
concentration of high lipid soluble agents rapidly.
4. Binding – binding of a drug to macromolecules in the
blood or a tissue compartment tends to increase the
drug’s concentration in that compartment
Example: warfarin bound to albumin restricts diffusion
of warfarin out of vascular compartment; chloroquine
bound to extravascular tissue proteins results in marked
reduction of the drug in the plasma
Phase II Reactions more lipophilic !
1.4 Metabolism of Drugs
⇐
- Drugs that are normally expelled by P-gp (become
toxic when given with an inhibitor): digoxin,
cyclosporine, saquinavir
=
inhibitor, ritonavir excretion.
- Suicide inhibitors: drugs that are metabolized to - Organ responsible is the kidneys
products that irreversibly inhibit the metabolizing - Volatile anesthetic drugs are eliminated via the
enzyme. lungs.
- Examples: ethinyl estradiol, norethindrone, - Small number of drugs combine irreversibly with
spironolactone, secobarbital, allopurinol, fluroxene their receptors, their disappearance from blood
and propylthiouracil stream is not equivalent to cessation of drug action
- Metabolism may also be decreased by ---- result to prolonged action
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pharmacodynamic factors such as reduction in - Example: Phenoxybenzamine
blood flow (example. Propranolol reduces hepatic o irreversible inhibitor of a adrenoreceptors
blood flow) o eliminated from the blood stream in less
than 1 hour after administration
o action lasts for 4 hours – time required for
turnover of receptors.
First Order Elimination coin
=
- Happens to most drugs at most doses
- Also found in blood brain barrier and in drug
resistant cancer cells. Zero Order Elimination
- Drugs that inhibit intestinal P-gp mimic drug
metabolism by increasing bioavailability. - Rate of elimination is constant regardless of
concentration.
⇐
mechanisms at concentrations of clinical interest.
- Concentrations of these drugs in plasma decrease
in a linear fashion.
- Such drugs do not have a constant half-life
- Typical of ethanol (over most of its plasma
concentration range) , phenytoin and aspirin ( high
therapeutic or toxic concentrations. ( EPA)
2. Reproductive Toxicity
- Study of fertility effects of candidate drug and its
teratogenic and mutagenic toxicity.
- Teratogenesis: induction of developmental defects
in the somatic tissues of the fetus.
- Teratogenic drugs: thalidomide, isotretinoin,
valproic acid, ethanol, glucocorticoids. Warfarin,
lithium, androgens
- Mutagenesis: induction of changes in the genetic
material of the animals of any age and therefore
induce hereditable abnormalities.
- Ame’s test: standard in vitro test for mutagenesis
that uses a specific strain of salmonella bacteria
that depend on specific nutrients in culture
medium; loss of dependence signals mutation.
- Dominant lethal dose test: in vivo mutagenicity
test carried out in male mice, where in male mice
are exposed to mutagenic substance before
mating; resulting in abnormalities of offspring
(deformed fetuses, loss of embryos)
3. Carcinogenesis
- Induction of malignant characteristics in cells.
- Agents with known carcinogenic effects: coal tar,
aflatoxin, nitrosamines, urethane, vinyl chloride,
tobacco smoke (polycyclic hydrocarbons)
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of the proposed clinical use the spectrum of
beneficial actions of the new drug compared to
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peut a placebo or old therapy.
- Discover toxicities if any that occur so
infrequently that it was not detected in Phase 2
Drug Development Process
- If drug successfully complete Phase 3 , an NDA is
submitted to the FDA.
- If NDA is approved the drug can be marketed
and proceed to Phase 4.
Phase 4 Clinical Trial
- Represents post marketing surveillance phase of
evaluation
- The hope is that toxicities that occur very
infrequently will be detected and reported early
enough to prevent major therapeutic disasters.
- Manufacturers are required to inform the FDA
of all reported untoward drug reactions.
PHARMACODYNAMICS
=*÷
drug for its receptor.
-
required to bind 50% of the receptor sites
Useful measure of the affinity of a drug for its
attrib spare receptors
receptor.
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Cheer up future doctor!!!! three
LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
- Determined by comparing maximal effect (EC50) - Drug that counters the effects of another by
with the concentration for 50% of maximal binding binding to a different receptor and causing
(Kd) opposing effects.
- Duration of effector activation may be much - Example: antagonism of the bronchoconstrictor
greater than the duration of the drug receptor action of histamine by epinephrine’s
interaction. bronchodilators action; glucagon’s antagonism of
- Actual number of receptors may exceed the the cardiac depressant effects of propranolol
number of effector molecules available
- Presence of spare receptors increase sensitivity to
the agonist because the likelihood of a drug
In against
receptor interaction increases in proportion to the
CHEMICAL ANTAGONIST bind day
not
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number of receptors available.
AGONISTS - Drug that counters the effects of another by
binding the agonist drug (not the receptor).
Constitutive activity: activity in the absence of a ligand. - Example: dimercaprol, a chelator of lead;
pralidoxime that combines avidly with phosphorus
FULL AGONIST: a drug capable of fully activating the in organophosphate cholinesterase inhibitors
effector system when it binds to the receptor; high
affinity for activated receptor conformation and a ALLOSTERIC AGONIST, ANTAGONIST alhs upon
sufficiently high concentration results in all receptors
achieving activated state. - Drug that binds to a receptor molecule without
interfering with normal agonist binding but alters
PARTIAL AGONIST: produce less than the full effect the response to the normal agonist.
even when it has saturated all the receptors; when
there is a full agonist a partial agonist acts as an
inhibitor. SIGNALLING MECHANISMS
INVERSE AGONISTS: have higher affinity for inactive
state and decrease or abolish any constitutive activity.
ANTAGONISTS
NEUTRAL ANTAGONIST
- Bind with equal affinity to activated and
inactivated states, preventing any deviation from
the constitutive activity.
PHARMACOLOGIC ANTAGONIST prevent
action
- Drug that binds without activating its receptor and
thereby prevents activation by an agonist.
COMPETITIVE ANTAGONIST
- Pharmacologic antagonist that can be overcome by
increasing the concentration gradient.
IRREVERSIBLE ANTAGONIST
- Pharmacologic antagonist that cannot be
overcome by increasing agonist concentration.
PHYSIOLOGIC ANTAGONIST
Answer: D
O.O
Sample Question:
HALF-LIFE
- The time required for the amount of drug in the
body or blood to fall by 50%.
- Derived from volume distribution and clearance.
- For drugs eliminated by first-order kinetics, this
number is a constant regardless of the
concentration
CLEARANCE
- disease, age and other variables alter the clearance
- Rate of elimination to the plasma concentration. of the drug much more than they alter Vd.
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- A drug eliminated through first order has a - Determines the rate at which blood concentration
constant clearance; ratio of the rate of elimination rises during a constant infusion and falls after
to plasma concentration is the same over a broad administration is stopped.
range of plasma concentration.
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Clearance depends on: the drug, blood flow, and
the condition of the organs responsible for
elimination in a particular patient
Answer: 4 hours
rare in plan w.
⑨ m
- Ratio of - More clinically
TD50(median toxic) useful index of
/ LD50 (median safety.
lethal) to the - Describes the
:
ED50(median dosage range
effective) between the
- Represents an minimum effective
estimate safety of a therapeutic
drug. concentration /
- A very safe drug dose and the
might be expected minimum toxic
to have a very large concentration /
toxic dose and a dose.
much smaller - Data are used to
effective dose. determine the
acceptable range of
plasma levels when
designing a dosing
regimen,
CHOLINERGIC TRANSMISSION
1. Vesicles synthesized in the neuron cell body are carried to the terminal by axonal transport.
2. Large numbers of clear, small membrane bound vesicles contain ACETYLCHOLINE. They are
located near the portion of the cell membrane facing the synapse.
3. Smaller number of large dense-cored vesicles contain PEPTIDE transmitters. They are located
farther away from the synaptic membrane.
4. Ultra- fast neuronal firing of synapses is supported by recycling of Clathrin coated vesicles from
endosomes in the nerve terminal.
5. Vesicles are provided with VAMPs (vesicle-associated membrane proteins)
VAMPs serve to align vesicles with release sites on the inner neuronal cell
membrane; participate in triggering transmitter release
6. The release site on the inner surface of the nerve terminal membrane contains SNAPs
(synaptosomal nerve-associated proteins).
SNAPs interact with VAMPs. Both are collectively called fusion proteins.
symporter blocked by
HEMICHOLINIUMS.
9. Acetyl-CoA and choline through the catalytic action of choline acetyltransferase (ChAT)
synthesize ACETYLCHOLINE.
Acetylcholine synthesis is a rapid process supporting a very high rate of
transmitter release.
10. Acetylcholine is transported from cytoplasm into vesicles by VAT (vesicle – associated
transporter), driven by a proton efflux.
antiporter blocked by VESAMICOL.
21. After release from pre synaptic terminal, acetylcholine molecules bind to and activate
CHOLINORECEPTORS.
22. Eventually (usually very rapidly), all of the acetylcholine released diffuses within range of an
acetylcholinesterase (AChE) molecule. Half life of acetylcholine molecules in the synapse is
very short (a fraction of a second).
ADRENERGIC TRANSMISSION
1. Adrenergic neurons transport the precursor amino acid TYROSINE into nerve endings.
2. Tyrosine is converted to DOPA by TYROSINE HYDROXYLASE.
3. DOPA is converted to a catecholamine transmitter (DOPAMINE, NOREPINEPHRINE,
EPINEPRHINE)
4. Catecholamines are stored in membrane bound vesicles and in most postganglionic neurons,
norepinephrine is the final product. In the adrenal medulla and the brain, norepinephrine is further
converted to epinephrine.
5. Dopaminergic neurons, synthesis stops with DOPAMINE.
• VMAT (vesicle monoamine transporter): high affinity antiporter for catecholamines located
in the wall of storage vesicle --- inhibited by: RESERPINE (alkaloids). Reserpine and related
drugs (TETRABENAZINE, DEUTETRABENAZINE) deplete transmitter stores.
• NET (norepinephrine transporter): carries norepinephrine and similar molecules back into
the cell cytoplasm from the synaptic cleft; also called UPTAKE 1 / REUPTAKE 1; partially
responsible for termination of synaptic activity --- inhibited by: COCCANE AND
ANTIDEPRESSANTS – result to: increase in transmitter activity in the synaptic cleft
6. Release of vesicular transmitter store from noradrenergic nerve endings is similar to the calcium
dependent process for cholinergic terminals.
7. In addition to primary transmitter = norepinephrine: ATP, dopamine beta hydroxylase, and
peptide transmitters are also released.
Action of TYRAMINE, AMPHETAMINE, EPHEDRINE (TAE): indirectly acting, mixed action
sympathomimetics; poor agonists at adrenoreceptors but excellent substrates for monoamine
transporters—inhibit monoamine oxidase—result to: increased norepinephrine activity in the
synapse.
1. Action of these drugs do not require vesicle exocytosis.
2. Drugs avidly taken up into noradrenergic nerve endings by NET.
3. In the nerve ending, they are transported by VMAT into vesicles, displacing norepinephrine.
4. Norepinephrine expelled into synaptic space by reverse transport via NET.
What is monoamine oxidase?
Present on mitochondria in the adrenergic nerve ending and inactivates a portion of the dopamine and
norepinephrine in the cytoplasm
8. Termination of noradrenergic transmission results from: (a.) simple diffusion away from receptor
site and subsequent metabolism in the plasma or liver, (2.) reuptake into nerve terminal by NET.
Co - Transmitters in Cholinergic and Adrenergic Nerves and their Receptors
Autonomic Receptors
The most selective effect is achieved by drugs acting at receptors that mediate very selective actions.
Effects of automatic nerve activity on organ systems:
AUTONOMIC TRANSMISSION EFFECT OF DRUGS
Chapter 7: Cholinoceptor Activating & Cholinesterase Drugs
- Direct acting cholinomimetic agents: activate
muscarinic or nicotinic receptors.
- Indirect acting agents: produce their primary effects
by inhibiting acetylcholinesterase increasing the
endogenous concentration of acetylcholine; acts on
where acetylcholine is physiologically released.
Mechanisms of Action:
• Muscarinic mechanisms
1. G protein coupling of M1 and M3 muscarinic receptors to phospholipase C
2. Activation of Phospholipase C leads to release of the second messengers: diacylglycerol (DAG)
and inositol- 1, 4, 5 triphosphate (IP3)
Myasthenia Gravis: autoimmune disorder affecting the skeletal muscle neuromuscular junction.
Antibodies are produced against the main immunogenic region found on a1 subunits of nicotinic
receptor channel complex. Antibodies reduce function by:
(1) cross linking receptors (stimulates their internalization and degradation)
(2) cause lysis of the post synaptic membrane
(3) binding to nicotinic receptor and inhibiting function.
Clinical manifestations: ptosis, diplopia, difficulty in swallowing and speaking, extremity weakness,
respiratory muscle dysfunction
Diagnostic tool: edrophonium test; (+) edrophonium test seen as an improvement of muscle strength
that lasts 5 minutes.
Treatment: direct acting cholinoreceptors agonists (alkaloids) / cholinesterase inhibitors ex.
Neostigmine ; thymectomy, immunosuppression
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TETRACYCLINES
I
• Enter susceptible organism via passive diffusion and by an energy dependent transport protein
mechanism found on bacterial inner cytoplasmic membrane.
• Concentrate intracellularly in susceptible organisms.
• Commonly used for treatment of: acne and Chlamydia infections.
• Tetracycline + Gentamicin = DOC for Brucella species
• Resistance: efflux pump.that expels drug out of the cell preventing intracellular accumulation.;
enzymatic inactivation of the drug via bacterial proteins that prevent binding of drug to ribosomes
• Pharmacokinetics:
o Adequately absorbed after oral ingestion
o Most tetracyclines are reabsorbed from bile
o Metabolized to glucuronides
o Tetracyclines concentrate well in bile, liver, kidney, gingival fluid and skin
o Bind to tissues undergoing calcification (teeth and bones) or to tumors that have high
calcium content.
o All tetracyclines cross the placental barrier and concentrate in fetal bones and
dentition.
o Contraindications: not to be used in pregnant or breast-feeding women or children
less than 8 years old.
o
1. Demeclocycline – phototoxicity
2. Doxycycline – PO and IV; achieve therapeutic concentrations in CSF; Doxycycline glucuronide
is excreted via bile; preferred in patients with renal dysfunction – eliminated via bile onto
feces
3. Minocycline – PO and IV; achieve therapeutic concentrations in CSF, saliva and tears – useful
for eradicating meningococcal carrier state; hepatic metabolism
4. Tetracycline (generic only) - Dairy products or substances that contain divalent or trivalent
cations (magnesium, calcium and aluminum antacids or iron supplements --- decreases
absorption of tetracycline due to formation of chelates; eliminated unchanged in the urine
Adverse effects of Tetracyclines:
1. Gastric discomfort
o Epigastric distress results from irritation of gastric mucosa – noncompliance with
tetracyclines
o Esophagitis --- minimized through coadministration with food (no dairy products) or
fluids and the use of capsules rather than tablets
o Note: Tetracycline should be taken on an empty stomach.
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2. Effects on calcified tissues
o Limited use in pediatrics
o May cause discoloration and hypoplasia of teeth and temporary stunting of growth
o Deposition in the bone and primary dentition during calcification process in growing
children.
3. Hepatotoxicity
4. Phototoxicity
o Severe sunburn when exposed to sun or UV rays
o Encountered more frequently with: Tetracycline and Demeclocycline
5. Vestibular dysfunction
o Minocycline: dizziness, vertigo and tinnitus – concentrates in the endolymph of ear and
affects function
6. Pseudo motor cerebri
o Benign intracranial hypertension
o Characterized by: headache and blurred vision
o Discontinuation reverses condition
Therapeutic Application of Tetracyclines:
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1. Peptic Ulcer Disease
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o Causative agent: Helicobacter pylori (Gram negative rod)
o Treatment: Bismuth, Metronidazole, Tetracycline and proton pump inhibitor
2. Lyme Disease
o Causative agent: Borrelia burgdorferi (spirochete)
o Transmission: bite of infected ticks
o Clinical features: skin lesions, headache and fever, followed by meningoencephalitis and
eventually arthritis
o Hallmark / Pathognomonic sign: Bull’s eye pattern rash with erythema
- migrans (red outer
ring)
FEE
o DOC: Doxycycline
3. Mycoplasma Pneumoniae
o Also called “walking pneumonia”
o Common cause of community acquired pneumonia in young adults and in people who
live in close confines (military camps).
o DOC: Macrolide or Doxycycline
4. Cholera
o Causative agent: Vibrio cholera (Gram negative rod)
o Transmission: ingestion of fecally contaminated food or water
o Organism multiplies in GI tract where organism releases enterotoxin --- caused diarrhea
(need fluid replacement)
o DOC: Doxycycline – reduces number of intestinal vibrios
5. Chlamydial Infections
o Causative agent: Chlamydia trachomatis
o Major cause of sexually transmitted disease
o Clinical features: nongonococcal urethritis; pelvic inflammatory disease,
lymphogranuloma venereum
o Causative agent: Chlamydia psittaci
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Psittacosis takes the form of pneumonia; other clinical forms: hepatitis, myocarditis,
o
|-O
coma
o DOC: Doxycycline or Azithromycin
6. Rocky Mountain Spotted Fever
o Causative agent: Rickettsia rickettsi
o Clinical features: fever, chills, aches in bones and joints
o DOC: Tetracyclines (prompt response if started early in disease process)
GLYCYLCYCLINES
O 1. Tigecycline
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• Derivative of minocycline
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• Bacteriostatic action by reversibly binding to 30S ribosomal,subunit and inhibiting
protein synthesis.
.
• First member of glycylcycline antimicrobial class
• Large volume of distribution and penetrates tissues well
• Low plasma concentrations – tigecycline is a poor option for bloodstream infections
• Primary route of elimination: biliary / fecal
• No dosage adjustment for renal impairment
• Dose reduction recommended in severe hepatic dysfunction
• All-cause mortality in tigecycline is higher than other agents
• Boxed warning states: for use in situations when alternative measures are not
suitable
• Broad-spectrum activity against:
o MRSA
o VRE
o Multidrug resistant streptococci
o Extended spectrum B lactamase producing gram negative bacteria
o Acinetobacter baumannii (anaerobic)
• Not active against: MPPP
o Morganella
o Proteus
o Providencia
o Pseudomonas spp.
• Indication:
o complicated skin and soft tissue infections
o complicated intra-abdominal infections
o community acquired pneumonia
• Developed to overcome emergence of tetracycline class resistant organisms that utilize
efflux pump and ribosomal protection to confer resistance.
0
• Resistance to tigecycline – overexpression of efflux pumps
Adverse effects of Tigecycline:
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1. Nausea and vomiting
2.
3.
Acute pancreatitis with fatality
Elevations in liver enzymes and
.
. serum creatinine
4. Photosensitivity
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5. Pseudo motor cerebri
6. Discoloration of permanent teeth when used during teeth development
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7. Fetal harm when administered during pregnancy
8. r
Decrease clearance of WARFARIN – monitor INR when tigecycline is co administered with
warfarin
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AMINOGLYCOSIDES
• Bind to 30S subunit distorting its structure and causing misreading of the mRNA.
•
•
•
Clinical utility is limited due to serious toxicities ⑥-
Indication: treatment of serious infections due to gram negative bacilli
o
• Dosing strategy reduces risk of nephrotoxicity and increases convenience.
• Antibacterial spectrum:
o Majority of aerobic gram-negative bacilli including those that multidrug resistant. (PKE)
f
o Pseudomonas aeruginosa
o Klebsiella pneumoniae
o Enterobacter spp.
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o Combined with a beat lactam antibiotic to employ synergistic effect in treatment of
infective endocarditis caused by:
▪ Enterococcus faecalis
▪ Enterococcus faecium
• Resistance to aminoglycosides:
o
▪ Enterococcus species and Streptococcus agalactiae: ampicillin + gentamicin
-
o Efflux pumps
o Decreased uptake I
o Modification and inactivation by plasmid associated synthesis of enzymes (Amikacin is
less vulnerable to enzymes.)
• Pharmacokinetics:
o Polycationic structure prevents adequate absorption after oral administration.
o Concentrations in CSF is inadequate even with inflamed meninges
o For CNS infections, intrathecal or intraventricular routes may be utilized.
o All aminoglycosides cross placental barrier and may accumulate in the fetal plasma and
amniotic fluid.
o More than 90% of parenteral aminoglycosides are excreted unchanged in the urine.
o Accumulation occurs in renal dysfunction.
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o Neomycin is primarily excreted unchanged in feces.
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1. Amikacin (generic only): parenteral
2. Gentamicin (generic only): parenteral
-
3. Neomycin (generic only): only one that is not give parenteral – avoid severe nephrotoxicity;
*
topical administration for skin infections; oral administration to decontaminate the GI tract prior
to colorectal surgery;
4. Streptomycin (generic only) – Yersinia pestis
5. Tobramycin
Therapeutic Application of Aminoglycosides:
1. Tularemia
f-
o Rare zoonotic lymphoid disease
o Transmission: acquired during rabbit hunting season by hunters skinning infected
animals.
o Pneumonic tularemia: bacterial seeding of lungs or infection via respiratory route
o DOC: Gentamicin
2. Infections due to Pseudomonas Aeruginosa
o Organism rarely attacks healthy individuals
o Cause infections in patients with specific risk factors:
▪ Recent antibiotic exposure
▪ Prolonged hospitalization
▪ Bronchiectasis
for
o DOC: Urinary Tract Infection – Tobramycin; Pneumonia – combination with
antipseudomonal B lactam antibiotic
Adverse effects of Aminoglycosides:
1. Ototoxicity
o Aminoglycosides accumulate in the endolymph and perilymph of the inner ear
o Deafness may be reversible and known to affect developing fetus
°
o Patients simultaneously receiving ototoxic drugs: cisplatin or loop diuretic – high
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risk
o Vertigo (in patients receiving streptomycin) may also occur.
2. Nephrotoxicity
o Retention of aminoglycosides by proximal tubular cells disrupts calcium mediated
transport processes ----- results to kidney damage
3. Paralysis
o Adverse effect associated with a rapid increase in concentration or high doses infused
over a short period
o Concurrent administration with: neuromuscular blockers
o Myasthenia gravis – high risk
o Calcium gluconate or neostigmine: reverse the block that causes neuromuscular
paralysis
4. Skin rash
o Contact dermatitis – topically applied Neomycin
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✓ MACROLIDES / KETOLIDES
• °
Bind to the 50S subunit this inhibiting translocation
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• Bactericidal in high doses
• Binding site identical or in close proximity to that for clindamycin and chloramphenicol.
• All macrolides concentrate in the liver
Resistance to Macrolides or Ketolides:
o Inability of organism to take up the antibiotic
o 0
Prescence of efflux pumps
o Decreased affinity of the 50S ribosomal subunit for the antibiotic1
due to methylation of an
adenine in the 23S bacterial ribosomal RNA (Gram positive organisms)
,
o Prescence of plasmid associated erythromycin esterase (Gram negative organisms;
stur.in#-!-
Enterobacteriaceae)
y /* 1. Azithromycin (larger lactone ring): less active than erythromycin against streptococci and
staphylococci; more active against respiratory pathogens ---- H. influenzae and Moraxella
÷:÷÷¥¥→
catarrhalis; stable in stomach acid with adequate oral absorption; food decreases absorption;
available in IV formulation; widely distributed in tissues; concentrates in neutrophils,
macrophages and fibroblasts with low serum concentrations; largest volume distribution of its
putt class. ---- excreted in bile as active drug
2. Clarithromycin (methylated form of erythromycin): similar to erythromycin; effective against –
Haemophilus influenzae; greater activity against – intracellular pathogens such as ----
Chlamydia, Legionella, Moraxella, Ureaplasma spp and Helicobacter pylori; stable in stomach
acid with adequate oral absorption; food increases absorption; widely distributed in tissues ;
interfere with the metabolism of theophylline , statins and antiepileptics – hepatically
metabolized and excreted in urine ; dosage adjustment for renal impairment
3. Erythromycin: first of its class to have clinical application both as DOC or alternative to
individuals with penicillin allergy; effective against the same organisms as penicillin G;
destroyed by gastric acid (administer enteric coated tablet or esterified form); food decreases
absorption; available in IV formulation; diffuse well into all body fluids except CSF; diffuse
into prostatic fluid and accumulate in macrophages; hepatic metabolism with inhibition to
✓
certain drugs via cytochrome P450 system --- excreted in bile with partial reabsorption via
enterohepatic circulation
4. Telithromycin (generic only; ketolide and derivative of erythromycin): spectrum similar to
azithromycin; ketolides neutralize the most common mechanisms that render macrolides
ineffective; stable in stomach acid with adequate oral absorption; administered without regards to
meals; widely distributed in tissues; hepatic metabolism with inhibition to certain drugs via
cytochrome P450 system
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Therapeutic Application of MACROLIDES/KETOLIDES:
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1. Corynebacterium diphtheriae
o DOC: Erythromycin or Penicillin; used to eliminate carrier state
2. Chlamydial infections
o DOC: Azithromycin or Doxycycline
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o Leads to patient non compliance
o Erythromycin at higher doses lead to smooth muscle contractions that result in
movement of gastric contents into the duodenum---- Tx for gastroparesis or
postoperative ileus
2. Cholestatic jaundice
o Occurs with estolate form of erythromycin
3. Ototoxicity
o Transient deafness: Erythromycin
o Irreversible sensorineural hearing loss: Azithromycin
4. QT c prolongation
Contraindications of Macrolides and Ketolides:
o Hepatic dysfunction: treat cautiously with azithromycin, erythromycin, telithromycin –
accumulate in the liver
o Telithromycin – cause severe hepatotoxicity and is of limited use
Drug Interaction of Macrolides and Ketolides:
o Interaction with DIGOXIN – macrolides eliminate intestinal flora that inactivates digoxin
leading to greater absorption of digoxin
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MACROCYCLIC
f.
•
1. Fidaxomicin
o acts on the sigma subunit of RNA polymerase, thereby disrupting bacterial transcription,
terminating protein synthesis and resulting in cell death in susceptible organisms
•
o narrow spectrum of activity limited to gram-positive aerobes and anaerobes.
o used primarily for bactericidal activity against Clostridium difficile
o unique target site; no cross resistance has been reported
o minimal systemic absorption and primarily remains in the GIT
o Most common adverse effects: nausea, vomiting and abdominal pain; infrequent --- anemia
and neutropenia
→
o Hypersensitivity reactions: angioedema, dyspnea and pruritus’
o Used with caution on patients with macrolide allergy.
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LINCOSAMIDES
1. Clindamycin
• Mechanism of action similar to macrolides
• Bind to the 50S subunit this inhibiting translocation .
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-
• Available in IV and oral formulations; use of oral clindamycin is limited to GI tolerance
• Distributes well into all body fluids; poor entry into CSF
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• Undergo extensive oxidative metabolism to active and inactive products – excreted into
bile and urine
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• Low urinary excretion of the drug limits its use for UTI.
• Accumulation of drug occurs with severe hepatic or renal dysfunction.
• Most common adverse effect: skin rash and diarrhea – pseudomembranous colitis caused
by overgrowth of Clostridium difficile
• DOC for Clostridium difficile: Metronidazole or Vancomycin
OXAZOLIDINONES
• Bind the 23S ribosomal RNA of the 50S subunit preventing formation of the 70S initiation
complex and translation of bacterial proteins.
• synthetic oxazolidinones developed to combat gram positive organisms, staphylococci,
streptococci, and enterococci, Corynebacterium species and Listeria monocytogenes-----
including resistant isolates: MRSA, VRE, and penicillin-resistant streptococci.
• moderately active against Mycobacterium tuberculosis
• main clinical use of linezolid and tedizolid is to treat infections caused by drug-resistant
Eof
gram-positive organisms.
•
=
Oxazolidinones are bacteriostatic drugs, not recommended as first line treatment for MRSA
bacteremia.
• Resistance: reduced binding at target site
• Reduced susceptibility and resistance have been reported in S. aureus and Enterococcus sp.
• No dose adjustments are required for either agent for renal or hepatic dysfunction.
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o Most common adverse effects: GI upset, nausea, diarrhea, headache and rash.
o Thrombocytopenia: patients taking the drug for more than 10 days.
o Linezolid and tedizolid: possess nonselective monoamine oxidase activity ---- lead to
serotonin syndrome
o Occur when taken with large quantities of tyramine-containing foods, SSRIs, or MAO
inhibitors.
o The condition is reversible when the drug is discontinued.
o Irreversible peripheral neuropathies and optic neuritis causing blindness: associated with
greater than 28 days of use.
o Limited utility for extended-duration treatment
OTHERS
1. Chloramphenicol (generic only)
LSL
o Binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis
at the peptidyl transferase reaction
Broad spectrum antibiotic; restricted use to life threatening infections for which no
On
o
alternatives exist.
o At high concentrations --- causes bone marrow toxicity
o The oral formulation of chloramphenicol was removed from the US market because of its
toxicity.
☒
o active against many types of microorganisms including: Chlamydia, Rickettsia,
Spirochetes, and anaerobes.
o primarily bacteriostatic, but it may exert bactericidal activity depending on the dose
and organism.
o Resistance: prescence of enzymes that inactivate chloramphenicol; decreased ability to
penetrate the organism; ribosomal binding site alterations
o Administered IV and widely distributed throughout the body
o Reaches therapeutic concentrations in the CSF
o Undergoes hepatic metabolism to inactive glucuronide -- secreted in the renal tubule
and eliminated in the urine
o Dose reduction for patients with cirrhosis.
o Chloramphenicol is secreted into breastmilk and should be avoided in breastfeeding
mothers.
Adverse Effects of Chloramphenicol:
00
o Anemias
▪ Dose related anemia, hemolytic anemia (observed - in patients with G6PD) and
aplastic anemia (independent of dose and may occur after therapy has ceased).
o Gray Baby Syndrome
▪ Neonates have low capacity to glucuronidate the antibiotic and have
underdeveloped renal function --- decreases ability to excrete the drug
▪ Drug accumulation to concentrations that interfere with the function of
mitochondrial ribosomes
▪ Causes: poor feeding, depressed breathing, cardiovascular collapse, cyanosis
(“gray baby”), and death
▪ Adults who have received very high dosed of chloramphenicol may also exhibit
this toxicity.
Drug Interactions of Chloramphenicol
*
•
• I
Chloramphenicol inhibits some of the hepatic mixed-function oxidases
Preventing the metabolism of drugs such as: warfarin and phenytoin ---- potentiate their
effects.
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•
•
o
combination drug binds to a separate site on the 50S bacterial ribosome
-
Dalfopristin: disrupts elongation by interfering with the addition of new amino acids to
the peptide chain.
• Quinupristin: prevents elongation similar to the macrolides and causes release of
incomplete peptide chains.
• Synergistically interrupt protein synthesis
• Has a long Post antibiotic effect
• active primarily against gram-positive cocci, including those resistant to other
antibiotics.
• primary use: treatment of E. faecium infections, including VRE strains, against which it
is bacteriostatic.
• The drug is not effective against E. faecalis.
• Resistance:
o enzymatic processes – prescence of an enzyme that methylates the target bacterial
23S ribosomal RNA site which can interfere with Quinupristin binding.
o Plasmid associated acetyltransferase – inactivates Dalfopristin
o Efflux pump
• IV formulation – does not achieve therapeutic concentrations in the CSF
• Both undergo hepatic metabolism – excretion via feces
Adverse Effects of SYNERCID:
o Venous irritation --- occurs when drug is administered through a peripheral line rather than a
central line
o Hyperbilirubinemia --- 25% of patients; competition with the antibiotic for excretion
o Arthralgia and myalgia – higher doses
o Inhibit cytochrome P450 CYP3A4 --- drugs that are metabolized by this isoenzyme may lead to
toxicities.
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Mycobacterial Drugs
Lecturer: Dr. Amistad (09/15/2022)
• Latent tuberculosis infection (LTBI) --- treatment for 9 months with Isoniazid monotherapy
or 12 once weekly higher doses of INH and rifapentine.
• Active tuberculosis: multidrug therapy; 6 months for drug susceptible TB; 2 years for multidrug
resistant TB.
2mosi. nt#=00isonianid
• Standard short course chemotherapy for TB: ISONIAZID, RIFAMPIN, ETHAMBUTOL
AND PYRAZINAMIDE; duration: 2 months ---- INTENSIVE PHASE IPE
• " °
Followed by: ISONIAZID and RIFAMPIN; duration: 4 months ----- CONTINUATION PHASE
• Macrocyclic antibiotics, which are first line oral agents for TB.
1. Rifampin
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o Broader antimicrobial activity than INH – can be used as Tx of several different
bacterial infections (broad spectrum)
o Resistant strains rapidly emerge in monotherapy --- never given as a single agent as
treatment of active TB
. o Mechanism of action: blocks RNA transcription by interacting with the β subunit of
mycobacterial DNA-dependent RNA polymerase.
o Antimicrobial spectrum: M. tuberculosis, NTM such as M. kansasii, M. avium complex
(MAC); effective against gram positive and gram-negative organisms; prophylaxis for
individuals exposed to meningitis caused by meningococci or H. influenzae; also,
highly active against M. leprae
refer
o Resistance: mutations in the affinity of the bacterial DNA-dependent RNA polymerase
1 gene for the drug.
o Rifampin can induce hepatic cytochrome P450 enzymes and transporters leading to
numerous drug interactions.
'
urine o Rifampin undergoes autoinduction, leading to a shortened elimination half-life over the
first 1 to 2 weeks of dosing.
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o Elimination of rifampin and its metabolites is primarily through the bile and into the
feces; a small percentage (1/3 of dose) is cleared in the urine
o Note: Urine, feces, and other secretions have an orange-red color, patients should be
forewarned. Tears may even stain soft contact lenses orange-red.
②
o Modest increase in the incidence of hepatic dysfunction when rifampin is coadministered
with isoniazid and pyrazinamide.
o When rifampin is dosed intermittently, especially with higher doses, a flu-like syndrome
Indheb
can: fever, chills, and myalgia, sometimes extending to acute renal failure, hemolytic
anemia, and shock.
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o Rifampin decreases the half-lives of coadministered drugs that are metabolized by
cytochrome P450 enzymes. to
o This may necessitate:
▪ higher dosages for coadministered drugs
▪ a switch to drugs less affected by rifampin
▪ replacement of rifampin with rifabutin.
2. Rifabutin
o derivative of rifampin
o preferred for TB patients coinfected with the
human immunodeficiency virus (HIV) who are
receiving protease inhibitors or several of
the nonnucleoside reverse transcriptase inhibitors.
o Rifabutin is a less potent inducer
(Approximately 40% less) of cytochrome P450 enzymes
o Adverse effects: uveitis, skin hyperpigmentation,
and neutropenia.
-1
3. Rifapentine ✗ week
o longer half-life than that of rifampin
o In combination with isoniazid, rifapentine
may be used once weekly in patients with LTBI and in select HIV-negative patients with
minimal pulmonary TB.
ISONIAZID (INH) inhibit my colic acid
• Along with Rifampin, one of the two most important TB drugs.
liver 1. Mechanism of Action
toxicity ! o Prodrug
o Target enzymes: acyl carrier protein reductase (InhA) and beta ketoacyl synthase (KasA)
Vitamin o Enzymes are essential for synthesis of mycolic acid
o Inhibition of mycolic acid leads to disruption in the mycobacterial cell wall.
Bunting
2. Antibacterial spectrum
o Specific for treatment of M. tuberculosis (narrow spectrum)
o M. kansasii is susceptible at higher concentrations
Kenji;Ypam)
o Most NTM are resistant to INH
o Effective against rapidly growing bacilli and intracellular organisms.
3. Resistance
o Chromosomal mutations: mutation or deletion of KatG (incapable of prodrug
activation); mutations of acyl carrier proteins; overexpression of target enzyme InhA
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o Cross resistance between: Isoniazid and Ethionamide
4. Pharmacokinetics
o Readily absorbed after oral administration
o INH absorption impaired when taken with food – especially high fat meals
o Diffusion into all body fluids, cells and caseous material.
o Drug concentration in CSF and serum is similar.
o INH undergoes: N- acetylation and hydrolysis – result to inactive products
o Excretion through glomerular filtration – secretion is metabolites (fast acetylators)
o Excretion of parent compound – slow acetylators
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Pyrazinamide
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• synthetic, orally effective short-course agent used in combination with isoniazid, rifampin, and
ethambutol.
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• must be enzymatically hydrolyzed by pyrazinamidase to pyrazinoic acid, which is the active
form of the drug.
• Some resistant strains lack the pyrazinamidase enzyme.
• Active against tuberculosis bacilli in acidic lesions and in macrophages.
repaint •
•
distributes throughout the body, penetrating the CSF
Pyrazinamide contributes to liver toxicity.
• Uric acid retention is common, rarely precipitates a gouty attack.
• Most of the clinical benefit from pyrazinamide occurs early in treatment. Drug is usually
discontinued after 2 months of a 6-month regimen. optic oath -
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• Uric acid excretion is decreased by ethambutol, and caution should be exercised in patients
with gout.
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2. AMINOSALICYLIC ACID
• Para-amino salicylic acid (PAS) works via folic acid inhibition.
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• Replaced by ethambutol for drug susceptible TB
• PAS remains an important component of many regimens for MDR-TB.
/
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• a diarylquinoline, an ATP synthase inhibitor
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• approved for the treatment of MDR-TB.
• PO and active against many types of mycobacteria.
pay
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QT • Boxed warning for QT prolongation, and monitoring of the electrocardiogram is
recommended.
• Elevations in liver enzymes have also been reported and liver function should be
monitored during therapy.
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and cardio they
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foputrtooi
• metabolized via CYP3A4, and administration with strong CYP3A4 inducers (for
example, rifampin) should be avoided
4. CAPREOMYCIN
• parenterally administered polypeptide that inhibits protein synthesis similar to
aminoglycosides.
• primarily reserved for the treatment of MDR-TB.
• Careful monitoring of renal function and hearing ----- minimize nephrotoxicity and
ototoxicity
5. CYCLOSERINE
• orally effective, tuberculostatic drug
• Mechanism of action: disrupts D-alanine incorporation into the bacterial cell wall.
• distributes well throughout body fluids, including the CSF
• primarily excreted unchanged in urine.
• accumulation occurs with renal insufficiency
• Adverse effects: CNS disturbances (for example, lethargy, difficulty concentrating,
anxiety, and suicidal tendency), and seizures may occur.
6. ETHIONAMIDE
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• structural analog of isoniazid that also disrupts mycolic acid synthesis.
• widely distributed throughout the body, including the CSF.
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• Metabolism is extensive, most likely in the liver, to active and inactive metabolites.
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• Adverse effects that limit its use include: nausea, vomiting, and hepatotoxicity.
• Other adverse effects: Hypothyroidism, gynecomastia, alopecia, impotence, and CNS
effects also have been reported.
②②
7. FLUROQUINOLONES
• moxifloxacin and levofloxacin, treatment of multidrug-resistant tuberculosis.
M
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-
hyp 8. MACROLIDES
• azithromycin and clarithromycin are included in regimens for several NTM infections,
including MAC.
• Azithromycin may be preferred for patients at greater risk for drug interactions
↳
• Clarithromycin is both a substrate and inhibitor of cytochrome P450 enzymes.
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DRUGS USED TO TREAT LEPROSY (HANSEN’S DISEASE)
bacteriostatic pomatum
1. DAPSONE
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• structurally related to the sulfonamides
• inhibits dihydropteroate synthase in the folate synthesis pathway.
• bacteriostatic for M. leprae
• used in the treatment of pneumonia caused by Pneumocystis jirovecchi in
immunosuppressed patients
• well absorbed from the gastrointestinal tract and is distributed throughout the body
• high concentrations in the skin
• parent drug undergoes hepatic acetylation
• Both parent drug and metabolites are eliminated in the urine.
• Adverse reactions: hemolysis (especially in patients with glucose-6-phosphate
dehydrogenase deficiency), methemoglobinemia, and peripheral neuropathy.
bactericidal
2. CLOFAZIMINE
/
• a phenazine dye; mechanism of action may involve binding to DNA
• redox properties may lead to the generation of cytotoxic oxygen radicals that are toxic to the
bacteria.
• bactericidal to M. leprae, and it has potentially useful activity against M. tuberculosis and
NTM.
• drug is recommended by the World Health Organization as part of a shorter regimen (9 to 12
months) for MDR-TB
• Following oral absorption, clofazimine accumulates in tissues, allowing intermittent
piy%i
therapy but does not enter the CNS.
• Patients typically develop a pink to brownish-black discoloration of the skin and should
be informed of this in advance.
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• Eosinophilic and other forms of enteritis, sometimes requiring surgery, have been reported.
• Clofazimine has some anti-inflammatory and anti-immune activities.
• Erythema nodosum leprosum may not develop in patients treated with this drug.
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Antiarrhythmic Mechanism of Action Comment
Classification
CLASS I DPQ
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• bind more rapidly to open or inactivated sodium channels than to channels that are fully
repolarized.
• Drugs show greater degree of blockade in tissues that are frequently depolarizing. Risk:
• Use dependence or state dependence
• Enables drugs to block cells that are discharging at an abnormally high frequency without to
interfering with the normal beating of the heart. potential
• Use has declined due to proarrhythmic effects --- patients with reduced LV function and
atherosclerotic disease (contraindication)
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• well absorbed PO and extensive metabolism by CYP3A4 forming fewer active metabolites and
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several inactive metabolites; half of drug excreted by kidneys
• Anticholinergic side effects: dry mouth, urinary retention, blurred vision and constipation
Procainamide
• Similar to Quinidine
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• Less anticholinergic activity
• No alpha-adrenergic blocking activity
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• Only available IV formulation =
• Indication: acute atrial and ventricular arrythmias
• Has been replaced in clinical practice by: electrical cardioversion or defibrillation and
amiodarone
• Portion is acetylated in the liver to N- acetyl procainamide (NAPA); eliminated by kidneys
• Dosage adjustment for renal dysfunction
• IV admin. may cause hypotension
Quinidine - prototype Class IA drug
• Bind to open and inactivated sodium channels and prevents sodium influx, slowing the rapid
upstroke during phase 0.
• Decreases the slope of phase 4 spontaneous depolarization, inhibit potassium channels and
blocks calcium channels (class III activity)
• Slows conduction velocity and increase refractoriness
• Mild alpha-adrenergic blocking and anticholinergic effects
• Indication: atrial, AV junctional and ventricular tachyarrhythmias
• Rapidly and well absorbed PO
• Extensive metabolism by CYP3A4 forming active metabolites
• Adverse effect: large doses induce CINCHONISM (blurred vision, tinnitus, headache,
disorientation and psychosis)
• Quinidine is a CYP2D6 and P- glycoprotein inhibitor --- drug interactions
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• Given IV because of extensive hepatic first pass effect
• Dealkylated to two active metabolites by CYP1A2 (major) and CYP3A4 (minor)
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• Monitor use when giving with drugs affecting CYP isoenzymes
• Wide therapeutic index
• CNS effects: nystagmus (early indicator of toxicity), drowsiness, slurred speech, paresthesia ,
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agitation, confusion and convulsions --- limit duration of continuous infusions
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Mexiletine
• Chronic treatment of ventricular arrhythmias
• Combination
- with Amiodarone
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• Well absorbed after PO
• Metabolized by CYP2D6 in liver to active inactive metabolites
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• Excreted via biliary route
• Narrow therapeutic index; caution with drug inhibitors of CYP2D6
• Most common adverse effects: nausea, vomiting and dyspepsia
IC Na + channel blocker Markedly slows Phase 0 ventricular muscle fibers;
slow dissociation from resting sodium channels and show
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action potential and refractoriness
• Automaticity is reduced by an increase in the threshold potential, rather than a decrease in "
slope of phase 4 depolarization
• also blocks K+ channels, leading to increased duration of the action potential.
• maintenance of sinus rhythm in atrial flutter or fibrillation in patients without structural armb
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heart disease
• treatment of refractory ventricular arrhythmias
• well absorbed after oral administration and is metabolized by CYP2D6 to multiple
metabolites; renal elimination
• generally well tolerated, with blurred vision, dizziness, and nausea occurring most frequently
• should be used with caution with potent inhibitors of CYP2D6.
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Propafenone
-
• like flecainide, slows conduction in all cardiac tissues but does not block K+ channels
-
• possesses weak β-blocking properties.
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•
•
-
restricted mostly to atrial arrhythmias: rhythm control of atrial fibrillation or flutter and
paroxysmal supraventricular tachycardia prophylaxis in patients with AV reentrant
tachycardias.
• metabolized to active metabolites primarily via CYP2D6, and also by CYP1A2 and CYP3A4.
• The metabolites are excreted in the urine and the feces.
• may cause bronchospasm and should be avoided in patients with asthma.
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• Instead, they prolong the effective refractory period, increasing refractoriness.
• All class III drugs have the potential to induce arrhythmias.
• can widen QT interval ( along with macrolide antibiotics and antipsychotics)
III K+ channel blocker Prolongs phase 3 repolarization in ventricular muscle
fibers
Amiodarone * dnt a. p =
+
• contains iodine and is related structurally to thyroxine.
• complex effects showing class I, II, III, and IV actions, as well as α-blocking activity.
• dominant effect is prolongation of the action potential duration and the refractory period
by blocking K+ channels.
• treatment of severe refractory supraventricular and ventricular tachyarrhythmias.
• mainstay of therapy for the rhythm management of atrial fibrillation or flutter.
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• Despite its adverse effect profile, amiodarone is thought to be the least proarrhythmic of the
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• drug interactions, since it is metabolized by CYP3A4
• serves as an inhibitor of CYP1A2, CYP2C9, CYP2D6, and P - glycoprotein.
Dronedarone
• benzofuran amiodarone derivative, which is less lipophilic and has a shorter half-life than
amiodarone. -
• does not have the iodine moieties that are responsible for thyroid dysfunction
-
• Like amiodarone, it has class I, II, III, and IV actions.
• Dronedarone has a better adverse effect profile than does amiodarone but may still cause liver
-
failure.
=-
• contraindicated in those with symptomatic heart failure or permanent atrial fibrillation due
to an increased risk of death.
-
• used to maintain sinus rhythm in atrial fibrillation or flutter, but it is less effective than
attributing
amiodarone.
Sotalol ,
• also has nonselective β-blocker activity.
• blocks a rapid outward K+ current, known as the delayed rectifier current.
• blockade prolongs both repolarization and duration of the action potential, thus lengthening the
effective refractory period.
• Used for maintenance of sinus rhythm in patients with atrial fibrillation, atrial flutter, or
refractory paroxysmal supraventricular tachycardia
• treatment of ventricular arrhythmias.
• Since sotalol has β-blocking properties, it is commonly used for these indications in patients
with left ventricular hypertrophy or atherosclerotic heart disease.
• typical adverse effects associated with β-blockers
• low rate of adverse effects when compared to other antiarrhythmic agents.
• dosing interval should be extended in patients with renal disease, since the drug is renally
eliminated.
• To reduce the risk of proarrhythmic effects, sotalol should be initiated in the hospital to
monitor QT interval.
Dofetilide
• pure K+ channel blocker.
y
• can be used as a first-line antiarrhythmic agent in patients with persistent atrial fibrillation
and heart failure or in those with coronary artery disease.
• Dofetilide initiation is limited to the inpatient setting because of the risk of arrhythmia most
• The half-life of this oral drug is 10 hours.
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• mainly excreted unchanged in the urine.
• [Contraindication] Drugs that inhibit active tubular secretion are contraindicated with
Dofetilide.
Ibutilide
• a K+ channel blocker that also activates the inward Na+ current (mixed class III and IA
o
actions).
-
• drug of choice for chemical conversion of atrial flutter, but electrical cardioversion has
supplanted its use.
÷-
• undergoes extensive first-pass metabolism and is not used orally.
• Initiation is also limited to the inpatient setting due to the risk of arrhythmia.
Class IV
• dihydropyridine Ca2+ channel blockers verapamil and diltiazem
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• the major effect of Ca2+ channel blockers is on vascular smooth muscle and the heart.
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• Both drugs show greater action on the heart than on vascular smooth muscle, but more so with
verapamil.
• verapamil and diltiazem bind only to open depolarized voltage-sensitive channels, thus
decreasing the inward current carried by Ca2+.
• use dependent in that they prevent repolarization until the drug dissociates from the
channel, resulting in a decreased rate of phase 4 spontaneous depolarization.
• slow conduction in tissues that are dependent on Ca2+ currents, such as the AV and SA
nodes
• more effective against atrial than against ventricular arrhythmias
• useful in treating reentrant supraventricular tachycardia and in reducing the ventricular
rate in atrial flutter and fibrillation.
• Common adverse effects: bradycardia, hypotension, and peripheral edema.
• Both drugs are metabolized in the liver by CYP3A4.
• Dosage adjustments may be needed in patients with hepatic dysfunction.
-0• CYP3A4 inhibitors, as well as substrates and inhibitors of P- glycoprotein ---- drug interaction
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IV Ca2+ channel blocker Inhibits action potential in SA and AV nodes
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DIGOXIN
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• inhibits the Na+/K+-ATPase pump, ultimately shortening the refractory period in
.
atrial and ventricular myocardial cells while prolonging the effective refractory period
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and diminishing conduction velocity in the AV node.
• used to control ventricular response rate in atrial fibrillation and flutter
• however, sympathetic stimulation easily overcomes the inhibitory effects of digoxin
ji • At toxic concentrations, digoxin causes ectopic ventricular beats that may result in
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VT and fibrillation
• Serum trough concentrations of 1.0 to 2.0 ng/mL are desirable for atrial fibrillation
or flutter
• lower concentrations of 0.5 to 0.8 ng/mL are targeted for systolic heart failure.
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ADENOSINE
• naturally occurring nucleoside
• at high doses, the drug decreases conduction velocity, prolongs the refractory
period, and decreases automaticity in the AV node.
acut
• Intravenous adenosine is the drug of choice for converting acute supraventricular
tachycardias.
• low toxicity but causes flushing, chest pain, and hypotension.
• extremely short duration of action (approximately 10 to 15 seconds) due to rapid
uptake by erythrocytes and endothelial cells.
RANOLAZINE
• antianginal drug with antiarrhythmic properties similar to amiodarone.
• main effect is to shorten repolarization and decrease the action potential duration
similar to mexiletine.
• treat refractory atrial and ventricular arrhythmias, often in combination with other
antiarrhythmic drugs.
• Well tolerated with dizziness and constipation as the most common adverse effects.
• Extensively metabolized in the liver by CYP3A and CYP2D6 isoenzymes
• mainly excreted by the kidney.
• Concomitant use with strong CYP3A inducers or inhibitors is contraindicated.
Reference: Katzung Basic Clinical Pharmacology 14th ED
• Rare serious toxicities: neutropenia, anemia, hemolysis, elevated; liver enzymes and allergic reactions.
• Delayed hemolysis 2 -3 weeks after therapy is common in severe malaria.
• 1st trimester WHO recommendation: QUININE + CLINDAMYCIN
• 2nd and 3rd trimester WHO recommendation: Artemisin based combinations.
• IV artesunate: treatment of severe malaria during all stages of pregnancy.
QUININE AND QUINIDINE (Class: Quinoline methanol)
• Important therapies for severe falciparum malaria; toxicity may complicate therapy
• Derived from the bark of cinchona tree traditionally a remedy for intermittent fevers from South America.
• QUININE – PO and IV; rapidly absorbed; reaches peak plasma levels in 1 – 3 hours; increased protein binding; half-
life 18 hours in severe malaria
• QUINIDINE – IV; shorter half-life; decreased protein binding
• Use of loading dose in severe malaria allows the achievement of peak levels.
• Rapidly acting highly effective blood schizonticide vs 4 species of human malaria parasites.
• Gametocidal vs P. vivax and P. ovale, but not P. falciparum
• Not active against liver stage parasites.
• Resistance high in South East Asia, especially border areas of Thailand where failure is common if used alone to
treat falciparum malaria.
• IV Quinidine – cardiac toxicity; administer slowly
• Quinine dihydrochloride or Quinidine gluconate - parenteral treatment of severe falciparum malaria
• Quinine sulfate – oral treatment of falciparum malaria; uncomplicated cases except when infection was transmitted in
an area without document chloroquine resistance.
•
Quinine is commonly used with a 2nd drug to shorten duration of use. (Adults: Doxycycline; Children:
Clindamycin)
• Quinine is not generally used to treat nonfalciparum malaria.
• Malaria chemoprophylaxis: not generally used due to its toxicity; 325 mg is effective
• Babesiosis: Quinine is 1st line therapy in combination with Clindamycin.
• Adverse Effects: CINCHONISM --- constellation of symptoms that include; tinnitus, headache, nausea, dizziness,
flushing and visual disturbances.
• Do not discontinue if symptoms are mild.
• Severe findings: visual and auditory abnormalities, vomiting, diarrhea and abdominal pain.
• Hypersensitivity reactions: skin rashes, urticaria, angioedema, bronchospasm
• Hematologic abnormalities: hemolysis (G6PD deficiency), leukopenia, agranulocytosis and thrombocytopenia.
• Therapeutic doses may case hypoglycemia – problem for severe infections and in pregnant patients.
• Quinine can stimulate uterine contraction in the 3rd trimester (mild); can still be used for severe falciparum malaria
infection during pregnancy.
• IV infusions may cause thrombophlebitis.
• Too rapid infusion = severe hypotension
• ECG abnormalities = QT interval prolongation; common with IV Quinidine; dangerous arrythmias are uncommon when
the drug is administered and monitored appropriately.
• BLACKWATER FEVER: rare severe illness thought to be a hypersensitivity reaction that includes marked hemolysis
+ hemoglobinuria in the setting of quinine therapy.
• DISCONTINUE if: severe cinchonism, hemolysis, hypersensitivity
• Use with CAUTION: underlying visual or auditory problems and cardiac abnormalities
• DO NOT GIVE QUININE CINCORRENTLY WITH MEFLOQUINE. Use with caution if patient has exposure to
mefloquine.
• Absorption may be blocked by aluminum containing antacids.
• Quinine can raise plasma levels of WARFARIN and DIGOXIN.
MEFLOQUINE (Class: Quinoline methanol)
• Effective therapy for chloroquine resistant strains of P. falciparum
• Toxicity is a concern
• Recommended chemoprophylactic drugs for use in most malaria endemic regions with chloroquine resistant strains.
• Chemically related to quinine
• Only given orally because severe local irritation occurs with parenteral use.
• Peak plasma concentrations 18 hours
• High protein bound and extensively distributed to tissues and slowly eliminated --- allow single dose regimen
• Terminal elimination half-life: 20 days --- allow weekly dosing for chemoprophylaxis
• Excreted mainly in the feces
• Strong blood schizonticidal ability against P. falciparum and P. vivax
• Not active against hepatic stages or gametocytes.
• Uncommon resistance except in regions in South East Asia.
• Mefloquine resistance is not related to chloroquine resistance.
• Chemoprophylaxis, except for: areas with no chloroquine resistance and in rural areas of South East Asia where there
is resistance to mefloquine.
• Eradication of P. vivax and P. ovale: require Primaquine
• Treatment: uncomplicated falciparum malaria; not appropriate for complicated or severe malaria ---- give: Quinine,
Quinidine or Artemisins
• BLACK BOX WARNING: potential neurologic and psychiatric toxicities
• Can also alter cardiac conduction – arrythmias and bradycardia
• CONTRAINDICATION: epilepsy, psychiatric disorders, arrythmias or cardiac conduction defects.
• DO NOT GIVE OR CO ADMINISTER WITH QUININE, QUINIDINE, HALOFANTRINE
• Not advised to give to patients receiving B- adrenoreceptor therapy.
• Mefloquine is safe in young children and it is the only chemoprophylactic drug other than chloroquine approved for
children weighing less than 5 kg.
• Older recommendation to avoid mefloquine is aimed at those requiring fine motor skills like airline pilots.
• DISCONTINUE: appearance of neuropsychiatric symptoms.
PRIMAQUINE (Class: 8 - Aminoquinoline)
• DOC for the eradication of dormant liver forms of P. vivax and P. ovale
• Peak plasma levels 1- 2 hours
• Plasma half-life 3 – 8 hours
• Active against hepatic stages of all human malarial parasites
• Only available agent against against hypnozoites of P. vivax and P. ovale
• Gametocidal against 4 human malaria species
• Weak activity against erythrocytic stage parasites
• Clinical use: Radical cure for acute vivax and ovale malaria
• Standard therapy for vivax and ovale malaria is CHLOROQUINE to eradicate erythrocytic forms and
PRIMAQUINE to eradicate liver hypnozoites.
• PREVENT RELAPSE
• Primaquine is withheld until G6PD status is known.
• Primaquine most effective when instituted before completion of dosing with Chloroquine.
• TERMINAL PROHYLAXIS of vivax and ovale malaria
• Chemoprophylaxis of malaria: 30 mg (0.5 mg/kg) of primaquine daily
• Gametocidal – used to decrease transmission
• PNEUMOCYSTIS JIROVECI INFECTION – Primaquine + Clindamycin; mild to moderate disease
• Standard dose of Primaquine may cause hemolysis or methemoglobinemia (manifests as cyanosis) in persons with
G6PD deficiency or other hereditary metabolic defects.
• Contraindications: history of granulocytopenia or methemoglobinemia, myelosuppressive drugs like quinidine and
those with myelosuppressive conditions.
• G6PD deficient individuals of Mediterranean and Asian ancestry – severe deficiency
• Primaquine should be avoided in pregnancy because the fetus is relatively G6PD deficient and is at risk for hemolysis.
• DISCONTINUE: hemolysis or anemia
ATOVAQUONE (Class: Hydroxynaphthoquinone)
• Component of Malarone – recommended for treatment and prevention of malaria – fixed combination of
Atovaquone ( 250 mg) and Proguanil ( 100 mg )
• Malarone is a quinone -folate antagonist
• Also approved for treatment of mild to moderate pneumocystis jirovecchi pneumonia.
• Efficacy is lower than Trimethoprim – Sulfamethoxazole.
• Standard dosing: 750 mg taken with food twice daily for 21 days.
• Only administered orally with bioavailability low and erratic.
• Absorption increased by fatty food; should be taken with food
• Heavily protein bound with half-life 2 – 3 days
• Eliminated unchanged in the feces
• MOA: acts against plasmodia by disrupting mitochondrial electron transport; active against tissue and erythrocytic
schizonts
• Chemoprophylaxis discontinued only 1 week after the end of exposure (vs. 4 weeks for mefloquine and
doxycycline, which lack activity against tissue schizonts)
• For chemoprophylaxis Malarone is taken daily.
• Advantage vs Mefloquine and Doxycycline: require shorter period of treatment before and after the period at risk for
malarial transmission.
• Disadvantage: expensive
• Safety in pregnancy is unknown.
• Safe for use in children with body weight above 5 kg.
• Plasma concentrations of atovaquone are decreased 50% by co administration of TETRACYCLINE of
RIFAMPIN.
Inhibitors of Folate Synthesis
• Pyrimethamine (Class: 2, 4 – diaminopyrimidine) related to trimethoprim
• Peak plasma levels 2 – 6 hours after oral dose
• Bound to plasma proteins; half-life 3.5 days
• Can be give once a week.
• Extensively metabolized before excretion.
• Proguanil (Class: Biguanide derivative)
• Peak plasma levels 5 hours after oral dose.
• Elimination half-life: 16 hours.
• Administered daily for prophylaxis.
• Prodrug; its triazine metabolite, cycloguanil, is active
• FANSIDAR: Sulfadoxine + Pyrimethamine (25 mg per tablet)
• Peak plasma levels 2-8 hours
• Half-life of Sulfadoxine is 170 hours.
• Pyrimethamine and Proguanil act slowly against erythrocytic forms.
• Proguanil has activity against hepatic forms.
• Neither drug is adequately gametocidal or effective against hypnozoites of P. vivax or P. ovale.
• Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or
gametocytes.
• MOA of Pyrimethamine and Proguanil: inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for
synthesis of folate.
• MOA of Sulfonamides and Sulfones: inhibit dihydropteroate synthase
• Clinical Uses: Intermittent preventative therapy; Treatment of chloroquine resistant falciparum malaria
• Fansidar is no longer recommended therapy for malaria; and should not be used in severe malaria since it is slower
acting.
• TOXOPLASMOSIS - Pyrimethamine + Sulfadiazine is first line therapy; for immunocompromised a high dose
therapy is required followed by chronic suppressive therapy; Folinic acid is included to limit myelosuppression.
• PNEUMOCYSTOSIS – causative agent responds to antiprotozoals not antifungals; Trimethoprim +
Sulfamethoxazole is first line therapy and standard chemoprophylactic drug
• Metronidazole single dose 2g for Trichomoniasis; Tinidazole for Metronidazole resistant organisms.
• Common Adverse Effects: nausea, headache, dry mouth, metallic after taste in the mouth.
• Infrequent Adverse Effects: vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine,
vertigo, paresthesia, encephalopathy and neutropenia.
• Rare Effects: pancreatitis and severe CNS toxicity (ataxia, encephalopathy, seizures)
• Metronidazole as DISULFRAM LIKE EFFECT – nausea and vomiting can occur if alcohol is ingested during
therapy
• Use with CAUTION in patents with CNS disease
• Metronidazole potentiates effect of coumarin type anticoagulants.
• PHENYTOIN and PHENOPABRBITAL = accelerate elimination of Metronidazole.
• CIMETIDE = decrease plasma clearance of Metronidazole.
• LITHIUM TOXICITY can occur with concurrent administration with Metronidazole.
• Metronidazole and its metabolites are mutagenic in bacteria and tumorigenic in mice.
• Metronidazole is best avoided in pregnant or nursing women.
IODOQUINOL (Class: halogenated hydroxyquinoline)
• Effective luminal amebicide; effective against organisms in the bowel lumen but not against trophozoites.
• 90% of drug is retained in the intestine and excreted in feces.
• Remainder of 10% enters circulation and is excreted in urine as glucuronides.
• Half-life 11 – 14 days
• Infrequent adverse effects: diarrhea – stops after several days; anorexia, nausea, vomiting, abdominal pain, headache,
rash and pruritis
• Other halogenated hydroxyquinolines can produce severe neurotoxicity with prolonged use; but not Iodoquinol when
given in its recommended dosage.
• Taken with meals to minimize GI upset and irritation.
• Use with CAUTION in patients with: optic neuropathy, renal disease, thyroid disease, non-amebic hepatic disease
• DISCONTINUED when: persistent diarrhea or signs of IODINE TOXICITY (dermatitis, urticaria, pruritus, fever).
• CONATRINDICATED in patients with: IODINE INTOLERANCE
DILOXANIDE FUROATE (Class: dichloroacetamide derivative)
• effective luminal amebicide but not effective against trophozoites.
• In the gut, it is split into diloxanide and furoic acid
• 90% of diloxanide is absorbed and then conjugated to glucuronide then excreted in urine
• Unabsorbed diloxanide is the active anti amebic substance.
• Flatulence is a common side effect.
• Nausea and abdominal cramps are infrequent, while rashes are rare.
• Drug is not recommended in pregnancy.
PAROMOMYCIN SULFATE (Class: aminoglycoside antibiotic)
• Not significantly absorbed from the GI tract.
• Used as a luminal amebicide and has no effect on extraintestinal organisms
• Drug may accumulate with renal insufficiency.
• Similar efficacy and less toxicity to other luminal amebicides.
• Superior to diloxanide furoate in clearing asymptomatic infections
• Anti-amebic luminal agent of choice in the USA.
• Also used to treat visceral leishmaniasis.
• Adverse effects: occasional abdominal distress and diarrhea.
EMETINE AND DEHYDROEMETINE
• Emetine is an alkaloid derived from ipecac
• Effective against tissue trophozoites of E. histolytica.
• Limited use to severe amebiasis because of toxicity
• Given only when metronidazole cannot be used.
• Dehydroemetine is preferred because it has a better toxicity profile.
• Drugs should be used for the minimum period needed to relieve severe symptoms 3 – 5 days
• Administered Subq or IM in supervised setting.
• Adverse effects: mild when used for 3 -5 days; pain tenderness and sterile abscesses at injection site; diarrhea, nausea
and vomiting; muscle weakness and discomfort, minor ECG changes
• Serious toxicities: arrythmias, heart failure and hypotension
OTHER PROTOZOAL DRUGS
PENTAMIDINE (Class: aromatic diamidine)
• Activity against traypanosomatid protozoans and against P. jirovecchi
• Toxicity is significant.
• Only administered parenterally
• Leaves the circulation very rapidly bound avidly to tissues; initial half-life 6 hours
• Terminal elimination half-life 12 days.
• Only trace amounts appear in the CNS so it is not effective against CNS African trypanosomiasis.
• Can also be inhaled as a nebulized powder for prevention of pneumocystosis. (300 mg inhaled monthly)
• Immediate reactions: fever, rash, headache, paresthesia, neuropathies, renal abnormalities (proteinuria) , chronic
diarrhea, hemolytic anemia and agranulocytosis.
MELARSOPROL (Class: trivalent arsenical)
• First line therapy for advanced CNS East African trypanosomiasis.
• Second line therapy for advanced West African trypanosomiasis.
• After IV administration it is excreted rapidly but relevant concentrations accumulate in the CNS within 4 days.
• Administered in propylene glycol by slow IV infusion
• Melasorpol is extremely toxic.
• The use of such drug is justified only by the severity of advanced trypanosomiasis and the lack of available alternatives.
• Immediate adverse effects: fever, vomiting, abdominal pain and arthralgia.
• Most important toxicity: reactive encephalopathy, appears during 1st week of therapy (5-10% of patients) due to the
disruption of trypanosomes in the CNS.
• Coadministrations of corticosteroids = decrease likelihood of encephalopathy
• Consequences of encephalopathy: cerebral edema, seizures, coma, and death
• Other serious toxicities: renal disease, cardiac disease, hypersensitivity reactions.
• Dug resistance increasing in parts of Africa leading to decreased efficacy.
EFLORNITHINE (Class: difluoromethylornithine)
• Inhibitor of ornithine decarboxylase
• The only new drug registered to treat African sleeping sickness in the last half century.
• 1st line drug for advances West African trypanosomiasis.
• Not as effective in East African sleeping sickness.
• Elimination half-life 3 hours
• Appears to be as effective as Melarsoprol against advances T brucei gambiense (East African sleeping sickness)
• Efficacy against T. brucei rhodiense is limited by drug resistance.
• Less toxic effects compared to Melarsoprol
BENZNIDAZOLE (Class: nitroimidazole)
• Orally administered for treatment of American trypanosomiasis (Chagas Disease)
• Improved efficacy and safety compared to Nifurtimox.
• Eliminate parasites and prevent progression when used to treat acute infection
• Activity against chronic Chagas disease is suboptimal.
• Treatment of Chagas cardiomyopathy with Benznidazole did not offer clinical benefit.
• Important toxicities (reversible): rash (20 – 30%), peripheral neuropathy, GI symptoms, myelosuppression
NIFURTIMOX (Class: nitrofuran)
• Standard drug for Chagas Disease
• Nifurtimox + Eflornithine = treatment for West African trypanosomiasis.
• Plasma half-life 3 hours
• Toxicity is common ---nausea, vomiting, abdominal pain, fever, rash, headache, restlessness, insomnia, neuropathies
and seizures
• Effects are reversible but often lead to cessation of therapy before completing of standard course.
AMPHOTERICIN (Class: antifungal)
• Alternative therapy for visceral leishmaniasis, especially in parts of India with high level resistance to sodium
stibogluconate
• Efficacy is lower in Africa
• Non liposomal amphotericin is more toxic, less expensive, also efficacious and widely used in India.
• Use of amphotericin in developing counties is limited by difficulty of administration, cost and toxicity.
MILTEFOSINE (Class: alkyl phosphocholine)
• The first effective oral drug for visceral leishmaniasis.
• Excellent efficacy in India
• Also effective for the treatment of New World leishmaniasis
• Vomiting and diarrhea are common but generally short-lived toxicities.
• Transient elevations in liver enzymes and nephrotoxicity is also seen.
• The drug is TERATOGENIC; should be avoided in pregnancy or in women who may become pregnant within 2
months of treatment.
• May become treatment of choice due to limitation of other drugs – parenteral administration, toxicity and resistance.
PAROMOMYCIN (Class: aminoglycoside antibiotic)
• Also used in parasitology for oral therapy of intestinal parasitic infections.
• Less expensive than Amphotericin or Miltefosine
• Effective in India for the treatment of visceral Leishmaniasis
• Cure rate is significantly inferior to sodium stibogluconate
• Mild injection pain, uncommon ototoxicity, no nephrotoxicity
• Good efficacy for topical administration and can be used for cutaneous Leishmaniasis.
NITROGEN OXIDES (14% air pollution): brownish irritant gas sometimes associated with fires; it is
formed from fresh silage; exposure of farmers to NO2 in the confines of a silo can lead to “silo-filler’s
disease “, a severe and potentially lethal form of acute respiratory distress syndrome.
1. Mechanism of Action
o NO2 is a relatively insoluble deep lung irritant that is capable of producing pulmonary
edema and ARDS. Inhalation damages lung infrastructure that produces the surfactant
necessary to allow smooth and low effort lung alveolar expansion.
o At acute and mild exposure: type I cells are chiefly affected. Acute period of severe
distress ensues that is treated with modern ventilation equipment and ventilations.
Some patients develop “twitchy airway disease”.
o Higher exposure: affects both Type I and II alveolar cells; progressive fibrosis ensues
that leads to permanent restrictive respiratory disease.
o Exposure to 25ppm of NO2: irritating to some individuals
o Exposure to 50ppm of NO2: irritating to the eyes and nose
o Exposure to 50ppm of NO2 for 1 hour: pulmonary edema and possible subacute or
chronic pulmonary lesions.
o Exposure to 100ppm of NO2: pulmonary edema and death
2. Clinical Effects
o S/sx: irritation of the eyes nose, cough, mucoid or frothy sputum production, dyspnea
and chest pain
o Pulmonary edema may occur after 1 -2 hours.
o Clinical signs may subside in about 2 weeks then pass to a second stage of abruptly
increasing severity.
o 2nd stage: pulmonary edema and fibrotic destruction of terminal bronchioles
(“bronchiolitis obliterans”)
3. Treatment
o No specific treatment for acute intoxication by NO2
o Therapeutic measure for the management of deep lung irritation and non-cardiogenic
pulmonary edema are used.
o Maintenance of gas exchange with adequate oxygenation and alveolar ventilation.
o Drug therapy: bronchodilators, sedatives and antibiotics.
OZONE AND OTHER OXIDES (4% air pollution): bluish irritant gas found in the Earth’s
atmosphere, where it is an important absorbent of ultraviolet light at high altitude. At ground level,
ozone is an important pollutant. Nitrogen oxides are emitted from power plants, motor vehicles and
other sources of high heat combustion.
1. Mechanism of Action: Ozone is an irritant of mucous membranes. Mild exposure produces
upper respiratory tract irritation. Severe exposure can cause deep lung irritation with
pulmonary edema. O3 toxicity resemble those seen in radiation – formation of reactive free
radicals. Airway hyperresponsiveness and airway inflammation observed.
2. Clinical Effects:
o Shallow rapid breathing and a decrease in pulmonary compliance
o Enhanced sensitivity of the lung to bronchoconstrictors.
o Exposure around 0.1 ppm of O3 for 10 – 30 minutes: irritation and dryness of the
throat.
o Exposure around above 0.1 ppm of O3: changes in visual acuity, substernal pain and
dyspnea.
o Exposure above 0.8ppm = impairment of pulmonary function.
3. Treatment
o No specific treatment for acute intoxication by O3
o Therapeutic measure for the management of deep lung irritation and non-cardiogenic
pulmonary edema are used.
SOLVENTS
HALOGENATED ALIPHATIC HYDROCARBONS: wide use as industrial solvents, degreasing
agents and cleaning agents.; carbon tetrachloride chloroform, trichloroethylene, tetrachloroethylene.
1. Mechanism of Action and Clinical Effects:
o Neurotoxic – CNS depression with impaired memory and peripheral neuropathy.
o Hepatotoxic – common in chronic exposure
o Nephrotoxic – carbon tetrachloride, chloroform, trichlorethylene
o Cardiotoxic
o Known carcinogens – Trichloroethylene is a Class 1 carcinogen
Aromatic Hydrocarbons
1. Benzene: component of gasoline
o CNS depressant
o Exposure to 7500 ppm for 30 minutes can be fatal
o Exposure to greater than 3000 ppm may cause euphoria, nausea, locomotor problems
and coma.
o Expire of 250 – 500 ppm cam cause vertigo, drowsiness, headache and nausea.
o Chronic exposure = bone marrow injury; leukemia
o Potent “clastogen” = mutagen that acts by causing chromosomal breakage
2. Toluene
o CNS depressant and a skin and eye irritant
o Not myelotoxic
o Not associated with leukemia
o Exposure to 800ppm can lead to severe fatigue and ataxia
o Exposure to 10, 000 ppm can produce rapid loss consciousness.
3. Xylene: degreasing solvent; substitute for benzene
o CNS depressant and a skin irritant
o Not myelotoxic and not associated with leukemia
PESTICIDES
Organochlorine Pesticides
o DDT – used in domestic mosquito elimination in malaria infested areas.
o Known endocrine disrupters = postulated cause of carcinogenesis
o Cause severe environmental damage
1. Mechanism of Action: agents interfere with inactivation of the sodium channel in excitable
membranes and cause rapid repetitive firing in most neurons; calcium ion transport is inhibited;
affect repolarization and enhance excitability in neurons
2. Clinical Effects: CNS stimulation; Tremors (first manifestation) that progress to convulsions
with DDT
Organophosphate Pesticides
o Useful pesticides for direct contact with insects or for plant systemics
o Spread widely by wind and weather
o Absorbed by skin and in the respiratory and GI tracts
Carbamate Pesticides
o Also inhibit acetylcholinesterase
o Weak binding, disassociation occurs after minutes to hours and clinical effects are shorter
duration compared to organophosphates pesticides.
Botanical Pesticides
HERBICIDES
Chlorophenoxy Herbicides
Glyphosate
o Principle ingredient in Roundup, the most widely used herbicide in the world
o Involved in suicide involving pesticides
o Skin and eye irritant
o Causes mild to moderate esophageal erosion
Bipyridyl Herbicides
1. Paraquat
o Slowly accumulates in the lung b an active process and causes lung edema, alveolitis
and progressive fibrosis.
o MOA: involves single electron reduction of the herbicide to free radical species;
inhibits superoxide dismutase resulting in intracellular free radical oxygen toxicity.
o First s/sx: hematemesis and bloody stools
o Few days: respiratory distress and the development of congestive hemorrhagic
pulmonary edema.
o Adsorbents (activated charcoal) are given t bind Paraquat and minimize GI
absorptions.
o Antioxidants like acetylcysteine and salicylate are also beneficial to scavenge free
radicals.
ENVIRONMENTAL POLLUTANTS
Polychlorinated and Polybrominated Biphenyls (PCBs)
Perfluorinated Compounds
Endocrine Disruptors
Asbestos
METALS
Beryllium
Cadmium
Nanomaterials
DEFEROXAMINE
• isolated from Streptomyces pilosus.
• MOA: binds iron avidly but binds essential trace metals poorly; though competing for loosely
bound iron in iron carrying proteins (hemosiderin and ferritin), it fails to compete for
biologically chelated iron, as in microsomal and mitochondrial cytochromes and hemoproteins.
• Indication: parenteral chelator of choice for iron poisoning
• Deferoxamine + hemodialysis = treatment of aluminum toxicity in renal failure.
• administered intramuscularly or, preferably, intravenously
• Iron-chelator complex is excreted in the urine, often turning the urine an orange-red color.
• Rapid intravenous administration may result in hypotension.
• Pulmonary complications (eg, acute respiratory distress syndrome): Therapy longer than 24
hours
• Neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia
enterocolitica): long-term therapy of iron overload conditions (eg, thalassemia major).
DEFERASIROX AND DEFERIPRONE
• Deferasirox: tridentate chelator with a high affinity for iron and low affinity for other metals,
eg, zinc and copper.
• MOA: In the circulation, it binds iron, and the complex is excreted in the bile.
• Indication: oral treatment of iron overload caused by blood transfusions, a problem in the
treatment of thalassemia and myelodysplastic syndrome.
• Deferiprone – excreted via the kidney; second-line oral chelator for patients with trans
fusional iron overload due to thalassemia.
• Deferiprone appears to be relatively more efficient in decreasing cardiac iron but less
efficient in decreasing hepatic iron.
PRUSSIAN BLUE (FERRIC HEXACYANOFERRATE)
• is a hydrated crystalline compound in which Fe2+ and Fe3+ atoms are coordinated with
cyanide groups in a cubic lattice structure.
• Primarily by ion exchange, and secondarily by mechanical trapping or adsorption, the
compound has high affinity for certain univalent cations, particularly cesium and thallium.
• MOA: complexes it forms with cesium or thallium are nonabsorbable, oral administration
of the chelator diminishes intestinal absorption or interrupts enterohepatic and enteroenteric
circulation of these cations, thereby accelerating their elimination in the feces.
• use of Prussian blue has been associated with a decline in the biologic half-life of radioactive
cesium and thallium.
Quinolones, Folic Acid Antagonists and Urinary Tract Antiseptics (Dr. Pepito)
FLUOROQUINOLONES
1. What is the mechanism of action of Quinolones? Ans. Block bacterial DNA synthesis by
inhibiting bacterial topoisomerase enzymes.
2. Another name for Topoisomerase II? Ans. DNA gyrase
3. What bacterial enzyme that when inhibited prevents the relaxation of positively supercoiled DNA
that is required for normal transcription and replication? Ans. Topoisomerase II / DNA gyrase
4. What bacterial enzyme that when inhibited interferes with separation of replicated chromosomal
DNA into the respective daughter cells during cell division? Ans. Topoisomerase IV
5. Fluroquinolones target what bacterial enzyme in gram negative bacteria? Ans. DNA gyrase
6. Fluroquinolones target what bacterial enzyme in gram positive bacteria? Ans. Topoisomerase IV
7. Are Fluoroquinolones bactericidal or bacteriostatic? Ans. Fluoroquinolones are bactericidal and
their administration results to rapid bacterial cell death
8. What does it mean when fluoroquinolones exhibit area- under-the-curve / minimum inhibitory
concentration dependent killing? Ans. AUC/ MIC dependent killing means that the higher the
drug concentration relative to the MIC of the pathogen, the greater the rate and extent of
antimicrobial killing.
9. Modifications to the quinolone nucleus has what effect on antimicrobial spectrum of quinolones?
Ans. Improved topoisomerase inhibitory activity and facilitate bacterial cell wall penetration
10. Example of First-Generation Fluoroquinolone? Ans. Nalidixic Acid
11. What is the spectrum of activity of Nalidixic Acid (1 st Gen Quinolone)? Ans. Narrow spectrum
O
12. What organisms are susceptible against 1st generation fluroquinolones? Ans. Aerobic Gram-
-
cNo=
-
bM_
20. Delafloxacin and moxifloxacin have activity against which organisms? Ans. Bacteroides
fragilis, Prevotella spp., Mycobacteria spp while maintaining activity against Enterobacteria and
2-
Haemophilus influenza (BPMEH)
21. The drug of choice for postexposure prophylaxis and for treatment of anthrax?
Ans. Ciprofloxacin (2nd Gen)
22. Drugs that are prescribed and are effective in the treatment of uncomplicated and complicated
urinary tract infections? Ans. Ciprofloxacin (2nd Gen) and Levofloxacin (3rd Gen)
PHARMA RENAL ASSESSMENT NOTES - LUNOD
23. What is the drug of choice for anaerobic infections? Moxifloxacin (4th Gen)
24. Drugs that are often effective in treating respiratory infections due to their activity against S.
pneumonia? Ans. Levofloxacin (3rd Gen) and Moxifloxacin (4th Gen)
25. Why is Ciprofloxacin (2nd Gen) not the drug of choice for pneumonia or sinusitis? Ans. The drug
has weak activity against S. pneumonia which is a common causative agent for those conditions.
26. Highly efficacious in treating acute diarrheal illnesses due to enteric pathogens?
Dej
Ans. Ciprofloxacin (2nd Gen)
27. Drug indicated for traveler’s diarrhea, typhoid fever and anthrax? Ans. Ciprofloxacin
28. Ciprofloxacin is a second line agent for infections arising where? Ans. Intrabdominal, lung, skin
-000
or urine
29. Drug that has a similar activity to Ciprofloxacin and they are often interchanged when managing
gram negative bacilli, including P. aeruginosa? Ans. Levofloxacin (3rd Gen)
30. Has enhanced activity against S, pneumonia and is used in the therapy for community acquired
pneumonia? Ans. Levofloxacin
31. Levofloxacin is a second line agent for the treatment of infection with what organism? Ans. S.
maltophilia
32. Has enhanced activity against gram positive organisms (S. pneumonia), gram negative anaerobes
and Mycobacterium spp. Ans. Moxifloxacin (4th Gen) -
poor psmdc.mil Ca ,
33. Moxifloxacin can be used for CAP but not hospital acquired pneumonia, due to? Ans. The drug
has poor coverage against P. aeruginosa
y
34. Considered for mild to moderate intra-abdominal infections but should be avoided if patients
have fluoroquinolone exposure within the previous 3 months. Ans. Moxifloxacin
35. What organism has increasing resistance against Moxifloxacin? Ans. Bacteroides fragilis
€¥€
36. Moxifloxacin is a second line agent for the management of what infection? Ans. Tuberculosis
37. Drug is only available in oral formulation and is indicated for management of community
acquired respiratory infections? Ans. Gemifloxacin (4th Gen)
38. Improved activity against gram positive cocci, including MRSA and Enterococcus and is
available as IV or Oral formulation. Ans. Delafloxacin
39. Delafloxacin is an option for managing what kind of infections? Ans. Acute bacterial skin and
skin structure infections
←
40. Mutations in bacterial genes encoding DNA gyrase and topoisomerase IV result to? Ans. Alter
target site structure and reduce binding of fluroquinolones
Find
41. Limitation in drug access to topoisomerases and decreased drug accumulation is brought about
by? Ans. Reduction in outer membrane proteins and efflux pumps
42. 2 Fluoroquinolones that have a bioavailability that exceeds 90%? Ans. Levofloxacin and
Moxifloxacin
43. What drugs that when ingested with fluoroquinolones can decreased its absorption?
Ans. Sucralfate, aluminum or magnesium containing antacids or dietary supplements containing
iron or zinc, calcium and other divalent cations
44. Oral fluroquinolones should be taken how many hours before or after any products containing
00
divalent cations are to be ingested? 2 hours before or 4 hours after
45. Distribution and concentration of fluoroquinolones are high in which organs or fluids? Ans.
→
Bone, urine, kidney, prostatic tissue (not prostatic fluid) and lungs
✗ urine
g-
46. What fluoroquinolone is not distributed well to urine? Ans. Moxifloxacin
47. Fluoroquinolones can accumulate in macrophages and polymononuclear leukocytes that results in
activity against intracellular organisms such as?
Ans. Listeria, Chlamydia and Mycobacterium (LCM)
cabin ,
Mrn .
PHARMA RENAL ASSESSMENT NOTES - LUNOD
48. What is the primary excretion of Fluroquinolones? Ans. Renal excretion (dosage adjustments are
needed for renal dysfunction)
E-
49. Fluroquinolone that is metabolized primarily by liver and require no dose adjustment for renal
a-
impairment? Ans. Moxifloxacin
50. What are the boxed warnings for Fluroquinolones? Ans. Tendinitis, tendon rupture, peripheral
neuropathy and CNS effects
51. For patients taking fluroquinolones they must be reminded to use sunscreen and avoid excessive
exposure to UV light because? Ans. Fluoroquinolones can cause phototoxicity that results in
exaggerated sunburn reactions.
→
52. What adverse reactions are commonly reported with use of fluoroquinolones in pediatrics?
Ans. Arthralgia and arthritis
53. Use in the pediatric population should be limited only to distinct clinical scenarios such as?
Ans. Cystic fibrosis exacerbation
E- ←
54. Common adverse reactions that lead to discontinuation of fluroquinolones are? Ans. Nausea and
vomiting, headache and dizziness
55. Why are fluroquinolones avoided in patients predisposed to arrythmias? Ans. Fluoroquinolones
can prolong QT interval.
56. Ciprofloxacin inhibits which PY450 enzymes? Ans. 1A2 and 3A4
57. What medications will exhibit an increase in serum concentrations when administered with
Ciprofloxacin? Ans. Theophylline, Tizanidine, Warfarin, Ropinirole Duloxetine, Caffeine,
Sildenafil and Zolpidem
FOLATE ANTAGONISTS
1. Is a coenzyme essential in the synthesis of RNA, DNA and certain amino acids? Ans. Folic acid
2. What happens when there is absence of folate? Ans. Cells cannot grow or divide.
3. Humans use dietary folate to synthesize the critical folate derivative? Ans. Tetrahydro folic acid
4. What enzyme do microorganisms use to create dihydrofolic acid from precursor molecule p-
aminobenzoic acid (PABA)? Ans. Dihydropteroate synthetase
5. Drugs that considered synthetic analogs of PABA? Ans. Sulfonamides
6. What is the mechanism of actions of Sulfonamides? Ans. Sulfonamides compete with PABA to
inhibit dihydropteroate synthetase halt the formation of bacterial dihydrofolic acid.
7. Are sulfonamides and cotrimoxazole bactericidal or bacteriostatic? Ans. Bacteriostatic because
they do not actively kill the bacteria but rather target cellular process that inhibit bacterial growth
and survival.
8. What is the antimicrobial coverage of Sulfonamides? Ans. Gram negative and Gram positive,
(EHSSN) Enterobacteria, Haemophilus influenza, Streptococcus spp., Staphylococcus spp., and
Nocardia
9. Organism whose growth is stimulated by the administration of Sulfonamides? Ans. Rickettsia
spp.
10. Sulfa drugs have poor activity against? Ans. Anaerobic bacteria
11. What organism is intrinsically resistant to sulfonamide antibiotics? Ans. Pseudomonas aeruginosa
12. DOC and preferred treatment for toxoplasmosis? Ans. Sulfadiazine + Pyrimethamine
13. Acquired bacterial resistance to the sulfa drugs can arise from? Ans. Plasmid transfer or random
mutations
14. Resistance to sulfa drugs is brought about by? Ans. Altered dihydropteroate synthetase that
decreases cellular permeability to sulfa drugs and enhance production of natural substrate, PABA
PHARMA RENAL ASSESSMENT NOTES - LUNOD
15. If a patient is resistant to Sulfadiazine, can we still administer other agents in this drug class?
Ans. No. Organisms resistant to one member of the sulfa drug family are resistant to all.
16. What are the oral, absorbable Sulfa drugs? Ans. Sulfamethoxazole, Sulfadiazine, Sulfadoxine
17. Sulfa drug that is oral, nonabsorbable? Ans. Sulfasalazine
18. What are the topical sulfa drugs? Ans. Sodium sulfacetamide, Mafenide acetate, silver
sulfadiazine
19. First line therapy for treatment of acute toxoplasmosis? Ans. Sulfadiazine
20. Long-acting sulfonamide, that is coformulated with pyrimethamine (Fansidar)? Ans. Sulfadoxine
21. Used in ulcerative colitis, enteritis and other inflammatory bowel disease? Ans. Sulfasalazine
22. Ophthalmic solution or ointment effective in treatment of bacterial conjunctivitis and as
adjunctive therapy for trachoma? Ans. Sodium sulfacetamide
23. Used topically but can be absorbed from burn sites, this drug and its primary metabolite inhibit
carbonic anhydrase that can cause metabolic acidosis which limits its usefulness. Ans. Mafenide
acetate
24. Less toxic and preferred sulfonamide for prevention of infection of burn wounds. Ans. Silver
sulfadiazine
25. The acetylated product of sulfa drugs is devoid of antimicrobial activity but retains the toxic
potential to? Ans. Precipitate neutral or acidic pH that causes crystalluria / stone formation which
can potentially damage the kidney.
26. What is the most common adverse effect of Sulfa drugs? Ans. Crystalluria and Nephrotoxicity
27. Prevents development of nephrotoxicity when taking sulfa drugs by reducing the concentration of
drug promoting its ionization. Ans. Adequate hydration and alkalinization of urine
28. What are the 4 main adverse reactions of Sulfonamides? Ans. Crystalluria, Hypersensitivity,
Hemolytic Anemia and Kernicterus (CHHK)
29. Hypersensitivity reactions that occur with administration of Sulfonamides? Ans. Rashes
angioedema, Steven Johnson’s syndrome
30. Hemolytic anemia is encountered in patients with what underlying condition? G6PD deficiency
31. Fatal reactions from sulfa drugs have been reported associated with? Ans. Agranulocytosis,
aplastic anemia and other blood dyscrasias
32. Why does bilirubin associated brain damage occur in newborns whose mother took sulfa drugs
while pregnant? Ans. Sulfa drugs displace bilirubin from binding sites on serum albumin,
allowing bilirubin to pass into CNS because the blood brain barrier of the newborn is not fully
developed.
33. Sulfonamides displace what drug from its binding sites on serum albumin? Ans. Warfarin
34. Sulfonamide that potentiates the anticoagulant effect of warfarin due to inhibition of CYP2C9?
Ans. Sulfamethoxazole
35. Levels of this drug may rise through protein binding displacement when given with Sulfa drugs?
Ans. Methotrexate
36. Other CYP2C9 substrates that may have increased concentrations when give with sulfonamides?
Ans. Phenytoin
37. Due to danger of kernicterus sulfa drugs should be avoided in? Ans. Newborns and infants less
than 2 months of age and in pregnant women at term
38. Why should sulfonamides NOT be given to patients receiving Methenamine? Ans. Sulfonamides
can crystallize in the prescence of formaldehyde produced by Methenamine.
39. What enzyme is inhibited by Trimethoprim? Ans. Dihydrofolate reductase
40. Mechanism of action of Trimethoprim? Ans. Prevents microorganisms from converting
dihydrofolic acid to tetrahydro folic acid that interfere with normal bacterial cell functions.
PHARMA RENAL ASSESSMENT NOTES - LUNOD
41. The combination of Trimethoprim with which sulfonamide provides synergistic effect?
Ans. Sulfamethoxazole
42. Antibacterial spectrum of Trimethoprim is similar to? Ans. Sulfamethoxazole
43. How much more potent is Trimethoprim compared to sulfonamides? Ans. 20 to 50-fold more
potent
44. What are the indications of use for Trimethoprim? Ans. Urinary tract infections and bacterial
prostatitis
45. Preferred treatment for bacterial prostatitis? Ans. Fluroquinolones and Cotrimoxazole
46. What causes resistance in gram negative bacteria to trimethoprim? Ans. Prescence of an altered
dihydrofolate reductase that has lower affinity for trimethoprim
47. Trimethoprim is a weak bases and higher concentrations are achieved in relatively acidic fluids
such as? Ans Prostatic and vaginal fluids
48. Main adverse effect of Trimethoprim? Ans. Folic acid deficiency (megaloblastic anemia,
leukopenia and granulocytopenia)
49. Blood disorders caused by adverse reactions to Trimethoprim may be reversed with the
administration of? Ans. Leucovorin (Folinic acid)
50. What electrolyte increases with administration of Trimethoprim? Ans. Potassium. Trimethoprim
has potassium sparring effect and may cause hyperkalemia.
51. What is the mechanism of action of Cotrimoxazole? Ans. Inhibition of sequential steps in the
synthesis of tetrahydrofolate acid
52. What does Sulfamethoxazole contribute to the synergistic action of Cotrimoxazole?
Ans. Sulfamethoxazole inhibits incorporation of PABA into dihydrofolic acid precursors
53. What does Trimethoprim contribute to the synergistic action of Cotrimoxazole?
Ans. Prevents reduction of dihydrofolate to tetrahydrofolate.
54. Indications for Cotrimoxazole? Ans. UTI, Respiratory tract infections, Skin and Soft tissue
infections, Pneumocystis jirovecchi infection, Toxoplasmosis, Listeria monocytogenes and
Salmonella, MRSA
55. Cotrimoxazole is the drug of choice for infections caused by? Ans. Nocardia spp. and S.
maltophilia
56. Cotrimoxazole is indicated for treatment of respiratory infections because it is effective against?
Ans. Haemophilus influenzae
57. Most effective therapy for pneumocystis jirovecchi pneumonia, a common opportunistic infection
complicating AIDS? Ans. Cotrimoxazole
58. Prophylaxis with cotrimoxazole is recommended for HIV infected patients with a CD4 count of?
Ans. Less than 200 CD4 cells /mL
59. Effective in treating septicemia and meningitis caused by Listeria monocytogenes?
Ans. Cotrimoxazole and Ampicillin
60. Chronic urinary tract infections respond to? Ans. Cotrimoxazole
61. Useful in treatment of shigellosis and on typhoid salmonella and can also manage carriers os S.
typhi. Ans. Cotrimoxazole
62. What component of Cotrimoxazole concentrates in the relatively acidic milieu of prostatic fluids?
Ans. Trimethoprim
63. Cotrimoxazole is given intravenously for what indication? Ans. Severe pneumonia caused by
pneumocystis jirovecchi
64. The most common adverse reactions of Cotrimoxazole? Ans. Nausea and vomiting, skin rash,
hematologic toxicity and hyperkalemia
PHARMA RENAL ASSESSMENT NOTES - LUNOD
fulminant
19. Rare complications of nitrofurantoin therapy associated with prolonged exposure greater than 1
month include? Ans. Pulmonary fibrosis, neuropathy and autoimmune hepatitis
20. Patients with which underlying condition should not receive nitrofurantoin due to an increased
firm
"
-0
risk of adverse events. Ans. Patients with impaired renal function.