LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022

PHARMACOLOGY LECTURE 1 - Most weight between 100 – 1000

Date: August 10, 2022
Lecturer: Dr. Vince Edward C. Araneta, MD
Lecture Topic: Basic Principles of Pharmacology
Pharmacology – body of knowledge concerned with the
action of chemicals on biologic systems.
Medical Pharmacology – area of pharmacology,
concerned with the use of chemicals in the prevention,
diagnosis and treatment of disease in living organisms,
especially humans.
Toxicology- area of pharmacology, concerned with the
“undesirable effects” of chemicals on biologic systems.
Pharmacokinetics
- Smaller than MW 100 --- rarely sufficiently selective
in their actions
- Larger than MW 1000 --- poorly absorbed and
poorly metabolized
- MW 7 --- lithium
- MW 50, 000 --- thrombolytic enzymes, antibodies,
other proteins
4. Drug- Receptor bonds
- Strength of chemical bonds:
o Covalent bonds – very strong, result to
irreversible action
o Electrostatic bonds – somewhat weaker;
occur between a cation and an anion
o Hydrogen, Van der Waals, Hydrophobic
bonds – much weaker interactions

- Action of body to the drug Pharmacodynamic Principles

- Movements of drugs in the body
- Absorption, Distribution, Metabolism, Elimination a. RECEPTORS
- Specific molecules in biologic systems with which
Pharmacodynamics drugs interact to produce changes in the function of
the system
- Effects of the drug to the body - Most are large molecules that influence important
- Mechanism of action, therapeutic effect, toxic biochemical and physiological processes.
effect - Ligand Binding Characteristics:
- Receptor, receptor sites 1. Selective – so as to respond to the proper
- Inert binding sites chemical signal and not to meaningless ones.
The Nature of Drugs 2. Modifiable – so as to bring about functional
change
- Many drugs in nature are “alkaloids” --- molecules - AGONIST: ligand binding results to activation of the
that have a basic pH in solution as a result of amine receptor
groups in their structure - ANTAGONIST: ligand binding results to inhibition
- Many biologically important endogenous and - Some drugs mimic agonist molecules by inhibiting
exogenous drugs are” optically active --- contain metabolic enzymes (Example: acetylcholinesterase
one or more asymmetric centers; exist as inhibitors)
“enantiomers” - DOSE RESPONSE CURVES: quantification of the
- Enantiomers may be metabolized at different rates effects of drug-receptor binding and provide
in the body. information about the drug-receptor interaction.
- - A few drugs are enzymes themselves; they do not
1. Composition: act on endogenous receptors but on substrate
o Inorganic ions molecules (Example: thrombolytic enzymes,
o Nonpeptide organic molecules pancreatic enzymes)
o Small peptides and proteins
o Nucleic acids
o Lipids
o Carbohydrates

2. Source: plants or animals, but many are partially

synthetic
3. Size and Molecular Weight
Cheer up future doctor!!!!
LSL – SWU PHINMA BATCH MEDICO SANGUINE
B. RECEPTOR AND INERT BINDING SITES
- most ligand molecules are smaller than their
receptor molecules
RECEPTOR SITES / RECOGNITION SITES
- specific regions of receptor molecules that provide
local areas responsible for drug binding.
INERT BINDING SITES
- binding of drugs to some non-regulatory molecules
in the body without producing a discernable effect.
- Play an important role in buffering the
concentration of a drug because a drug that is
bound does not contribute directly to the
concentration gradient that drives diffusion.
- ALBUMIN, OROSOMUCOID (a1 – glycoprotein): are
two important plasma proteins with significant drug
binding capacity
Pharmacokinetic Principles
1.1 The Movement of Drugs in the Body
- To reach its receptors and bring about biologic
effect, a drug must travel from site of
administration (GI tract) ---- site of action (brain)
- - Transporter for xenobiotics --- cancer drugs
A. PERMEATION
o Movement of drug molecules into and
within the biologic environment
Aqueous diffusion
- Passive movement of molecules through the
water extracellular and intracellular spaces
- Governed by Fick’s Law
Cheer up future doctor!!!!
AUGUST 2022
- Membranes of most capillaries have small water
filled pores that permit this process
- Only molecules the size of small proteins can pass
between the blood and the extravascular space.
- Capillaries in the brain, testes and some organs
lack aqueous pores = tissues less exposed to
some drugs
Lipid diffusion
- Passive movement of molecules through
membranes and other lipid barriers.
- Governed by Fick’s Law
Transport by special carriers
- Drugs that do not readily diffuse through
membranes use special carriers
- Not governed by Fick’s Law
- Capacity limited
- After release amine neurotransmitters are
recycled into nerve endings by transport
molecules.
- Selective inhibitors for transporters = clinical
value
- Antidepressants = inhibit recycling of
neurotransmitters by blocking the transporters
Examples:
- Transporter for ions (Na+ /K+ ATPase)
- Transporter for neurotransmitters (serotonin,
norepinephrine)
- Transporter metabolites (glucose and amino
acids)
Endocytosis
1. Molecule binds to receptor on cell membrane
2. In folding of that area of the membrane
3. Internalization
4. Intracellular vesicle
5. Contents of vesicle released into cytoplasm
of cell.
- Substances to be transported must combine with
membrane receptor --- very selective
- Permits very large molecules (proteins), very lipid
insoluble molecules and smaller, polar
substances (Vit. B12 and iron) to cross cell
membranes
- Polar substances must combine with special
proteins and form complexes to enter the cell (vit
B12 with intrinsic factor, iron with transferrin)
LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
- Small intestine vs stomach --- absorption faster
from organs with large surface areas
- Lungs vs skin --- faster from organs with thin
Exocytosis membranes compared to thick barriers
- Reverse of endocytosis
- Expulsion of material that is membrane
encapsulated inside the cell from the cell.
- Most neurotransmitters are released via this C. WATER AND LIPID SOLUBILITY OF DRUGS
process. 1. Solubility
- Lipid solubility of a molecule is inversely
proportional to its charge.
Sample Question:
- Aqueous solubility of a drug is a function of the
electrostatic charge (degree of ionization, polarity)
of the molecule
- Water molecules behave as dipoles and are
attracted to “charged drug molecules” --- form an
aqueous shell around them
- Many drugs are weak acids or weak bases --- pH of
medium determines the fraction of molecules that
are charged (ionized) or uncharged (nonionized)

2. Ionization of weak acids and bases

Answer: C
Rationale:
- Endocytosis: important mechanism for transport of
very large molecules across membranes
- Aqueous diffusion is not involved in transport
across lipid barrier because it occurs through small
water pores.
- Lipid diffusion and special carrier transport are
common for smaller molecules
- Hydrolysis is not related to permeation; rather it is a Weak bases are “ionized” – more polar and more water
mechanism of drug metabolism soluble when “protonated”
Weak acids are not ionized --- less water soluble when
B. FICK’S LAW OF DIFFUSION “protonated”
- Predicts movement of molecules across a barrier.
- Predicts how rapidly a drug can reach the site of
action Henderson – Hessel Bach principle
- Concentration gradient (C1- C2), permeability
- Clinically important when it is necessary to estimate
coefficient for the drug, area and the thickness of
or alter the partition of drugs between
barrier membrane ---- rate of diffusion
compartments of differing pH.
- Nonionized forms of drugs diffuses easily across
lipid barriers in the nephron, this form may reach
equal concentrations in blood and urine
- Ionized forms are more water soluble and are easily
Where will drug absorption be faster excreted because they are not reabsorbed in the
according to Fick’s Law of Diffusion? tubule, this form may have higher concentrations in
the urine
ul -44pen
Cheer up future doctor!!!! : lipophilic Tank
nonionized →

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

etht - Influences absorption from IM and Subq sites

✗ 1st pay - In shock, it influences absorption from the GI tract
- High blood flow maintains high drug depot to
blood concentration gradient and thus facilitates
absorption
C. Concentration
- Concentration gradient is a major determinant of
rate of absorption (Fick’s Law)
local - Drug concentration in the vehicle is particularly
skin : effect important in drugs that are applied topically.
1.3 Distribution of Drugs

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

- drug metabolism is a mechanism for activation or

- Synthetic reactions that involve the addition
(conjugation) of subgroups to – OH, -NH2, -SH polar
coninck
.

termination of drug action. functions on the drug molecule.

- Occur primarily in the liver - Most of these groups are relatively polar and eain
- first pass metabolism = low bioavailability increase water solubility (less lipid soluble) than the
- Drug Metabolism --- Termination of Drug Action: original drug molecule Minim
conversion to an inactive metabolite = elimination
(action of drug is terminated before they are even
- Like phase 1 enzymes, phase II enzymes are not
very selective tmÑ .

excreted) ---- sympathomimetics, phenothiazines

- Drug Metabolism --- Drug Activation: “prodrugs”
(levodopa, minoxidil) are inactive when
administered and must be metabolized by the body
become active.
- Morphine, some benzodiazepines are active when
administered and have active metabolites.,
- Drug Elimination Without Metabolism: Lithium,
and some drugs are not modified by the body, they
continue to act until they are excreted. Determinants of Biotransformation Rate
Phase 1 Reactions
mom WGHY why
,
- Rate of biotransformation is often the primary
determinant of clearance
- Reactions that convert parent drug to a more polar
A. Genetic Factors
(water soluble) or more reactive product by
- e.g., abnormal plasma cholinesterase, slow
inserting a polar functional group.
acetylators
- Include: oxidation. reduction, deamination,
hydrolysis
B. Effect of Other Drugs
- Oxidation by cytochrome p450 group of enzymes
- Coadministration of some agents may alter the
“mixed function oxidases”
disposition of many drugs. Mechanisms include the
- Enzymes found in high concentration in the smooth
following:
ER of the liver
- Not highly selective in their substrates so they are Enzyme induction
able to metabolize thousands of drugs
- Metabolize 75% of drugs by phase 1 reaction: - Increase rate and extent of metabolism
- Result from increased synthesis of cytochrome p450
CYP3A4 and CYP2D6
duet
hndupiith
drug-oxidizing enzymes in the liver, as well as the
make cofactor “heme”.
Cheer up future doctor!!!!
LSL – SWU PHINMA BATCH MEDICO SANGUINE
- The most common strong inducers of drug
metabolism: carbamazepine, phenobarbital,
phenytoin, and rifampin
P CRABS
Enzyme inhibition
G PACMAN
- Inhibitors of drug metabolism that are most likely
involved in serious drug interactions: amiodarone,
cimetidine, furanocoumarins (present in grapefruit
juice), azole antifungals and the HIV protease
inhibitor, ritonavir
- Suicide inhibitors: drugs that are metabolized to
products that irreversibly inhibit the metabolizing
enzyme.
- Examples: ethinyl estradiol, norethindrone,
spironolactone, secobarbital, allopurinol, fluroxene
and propylthiouracil
- Metabolism may also be decreased by
pharmacodynamic factors such as reduction in
blood flow (example. Propranolol reduces hepatic
blood flow)
Inhibitors of intestinal P-glycoprotein
- Also known as MDR 1
- Modulator of intestinal drug transport
- Functions to expel drugs from the intestinal mucosa
to the lumen
- Contributes to first pass elimination
- Also found in blood brain barrier and in drug
resistant cancer cells.
- Drugs that inhibit intestinal P-gp mimic drug
metabolism by increasing bioavailability.
Cheer up future doctor!!!!
AUGUST 2022
- Coadministration of P-gp inhibitors may result in
toxic plasma concentrations of drugs given at
normally nontoxic dosage.
- P-gp inhibitors: verapamil, furanocoumarin
components of grapefruit.
V¥
⇐
- Drugs that are normally expelled by P-gp (become
toxic when given with an inhibitor): digoxin,
cyclosporine, saquinavir
1.5 Elimination of Drugs
- -along with dosage, the rate of elimination
following last dose determines “duration of action”
for most drugs
- Rate of elimination: disappearance of the active
molecules from the site of action, the bloodstream
and the body.
- Drug elimination is not equivalent to drug
=
excretion.
- Organ responsible is the kidneys
- Volatile anesthetic drugs are eliminated via the
lungs.
- Small number of drugs combine irreversibly with
their receptors, their disappearance from blood
stream is not equivalent to cessation of drug action
---- result to prolonged action
%÷µñn
- Example: Phenoxybenzamine
o irreversible inhibitor of a adrenoreceptors
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
- indicates the rate if elimination is proportional to
the concentration.
- The higher the concentration, the greater the
amount of drug eliminated per unit time.
- Drug’s concentration in plasma decreases
exponentially.
- Drugs with first order elimination have “half-life
elimination” that is constant regardless of the
amount of drug in the body.
- Concentration of the drug decreases by 50% for
every half – life.
=
- Happens to most drugs at most doses
Zero Order Elimination
- Rate of elimination is constant regardless of
concentration.
LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
- Occurs with drugs that saturate their elimination Drug Evaluation and Regulation

⇐
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)

Types of Animal Testing

1. Pharmacologic Profile
- Description of all the pharmacologic effects of a
drug (effects on cardiovascular fx, gastrointestinal
activity, respiration, hepatic and renal fx,
endocrine function, CNS)

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)

Cheer up future doctor!!!!

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
FDA RATING FOR DRUG SAFETY IN PREGNANCY - Acute effects of the agent are studied over a
broad range of dosages
- Starting dose produces no detectable effect and
progressing to one that produces either a
significant physiologic response or a very minor
toxic effect.
Phase 2 Clinical Trial
- Evaluation of a drug in a moderate number of
controlled sick patients (100-200).
no studies - Placebo or positive control is included in a single
on
women
blind or double-blind design.
in
1st - Carried out under very carefully controlled
tis
patriot
.

conditions where patients are closely

animal't aduinednut , "ñ% Nox monitored.
str.dk - Goal is to determine whether the agent has the
benefit desired efficacy at a dose tolerated by the sick
outwright patients.
is the
- Detailed data about pharmacokinetics and
pharmacodynamics are collected.
puttin of Phase 3 Clinical Trial
eiidih I - Involves many patients (1000-6000) and many
Glad rn clinicians who are using the drug in the manner
proposed for its ultimate general use.
- Goal is to explore further, under the conditions

ñYnµiÑ
of the proposed clinical use the spectrum of
beneficial actions of the new drug compared to
"
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.

Phase 1 Clinical Trial

- Careful evaluation of the dose response
-

relationship and the pharmacokinetics of the

new drug in a small number of normal human
volunteers (20-100).

Cheer up future doctor!!!!

 dissociation ,

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022

- The smaller the KD , the greater the affinity of the

PHARMACODYNAMICS
=*÷
drug for its receptor.

QUANTAL DOSE-RESPONSE RELATIONSHIP

RECEPTORS
- Minimum dose required to produce a specified
- Specific molecules in a biologic system with which response
drugs interact to produce changes in the function - Example: BP lowering drug might be studied by
of the system. measuring dose required to lower mean arterial
- Selective and modifiable pressure by 20mmHg in 100 hypertensive patients.
- Manu drugs are classified on the basin of their - Median effective dose (ED50), median toxic dose
primary receptor affinity. (TD50), and in animals, medial lethal dose (LD50)
RECEPTOR SITE are derived from this data.
- Unlike graded dose response, no attempt is made
- Recognition site for a drug is the specific binding to determine maximal effect of drug.
region of the receptor macromolecule and have a - Provide information of the variation in the
relatively high and selective affinity for the drug sensitivity to the drug.
molecule. - If the variation is small, the curve is steep.
- Interaction of the drug with its receptor is the
fundamental event that initiates the action of the Efficacy / maximal Potency
drug. Efficacy - The amount of drug
- Greatest effect an needed to produce
EFFECTORS agonist can produce a give effect.
if the dose is taken - Determined mainly
- Molecules that translate the drug-receptor
up to the highest by the affinity of the
interaction into a change in cellular activity.
tolerated level. receptor for the
- Examples are enzymes
- Determined mainly drug and the
DOSE RELATIONSHIPS by the nature of the number of receptors
drug and the available
GRADED DOSE-RESPONSE RELATIONSHIP receptor and its - (ED50), (TD50, LD50) :
- Response of a particular receptor-effector system associated effector potency variables
measured against increasing concentrations of the system. - Can be obtained
drug - Measured with from graded dose
- Response vs drug concentration graded-dose response curve and
- Sigmoid curve response curve. quantal dose
- Efficacy (Emax) and potency (EC50) are derived from - Cannot be measure response curve , but
this data. by a quantal-dose numbers obtained
- EC50/ ED50 concentration or dose that causes 50% response curve. are not identical and
of the maximal effect or toxicity. have different
- The smaller the EC50 /ED50, the greater the potency meanings.
of the drug.
smaller doll 2 IN the p
GRADED DOSE-BINDING RELATIONSHIP
SPARE RECEPTORS
- Measure the percentage of receptors bound by a
drug, by plotting this percentage against the log of - Said to exist if the maximal drug response (Emax) is
the concentration of the drug. obtained at less than 100% occupation of the
- KD : dissociation constant; concentration of drug receptors (Bmax). – if equal then there are no

-
required to bind 50% of the receptor sites
Useful measure of the affinity of a drug for its
attrib spare receptors

receptor.
goy
Cheer up future doctor!!!! three
LSL – SWU PHINMA BATCH MEDICO SANGUINE
- Determined by comparing maximal effect (EC50)
with the concentration for 50% of maximal binding
(Kd)
- Duration of effector activation may be much
greater than the duration of the drug receptor
interaction.
- Actual number of receptors may exceed the
number of effector molecules available
- Presence of spare receptors increase sensitivity to
the agonist because the likelihood of a drug
receptor interaction increases in proportion to the
CHEMICAL ANTAGONIST
number of receptors available.
AGONISTS
Constitutive activity: activity in the absence of a ligand.
FULL AGONIST: a drug capable of fully activating the
effector system when it binds to the receptor; high
affinity for activated receptor conformation and a
sufficiently high concentration results in all receptors
achieving activated state.
PARTIAL AGONIST: produce less than the full effect
even when it has saturated all the receptors; when
there is a full agonist a partial agonist acts as an
inhibitor.
INVERSE AGONISTS: have higher affinity for inactive
state and decrease or abolish any constitutive activity.
ANTAGONISTS
AUGUST 2022
- Drug that counters the effects of another by
binding to a different receptor and causing
opposing effects.
- Example: antagonism of the bronchoconstrictor
action of histamine by epinephrine’s
bronchodilators action; glucagon’s antagonism of
the cardiac depressant effects of propranolol
In against
bind day
not
Topi
- Drug that counters the effects of another by
binding the agonist drug (not the receptor).
- Example: dimercaprol, a chelator of lead;
pralidoxime that combines avidly with phosphorus
in organophosphate cholinesterase inhibitors
ALLOSTERIC AGONIST, ANTAGONIST alhs upon
- Drug that binds to a receptor molecule without
interfering with normal agonist binding but alters
the response to the normal agonist.
SIGNALLING MECHANISMS

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

Cheer up future doctor!!!!

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
Receptor regulation

1. Tachyphylaxis: frequent or continuous PHARMACOKINETICS

exposure to agonists often results in short term
diminution of the receptor response.
2. Downregulation: long term reduction in
number of rectors that occur in response to
continued exposure.
3. Upregulation: increase in receptor number that
occurs when receptor activation is blocked for
prolonged periods by pharmacologic
antagonists or by denervation.
PEAK AND TROUGH CONCENTRATIONS
Sample Question
- The maximum and minimum drug concentrations
achieved during repeated dosing cycles
FIRST PASS EFFECT
- Pre-systemic elimination
- The elimination of drug that occurs after
administration but before it enters the systemic
circulation (eg, during passage through the gut
wall, portal circulation, or liver for an orally
administered drug)
Answer: A. Chemical antagonists interact directly with STEADY STATE
the drug, not the receptor.
- In pharmacokinetics, the condition in which the
average total amount of drug in the body does not
change over multiple dosing cycles (ie, the
condition in which the rate of drug elimination
equals the rate of administration)

EFFECTIVE DRUG CONCENTRATION

- Concentration of a drug at the receptor site.
- If rate pf input is unknown, the remaining
processes are well described by 2 parameters:
apparent volume distribution (Vd) and clearance
(CL)
VOLUME DISTRIBUTION

- Relates the amount of drug in the body to the

plasma concentration.

Answer: D

Cheer up future doctor!!!!

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
- Vd of drugs that are normally bound to plasma Sample Question:
proteins (albumin) can be altered by liver disease
(through reduced protein synthesis) or by kidney
disease (through urinary protein loss)
- If a drug is avidly bound in peripheral tissues, the
drugs concentration in plasma may drop to very
low values even though the total amount in the
body is large.
FI

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.

EE
- A drug eliminated through first order has a
constant clearance; ratio of the rate of elimination
to plasma concentration is the same over a broad
range of plasma concentration.
- Determines the rate at which blood concentration
rises during a constant infusion and falls after
administration is stopped.

-0-0
Clearance depends on: the drug, blood flow, and
the condition of the organs responsible for
elimination in a particular patient

Answer: 4 hours

Cheer up future doctor!!!!

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022
BIOAVAILABILITY DOSAGE REGIMENS
- The fraction (or percentage) of the administered - Plan for drug administration over a period of time.
dose of drug that reaches the systemic circulation. - Optimal dosage regimen results to the
- Defined as unity (100%) in the case of intravenous achievement of therapeutic levels of the drug in
administration. the blood without exceeding the minimum toxic
- After administration, bioavailability is generally concentration.
reduced by incomplete absorption, first pass effect
and any distribution into other tissues that occurs Maintenance dose Loading dose
before the drug enters the systemic circulation. - Maintain plasma - To achieve a target
concentration plasma level of a
within a specified drug rapidly.
range over long - To load up the
periods of therapy. volume distribution
- Doses given per day of a drug.
is determine by: - Based on
half-life of drug and knowledge of:
the difference minimum
between minimum therapeutic and
EXTRACTION therapeutic and minimum toxic
minimum toxic concentrations,
- Removal of a drug by an organ can be specified as concentrations volume distribution
the extraction ratio (Therapeutic and clearance.
- The fraction or percentage of the drug removed window)
form the perfusing blood during its passage - If therapeutic
through the organ. window is small,
- Large hepatic extraction ratio = large first pass then smaller and
effect = low availability more frequent
doses must be
administered to
prevent toxicity.

Cheer up future doctor!!!!

LSL – SWU PHINMA BATCH MEDICO SANGUINE AUGUST 2022

rare in plan w.

Therapeutic index Caught

Therapeutic window

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,

ADJUSTMENT OF DOSAGE WHEN ELIMINATION IS

ALTERED BY DISEASE

- Renal disease, reduced cardiac output often

reduces the clearance of drugs that depend on
renal elimination.
- Alternation of clearance by liver disease is less
common.
- The most important renal variable in drug
elimination is Glomerular Filtration Rate (GFR).
- Creatinine Clearance is a convenient
approximation of GFR.
- Creatine clearance ca be measured directly but
this requires careful measurement of both serum
and urine creatine clearance.

Cheer up future doctor!!!!

Chapter 6: Introduction to Autonomic Pharmacology (Katzung)
Neurotransmitter Chemistry of the Autonomic Nervous System

- Classification of autonomic nerves according to primary transmitter molecules: acetylcholine and

norepinephrine
- Acetylcholine = cholinergic fibers; Norepinephrine = adrenergic fibers
- Almost all efferent fibers leaving the CNS, most parasympathetic postganglionic fibers, some
sympathetic postganglionic fibers--- CHOLINERGIC
- Nitric oxide / peptides = co transmitter for cholinergic fibers
- Most postganglionic sympathetic fibers ---- ADRENERGIC
- Dopamine = co transmitter for adrenergic fibers
5 key features of neurotransmitter function that provide potential targets for pharmacologic
therapy:
1. Synthesis
2. Storage
3. Release
4. Termination of action (of the transmitter)
5. Receptor effects

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.

7. Acetyl-CoA is synthesized in mitochondria present in large numbers in the nerve ending.

8. Choline is transported from extracellular fluid into the neuron terminal by a sodium -dependent
membrane CHT (choline transporter).

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.

11. Storage of acetylcholine accomplished by packing of “quanta” of acetylcholine molecules (1000

– 50, 000) molecules in each vesicle.
12. Most of vesicular acetylcholine (positive charge quaternary amine) is bound to negatively
charged VPG (vesicular proteoglycan)
13. Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through
interaction of SNARE proteins on the vesicle and on the inside of the cell membrane.

On the vesicle: subgroup of VAMPs called v-SNAREs especially SYNAPTOBREVIN.

On the inside of the cell membrane: SNAPs called t-SNAREs especially SYNTAXIN and SNAP-25.

14. Physiologic release of transmitter from vesicles is dependent on extracellular calcium.

15. Action potential reaches terminal and triggers sufficient influx of calcium ions via N-type
calcium channels.
16. Calcium interacts with the (VAMP) SYNAPTOTAGMIN on the vesicle membrane.
17. Interaction triggers fusion of the vesicle membrane with the terminal membrane.
18. A pore opens into the synapse.
19. The opening of pore and inrush of cations results in RELEASE OF ACETYLCHOLINE from
VPG (vesicle proteoglycan).
20. Acetylcholine expelled into the synaptic cleft as well as several co transmitter.
BOTULINUM TOXIN blocks acetylcholine vesicle release process through enzymatic cleavage
of two amino acids from one or more fusion proteins.

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).

ACETYLCHOLINESTERASE splits acetylcholine into choline and acetate, neither of which

has significant transmitter effect ---- TERMINATION OF ACTION
 Acetylcholinesterase is also found in red blood cells.
BUTYRYLCHOLINESTERASE = PSEUDOCHOLINESTERASE; lower specificity for acetylcholine
- FOUND IN: blood plasma, liver, glia

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.

Potential sites of drug action in adrenergic nerve terminals:

• 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

Sites of Autonomic Drug Action:

1. CNS centers
2. Ganglia
3. Postganglionic nerve terminals
4. Effector cell receptors
5. Mechanisms responsible for: synthesis, storage, release and termination of action

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.

Acetylcholine: prototype that acts directly at

both muscarinic and nicotinic receptors.
Neostigmine: prototype for the indirect-
acting cholinesterase inhibitors.

GENERAL EFFECTS OF CHOLINOMIMETICS

DIRECT ACTING CHOLINOMIMETIC AGONISTS
- Choline esters: ACETYLCHOLINE, METHACHOLINE, CARBACHOL, BETHANECHOL (poor
lipid solubility)
- Naturally occurring alkaloids: MUSCARINE, PILOCARPINE, NICOTINE, LOBELINE ( high
lipid solubility)

Muscarinic agonists: parasympathomimetic; 5 groups of muscarinic receptors

have been identified.
Nicotinic agonists: act on both ganglionic or neuromuscular cholinoreceptors;
agonist selectivity is limited.

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)

DAG modulates the action of protein kinase C, an enzyme important in secretion.

IP3 evokes the release of calcium from intracellular storage sites, which in smooth
muscle results to contraction.
u
3. M2 receptors couple to adenyl cyclase through inhibitory G1 coupling protein.
4. M2 receptors can also couple with beta gamma subunit of the G protein to potassium channels in
the heart and elsewhere. Muscarinic agonists facilitate opening of these channels.
5. M4 and M5 receptors may be important in the CNS but have not been shown to play a major role
in the peripheral organs.
• Nicotinic mechanisms:
1. The nicotinic acetylcholine receptor is located on a channel protein that is selective for sodium
and potassium.
2. Activation of receptors open the channel and depolarization of cell occurs.
3. Influx of sodium results to development of excitatory postsynaptic action potential (EPSP).
4. If large enough, EPSP propagates potential in the surrounding membrane.
Tissue and Organ Effects
- Vasodilation is not a parasympathomimetic response (not evoked by
parasympathetic nerve discharge, even though directly acting cholinomimetics
cause vasodilation.)
- Vasodilation results from endothelium derived relaxing factor (EDRF)
in the vessels mediated by unenervated muscarinic receptors on the
endothelial cells.
- Injections of small to moderate amounts of direct acting cholinomimetics
Cause tachycardia.
- Parasympathetic nerve vagal discharge causes bradycardia.
- Another effect of cholinomimetic drugs but not with parasympathetic nerve stimulation is
thermoregulatory (eccrine) sweating.
- Blood vessels are dominated by sympathetic innervation; nicotinic receptor activation causes
vasoconstriction.
- The gut is dominated by parasympathetic control; nicotinic receptors increase motility and secretion
parasympathetic neuron discharge.
- Nicotinic neuromuscular end plate activation by direct acting drugs causes fasciculations and spasms.
- Prolonged nicotinic activation results to paralysis, a hazard of exposure to nicotine containing
and organophosphate insecticides.
Clinical Use
1. Glaucoma – reduce IOP by causing contraction of ciliary body facilitating drainage of aqueous
humor.
2. Sjogren’s syndrome – dry mouth treated with Cevimeline
3. Loss of normal PANS activity in the bowel and bladder. – bethanechol most widely used for
GERD; neostigmine most widely used for paralytic ileus or atony of the urinary bladder
4. Smoking cessation (direct acting nicotinic agonists)
5. Produce skeletal muscle paralysis (Succinylcholine)
6. Indirect acting agents are used when increased nicotinic activation is needed at NMJ. (Myasthenia
Gravis)

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

7. Pilocarpine has long been used to increase salivary secretion.

8. Anti-muscarinic drug that is used to reverse toxic muscarinic effects: ATROPINE
9. Antimuscarinic drug intoxication – give cholinesterase inhibitor
10. Over dose of tricyclic antidepressants = severe muscarinic blockade. – overcome by increasing
endogenous acetylcholine
11. Tacrine – first drug with anticholinesterase and other cholinomimetic actions used to treat
Alzheimer’s disease.
Protein Synthesis Inhibitors
Lecturer: Dr. Amistad (09/15/2022)

• Bacteriostatic action = antimicrobial effect by targeting bacterial ribosomes and inhibiting

bacterial protein synthesis resulting to growth arrest of bacteria.
• Bacterial ribosomes --- 30S and 50S
• Mammalian ribosomes --- 40S and 60S

%
TETRACYCLINES

• Target the 30S subunit and prevent binding of tRNA to mRNA

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.

LSL
 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:

"
1. Peptic Ulcer Disease

¥0
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

LSL
 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
r
• Derivative of minocycline

p¥do
• 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:

¥
1. Nausea and vomiting
2.
3.
Acute pancreatitis with fatality
Elevations in liver enzymes and
.
. serum creatinine
4. Photosensitivity

LSL
 '
5. Pseudo motor cerebri
6. Discoloration of permanent teeth when used during teeth development

o
7. Fetal harm when administered during pregnancy
8. r
Decrease clearance of WARFARIN – monitor INR when tigecycline is co administered with
warfarin

②
- aennn
gram

¥÷÷#
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

Diffuse through porin channels in the outer membrane of susceptible organisms.

• Concentration dependent bactericidal activity – max concentration above minimum inhibitory
effect
• Exhibit Post Antibiotic Effect (PAE) – continued bacterial suppression after drug
concentrations fall below MIC
• The larger the dose, the longer the PAE.
• High dose extended interval dosing is commonly utilized.

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.

OT
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.
r
o Neomycin is primarily excreted unchanged in feces.

LSL
 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:

• Therapeutic drug monitoring of: gentamycin, tobramycin and amikacin

• Elderly are particularly susceptible to nephrotoxicity and ototoxicity.

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

y
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

LSL
 QT pmy
.

(
✓ MACROLIDES / KETOLIDES

• °
Bind to the 50S subunit this inhibiting translocation

-0,00
• 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
sun lot
A#
LSL
?⃝
Therapeutic Application of MACROLIDES/KETOLIDES:

"
1. Corynebacterium diphtheriae
o DOC: Erythromycin or Penicillin; used to eliminate carrier state
2. Chlamydial infections
o DOC: Azithromycin or Doxycycline

3. Legionnaires Disease (Legionellosis)

o Undiagnosed and asymptomatic conditions are common.
o DOC: Azithromycin or Fluroquinolones
4. Mycoplasma pneumonia
o Atypical pneumonia --- causative mycoplasma escapes isolation by standard
bacteriologic techniques.
o DOC: Azithromycin or Doxycycline
5. Mycobacterium Avium Complex (MAC infection)
o Treatment regimen: Clarithromycin + Rifampin + Ethambutol (CRE)
o Azithromycin is an alternative for Clarithromycin
o Once a week Azithromycin MAC prophylaxis for AIDS patients.
Adverse Effects of Macrolides and Ketolides:
1. Gastric distress and motility
o Most common adverse effect --- especially with erythromycin

88€
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

LSL
 Éimim
dip -

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.

6¥
LINCOSAMIDES
1. Clindamycin
• Mechanism of action similar to macrolides
• Bind to the 50S subunit this inhibiting translocation .

• treatment of infections caused by gram-positive organisms, including MRSA and

streptococcus, and anaerobic bacteria.
-
• C. difficile is resistant to clindamycin
• utility of clindamycin for gram negative anaerobes (for example, Bacteroides sp.) is
decreasing due to increasing resistance.
• Resistance mechanisms is the same with erythromycin.

É¥ñt
-
• 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

!
and
LSL u
?⃝
 • Undergo extensive oxidative metabolism to active and inactive products – excreted into
bile and urine

€Tm
• 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.

1. Linezolid: has bactericidal activity against streptococci; an alternative to Daptomycin for

infections causes by VRE; metabolized via oxidation to two inactive metabolites excreted both
by renal and nonrenal routes.
2. Tedizolid: metabolized by sulfation; elimination occurs via liver and drug is mainly excreted
through feces.
Adverse Effects of Oxazolidinones:

¥
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.

2. Quinupristin/ Dalforpristin (SYNERCID)

• mixture of two streptogramins in a ratio of 30 to 70 respectively.
• combination drug is normally reserved for the treatment of severe infections caused by
vancomycin-resistant Enterococcus faecium (VRE) in the absence of other therapeutic
options. ---- significant adverse effects

LSL
 •
•
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.

LSL
 Mycobacterial Drugs
Lecturer: Dr. Amistad (09/15/2022)

Chemotherapy for Tuberculosis

• 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

DRUGS USED TO TREAT TUBERCULOSIS (1 ST LINE)

• High efficacy and acceptable incidence of toxicity.

RIFAMYCINS: Rifampin, Rifabutin and Rifapentine

• Macrocyclic antibiotics, which are first line oral agents for TB.
1. Rifampin

¥÷
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.

LSL
 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.
to
attrib
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

LSL
 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

5. Adverse Effects of Isoniazid

o Hepatitis is the most serious adverse effect of INH. If unrecognized and INH is
continued --- fatal
o Incidence of hepatotoxicity increases with:
▪ Age greater than 35 years old
▪ Individuals who also take rifampin additive
east on her c-
-
▪ Chronic alcoholism it
1Mt
o Isoniazid caused Vitamin B6 or Pyridoxine deficiency—manifested by: peripheral
neuropathy, paresthesia of the hands and feet
o CNS adverse effects: convulsions in patients prone to seizures
o INH inhibit the metabolism of carbamazepine and phenytoin – potentiate adverse
effects of these drugs (nystagmus and ataxia)

LSL
 di' ' '

ath her

ftp.t.mil
2

Pyrazinamide
tepattreic ; nypruhwis
• synthetic, orally effective short-course agent used in combination with isoniazid, rifampin, and
ethambutol.

¥:*!
• 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 -

red / sun
'

Ethambutol eye
1 visual disturb, , dlimi wind ad's ,
coin bill
/
.

• bacteriostatic and specific for mycobacteria (narrow spectrum)

• Mechanism of action: inhibits arabinosyl transferase—an enzyme important for the synthesis of
visual the mycobacterial cell wall.
• Ethambutol distributes well throughout the body.
dirluvhni • Penetration into the CNS is variable, and it is questionably adequate for tuberculous meningitis.
•
¥1:*
parent drug and its hepatic metabolites are primarily excreted in the urine.
• Most important adverse effect: optic neuritis ----- results in diminished visual acuity; loss of
.
ability to discriminate between red and green.
•
hunk 1 •
Risk of optic neuritis increases with higher doses and in patients with renal impairment.
acid •
Visual acuity and color discrimination should be tested prior to initiating therapy and
periodically thereafter.
retention
.

• Uric acid excretion is decreased by ethambutol, and caution should be exercised in patients
with gout.

pyridoxine dd :

LSL enure indes

µµ-¥
 DRUGS USED TO TREAT TUBERCULOSIS (2 ND LINE)

• Less effective, more toxic and less extensively studied.

• Used for patients who cannot tolerate first line drugs or who are infected with resistant TB.

Eric
aciidnuiri

1. AMINOGLYCOSIDES (Streptomycin) Commented [LL1]:

• One of the first effective agents for TB
• Action greater against extracellular organisms.
• Streptomycin resistant organisms – DOC: Kanamycin or Amikacin (bacilli still
susceptible to these drugs)

2. AMINOSALICYLIC ACID
• Para-amino salicylic acid (PAS) works via folic acid inhibition.
0
• Replaced by ethambutol for drug susceptible TB
• PAS remains an important component of many regimens for MDR-TB.

3. BEDAQUILINE ATP ATP neutron inti

① -

/
/
• a diarylquinoline, an ATP synthase inhibitor
ECG
@
• approved for the treatment of MDR-TB.
• PO and active against many types of mycobacteria.

pay
. ①
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.

EEG + liner
pad
and cardio they
LSL

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

s¥i
• structural analog of isoniazid that also disrupts mycolic acid synthesis.
• widely distributed throughout the body, including the CSF.

00
• Metabolism is extensive, most likely in the liver, to active and inactive metabolites.
!
• 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
'
-

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.

I led my work

LSL
 DRUGS USED TO TREAT LEPROSY (HANSEN’S DISEASE)

bacteriostatic pomatum
1. DAPSONE

nm%t÷µ
• 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.

black
• 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.

skin

LSL
÷:÷÷""÷÷ Q
D D
Clan IA
:
.
.

Tim
class IB
:
Antiarrhythmic Mechanism of Action Comment
Classification
CLASS I DPQ
- .LM PF
• 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)
cause
mod

drrymmialswjnauoE.IM
.

0 IA Na + channel blocker Slows Phase 0 in ventricular muscle fibers; have

concomitant class III activity that prolong action potential; !
and can precipitate arrythmias that can progress to -0 truth
ventricular fibrillation
channels
Disopyramide - fast btsodium
• Similar to Quinidine
• More anticholinergic activity
-
prolong nepotism" pnlwyeap
pwhnj open
,

• No alpha-adrenergic blocking activity etmti

• Produces greater negative inotropic effect; caused peripheral vasoconstriction retract"
fibrillation
← or flutter 0
• Alternative treatment of ventricular arrythmias and may be used for rhythm control in atrial

• well absorbed PO and extensive metabolism by CYP3A4 forming fewer active metabolites and
pm
several inactive metabolites; half of drug excreted by kidneys
• Anticholinergic side effects: dry mouth, urinary retention, blurred vision and constipation
Procainamide
• Similar to Quinidine
/
• Less anticholinergic activity
• No alpha-adrenergic blocking activity
A- CURE punt
• 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
 armyminiAmioda@swFr.W
" for ventricular
reunion'Irrnm
"

IB Na + channel blocker Shorten Phase 3 in ventricular muscle fibers and

' decreases action potential; rapidly associate and
disassociate from sodium channels; actions are greater
when the cardiac cell is depolarized or firing rapidly;
drugs do not contribute to negative inotropy. Indication:
Ap
Lidocaine toxicity :
ventricular arrythmias
nystagmus !
Chopin etkoh
• Used as an alternative drug for ventricular fibrillation or ventricular tachycardia mom
• DOC for ventricular arrythmias: Amiodarone petrol "
• Lidocaine + Amiodarone for VT storm
• Does not markedly slow down conduction and has little effect on atrial or AV junction
pen
wide arrythmias.

amn
• Given IV because of extensive hepatic first pass effect
• Dealkylated to two active metabolites by CYP1A2 (major) and CYP3A4 (minor)

x.io intnmkr
• Monitor use when giving with drugs affecting CYP isoenzymes
• Wide therapeutic index
• CNS effects: nystagmus (early indicator of toxicity), drowsiness, slurred speech, paresthesia ,

0
agitation, confusion and convulsions --- limit duration of continuous infusions

61up④
Mexiletine
• Chronic treatment of ventricular arrhythmias
• Combination
- with Amiodarone

¥:
• Well absorbed after PO
• Metabolized by CYP2D6 in liver to active inactive metabolites

-00
• 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
retracts
v. army
www.sraifw
.

prominent effects even at normal heart rates; negative

inotropic and proarrhythmic effects --- structural
yVÑ heart disease (LV hypertrophy, heart failure,
atherosclerotic disease) [ Contraindication]
Flecainide ✗ Hit Purtime go .

• Suppresses phase 0 upstroke in Purkinje and myocardial fibers

• Marked slowing down of conduction in all cardiac tissue with minor effect on duration of the retract

¥
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
'

?
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.

¥ñwarrM¥ar ⑤
Propafenone
-
• like flecainide, slows conduction in all cardiac tissues but does not block K+ channels
-
• possesses weak β-blocking properties.

⑨
?⃝
?⃝
 •
•
-
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.

noc prn oEYHYAoipdirtnit.no/Catecholamb

• Propafenone is also an inhibitor of P-glycoprotein
• should be used with caution with potent inhibitors of CYP2D6.
Class II
• depress automaticity, prolong AV conduction, and decrease heart rate and contractility
• useful in treating tachyarrhythmias caused by increased sympathetic activity '
• used for atrial flutter and fibrillation and for AV nodal reentrant tachycardia.
• prevent life-threatening ventricular arrhythmias following a myocardial infarction.
II Beta adrenoreceptor Inhibit phase 4 depolarization in SA and AV nodes;
blocker
Metoprolol
• most widely used β-blocker for the treatment of cardiac arrhythmias.
• Compared to nonselective β-blockers, such as propranolol, it reduces the risk of bronchospasm.
I. wt
• It is extensively metabolized by CYP2D6
• CNS penetration (less than propranolol, but more than atenolol)
• Common adverse effects with β-blockers: bradycardia, hypotension, and fatigue
Atenolol
Esmolol w -
Emerging acute cerrtyminf !
• very short and fast-acting β-blocker used for intravenous administration in acute arrhythmias
that occur during surgery or emergency situations.
• rapidly metabolized by esterases in red blood cells; no pharmacokinetic drug interactions.
Class III
tinned
• block K+ channels and, thus, diminish the outward K+ current during repolarization of cardiac pine
/
cells.
• agents prolong the duration of the action potential without altering phase 0 of a .
.

depolarization or the resting membrane potential

rty¥mr%
• 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.
ADSDI
tnnrñd€wd
• Despite its adverse effect profile, amiodarone is thought to be the least proarrhythmic of the

¥k.④@
class I and III antiarrhythmic drugs. .

• TOXIC EFFECTS: pulmonary fibrosis, neuropathy, hepatotoxicity, corneal deposits, optic

neuritis, blue-gray skin discoloration, and hypo- or hyperthyroidism.
• low doses and close monitoring reduce toxicity, while retaining clinical efficacy.

¥÷¥it_ or
am
ventricular
. E-
?⃝
 * A¥É¥
• 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.

tdechie
• 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
D
• the major effect of Ca2+ channel blockers is on vascular smooth muscle and the heart.

1st ""
persistent afib .
:
Dokhblf
chemical convict a. Adi Kumi
 • 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

www.tibaintm.gakinmf
IV Ca2+ channel blocker Inhibits action potential in SA and AV nodes
Others:
peat
DIGOXIN

;¥
• inhibits the Na+/K+-ATPase pump, ultimately shortening the refractory period in
.
atrial and ventricular myocardial cells while prolonging the effective refractory period

pin
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

É^!
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.
wit
aah

1-
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.

acute SVT demit armpit

MAGNESIUM SULFATE - dingy
• Mg is necessary for the transport of Na+, Ca2+, and K+ across cell membranes
• slows the rate of SA node impulse formation and prolongs conduction time along
the myocardial tissue.
• Intravenous magnesium sulfate is the salt used to treat arrhythmias, as oral
magnesium is not effective in the setting of arrhythmia.
• Magnesium sulfate is the drug of choice for treating the potentially fatal arrhythmia
torsade’s de pointes and digoxin-induced arrhythmias.

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

Chapter 52: Antiprotozoals

ANTIMALARIAL DRUGS

CHLOROQUINE (Class: 4 - aminoquinoline)

• DOC for both treatment and chemoprophylaxis of malaria since 1940s
• Usefulness vs P. falciparum compromised by drug resistance
• Resistance more common to P. falciparum compared to P. vivax.
• PfCRT: primary mediator of resistance in P. falciparum.
• Agents that reverse chloroquine resistance: VERAPAMIL, DESIPARAMINE and CHLORPHENIRAMINE.
• DOC for treatment pf sensitive P. falciparum and other human malarial parasites
• Reaches max. plasma concentration in 3 hours with rapid distribution to tissues.
• Large apparent volume distribution (100- 1000 /kg).
• Excretion: urine
• Initial half-life: 3 - 5 days
• Terminal elimination half-life: 1 – 2 months
• Highly effective blood schizonticide.
• Not reliable vs liver stage parasites or gametocytes.
• MOA: concentrates parasites into food vacuoles preventing biocrystallization of the hemoglobin breakdown product
“heme” into “hemozoin”, resulting to parasite toxicity because of the build up of free heme.
• Treatment: DOC uncomplicated non falciparum and sensitive falciparum malaria.
• Dosage: 500 mg weekly
• Rapid termination of fever. (24 – 48 hours)
• Clears parasitemia caused by sensitive parasites. (48 – 72 hours)
• Artemisin based combination therapies have replaced Chloroquine as standard therapy to treat falciparum malaria in
endemic countries.
• Chemoprophylaxis: areas without resistant falciparum malaria
• Eradication of P. vivax and P. ovale requires PRIMAQUINE to clear hepatic stages.
• Amebic liver abscess: chloroquine reaches high liver concentrations and may be used when there is failure of initial
therapy with metronidazole.
• Adverse Effects: Pruritus common in Africans.
• Uncommon adverse effects: Nausea and vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision
and urticaria.
• Rare adverse effects: (G6PD deficiency) hemolysis, impaired hearing, confusion, psychosis, seizures,
agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension and ECG changes,
• Adverse effects from long term administration of chloroquine for rheumatologic diseases: irreversible ototoxicity,
retinopathy, myopathy and peripheral neuropathy.
• IM or IV infusions of chloroquine: severe hypotension and respiratory and cardiac arrest
• Contraindications and Cautions: Do not give to patients with psoriasis or porphyria; do not use when there is retinal
or visual field abnormalities or myopathy; Use with caution in patients with liver, neurologic or hematologic disorders.
• Kaolin (antidiarrheal) and Calcium & Magnesium containing antacids: interfere with the absorption of Chloroquine.
• Chloroquine is considered safe in pregnancy and for young children.
AMODIAQUINE (Class: 4 - aminoquinoline)
• Closely related to chloroquine and probable shares MOA and resistance.
• Widely used due to its low cost, limited toxicity and in some areas effective against chloroquine resistant strains of P.
falciparum.
• Toxicities that limit use include: agranulocytosis, aplastic anemia and hepatotoxicity. (uncommon)
• Most important current is combination therapy.
• Artesunate + Amodiaquine = first line therapy for treatment of uncomplicated falciparum malaria in many countries
in Africa.
• Increased toxicity with long term use.
• Short term season malaria prevention with Amodiaquine + Sulfadoxine – Pyrimethamine is recommended.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• Monthly treatment for 3-4 months during transmission season.

PIPERAQUINE (Class: Bisquinoline)
• Used widely to treat chloroquine resistant falciparum malaria in China in 1970s – 1980s.
• Dihydroartemisin + Piperaquine = efficacy and safety for the treat of falciparum malaria in South East Asia; first line
and leading treatment in Asia.
• Half-life: Piperaquine (28 days) > Amodiaquine (14 days) = Mefloquine (14 days) > Lumefantrine (4 days)
• Lead to a longer period of post treatment prophylaxis compared to other leading Artemisin based combinations.
• Advantageous in high transmission areas because it provides extended protection against malaria.
• Effective and safe for children and pregnant women in Africa.
ARTEMISINS AND ITS DERIVATIVES (Class: Sesquiterpene lactone endoperoxide)
• Qinghaosu; the active component of an herbal medicine that has been used as an antipyretic in China for more than
2000 years.
• Insoluble and can only be used orally.
• Analogs have increase solubility and improved antimalarial efficacy.
• Artemisinin resistance is not yet a widespread problem.
• ARTESUNATE: water soluble; PO, IV, IM, rectal
• ARTHEMETER: lipid soluble; PO, IM, rectal
• DIYHDROARTEMISIN: water soluble; PO
• Very rapidly acting blood schizonticides against all malarial parasites.
• Active against young, but not mature gametocytes
• MOA: antimalarial activity that result from the production of free radicals that follows the iron catalyzed cleavage of
the artemisinin endoperoxide bridge.
• Half-life after oral administration: 30 – 60 minutes (Artesunate and Dihydroartemisin); 2 – 3 hours (Artemether)
• Dihydroartemisin – is the active metabolite of Artemisin, Artesunate and Artemether
• Monotherapy for treatment of uncomplicated malaria is strongly discouraged.
• Artemether + Lumefantrine: COARTEM; new first line therapy in the USA for uncomplicated falciparum malaria;
not widely available
• IV Artesunate: available only through the CDC and will be released if there is indication of falciparum malaria with
sings of severe disease or inability to take oral medications.
• Artemisin based combinations therapy is now the standard of care for treatment of uncomplicated falciparum malaria in
nearly all endemic areas.

• 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.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

•
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.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• 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

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• High dose therapy entails significant toxicity in AIDS patients.

• Proguanil: mouth ulcers and alopecia.
• Fansidar: severe cutaneous reactions including erythema multiforme, Steven Johnsons syndrome and toxic epidermal
necrolysis.
• Folate antagonists should be used cautiously in the prescence of renal or hepatic dysfunction.
• Drugs safe in pregnancy; Fansidar should be give with high dose folate supplementation.
Antibiotics Against Malaria
• Tetracycline and Doxycycline are effective against erythrocytic schizonts; not active against liver stages
• Doxycycline is used to treat falciparum malaria in conjunction with Quinine; also used to complete treatment course of
IV Quine, Quinidine and Artesunate; 1 week treatment carried out; chemoprophylactic drug in areas of South East Asia
with high resistance to other antimalarials.
Commented [LL1]:
• Adverse effects of Doxycycline: GI symptoms, esophagitis, candida vaginitis and photosensitivity
• Clindamycin: given to those for whom doxycycline is not recommended; children and pregnant women
• Tetracycline and erythromycin: intestinal amebiasis
• Clindamycin: toxoplasmosis, pneumocystosis and babesiosis
• Spiramycin: macrolide antibiotic used to treat primary toxoplasmosis acquired during pregnancy.
HALOFANTRINE (Class: Phenanthrene methanol)
• Effective against erythrocytic but not other stages of malaria.
• Toxicity concerns when taken with meals.
• Half-life is 4 days
• Excreted via feces
• Not available in the US but FDA approved; available in malaria endemic countries
• Limited use because of cardiac toxicity --- prolongation of QT and PR intervals
• Contraindications: persons with cardiac conduction defects and those who have recently taken Mefloquine
LUMEFANTRINE (Class: Amyl alcohol)
• Fixed dose combination with Artemether (Coartem, Riamet)
• First line therapy for uncomplicated falciparum malaria in many countries.
• Coartem is approved in many nonendemic countries, including USA
• Half-life when combined: 3 -4 days
• Drugs levels may be altered by interaction with drugs that affect CYP324 metabolism.
• Lumefantrine is not associated with the toxicities of Halofantrine
• Coartem should be administered with fatty food to maximize antimalarial efficacy.
• Coartem is highly effective in treatment of falciparum malaria when administered twice daily for 3 days.
PYRONARIDINE (Class: Mannich based acridine)
• Used as monotherapy in China
• Combination with Artesunate (Pyramax)
• Half-life 8 days
• Primary renal elimination
• Efficacy against falciparum and vivax malaria.
• Adverse effects: eosinophilia and transaminitis
DRUGS FOR AMEBIASIS
1. Asymptomatic intestinal infection – not treated in endemic areas, in nonendemic areas treated with a luminal
amebicide; tissue amoebicidal drug is unnecessary; Standard luminal amebicides (DIP): Diloxanide furoate,
Iodoquinol and Paromomycin; eradication of 80 – 90%; Therapy of luminal amebicide is also required in
treatment of all other forms of amebiasis.
2. Amebic Colitis – Metronidazole + luminal amebicide --- Tx of choice of dysentery; alternative drugs for
moderate colitis but not effective against extraintestinal disease – tetracyclines and erythromycin;
Dehydroemetine or emetine can also be sued but avoided because toxicity.
3. Extraintestinal Infections – Metronidazole + luminal amebicide; 10-day course cures 95% of initial
uncomplicated liver abscesses; for failure of initial therapy aspiration of abscess and the addition of Chloroquine
should be considered
METRONIDAZOLE AND TINIDAZOLE (Class: Nitroimidazole)
• DOC for extraluminal amebiasis
• Kills trophozoites but not cysts of E. histolytica and effectively eradicates intestinal and extraintestinal tissue infections
• Tinidazole is a related nitroimidazole and appears to have a similar activity and a better toxicity profile.
• Peak plasma concentrations 1 – 3 hours.
• Protein binding of both is low (10 – 20%)
• Half-life of unchanged drug is 7.5 hours for Metronidazole; 12 – 14 hours for Tinidazole
• Plasma clearance is decreased with impaired liver function.
• Nitro group of Metronidazole: reduced by anaerobic bacteria and sensitive protozoans.
• MOA: reactive reduction products are responsible for antiprotozoal and antibacterial activity.
• Clinical Uses (AGT): Amebiasis, Giardiasis, Trichomoniasis
• Dosage for Giardiasis is lower than Amebiasis with better tolerance.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• 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)

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• Clinical Uses: Pneumocystosis, African trypanosomiasis (sleeping sickness), Leishmaniasis

• Well established alternative therapy for pulmonary and extrapulmonary disease by P. jirovecchi.
• Lower efficacy and greater toxicity compared to Trimethoprim- sulfamethoxazole.
• Standard dosage: 3mg/kg/day IV x 21 days
• Reserved for severe disease of pneumocystosis.
• Alternative agent for the primary or secondary prophylaxis against P. jirovecchi in AIDS and immunocompromised
patients.
• Pentamidine is the DOC to treat the early hemolymphatic stage of Trypanosoma brucei gambiense (West African
sleeping sickness)
• Inferior to Suramin for the treatment of East African sleeping sickness.
• Pentamidine should not be used to treat late trypanosomiasis with CNS involvement
• Dosage: 2 – 4 mg / kg/ daily x 10 – 15 doses
• Chemoprophylaxis for African trypanosomiasis 4mg /kg every 3 – 6 months
• Pentamidine is an alternative to sodium stibogluconate for treatment of Visceral Leishmaniasis; also successful for
Cutaneous Leishmaniasis but not routinely used.
• 2-4 mg / kg IM x 15 doses
• Pentamidines is highly toxic, adverse effects noted in 50% of patients receiving 4mg / kg / day.
• Rapid IV admin. = severe hypotension, tachycardia, dizziness and dyspnea (slow administration needed – over 2 hours
with patient in recumbent position)
• Pancreatic toxicity is common.
• Hypoglycemia due to inappropriate insulin release often appears 5 – 7 days after onset of treatment.
• Reversible renal insuffiency is also common.
• Over adverse effects: rash, metallic taste, fever, GI symptoms, abnormal liver function tests, acute pancreatitis,
hypocalcemia, thrombocytopenia, hallucinations and cardiac arrythmias.
• Inhaled pentamidine: generally, well tolerated but may cause cough, dyspnea and bronchospasm.
SODIUM STIBOGLUCONATE (Class: pentavalent antimonial)
• First line agents for cutaneous and visceral leishmaniasis except in India (Amphotericin and Miltefosine is
recommended)
• Initial elimination 2 hours
• Terminal half – life more than 24 hours
• 20 mg / kg IM or IV x 20 days = cutaneous leishmaniasis
• 20 mg / kg IM or IV x 28 days = visceral and mucocutaneous leishmaniasis
• Toxicity increases over the course of therapy.
• Adverse effects: GI symptoms, fever, headache, myalgias, arthralgias and rash.
• IM injections are very painful and can lead to sterile abscesses.
• T wave changes and QT prolongation – reversible but continued therapy may produce dangerous arrythmias.
NITAZOXANIDE (Class: nitro thiazolyl – salicylamide prodrug)
• Approved in the USA against Giardia lamblia and Cryptosporidium parvum
• MOA: Active metabolites inhibits the pyruvate-ferredoxin oxidoreductase pathway.
• Have activity against metronidazole resistant protozoal strains.
• Nitazoxanide appear to be free of mutagenic effects compared to Metronidazole.
• Organisms that are susceptible to Nitazoxanide: tape worms, E. histolytica, H. pylori, Ascaris lumbricoides, Fasciola
hepatica
• Recommended adult dosage is 500 mg twice daily x 3 days
OTHER DRUGS FOR TRYPANOSOMIASIS AND LEISHMANIASIS

SURAMIN (Class: sulfated naphthylamine)

• First line therapy for early hemolymphatic East African sleeping sickness (T. brucei rhodiense infection)
• Not effective against advances disease since it does not enter the CNS.
• Less effective than Pentamidine for West African Sleeping sickness
• IV administration; tight protein binding
• Short initial half-life; terminal half-life 50 days
• Slowly cleared by renal excretion
• Suramin is administered after a 200mg IV test dose.
• Combination therapy with Pentamidine may improve efficacy .

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• 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.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

Chapter 53: Anthelmintics

ALBENDAZOLE (Class: benzimidazole carbamate)
• Broad spectrum oral anthelminthic
• DOC in the USA for treatment of hydatid disease and cysticercosis.
• Undergoes first pass in the liver to the active metabolite albendazole sulfoxide.
• Max. plasma concentrations about 3 hours after 400 mg oral dose
• Plasma half-life 8 – 12 hours
• Sulfoxide is mostly protein bound; distributes well to tissues; enters bile, CSF and hydatid cysts.
• MOA: act against nematodes by inhibiting microtubule synthesis
• Has larvicidal effects – hydatid disease, cysticercosis, ascariasis and hookworm infection
• Has ovicidal effects – ascariasis, ancylostomiasis and trichuriasis.
• Administered on empty stomach = used against intraluminal parasites
• Administered with fatty meal = used against tissue parasites.
• Clinical uses: Ascariasis, trichuriasis, hookworm and pinworm infections ---Adults and children older than 2 years old
400 mg single dose PO daily x 2 - 3 days for heavy ascariasis infection and x 2 weeks for pinworm infection; For
hookworm and trichuriasis 400 mg PO once daily x 3 days
• Clinical uses: Hydatid cysts – useful adjunct to surgical removal or aspiration of cysts; more active against
Echinococcus granulosis > Echinococcus multilocularis; 400 mg BID with meals x 1 month
• Clinical uses: Neurocysticercosis – corticosteroid + antithelminthic drug to decrease inflammation caused by dying
organisms; Albendazole > Praziquantel due to shorter course, lower cost, improved penetration into the subarachnoid
space and increased drug levels when administered with corticosteroid; 400 mg BID x 21 days
• DOC for cutaneous larva migrans, visceral larval migrans, intestinal capillarisis, microsporidia infections
• Has activity against taeniasis
• Included in the programs to control lymphatic filariasis.
• Recommended empiric therapy to treat those who return from tropics with persistent unexplained eosinophilia
• Has activity against Giardiasis but decreased efficacy vs Tinidazole.
• 1 – 3-day therapy = free of significant adverse effects
• Blood counts and liver function should be monitored during long-term therapy.
• DO NOT GIVE TO CIRRHOTIC PATIENTS.
• Exposure to albendazole is increased by = dexamethasone, praziquantel and cimetidine
• Exposure to albendazole is decreased by = phenytoin, phenobarbital, carbamazepine and ritonavir
BITHIONOL
• Alternative to Triclabendazole for treatment of Fascioliasis
• Alternative to Praziquantel for treatment of Paragonimiasis
• Peak blood level 4 – 8 hours
• Excretion mainly via kidney
• Dosage is 30 – 50 mg / kg x 2 or 3 divided doses given orally after meals on alternate days for 10 – 15 doses
• Pulmonary paragonimiasis = 90% cure rate
• Cerebral paragonimiasis = repeated courses may be necessary
• Adverse effects 40% of patients; mild and transient
• If severe== will interrupt therapy: diarrhea, abdominal cramps, anorexia, nausea and vomiting, dizziness and headache
• Rashes after 1 week or more of therapy suggest a reaction to antigens release from dying worms.
• Use with CAUTION: children younger than 8 years
DIETHYLCARBAMAZINE CITRATE (Class: synthetic piperazine derivative)
• DOC for Filariasis, Loiasis and Tropical eosinophilia
• Replaced by Ivermectin for treatment of Onchocerciasis
• Peak plasma levels 1 – 2 hours.
• Plasma half -life 2 - 3 hours in acidic urine; 10 hours if urine is alkaline ( Henderson – Hasselback trapping effect)
• Drug rapidly equilibrates with all tissues except fat.
• Excreted unchanged in the urine; renal dosage adjustment needed for kidney impairment.
• MOA: immobilizes microfilariae and alters their surface structure displacing them from tissues and making them more
susceptible to destruction by host defense mechanisms.
• The drug should be taken after meals.
• Clinical Uses: Wuchereria bancrofti, Brugia malayi, Brugia timori and Loa loa
• Combined with Ivermectin o Albendazole – reduce W. bancrofti prevalence
• Effective against Mansonella streptocerra infections
• Reactions to dying microfilariae are mild in W. bancrofti, more intense in B. malayi and occasionally severe in L. loa.
• Reactions include: fever, malaise, papular rash, headache, GI symptoms, cough, chest pain, and muscle or joint pain.
• Leukocytosis is common and eosinophilia may increase with treatment.
DOXYCYCLINE
• Macrofilaricidal effect against W. bancrofti
• Better activity than any other drug against adult worms.
• Activity also seen against Onchocerciasis.
• MOA: acts indirectly by killing Wolbachia, an intracellular symbiont of filarial parasites

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• Important for treatment of active disease and in mass chemotherapy campaigns.

IVERMECTIN (Class: semisynthetic macrocyclic lactone)
• DOC in strongyloidiasis and onchocerciasis.
• Derived from soil Actinomycete
• Only available in oral administration.
• Max. plasma concentrations after 12 hours after a 12 mg dose
• Wide tissue distribution and volume distribution 50L.
• Half-life is 16 hours.
• Excretion of drug via feces.
• MOA: paralyze nematodes and arthropods by intensifying GABA mediated transmission of signals in peripheral
nerves.
• In onchocerciasis: Ivermectin is microfilaricidal; does not effectively kill adult worms but blocks the release of
microfilariae for some months after therapy.
• After acute therapy treatment is repeated at 12-month intervals until adult worms die – takes 10 years or longer.
• With first treatment only, patients with microfilariae in the cornea or anterior chamber may be treated with
corticosteroids to avoid inflammatory eye reactions.
• Also effective in controlling scabies, lie, and cutaneous larva migrans and eliminates large proportion of ascarid worms.
• Adverse effects are from reactions of dying worms. Starts 1st day and peaks at the second day.
• More intense reactions: high fever, hypotension and bronchospasm.
• Best to avoid the use of Ivermectin with other drugs that enhance GABA activity – barbiturates, benzodiazepines
and valproic acid.
• Ivermectin should not be used during pregnancy.
MEBENDAZOLE (Class: synthetic benzimidazole)
• Wide spectrum, of anthelmintic activity and low incidence of adverse effects.
• The drug kills hookworm, Ascaris and Trichuris eggs.
• 90% protein bound; rapidly converted to in active metabolites during hepatic first pass
• Half-life 2 – hours
• Excreted primarily in urine and also in bile.
• Absorption increased when ingested with a fatty meal.
• MOA: acts by inhibiting microtubule synthesis.
• Efficacy of the drug varies with GI transit time, intensity of infection and perhaps with strain of parasite.
• Clinical Uses: Ascariasis, Trichuriasis, Hookworm and Pinworm infections.
• Can be taken before or after meals; tablets should be chewed before swallowing,
• Pinworm infection: 100 mg once, repeated at 2 weeks
• Ascariasis, Trichuriasis, Hookworm and Trichostrongylus infections: 100g BID x 3 days
• Cure rates are good for pinworm infections and ascariasis.
• Low cure rates for hookworm—decrease worm burden
• Mebendazole is TERATOGENIC in animals and contraindicated in pregnancy,
• Used with CAUTION in patients with CIRRHOSIS.
• Plasma levels decrease with concomitant use: carbamazepine, phenytoin or ritonavir
• Plasma levels increase with concomitant use: cimetidine
METRIFONATE (Class: organophosphate)
• Safe and low-cost alternative drug for the treatment of Schistosoma haematobium.
• Not active against Schistosoma mansoni and Schistosoma japonicum.
• Rapidly absorbed after oral dose; peak blood level 1 -2 hours
• Half-life 1.5 hours
• Clearance through nonenzymatic transformation to dichlorvos, active metabolite.
• Completely eliminated in 24 – 48 hours.
• MOA: cholinesterase inhibition, temporarily paralyzing adult worms resulting in their transit from bladder
vasculature to small arterioles in the lungs where they are killed.
• Not effective against S. haematobium eggs; live eggs will continue to pass in the urine for several months after all
adult worms have been killed.
• Also effective as a prophylactic and used in mass treatment programs.
• For mixed haematobium and mansoni infections= metrifonate + oxamniquine
• Mild and transient cholinergic symptoms: nausea and vomiting, diarrhea, abdominal pain, bronchospasm, headache,
sweating, fatigue, weakness, dizziness and vertigo.
• SHOULD NOT BE USED AFTER RECENT EXPOSURE TO INSECTICIDES OR DRUGS THAT
POTENTIATE CHOLINESTERASE INHIBITION.
• Contraindicated in pregnancy.
NICLOSAMIDE (Class: salicylamide derivative)
• Second line drug for the treatment of most tapeworm infections.
• Adult worms, but not ova, are rapidly killed.
• MOA: due to inhibition of oxidative phosphorating or stimulation of ATPase activity.
• Adult dose is 2g, give once in the morning on an empty stomach.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

• Tablets must be chewed thoroughly and then swallowed with water.

• Clinical Uses: Beef tapeworm, pork tapeworm (95% cure rate), fish tapeworm (85% cure rate), dwarf tapeworm
(Praziquantel is a superior DOC); intestinal fluke infections
• Niclosamide is not effective against cysticercosis or hydatid disease.
• Alcohol should not be consumed during or 1 day after treatment.
OXAMNIQUINE (Class: semisynthetic tetrahydroquinoline)
• Alternative to Praziquantel for treatment of Schistosoma mansoni infections.
• Has been effective in instances of Praziquantel resistance.
• Not effective against Schistosoma japonicum and haematobium.
• Drug should be taken by food. Half-life 2.5 hours.
• Extensively metabolized to inactive metabolites and excreted in urine; 75% in first 24 hours.
• Active against both mature and immature stages of S. mansoni but does not appear to be cercaricidal.
• Contraction and paralysis of the worms’ results in detachment from terminal venules in the mesentery and transit to the
liver where many die; surviving females return to mesenteric vessels but cease to lay eggs.
• Drug is safe and effective in all stages of S. mansoni disease including hepatosplenomegaly.
• CNS symptoms are most common (dizziness or drowsiness); also: diarrhea colic, pruritus and urticaria.
• CAUTION in patients whose work or activity requires mental alertness (no driving for 24 hours.
PIPERAZINE
• Alternative for treatment of Ascariasis
• Cure rates over 90% when taken 2 days
• Not recommended for other helminth infections.
• Max. plasma levels 2 – 4 hours.
• Most excreted unchanged in urine in 2 – 6 hours; excretion complete in 24 hours.
• MOA: causes paralysis of ascaris by blocking acetylcholine at myoneural junction; live worms are expelled by
peristalsis.
• SHOULD NOT BE GIVEN TO: pregnant women, patients with impaired renal or hepatic function or those with a
history of epilepsy or chronic neurologic disease.
PRAZIQUANTEL (Class: synthetic isoquinoline-pyrazine derivative)
• Effective in the treatment of schistosome infections of all species and most other trematode and cestode infections,
including cysticercosis
• Effective against adult worms and immature stages.
• Prophylactic against cercarial infection.
• Bioavailability 80% after oral administration.
• Peak serum concentrations 1 – 3 hours.
• CSF concentrations reach 14 – 20-% of drug’s plasma concentration.
• 80% of drug is bound to plasma proteins.
• Half-life is 0.8 – 1.5 hours.
• Excretion mainly via kidney (60 – 80%) and bile (15 – 35 %)
• Plasma concentration increase: high carbohydrate meal or taken with Cimetidine
• Bioavailability reduced by: phenytoin, carbamazepine or corticosteroids
• MOA: appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis,
dislodgement and death.
• Drug is taken with liquid after a meal, swallowed without chewing because bitter taste can induce retching and
vomiting.
• Clinical Uses: Schistosomiasis, Clonorchiasis, Opsithorchiasis, Paragonimiasis, Taeniasis (Praziquantel does not kill
eggs) and Diphyllobrothiasis.
• Neurocysticercosis – Albendazole is preferred drug but Praziquantel has similar efficacy.
• Praziquantel has diminished bioavailability when taken with corticosteroid.
• Praziquantel is the DOC and first drug to be highly effective against H. nana (dwarf tapeworm).
• Praziquantel is contraindicated in ocular cysticercosis because parasite destruction in the eye may cause irreparable
damage.
• Praziquantel can induce dizziness and drowsiness.
PYRANTEL PAMOATE (Class: tetrahydropryrimidine derivative)
• Broad spectrum anthelminthic
• Highly effective for treatment of Pinworm, Ascaris and Trichostrongylus
• Moderately effective against both species of Hookworm.
• Not effective against Trichuriasis or Strongyloidiasis.
• Oxantel Pamoate: analog; better efficiency against Trichuriasis than any other single agent.
• Peak plasma levels 1 – 3 hours
• Effective against mature and immature forms of susceptible helminths within the intestinal tract.
• Not effective against migratory stages in the tissues or against ova.
• MOA: neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase that results
in paralysis of worms followed by expulsion.
• Use with CAUTION in patients with liver dysfunction.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

THIABENDAZOLE (Class: benzimidazole compound)

• Alternative to Ivermectin or Albendazole for treatment of Strongyloidiasis and Cutaneous larva migrans.
• Chelating agent that forms stable complexes with a number of metals, including iron, it does not bind calcium.
• Plasma peak within 1 – 2 hours.
• Half-life 1.2 hours
• 90% excreted in urine in 48 hours.
• Drug can also be absorbed from the skin.
• MOA: inhibition of microtubule synthesis.
• The drug has ovicidal effects against some parasites.
• Drug should be given after meals and tablets should be chewed.
• For Strongyloides infection, treatment is for 2 days.
• Cure rates are 93 %.
• Topical administration for cutaneous larva migrans; or oral drug (but albendazole is preferred)
• More toxic than other benzimidazoles, more toxic than Ivermectin.
• Should not be used: pregnancy, hepatic or renal disease.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

Chapter 56: Introduction to Clinical Toxicology: Environmental and Occupational

SPECIFIC CHEMICALS
AIR POLLUTANTS
CARBON MONOXIDE (52% of air pollution): colorless, tasteless, odorless and non-irritating gas; a
byproduct of incomplete combustion.
1. Mechanism of Action: CO combines tightly but reversibly with the oxygen biding sites of
Hemoglobin and has affinity for hemoglobin 220 times that of oxygen—product formed is
“carboxyhemoglobin”, which cannot transport oxygen and interferes with the disassociation of
oxygen from remaining oxyhemoglobin as a result of Bohr Effect. Resulting to decreased
oxygen delivery to tissues. Organs with highest oxygen demand are most affected ( brain, heart
kidneys)
2. Clinical Effects:
o Principal sign – hypoxia
o (1) psychomotor impairment
o (2.) headache and tightness in the temporal area
o (3.) confusion and loss of visual acuity
o (4.) tachycardia, tachypnea, syncope and come
o (5.) deep coma, convulsions, shock and respiratory failure.
o Carboxyhemoglobin level below 15%: headache and malaise
o Carboxyhemoglobin at 25%: headache, fatigue, decreased attention span and loss of
fine motor coordination.
o Carboxyhemoglobin level above 60%: death may ensue as a result of irreversible
damage to the brain and myocardium.
o Aggravating factors: heavy labor, high altitudes and high ambient temperatures.
3. Treatment:
o Remove patient from CO exposure immediately.
o High flow respiration and concentration of oxygen – specific antagonist to CO
o If with respiratory failure – mechanical ventilation
SULFUR DIOXIDE (14% air pollution): colorless irritant gas generated primarily by combustion of
sulfur containing fossil fuels; principal source of urban SO2 is burning of coal, for domestic heating or
from coal fired power plants.
1. Mechanism of Action: High solubility of SO2 enables it to get in contact with moist
membranes, where it transiently forms sulfurous acid--- severe irritant effects on the eyes,
mucous membranes and skin. The site of principal effect is upper respiratory tract. Inhalation
causes bronchial constriction and produces profuse bronchorrhea; parasympathetic reflexes and
altered smooth muscle tone appears to be involved. The clinical outcome is “acute irritant
asthma”.
2. Clinical Effects
o Exposure to 5ppm SO2 for 10 minutes = increased resistance to airflow in most
humans.
o Exposure between 5 – 10 ppm = cause severe bronchospasm.
o S/sx: irritation of the eyes, nose, throat; reflex bronchoconstriction and increased
bronchial secretions.
o In asthmatic patients’ exposure may result in an acute asthmatic episode.
o Severe exposure = delayed onset pulmonary edema
3. Treatment
o None specific but depends on therapeutic maneuvers used to treat irritation of the
respiratory tract and asthma.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

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.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

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

1. Mechanism of Action: inhibition of acetylcholinesterase and acute accumulation of

acetylcholine; also phosphorylates neuropathy target esterase in neural tissue – leads to
progressive demyelination of the longest nerves.
2. Clinical Effects: (Chronic) Neuromuscular transmission failure that leads to weaking of
respiratory muscles; polyneuropathy that begins as burning and tingling sensations in the feet
and progress to motor weakness
3. Treatment: Physostigmine and cholinergic antagonists for acute intoxication.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

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

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

CHELATORS IN HEAVY METAL INTOXICATION / POISONING

- Drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to
accelerate the elimination of the metal from the body.
- By forming a complex with the heavy metal, the chelating agent renders the metal unavailable for toxic interactions with
functional groups of enzymes or other proteins, coenzymes, cellular nucleophiles, and
membranes.
- Metal-mobilizing effect of a therapeutic chelating agent may not only enhance that metal’s excretion—a
desired effect—but may also redistribute some of the metal to other vital organs.
- Although several chelating agents have the capacity to mobilize cadmium, their tendency to redistribute cadmium to the
kidney and increase nephrotoxicity has negated their therapeutic value in cadmium intoxication.
LEAD (SKELETON) – EDTA AND DIMERCAPROL; SUCCIMER symptomatic lead
intoxication without encephalopathy. --- CNS, ANEMIA, PERIPHERAL NEUROPATHY;
HYPERTENSION, REPRODUCTIVE TOXICITY
ARSENIC (LIVER) – UNITHIOL / DIMERCAPROL; SUCCIMER has a higher therapeutic index
but available only PO so not advisable in acute arsenic poisoning where there is severe gastroenteritis
and splanchnic edema; CARDIOVASCULAR SHOCK; ARRHYTMIA; CNS ENCEPHALOPATHY;
GASTROENTERITIS; PANCYTOPENIA; METABOLIC ACIDOSIS
- Arsine Gas = massive intravascular hemolysis --- massive effects on respiration, oliguric renal failure;
chelating agents have no clinical value
MERCURY (KIDNEY) – IV (Unithiol), IM (Dimercaprol), PO (Succimer); ACUTE
GINGIVOMATITIS; CHEMICAL PNEUMONITIS; Chronic inhalation of mercury vapor: (triad)
tremor, neuropsychiatric disturbance and gingivomatitis.
Erethism: behavioral pattern of insidious change of mood to shyness, withdrawal and depression along
with explosive anger or blushing.
Acrodynia: mainly occurs in children; painful erythema of the extremities and many be associated
with hypertension, diaphoresis, anorexia, insomnia, irritability or apathy and a miliary rash.
- Mercuric chloride: corrosive and potentially life-threatening hemorrhagic gastroenteritis followed by
acute tubular necrosis and oliguric renal failure.
-Methyl mercury: CNS; paresthesia, ataxia, hearing impairment, dysarthria and progressive constriction
of the visual fields; high dose prenatal exposure = cerebral palsy like syndrome in offspring
Unithiol and Succimer increase urine mercury excretion.
Dimercaprol redistributes mercury to the CNS from other tissue sites and should not be used in
elemental or organic mercury intoxication.
DIMERCARPOL (2, 3 – DIMERCAPTOPROPANOL)
• British anti-lewisite, or BAL.
• oily, colorless liquid with a strong, mercaptan-like odor
• in Great Britain during World War II
• therapeutic antidote against poisoning by the arsenic-containing warfare agent lewisite.
• administered by intramuscular injection, which is often painful
• MOA: prevents and reverses arsenic induced inhibition of sulfhydryl-containing enzymes and,
if given soon after exposure, may protect against the lethal effects of inorganic and organic
arsenicals.
• Therapeutic benefit: increase the rate of excretion of arsenic and lead; treatment of acute
intoxication by arsenic, lead, and mercury; treatment of severe lead poisoning when used in
conjunction with edetate calcium disodium (EDTA)
• dimercaprol may redistribute arsenic and mercury to the central nervous system, and it is not
advocated for treatment of chronic poisoning.
• Adverse effects: hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever
(Particularly in children), and pain at the injection site; thrombocytopenia and increased
prothrombin time—factors that may limit intramuscular injection because of the risk of
hematoma formation at the injection site.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

SUCCIMER (DIMERCAPTOSUCCIBIC ACID, DMSA)

• water-soluble analog of dimercaprol
• MOA: increase in urinary lead excretion and a decrease in blood lead concentration; may also
decrease the mercury content of the kidney, a key target organ of inorganic mercury salts.
• Administered PO
• Therapeutic benefit: approved for the treatment of children with blood lead concentrations
>45 mcg/dL, but it is also commonly used in adults.
• Oral administration of Succimer is comparable to parenteral EDTA in reducing blood lead
concentration and has supplanted EDTA in outpatient treatment of patients who are capable of
absorbing the oral drug.
• Adverse effects: Gastrointestinal disturbances, including anorexia, nausea, vomiting, and
diarrhea
EDETATE CALCOUM DISODIUM (EDTA)
• Efficient chelator of many divalent and trivalent metals in vitro.
• To prevent potentially life-threatening depletion of calcium, treatment of metal intoxication
should only be performed with the calcium disodium salt form of EDTA (edetate calcium
disodium).
• MOA: EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular
metal ions much more effectively than intracellular ions.
• EDTA should be administered by intravenous infusion.
• Therapeutic benefit: mobilizes lead from soft tissues, causing a marked increase in urinary
lead excretion and a corresponding decline in blood lead concentration; have usefulness in
poisoning by zinc, manganese, and certain heavy radionuclides.
• Contraindicated in anuric patients.
UNITHIOL (DIMERCAPTOPROPANESULFONIC ACID, DMPS)
• dimercapto chelating agent that is a water-soluble analog of dimercaprol
• increases the excretion of mercury, arsenic,
• increases the excretion of mercury, arsenic and lead in humans.
• Intravenous unithiol offers advantages over intramuscular dimercaprol or oral Succimer in
the initial treatment of severe acute poisoning by inorganic mercury or arsenic.
• Oral unithiol may also be considered as an alternative to oral Succimer in the treatment of
lead intoxication.
• Adverse effects: Self-limited dermatologic reactions (drug exanthems or urticaria); rapid
intravenous infusion may cause vasodilation and hypotension
PENICILLAMINE (D- DIMETHLCYSTEINE)
• white, crystalline, water-soluble derivative of penicillin; readily absorbed from the gut and is
resistant to metabolic degradation.
• Indication: used chiefly for treatment of poisoning with copper or to prevent copper
accumulation, as in Wilson’s disease (hepatolenticular degeneration); used occasionally in the
treatment of severe rheumatoid arthritis
• MOA: increase urinary excretion of lead and mercury had occasioned its use in outpatient
treatment for intoxication with these metals.
• Succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has
generally replaced penicillamine for these purposes
• Adverse effects: Hypersensitivity reactions include rash, pruritus, and drug fever, and the drug
should be used with extreme caution, if at all, in patients with a history of penicillin allergy.
• Pancytopenia has been associated with prolonged drug intake.
• Pyridoxine deficiency is a frequent toxic effect of other forms of the drug but is rarely seen
with the " isomer.

LUNOD MEDICO SANGUINE

Reference: Katzung Basic Clinical Pharmacology 14th ED

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.

LUNOD MEDICO SANGUINE

PHARMA RENAL ASSESSMENT NOTES - LUNOD

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-
-

Negative bacilli, Enterobacteria (E. coli, Salmonella, Shigella) Ess

-

cNo=
-

13. Examples of Second-Generation Fluoroquinolones? Ans. Ciprofloxacin, Norfloxacin, Ofloxacin

14. What is the difference between 1st Generation and 2nd Generation fluoroquinolones? Ans. 2nd
Generation has improved intracellular penetration and broadened coverage
15. What organisms are susceptible against 2nd generation fluroquinolones? Ans. Enterobacteria,
Pseudomonas aeruginosa, Haemophilus influenza, Neisseria spp., Chlamydia spp., Legionella
←
- - -
spp. (E-PHNCL)
16. Example of Third-Generation Fluoroquinolone? Ans. Levofloxacin
17. What is the bacterial spectrum of Third-Generation Fluoroquinolones? Ans. Bacterial spectrum of
2nd Gen agents + improved activity against: Streptococcus spp., S. pneumoniae, methicillin
susceptible Staphylococcus aureus, Stenotrophomonas maltophilia and Mycobacterium spp.
18. What is the great advantage of 4th Generation Fluoroquinolones? Ans. Enhanced activity against
gram positive bacteria and has activity against MRSA, Enterococcus faecalis and Pseudomonas
aeruginosa (MEP)
19. Examples of Fourth-Generation Fluoroquinolones? Ans. Moxifloxacin, Gemifloxacin,
Delafloxacin

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

Urinary Tract Antiseptics (Methenamine, Nitrofurantoin, Fosfomycin)

1. Drug is hydrolyzed to ammonia and formaldehyde in acidic urine. Ans. Methenamine
2. What is the mechanism of action of formaldehyde in Methenamine? Ans. Denatures proteins and
nucleic acids resulting in bacterial cell death.
3. Methenamine is combined with a weak acid, for example, hippuric acid because? Ans. To
maintain urine acidity and promote production of formaldehyde
4. What is the primary use of Methenamine? Ans. Chronic suppressive therapy to reduce frequency
of UTIs.
5. Methenamine is active against? Ans. E. coli, Enterococcus spp., Staphylococcus spp. (EES)
6. Urine pH must be kept acidic to achieve bactericidal activity against what organisms? Ans.
Proteus spp. and Pseudomonas aeruginosa
7. What is the main benefit of methenamine? Ans. Lack of selection for resistant organisms
8. Due to ammonia formation, methenamine should be avoided in patients with? Ans. Hepatic
insufficiency
9. What is the major adverse effect of methenamine? Ans. GI distress
10. Methenamine mandelate is contraindicated in patients with? Ans. Renal insuffiency
11. When the patient has renal impairment what methenamine formulation should be used? Ans.
Methenamine hippurate
12. At higher doses, what are the adverse effects of methenamine? Ans. Albuminuria, hematuria and
rashes
13. Why are sulfonamides, such as cotrimoxazole not to be used concomitantly with methenamine?
Ans. The combination increases risk for crystalluria and mutual antagonism .
14. Nitrofurantoin was introduced into clinical practice in the 1950s for the management of?
Ans. Cystitis
15. Why is the use of nitrofurantoin increasing today? Ans. Because of the rise of antibiotic
resistance among enterobacteria.
16. Nitrofurantoin is considered first line therapy for? Ans. Uncomplicated cystitis
17. What is the mechanism of action of Nitrofurantoin? Ans. Works by inhibiting DNA and RNA
synthesis
18. What is the antibacterial spectrum of Nitrofurantoin? Ans. E. coli, Klebsiella spp.,
Staphylococcus spp. (EKS)

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.