PHARMACOLOGY INTRODUCTION

- Pharmacology
o The study of the effects of drugs and their action on living organisms
o Toxicology
 The branch of pharmacology that deals with the undesirable effects of chemicals on living
systems, from individual cells to humans to complex ecosystems
 Poisons
 Drugs that have almost exclusively harmful effects
 Paracelsus - The dose makes the poison
 Toxins
 Poisons of biologic origin like those synthesized by plants and animals

- Drug Names
Drug Name Example Explanation
Chemical name (scientific Example: ethyl 4-(8-chloro-5,6- Gives the exact chemical makeup of the drug and
name) dihyfro-11 H- placing of the atoms or molecular structure; the
benzo[5,6]cyclohepta[1,2-b]- chemical name is not capitalized
pyridin-11-ylidene)-1-
piperidinecarboxylate
Generic name Example: Loratadine Name given to a drug before it becomes official;
(nonproprietary) may be used in all countries, by all manufacturers,
the generic name is not capitalized
Official name Example: Loratadine Name listed in the United States Pharmacopeia –
National Formulary; may be the same as the generic
name
Trade name (brand name) Example: Claritin® Name that is registered by the manufacturer and is
followed by the trademark symbol; the name can be
used only by the manufacturer; a drug may have
several trade names, depending on the number of
manufacturers; the first letter of the trade name is
capitalized

- Routes of administration
o Enteral
 Term used to describe drugs given via GIT
o Parenteral
 Drugs delivered by injection

Route Advantages Disadvantages

Enteral
Oral Convenient Often low bioavailability following first-pass
metabolism by liver
Cost-effective More difficult to adjust plasma concentration
Relatively safe Requires a functional GI tract
Desired therapeutic concentration is
achieved gradually
Rectal Useful when patient is vomiting Not well accepted
Can be used in the unconscious patient Irregular absorption can compromise safety
Limited first-pass metabolism Irritation to rectal mucosa
Relatively painless
Tolerated well in children
Sublingual (buccal) Rapid absorption Only useful for small amount of drug
Avoids first-pass metabolism Requires prolonged contact with mucosa
Unpleasant taste

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Parenteral
Intravenous Allows for rapid administration of a Drug cannot be recalled once administered
precise amount of drug
Avoids first-pass metabolism More complications from administration (e.g.,
infection and hematoma)
Dosage is easily adjusted Adverse reactions more likely, so monitoring by
clinician is vital
Suitable for large volumes IV access often difficult to establish
Very useful in the unconscious patient
No issues with compliance by patients
Intramuscular Relatively easy to administer Painful
Fairly rapid absorption under normal Can cause nerve damage
circumstances
May be used to deliver depot injections, Can cause bleeding, so contraindicated in
where the active compound of a drug is bleeding disorders
released consistently over time
Can only be used for relatively small injection
volumes
Subcutaneous Easy to administer Can only be used for very small volumes of drug
Slow and constant absorption Potential tissue irritation
Minimal pain involved
May be used to deliver depot injections,
where the active compound of a drug is
released consistently over time
Other Methods
Topical Applied to various surfaces, commonly May cause irritation
the skin, eyes, nose, and vagina, to
produce a local effect
Transdermal Controlled release preparations may be Rate of absorption variable
used via this mode of application
Can achieve systemic effects May cause irritation
Inhalation Rapid absorption
Ideal for drugs that can be administered Variable systemic distribution (not considered a
as an aerosol disadvantage for the current drugs administered
by this route
Ideal for treating lung disease, as drug is May cause irritation of the respiratory tract
essentially exerting a local effect

- Drug classes and categories

o Prescription drugs
 Also called legend drugs
 Drugs designated as potentially harmful unless their use is supervised by a licensed
healthcare provider, such as a physician, dentist, nurse practitioner or a prescribing
pharmacist
 The largest category of drugs and are prescribed by a licensed healthcare provider
 Some information in the prescription
 Name of the drug
 The dosage
 Method of administration
 Frequency of administration
 Signature of the licensed healthcare provider
o Nonprescription drugs
 Also called over-the-counter drugs or OTC drugs
 Designated as safe (when taken as directed) and can be obtained without a prescription
o Controlled substances
 Most carefully monitored of all drugs
 These drugs have high potential for abuse and may cause physical or psychological
dependency
 Physical dependence
 The habitual use of a drug, in which the negative physical withdrawal symptoms
result from abrupt discontinuation; it is the body’s dependence on repeated
administration of a drug

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  Psychological dependence
 A compulsion or craving to use a substance to obtain a pleasurable experience; it is
the mind’s desire for the repeated administration of a drug

- Orphan drug
o Drugs for rare diseases affecting fewer than 200,000 individuals (in the US) so the cost of producing
and marketing a drug to treat the condition would not be recovered by sales of the said drug

- Drug activity within the body

o Pharmaceutic phase
 The drug dissolves
 Drugs must be soluble to be absorbed
 Drugs that are liquid or drugs given by injection (parenteral drugs0 are already dissolved and
are absorbed quickly
 A tablet or capsule (solids) goes through this phase as it disintegrates into small particles and
dissolves into the body fluids in the GI tract
 Tablets that have an enteric coating or time-release capsules do not disintegrate until they
reach the alkaline environment in the small intestine
o Pharmacokinetic phase
 Refers to the activities within the body after a drug is administered
 Includes the following:
 Absorption
o Follows administration and is the process by which a drug is made available
for use in the body
o Ways of absorption:
 Active transport
 Cellular energy is used to move the drug from an area of
low concentration to one of high concentration
 Passive transport
 No cellular energy is used as the drug moves from an area
of high concentration to an area of low concentration small
molecules diffuse across the cell membrane0)
 Pinocytosis
 Cells engulf the drug particle (the cell forms a vesicle to
transport the drug into the inner cell)
 Endocytosis and exocytosis
 Transport drugs of exceptionally large size across the cell
membrane
 Facilitated diffusion
 Other agents can enter the cell through specialized
transmembrane carrier proteins that facilitate the passage
of large molecules
 Distribution
o Through systemic circulation
o Factors that affect distribution
 Protein binding
 Drug comes in contact with plasma protein albumin, it may
be:
o Free
 Produces the therapeutic effect
o Bound to protein
 Highly protein bound drug is said to be
bound by more than 80%
 Α1 acid glycoprotein
 Blood flow
 A drug is distributed quickly to areas with a large blood
supply:
o Heart
o Liver
o Kidneys

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  Other areas that are less vascular will give slow distribution:
o Internal organs
o Skin
o Muscle
 Solubility
 Lipid soluble
o Drugs easily cross the cell membrane
 Water soluble
o Drugs do not easily cross the cell membrane
o Volume of distribution
 Pharmacological term that is defined as the volume in which a drug
would need to be uniformly distributed to produce the same
concentration throughout the body as found in plasma
 Metabolism
o Also called biotransformation
o The process by which the body changes a drug to a more or less active form
that can be excreted
o Metabolite
 An inactive form of the drug that is excreted
o Phases
 Phase 1 metabolism
 Converts a drug to a less active form
 Involves the oxidation, reduction or hydrolysis of a drug,
making it more polar by adding or exposing a functional
group (-OH, -NH2, -SH, -COO-) where these functional
groups can act as the site of conjugation
 Phase 2 metabolism
 Drug conjugations
 Excretion
o Elimination of drugs from the body
o Kidney
 The main organ involved in excretion
o Children have immature kidney function and may require dosage reduction
and kidney function tests
Half-life
 The time required for the body to eliminate 50% of the drug
 Measure of the rate at which drugs are removed from the body
 First-pass effect
 When a drug is absorbed by the small intestine, it travels to the liver before being
released to circulate to the rest of the body
 Three factors that are important when considering a drug’s pharmacokinetics:
 Onset of action
o Time between administration of the drug and onset of its therapeutic effect
 Peak concentration
o When absorption rate equals the elimination rate (not always the time of
peak response)
 Duration of action
o Length of time the drug produces a therapeutic effect
o Pharmacodynamic phase
 The study of the drug mechanisms that produce biochemical or physiologic changes in the
body
 Most drugs produce more than one effect in the body
 Primary effect
 The desired or therapeutic effect
 Secondary effect
 All the other effects, desirable or undesirable, produced by the drug
 Target sites
 Specific areas where most drugs have an affinity where they exert their greatest
action at the cellular level

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 o Pharmacogenomics
 Also called pharmacogenetics (?, from Katzung)
 The study of how people’s responses to medications are variable due to individual genetic
variation

- Bioavailability
o The fraction of the administered dose of a drug that reaches the systemic circulation in an unchanged
form

- Drug reactions
o Adverse drug reaction
 Undesirable drug effects
 May be any of the following:
 Mild
 Severe
 Life-threatening
 Often, an adverse reaction is unpredictable, although some drugs are known to cause certain
adverse reactions in many patients
 Side effects
 Explain mild, common and nontoxic reactions
 Adverse reactions
 Describe more severe and life-threatening reactions
o Allergic drug reaction
 An immediate hypersensitivity reaction
 Usually begins to occur after more than one dose of the drug is given
 Occurs because the individual’s immune system responds to the drug as a foreign substance
 Antigen
o The foreign substance
 Antibodies
o Protein substances in the body that protect against antigens
 Anaphylactic shock
 Extremely serious allergic drug reaction that usually occurs shortly after the
administration of a drug to which the individual is sensitive
 Can be fatal if the symptoms are not identified and treated immediately
 Symptoms of anaphylactic shock
Body Systems Symptoms
Respiratory Bronchospasm
Dyspnea (difficult breathing)
Feeling of fullness in the throat
Cough
Wheezing
Cardiovascular Extremely low blood pressure
Tachycardia (heart rate > 100 bpm)
Palpitations
Syncope (fainting)
Cardiac arrest
Integumentary Urticaria (hives)
Angiodema
Pruritus (itching)
Sweating
Gastrointestinal Nausea
Vomiting
Abdominal pain
 Treatment of anaphylactic shock
o Raise blood pressure
o Improve breathing
o Restore cardiac function
o Treat other symptoms as they occur
 Epinephrine (adrenalin)
o May be given by subcutaneous injection in the upper extremity or thigh and
may be followed by continuous IV infusion

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  Fluids and vasopressors
o Treats hypotension and shock
 Bronchodilators
o Given to relax the smooth muscles of the bronchial tubes
 Antihistamines and corticosteroids
o Given to treat urticaria and angiodema
 Angiodema
 Also called angioneurotic edema
 Manifested by the collection of fluid in subcutaneous tissues
 Areas most commonly affected
o Eyelids
o Lips
o Mouth
o Throat
 Dangerous because swelling may block airway and asphyxia may occur
o Drug idiosyncrasy
 The term used to describe any unusual abnormal reaction to a drug
 It is any reaction that is different from the one normally expected from a specific drug and
dose
 Cause is not clear and believed to be related to pharmacogenetics
o Drug tolerance
 Term used to describe a decreased response to a drug, requiring an increase in dosage to
achieve the desired effect
 Common in the following drugs
 Tranquilizers
 Opioids
 Sign of a physical dependence
 May occur in hospitalized patients
o Cumulative drug effect
 Usually seen in people with kidney or liver disease because these sites are for breakdown
and excretion
 Occurs when the body is unable to metabolize and excrete one (normal) dose of a drug
before the next dose is given so if a second drug is given, some drug from the first dose
remains in the body
 Can be serious because too much of the drug can accumulate in the body and lead to
toxicity
o Toxic reactions
 Happens when large doses or when drug concentration levels exceed the therapeutic level

- Drug interactions
o Drug-drug interactions
 Occurs when one drug interacts with or interferes with the action of another drug
 Effects produced by drug-drug interaction
 Additive drug reaction
o Occurs when the combined effect of two drugs is equal to the sum of each
drug given alone
o 1+1=2
o Example is when taking the drug heparin with alcohol, it will increase
bleeding
 Synergistic drug reaction
o Occurs when drugs interact with each other and produce an effect that is
greater than the sum of their separate actions
o 1+1=3
o Example is when alcohol is taken simultaneously or shortly before or after
the hypnotic is taken, the action of the hypnotic increases considerably
 Antagonistic drug reaction
o Occurs when one drug interferes with the action of another, causing
neutralization or a decrease in the effect of one drug
o Example is the administration of protamine completely neutralizes the
effects of heparin in the body

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 o Drug-food interactions
 A drug taken on an empty stomach is absorbed into the bloodstream more quickly than when
the drug is taken with food in the stomach
 Drugs that should be taken in an empty stomach are administered 1 hour before or after
meals
 Other drugs especially those that irritate stomach (result in nausea or vomiting, or cause
epigastric distress) are best given with food to decrease epigastric distress
 Some drugs, when combined with food, forms an insoluble food-drug mixture which is
unabsorbable by the body and therefore no pharmacologic effect like when tetracycline is
administered with dairy products

- Polypharmacy
o Taking of numerous drugs that can potentially react with one another

- Factors influencing drug response

o Age
o Weight
o Sex
o Disease
o Route of administration

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 PHARMACOKINETIC & PHARMACODYNAMIC PRINCIPLES

Basic Pharmacokinetic Relationships

Absorption

- First-Pass Effect
o Blood perfusing virtually all the gastrointestinal tissues passes through the liver by means of the
hepatic portal vein
 Fifty percent of the rectal blood supply bypasses the liver (middle and inferior hemorrhoidal
veins)
 Drugs absorbed in the buccal cavity bypass the liver
o Drugs affected most by the first-pass effect are those with a high hepatic extraction ratio
o Example

Amitriptyline Labetalol Nitroglycerin

Desipramine Lidocaine Pentazocine
Diltiazem Metoprolol Propoxyphene
Doxepin Morphine Propranolol
Imipramine Nicardipine Verapamil
Isosorbide dinitrate Nifedipine

- Enterohepatic Recirculation
o Drugs are excreted by the bile into the duodenum, metabolized by the normal flora in the
gastrointestinal tract, and reabsorbed into the portal circulation
 o Occurs in drugs with the following
 Biliary (hepatic) elimination
 Good oral absorption
o Drug is concentrated in the gallbladder and expelled on sight, smell, or ingestion of food
o Examples of compounds excreted in bile and subject to enterohepatic cycling

Compound Entity in Bile

Chloramphenicol Glucurnide conjugate
Digoxin Parent
Estrogens Parent
Imipramine Parent and desmethyl metabolite
Indomethacin Parent and glucuronide
Nafcillin Parent
Rifampin Parent
Sulindac Glucuronides of parent and metabolites
Testosterone Conjugates
Tiagabine Glucuronide conjugate
Valproic acid Glucuronide conjugates
Vitamin A Conjugates

Distribution

- Definition d
o Apparent V Proportionality constant that relates the amount of drug in the body to an
observed concentration of drug

- Protein Binding

Protein Types of Drugs Molecular Normal Concentration

Bound Weight (g/L) (µmol)
Albumin Acidic 65,000 35-50 50-700
Α-1-acid Basic 44,000 0.4-1.0 9-23
glycoprotein
Lipoprotein Lipophilic and 200,000 – Variable Variable
basic 3,400,000

- P-glycoprotein
o It may be especially important with opioids—Induction of P-glycoprotein by chronic use of opioids
may decrease the opioid effect (tolerance)
o P-glycoprotein is also found in tumor cells, resulting in the efflux of chemotherapeutic agents out of
the cell and, ultimately, multidrug resistance.

Clearance

- Enzymes involved in drug metabolism

Oxygenases Conjugating enzymes Hydrolytic Enzymes
Cytochrome P450 Uridine diphosphate-glucuronyl Esterases
transferases
Monoamine oxygenases Glutathione S-transferases Amidases
Alcohol dehydrogenases Acetyltranferases Epixide hydrolases
Aldehyde dehydrogenases Methyltransferases Dipeptidases
Xanthine dehydrogenases
- Drug transport proteins
-
Transport Transport Protein Location and Function Drugs Affected by Transport
Protein (Gene[Protein]) Protein
Superfamily
SLC SLC10A1 [HTCP] Hepatocyte: Bile acid uptake Not applicable
SLCO1B1 [OATP1B1] Hepatocyte: Hepatic uptake of Pravastatin
drugs Rifampin
SLCO1B3 [OATP1B3] Hepatocyte: Hepatic uptake of Digoxin
drugs Rifampin
SLC22[OAT and OCT] Hepatocyte: Hepatic uptake of Salicylate
drugs Methotrexate
Renal tubule (interstitial side): Zidovudine
Secretion of drugs Tetracycline
Organic anions and cations
ABC ABCB11 [BSEP] Hepatocyte: Bile acid excretion Not applicable
into bile
ABCC2, 3, 4 and 5 [MRP2, Hepatocyte: Excreting water- Glucuronide, sulfate, and
3, 4 and 5] soluble drugs and metabolites into glutathione metabolites
blood Methotrexate
Renal tubule (luminal side): Pravastatin
Secretion of drugs Rifampin
ABCB1 [MDR1] (P- See texts in this hand-out ☻ See texts in this hand-out ☻
glycoprotein) Hepatocyte
Renal tubule (luminal side)
ABCG2[BCRP] Hepatocyte: Biliary excretion Daunorubicin
Doxorubicin
- Cytochrome P450
o Introduction
 A group of heme-containing enzymes responsible for phase 1 metabolic reactions
 Characteristic absorbance of light at 450 nm (thus, CYP)
 Primarily located in the membranes of the smooth endoplasmic reticulum in 1) liver, 2)
small intestine, and 3) brain, lung, and kidney
 Encoded by a supergene family or subfamily; separate genes code for different isoenzymes
 Drugs will generally have a high affinity for one particular CYP, but most drugs also have
secondary pathways
 Nomenclature

CYP 3 A 4
Specific enzyme

Subfamily (> 70% identical)

Family (> 40% identical)

GENE for mammalian cytochrome

o Distribution of CYP in human liver

Content Role in CYP-Mediated Drug Elimination

o Distribution of CYP isoenzymes in human gastrointestinal tract

 o Characteristics of CYP metabolism
 Inhibition is substrate-independent
 Some substrates are metabolized by more than one CYP (e.g., TCAs
[tricyclic antidepressants], SSRIs [selective serotonin reuptake inhibitors])
 Enantiomers may be metabolized by a different CYP (e.g., warfarin)
 Differences in inhibition may exist within the same class of agents (e.g., 2
fluoroquinolones, azole antifungals, macrolides, calcium channel blockers,
H2 blockers
 Substrates can also be inhibitors (e.g., erythromycin, verapamil, diltiazem)
 Most inducers and some inhibitors can affect more than one isozyme (e.g., cimetidine,
ritonavir, fluoxetine, erythromycin)
 Inhibitors may affect different isozymes at different doses (e.g., fluconazole inhibits
CYP2C9 at doses of 100 mg/day or greater, and inhibits CYP3A4 at doses of 400 mg/day
or greater)

- P-glycoprotein
o P-glycoprotein is an efflux pump that pumps drugs into the bile; the clinical effect of P-glycoprotein
drug interactions in the bile is unknown
o P-glycoprotein pumps drugs from renal tubules into the urine; it also potentially limits the degree of
reabsorption
o Examples of drug interactions: Quinidine/digoxin, cyclosporine/digoxin, and propafenone/digoxin

- Pharmacogenetics/Polymorphic Drug Metabolism

o Population in general is divided into poor metabolizers and extensive metabolizers; therefore,
metabolism is considered polymorphic
o Definition: Coexistence of more than one genetic variant (alleles), which are stable components in
the population (more than 1% of population)
o Clear antimode results

antimode

No. of Patients

PM EM URM

Metabolic ratio of unchanged drug to metabolite 

(increasing metabolic capacity)

EM = extensive metabolizer; PM = poor metabolizer; URM = ultrarapid extensive metabolizer.

- Phenotype: Expression of the trait

o Manifestation of the trait clinically
o Not necessarily constant

- Genotype: Genetic make

Pathway Substrate Enzyme Drug Examples

Oxidation Debrisquine, CYP2D6 Tertiary amines
dextromethorphan Fluoxetine
Flecainide
Propafenone
Metoprolol
Propanolol
Timolol
Codeine
Oxidation Warfarin CYP2C9 Amitriptyline
Phenytoin
Warfarin
Oxidation Mephenytoin CYP2C19 Tertiary amines (diazepam)
Phenytoin
Omeprazole
Acetylation Isoniazid, caffeine N-acetyltransferase Clonazepam
Dapsone
Hydralazine
Inamrinone
Procainamide
Sulfonamides

Non-linear Pharmacokinetics

- Michaelis-Menten pharmacokinetics

- Nonlinear elimination

Non-compartmental Pharmacokinetics

- Why use non-compartmental pharmacokinetics?

o Identification of the “correct” model is often impossible
o A compartmental view of the body is unrealistic
o Linear regression is unnecessary, it is easier to automate analysis
o Requires fewer and less stringent assumptions
o More general methods and equations
o There is no need to match all data sets to the same compartmental model

- Definitions
 - Pharmacokinetic parameter estimation

Data Collection and Analysis

- Timing of collection
o Ensure completion of absorption and distribution phases (especially digoxin and vancomycin, etc.)
o Ensure completion of redistribution postdialysis (especially aminoglycosides)

- Specimen requirements
o Whole blood
 Use anticoagulated tube
 Examples
 Cyclosporine
 Amiodarone
o Plasma
 Use anticoagulated tube and centrifuge; clotting proteins and some blood cells are
maintained
o Serum
 Use red top, allow a clot, and centrifuge
 Examples
 Most analyzed drugs including the following
o Aminoglycosides
o Vancomycin
o Phenytoin
o Digoxin

- Sample analysis
 o Assay terminology
 Precision (reproducibility)
 Closeness of agreement among the results of repeated analyses performed on the
same sample
o Standard deviation (SD)
 Average difference of the individual values from the mean
o Coefficient of variation (CV)
 SD as a percentage of the mean (relative rather than absolute
variation)

SD
CV = --------------
Mean

 Accuracy
 Closeness with which a measurement reflects the true value of an object
 Correlation coefficient–Strength of the relationship between two variables
 Predictive performance (accuracy)
 Precision: a.k.a. root mean squared error (RMSE)

 Bias: a.k.a. mean prediction error (ME)

 Prediction error (pe) is the prediction minus the true value

 Sensitivity
 Ability of an assay to quantitate low drug concentrations accurately, usually the
lowest concentration an assay can differentiate from zero
 Specificity (cross-reactivity)
 Ability of an assay to differentiate the drug in question from like substances

- Assay methodology
o Immunoassay
 Radioimmunoassay
 Advantages
o Extremely sensitive (pictogram range)
 Disadvantages
o Radioimmunoassay kits have limited shelf life because of the short t ½ of
labels, nuclear waste and cross-reactivity
 Clinical use for assaying digoxin and cyclosporine
 Enzyme immunoassay
 EMIT (enzyme multiplied immunoassay technique)
 Fluorescence immunoassay
 TDx (Abbott)
o Flourescence polarization immunoassay
o Most common therapeutic drug monitoring assay
o Advantages
 Simple, automated, highly sensitive, and stable reagents
o Disadvantages
 Background interference attributable to endogenous serum
fluorescence
o High-pressure liquid chromatography
o Flame photometry
 o Bioassay

- Population pharmacokinetics in therapeutic drug monitoring

o Population pharmacokinetics useful when
 Drug concentrations are obtained during complicated dosing regimens
 Drug concentrations are obtained before steady state
 Only a few drug concentrations are feasibly obtained (limited sampling strategy)
o Bayesian pharmacokinetics
 Prior population information is combined with patient-specific data to predict the most
probable individual parameters
 When patient-specific data are limited, there is greater influence from population parameters;
when patient-specific data are extensive, there is less influence
 With small amounts of individual data, Bayesian forecasting generally yields more precise
results

Pharmacokinetics in Renal Disease

- Estimation of GFR/CrCl
o Creatinine production and elimination
 Creatinine is produced in the liver
 Creatinine is the product of creatine metabolism in skeletal muscle
 Creatinine is filtered at the glomerulus, where it undergoes limited secretion
 Creatinine is useful in approximating GFR because
 At normal concentrations of creatinine, secretion is low
 The creatinine assay picks up a non-creatinine chromogen in the blood but not in the
urine
o CrCl calculation to estimate GFR
 CrCl is calculated from a 24-hour urine collection and the following equation

Volume of urine/1440 minutes x [creatinine] urine

CrCl (mL/minute) = -----------------------------------------------------------------------------------
[creatinine]plasma

 Normal CrCl
 Healthy young men = 125 mL/minute/1.73m 2
 Healthy young women = 115 mL/minute/1.73m 2
 After age 30, 1% of GFR is lost per year
o Creatine clearance estimation to estimate GFR
 Factors affecting SCr concentrations
 Sex
 Age
 Weight
 Renal function
o Caveats: Creatinine clearance estimations worsen as renal function worsens
(usually an overestimation)
 Jeliffe

98 – 0.8 (age – 20)

2
CrCl (mL/minute/1.73m ) = ----------------------------------------------
SCr

 Women: Use 90% of the above equation

 Limitations:
 Serum creatinine concentration must be stable
 Adults aged 20-80 years
 Controversy: rounding up SCr in patients with low concentrations (less than 0.7-1
mg/dL)
  Cockcroft and gault (C&G)

(140-age) * (IBW)
CrCl (mL/minute) = ------------------------------------------
72 * SCr

 Women: Use 85% of the above equation

o Ideal body weight (IBW) (men) = 50 kg + 2.3 kg for each inch over 5 feet
o IBW (women) = 45.5 kg + 2.3 kg for each inch over 5 feet
 Limitations
o Serum creatinine concentration must be stable
o It was developed for adults only
o Controversy: Rounding up SCr in patients with low concentrations (less than
0.7-1 mg/dL)
 Corrected versus uncorrected C&G

 Corrected C & G equation is normalized to a 72-kg person (similar to most other

estimation equations)
 Corrected C&G is not influenced by a patient’s weight (it is actually influenced by
height, because the uncorrected equation uses IBW – a function of height)
 Corrected C&G (or weight-adjusted C&G) is better to use for estimating renal
function to make dosage adjustments
 Modification of diet in renal disease study equation (MDRD)
 Full equation
o
 Simplified four-variable equation
o
 These equations actually directly estimate GFR (NOT CrCl)
 These equations are recommended by the American Kidney Foundation and the
European Renal Association to estimate renal function (significantly better than
C&G)
 Not as accurate when GFR is greater than 60 mL/minute/1.73 m 2
 Controversy: Rounding up SCr in patients with low concentrations (less than 0.7-1
mg/dL)
 This equation should be used with standardized serum creatinine concentrations
 Chronic kidney disease epidemiology collaboration equation (CKD-EPI)


 These equations directly estimate GFR (not CrCl

 These equations are more accurate than modification of diet in renal disease at
higher GFRs (i.e., greater than 60 mL/minute/1.73 m 2)
 Pediatric formulas
 Do not round up low SCr values in pediatric patients
o Factors influencing CrCl estimates
 Patient characteristics
 Age
o Decrease production of creatinine with age
 Female sex
o Decrease production of creatinine
 Race
o Increase production of creatinine in African Americans
 Disease states/clinical conditions
 Spinal cord injuries
o Decrease muscle mass
 o Decrease creatinine
 Amputations
o Decrease muscle mass
o Decrease creatinine
 Cushing syndrome
o Decrease muscle mass
o Decrease creatinine
 Muscular dystrophy
o Decrease muscle mass
o Decrease creatinine
 Guillain-Barre syndrome
o Decrease muscle mass
o Decrease creatinine
 Rheumatoid arthritis
o Decrease muscle mass
o Decrease creatinine
 Liver disease
o Decrease creatine
o Decrease creatinine
 Glomerulopathic disease
o Greater amount of creatine secretion in relation to filtration
 Diet
High-meat protein diets


o Increase creatinine ingestion

 Vegetarians
o Decrease creatinine ingestion
 Protein-calorie malnutrition
o Decrease creatinine ingestion
 Drugs/endogenous substances
 Laboratory interaction
o Kinetic alkaline picrate method
o Noncreatine chromogens: in blood but not I urine
o Cephalosporins (esp. cefoxitin): chromogenic causing false elevations-much
greater in urine than blood
o Acetoacetate (increased in fasting individuals, patients with DKA):
chromogenic causing false elevations
 Pharmacokinetic interaction
o Drugs compete with creatinine for renal secretion (causing false elevations),
trimethoprim, cimetidine, fibric acid derivatives (other than gemfibrozil, and
dronedarone

- Drug dosing in renal disease

o Loading dose
 In general, no alteration is required, but it should be given to hasten achievement of
therapeutic drug concentrations
 Alterations in loading dose must occur if the V d is altered secondary to renal dysfunction
 Example is digoxin
o Maintenance dose
 Alterations should be made in either the dose or the dosing interval
 Changing the dosing interval
 Use when the goal is to achieve similar steady-state concentrations
 Less costly
 Ideal for limited-dosage forms (i.e., oral medications)
 Changing the dose
 Used when the goal is to maintain a steady state therapeutic concentration
 More costly
 Changing the dose and the dosing interval
 Often required for substantial dosage adjustment with limited-dosage forms
 Often required for narrow therapeutic index drugs with target concentrations
o If a drug is given more than once daily, then adjust the interval
o If a drug is given once daily or less often, then adjust the dose
Pharmacokinetics in Hepatic Disease

- Drug adjustment in hepatic disease

o Clinical response in the most important factor in adjusting doses in hepatic disease
o Low hepatic extraction ratio drugs
 Adjustment of maintenance dose is necessary only when hepatic disease alters Cl int
 Alterations in protein binding alone do not require alteration of maintenance dose, eventough
total drug concentrations decline
 Loading doses may require reduction
o High hepatic extraction ration drugs
 Intravenous administration
 Usually necessary to decrease maintenance dose rate
 Consider effect of hepatic disease on protein binding
 Oral administration
 Usually necessary to decrease maintenance dose rate

- Rules for dosing in hepatic disease

o Hepatic elimination of high extraction ratio drugs is more consistently affected by liver disease than
low extraction ratio drugs
o The clearance of drugs that are exclusively conjugated is not substantially altered in liver disease

- Child-Pugh classification for liver disease

Pharmacodynamics

- Defined as the relationship between drug concentrations and the pharmacologic response

- Hill equation
 - Hysteresis loops
o Concentrations late after a dose produce an effect different from that produced by the same
concentration soon after the dose

Specific Drug Table

- CYP drug interactions

14
- PK terms

15
 AUTONOMIC DRUGS

Drug Map for Autonomics

- Direct Muscarinic Agonist o Isoproterenol

o Choline esters o Dobutamine
 Acetylcholine o Dopamine
 Bethanechol
 Carbachol - Direct Adrenoceptor Agonists
 Methacholine o Phenylephrine
o Alkaloids o Methoxamine
 Muscarine o Oxymetazoline
 Pilocarpine o Clonidine
o Ritodrine
- Direct Nicotinic Agonist o Terbutaline
o Nicotine o Albuterol
o Salmeterol
- Acetylcholinesterase Inhibitor
(Reversible) - Indirect-Acting Sympathominetics
o Neostigmine o Ephedrine
o Physostigmine o Pseudoephedrine
o Edrophonium o Cocaine
o Tyramine
- Acetylcholinesterase Inhibitor o Amphetamine
(Irreversible)
o Soman - Alpha Adrenoceptor Antagonists
o Parathion Prazosin
o
o Malathion Terazosin
o
o Isoflurophate Trimazosin
o
o Echothiophate Doxazosin
o

o Phentolamine
- Muscarinic Antagonist o Phenoxybenzamine
o Atropine Tolazoline
o
o Scopolamine Labetalol
o
o Ipratropium Yohimbine
o
o Pirenzepine
- Beta-adrenoceptor Antagonists
- Acetylcholinesterase Reactivator o Propranolol
o Pralidoxime Metoprolol
o

o Esmolol
- Ganglionic Blockers o Atenolol
o Mecamylamine Nadolol
o
o Hexamethonium Timolol
o
o Trimethaphan Pindolol
o

o Butoxamine
- Catecholamines
Epinephrine
o
- Adrenergic Neuron Blocking Drugs
o Norepinephrine Reserpine
o

o Guanethidine

1
Acetylcholine

- Abbreviated as “ACh”

- The most common neurotransmitter

- Henry Hallett dale

o Discovered ACh
o Awarded Nobel prize in Physiology/Medicine in 1936 for this discovery

- Otto Loewi
o Confirmed the existence of ACh
o Also awarded Nobel prize in Physiology/Medicine in 1936 for this discovery

- Located in both CNS and PNS and acts as a neuromodulator

- In the CNS, it acts as part of a neurotransmitter system and plays a role in

attention and arousal

- In the PNS, this is a major part of the ANS and works to activate muscles

2
- Acetylcholine binds to the following:
o Nicotinic receptor
 At the autonomic ganglia to trigger the release of norepinephrine (if a
sympathetic synapse is stimulated)
o Muscarinic receptor
 Produce parasympathetic or cholinergic response

- Miochol E
o Acetylcholine Chloride Intraocular Injection

o Indication
 Decreases pupil size during surgery like in cataract surgery,
keratoplasty, iridectomy and other anterior segment surgery where
rapid miosis is required

3
  Keratoplasty
 Replacement of the host cornea with a donor cornea
 Iridectomy
 Also called correctomy
 The surgical removal of part of the iris
o Mechanism of action
 Causes contraction of the sphincter muscles of the iris, resulting in
miosis and contraction of the ciliary muscle, leading to
accommodation spasm
o Administration
 Reconstitute vial with 2 mL supplied diluent to obtain 1% solution, use
immediately
 Instill gently into anterior chamber of eye with suitable atraumatic
cannula
 May use 2% pilocarpine or 0.25% physostigmine topically
immediately after surgery before application of dressing to maintain
miosis
 For cataract surgery, instill only after delivery of lens
 Miosis occurs promptly and persists for approximately 10 minutes
o Common side effect
 Fluid accumulation in the cornea of the eye causing swelling

Bethanechol

- A number of drugs target acetylcholine receptors, blockade of these receptors is

associated with anticholinergic (parasympatholytic) effect, while stimulation
causes activation of cholinergic (parasympathomimetic) effects

- Muscarinic receptors
o Also called Muscarinic acetylcholine receptors or mAChRs
o Acetylcholine receptors that form G protein-receptor complexes in the cell
membranes of certain neurons and other cells
o G protein-coupled receptor
 Constitute a large protein family of receptors that sense molecules
outside the cell and activate inside signal transduction pathways and,
ultimately, cellular responses

4
- Distribution of the different muscarinic receptors
o M1
 (CNS) Brain (cortex, hippocampus); salivary glands; symphatetic
ganglia
o M2
 Heart; hindbrain; smooth muscle
o M3
 Smooth muscle; salivary glands; brain
o M4
 (CNS) Brain (forebrain, striatum)
o M5
 (CNS) Eye (Substantia nigra); eye

- Urecholine
o Bethanechol Chloride

o Indication
 Treatment for urinary retention
 Useful in treating bladder atony (loss of muscle strength) which occur
in post operative period or post partum
o Mechanism of action
 A cholinergic agent that works by stimulating the bladder to contract,
which improves urine flow
 Acts on the muscarinic receptors mostly muscarinic 2 (M2) or
muscarinic 3 (M3) receptors. Bethanechol will not react with
muscarinic 1 receptor (M1) on the central nervous system due to
bethanechol inability to cross blood brain barrier
 Stimulates M3 receptors which cause an increase in contraction of
the bladder with relaxation of the sphincter of the bladder which leads
to urination

5
 o Administration
 Take 1 hour before or 2 hours after meals, usually 3 to 4 times daily
or as directed by the doctor
 Taking this medication with an empty stomach will help reduce
nausea and vomiting
o Common side effects
 Diarrhea, salivation and sweating due to activation of the M3 receptor
while bradycardia due to activation of the M2 receptor
o Contraindications
 Mecamylamine
 May cause seriously low blood pressure

Carbachol

- Isopto
o Carbachol Opthalmic Solution
o Indication
 Used alone or with other medications to treat high pressure inside the
eye due to glaucoma or other eye diseases like ocular hypertension
 Lowering high pressure inside the eye helps prevent blindness, vision
loss, and nerve damage
 Carbachol works by decreasing the amount of fluid within the eye
o Mechanism of action
 Targets Muscarinic acetylcholine receptor M1
 A parasympathomimetic that stimulates both muscarinic and nicotinic
receptors
 In topical ocular and intraocular administration its principal effects are
miosis and increased aqueous humour outflow
o Administration
 Administered as eye drops
 What is the proper way of administering eye drops?
o Common side effects
 Temporary irritation/burning/stinging of the eye, temporary blurred vision,
poor vision in dim light, headache, or brow ache may occur

6
Methacholine

- How doctors diagnose asthma?

o Review of asthma symptoms
 Coughing
 Wheezing
 Shortness of breath
 Chest tightness
o Medical and family history
 Allergies
 Eczema
o Lung function tests
o Physical exam
o Allergy tests
o Blood tests
o Chest and sinus x-rays

- Lung function tests

o Spirometry
 A simple breathing test that measures how much air you can blow out of
your lungs and how quickly
 Used to determine the amount of airway obstruction
 Can be done before and after inhaling a short-acting medication called a
bronchodilator (albuterol)
 The bronchodilator causes the airways to expand, allowing for air to pass
through freely
 This might also be done to determine the progress of the patient
o Methacholine challenge test
 Might be used if the symptoms and screening spirometry do not
convincingly establish diagnosis of asthma
 Methacholine is an agent that when inhaled, causes the airways to
spasm (contract involuntarily) and narrow if asthma is present
 During this test, the patient inhale increasing amounts of methacholine
aerosol mist before and after spirometry
 The methacholine test is considered positive, meaning asthma is
present, if the lung function drops by at least 20%
 A bronchodilator is always given at the end of the test to reverse the
effects of methacholine

- Provocholine
o Methacholine chloride
o Indication
 Lung function test
 Only used in this test to determine if a patient has asthma
 NOT used to treat asthma

7
o Mechanism of action
 By agonizing the muscarinic receptors, this drug induces
bronchoconstriction. This bronchoconstriction is used as a test in
asthmatics and in bronchial hyperreactivity
o Administration
 It should only be used in a setting where emergency medicines and
equipment are available to treat severe breathing problems if they occur
 Methacholine solution is usually administered at the doctor’s office,
hospital, or clinic
 Methacholine solution is for inhalation only. It should not be injected or
taken by mouth
o Common side effects
 May cause severe breathing problems in some patients
 Common side effects
 Headache
 Itching
 Lightheadedness
 Throat irritation
 Severe side effects
 Severe allergic reactions (rash; hives; itching; difficulty in
breathing; lightness in the chest; swelling of the mouth, face, lips,
or tongue)
 Chest pain
 Cough
 Fainting
 Severe dizziness
 Wheezing
o Contraindication
 Beta blockers (e.g., propranolol and betaxolol) because the side effects
of methacholine solution, such as difficulty in breathing may be
increased
 Should NOT be given to anyone who has apparent symptoms of asthma,
wheezing, or very low lung function tests

8
Muscarine

- A deadly alkaloid from various mushrooms (Amanita muscaria, the fly agaric) and
also from rotten fish

- The first parasympathomimetic substance ever studied and causes profound

activation of the peripheral parasympathetic nervous system that may end in
convulsions and death

- It is similar pharmacologically to acetylcholine, although it is not used in therapeutics

- Mechanism of action
o Mimics the reaction of acetylcholine by binding to muscarinic acetylcholine
receptors
o Binds to the muscarinic receptors which results in a decrease of intracellular
concentration of cyclic adenosine monophosphate (cAMP)
 cAMP
 A second messenger important in many biological processes
 Derived from adenosine triphosphate (ATP)
 Used for intracellular signal transduction in many different
organisms, conveying the cAMP-dependent pathway

- Toxidromes: SLUDGE & DUMBELS

9
- Atropine
o Poisoning antidote
o Treatment of choice

Pilocarpine

- Pilocarpine Hydrochloride Opthalmic Solution

o Same with Isopto
o Indication
 Used alone or with other medications to treat high pressure inside the
eye due to glaucoma or other eye diseases like ocular hypertension
 Lowering high pressure inside the eye helps prevent blindness, vision
loss, and nerve damage
 Used during certain eye surgeries and to reverse the effects of drugs
used to enlarge the pupil (e.g., during an eye exam)
 Works by causing the pupil of the eye to shrink and decreasing the
amount of fluid within the eye
o Mechanism of action
 A parasymphathomimetic that directly cholinergic receptors.
 It produces contraction of the iris sphincter muscle, resulting in pupillary
constriction (miosis); constriction of the ciliary muscle, resulting in
increased accommodation and reduction in intraocular pressure
associated with an increase in the outflow and a decrease in the inflow of
aqueous humor
 Chronic open-angle glaucoma

10
  The exact mechanism by which miotics lower intraocular pressure
in not precisely known; however, contraction of the ciliary muscle
apparently opens the intertrabecular spaces and facilitates
aqueous humor outflow
 There is also a decrease in the rate of inflow of aqueous humor

 Angle-closure glaucoma
 Constriction of the pupil apparently pulls the iris away from the
trabeculum, thereby reliveing blockage of the trabecular meshwork

o Administration
 The initial dose is one or two drops in the affected eye(s)

11
  This may be repeated up to three or four times daily or as directed by a
physician

 The frequency of instillation and concentration of pilocarpine

hydrochloride ophthalmic solution are determined by the severity of the
glaucoma and miotic response of the patient
 Individuals with heavily pigmented irides may require higher strengths
 During acute phases, the miotic must be instilled into the unaffected eye
to prevent an attack of angle closure glaucoma
o Common side effects
 Pilocarpine-induced miosis may cause difficulty in dark adaptation
 The patient should exercise caution when involved in night driving or
other hazardous activities in poor light
 Ocular
 Usually in younger patients
o Transient symptoms of stinging and burning may occur
o Ciliary spasm, conjunctival vascular congestion, temporal or
supraorbital headache, lacrimation and induced myopia may
occur
 Usually in older patients
o Reduced visual acuity in poor illumination
 May also cause retinal detachment
 Lens opacity
o Occurs with prolonged use
 Systemic
 Extremely rare
 Includes:
o Hypertension
o Tachycardia
o Bronchiolar spasm
o Pulmonary edema
o Salivation
o Sweating
o Nausea
o Diaarhea
o Contraindication
 Parasympathomimetics are contraindicated where miosis is undesirable
such as acute iritis or pupillary block glaucoma

Nicotine

- Nicotinic Acetylcholine receptors or nAChRs

o Neuron receptor proteins that signal muscular contraction upon a chemical
stimulus

12
 o Like mAChR, it is triggered by the binding of the neurotransmitter ACh but they
can also be opened by nicotine, hence the name “nicotinic”

- N1 or NM
o These receptors are located at the neuromuscular junction, acetylcholine
receptors of the NM subtype are the only acetylcholine receptors that can be
found in the neuromuscular junction

- N2 or NN
o Nicotinic receptors play a key role in the transmission of cholinergic signals in
the ANS
o Can be found in both cholinergic and adrenergic ganglia, but not at the target
tissues (e.g., heart, bladder, etc.)
o These receptors are also present in the CNS and adrenal medulla

- Nicotinic receptor versus Muscarinic receptor

13
- Adrenergic system and Cholinergic system

- Nicotine Patch

- Nicotine Lozenge

14
- Nicotine Nasal Spray

- Nicotine Inhaler

o Indication
 Aid in smoking cessation
o Mechanism of action
 Nicotine is released from the patches and absorbed through the skin
 Released nicotine binds to nicotine receptors in the body, reducing
nicotine craving and withdrawal symptoms associated with smoking
cessation
o Administration
 Nicotine Patch
 Choose a different place on your body to wear the patch each time
you put on a new one. Do not use the same skin area twice within
7 days
 Apply the patch to clean, dry and hairless skin on the outer part of
your upper arm or on your chest. Remove the patch after 24 hours
and replace it with a new one
 If Nicotrol patches are used, apply a new patch each morning and
remove it at bedtime. Do not wear the patch while you are
sleeping. If you are usinge Nicoderm CQ, you may wear the patch
for 16 to 24 hours. If you crave cigarettes when you wake up, you
may wear the patch for 24 hours. Do not wear the patch at night if
you have vivid dreams or trouble sleeping
15
  Nicotine Lozenge / Nicotine Gum
 Place a gum or a lozenge in your mouth
 Chew the gum several times and stop chewing when you notice a
tingling sensation or a peppery taste in the mouth
 “Park the gum between your cheek and gum and leave it there
until the taste or tingling sensation is almost gone
 Then slowly chew a few more times until the taste or sensation
returns
 Part the gum again in a different place in your mouth
 Chewing too much or too quickly can cause too much nicotine to
be released from the gum and you may have side effects such as
nausea, hiccups, or stomach problems
 Remove the gum after 30 minutes, or when the taste or tingle no
longer return when you chew the gum
 Allow the lozenge to dissolve slowly without chewing or
swallowing. You may notice a warm or tingling sensation in your
mouth
 Move the lozenge from one side of your mouth to the other while it
is dissolving
 Do not eat or drink for 15 minutes before using the gum or lozenge
while the medicine is in your mouth
 Nicotine Nasal spray
 Blow nose if it is not clear
 Tilt head back slightly
 Insert the tip of bottle into your nostril as far as comfortable
 Spray once in each nostril
 Do not sniff, swallow, or inhale while spraying
 If your nose runs, gently sniff to keep the medicine in
 Wait 2 or 3 minutes before blowing your nose
 Do not use more of the medication that is directed
 Recap the bottle after each use
 If you don’t use the nasal spray for 24 hours, prime the pump by
spraying several sprays into a tissue then throw the tissue away
 Do not get nicotine spray into your eyes or mouth or onyour skin. If
this does occur, rinse the area with water
 Nicotine Inhaler
 Inhale deeply or puff in short breaths
 As you inhale through the mouthpiece, nicotine turns into a vapor
and is absorbed into the muth and throat
 Nicotine in cartrides is used up after about 20 minutes of active
puffing
o Common side effects
 More common
 Acid or sour stomach
 Belching

16
  Coughing
 Heartburn
 Indigestion
 Mouth and throat irritation
 Stomach discomfort, upset, or pain
 Stuffy nose
 Less common
 Anxiety
 Back pain
 Change in taste
 Diarrhea
 Dizziness
 Feeling of burning, numbness, tightness, tingling, warmth or heat
 Feelings of drug dependence
 Flu-like symptonms
 General pain
 Hiccups
 Mental depression
 Pain in the jaw and neck
 Pain in the muscles
 Passing of gas
 Problems with teeth
 Trouble with sleeping
 Unusual tiredness or weakness
o Contraindication
 Do not use when pregnant
 Heart disease, an irregular heartbeat, high blood pressure or chest pain
 A jaw condition called TMJ (tempomandibular joint) disease
 An overeactive thyroid
 Diabetes
 Pheochromocytoma (tumor of the adrenal gland)
 Liver or kidney disease
 A stomach ulcer
 Asthma or chronic pulmonary disease
 Nicotine oral lozenges may contain phenylalanine, tell your doctor if you
have phenylketonuria
 Remove transdermal patch during an MRI, it may burn your skin

Neostigmine

- Myasthenia Gravis
o Chronic autoimmune neuromuscular disease characterized by varying degrees
of weakness of the skeletal (voluntary) muscles of the body
o Hallmark of the disease
 Muscle weakness that increases during periods of activity and improves
after periods of rest

17
o Muscles that may be involved
 Muscles that control the eye and eyelid movement
 Muscles involved in facial expression
 Chewing muscles
 Muscles in talking
 Muscles in chewing
 Muscles in swallowing
 Muscles that control breathing and neck and limb movements may also
be affected
o Causes of Myasthenia Gravis
 Defect in the transmission of nerve impulses to muscles
 It occurs when normal communication between the nerve and muscle is
interrupted at the neuromuscular junction, the place where nerve cells
connect with the muscles they control
 Normal nerve transmission
 Normally when impulses travel down the nerve, the nerve endings
release acetylcholine
 Acetylcholine travels from the neuromuscular junction and binds to
acetylcholine receptors which are activated and generate a muscle
contraction
 Transmission in Myasthenia Gravis
 In myasthenia gravis, antibodies block, alter or destroy the
receptors for acetylcholine at the neuromuscular junction, which
prevents the muscle contraction from occurring
 These antibodies are produced by the body’s own immune system
o Symptoms
 Weakness in the eye muscles
 First noticeable symptoms in most cases
 In others, the following may be the first signs
 Difficulty in swallowing
 Slurred speech
o Occurs in all ethnic groups and both gender, most commonly affects young
adult women (under 40) and older men (over 60), but it can occur at any age

18
- Tilstigmin
o Prostigmin
 Also a popular brand name
o Indication
 Myasthenia gravis
o Mechanism of action
 A cholinesterase inhibitor
 It works by improving the transmission of nerve impulses in muscles so
that the muscles are better able to work
o Administration
 Dosing and dosage form depends on the doctor
o Side effects
 Common
 Abdominal cramps
 Diarrhea
 Difficulty speaking
 Dilation of pupils
 Dizziness
 Drowsiness
 Excess saliva
 Frequent urination
 Gas headache
 Increased sweating
 Joint pain
 Muscle twitching
 Weakness
 Severe
 Severe allergic reactions (rash; itching; hives; difficulty breathing;
tightness in the chest; swelling of the mouth, face, lips or tongue)
 Fainting
 Increased muscle weakness
 Interrupted breathing
 Irregular heartbeat
 Seizures
 Vision changes
o Contraindication
 May decrease effectiveness
 Procainamide
 Quinine derivative like quinidine
 General anesthetics like cyclopropane
 May increase the side effects of the following drugs
 Beta-blockers
o Succinylcholine
o Propanolol

19
Physostigmine

- Physostigmine Salicylate Injection

o Indication
 Reversal of anticholinergic activity
 Of particular interest is the drug’s capability to reverse excessive
somnolence or paradoxical responses caused by intravenous
diazepam (Valium) and other clinically available benzodiazepines
 Paradoxical reaction
o Relatively uncommon and occur in 1% of the patients
treated with benzodiazepines
o Characterized by increased talkativeness, emotional
release, excitement and excessive movement
 Increases the amount of fluid that drains from the eye
o Mechanism of action
 Inhibition of the destructive action of anticholinesterase and thereby
prolongs and exaggerates the effect of acetylcholine
o Administration
 It comes as a solution for injection, to be administered by a healthcare
provider into the vein
o Common side effects
 Low heart beat
 Epilepsy
 Nausea, vomiting and salivation
o Contraindication
 Asthma, gangrene, diabetes, CV disease, mechanical obstructon of the
intestine or urogenital tract or any vagotonic state, and in patients
receiving choline esters or depolarizing neuromuscular blocking agents
(decamethonium, succinylcholine)
 Concomitant use of atropine when physostigmine is used during
postanesthesia

Edrophonium

- Acetylcholinesterase
o Also known as acetylhydrolase (AChE)
o A hydrolase that hydrolyzes acetylcholine

20
 o Found at mainly neuromuscular junctions and cholinergic brain synapses,
where its activity serves to terminate synaptic transmission

- Enlon
o Edrophonium Chloride Injection
o Indication
 Used as part of a medical test to help diagnose Myasthenia gravis
 Sometimes used to reverse the effects of certain medications used to
prevent muscle contractions during surgical procedures

21
 o Mechanism of action
 Woks by prolonging the action of acetylcholine which is found naturally in
the body
 It does this by inhibiting the action of the enzyme acetylcholinesterase
o Administration
 IM or IV administration by a healthcare provider
 Given in small doses over 15 to 45 seconds
 Tensilon test
 The healthcare provider gives the medicine through one of the
veins (IV)
 Atropine may also be given before receiving Tensilon so that
blinding is facilitated
 After each dose, the patient will be observed for certain reactions
to this medicine (muscle twitching, vision changes, increased
muscle weakness, sweating, stomach cramps, nausea and other
symptoms)
 The healthcare provider will check for improvement in muscle
strength
o Common side effects
 Watery eyes
 Vision problems
 Changes in the voice
 Mild nausea, vomiting, diarrhea, stomach pain
 Weakness
 Muscle twitching
o Contraindication
 Should not be given if the patient have
 A blockage in the intestines
 Unable to urinate

Soman

- Inhibitor of both acetylcholinesterase and butyrylcholinesterase

- An extremely toxic chemical substance used as a chemical weapon and classified as

a weapon of mass destruction by the UN

- A nerve agent, interfering with normal functioning of the mammalian nervous system
by inhibiting cholinesterase enzyme

- Mechanism of action
o Inhibits acetylcholine esterase

22
- G-series nerve agents
o Tabun
o Sarin
 Sarin gas
 Closely related to Soman
 Used in attacking Syrian civilians last 2014 by pro-government forces
o Cyclosarin

- Miosis
o Fisrt observable signs of a Soman poisoning

Parathion

- Also known as Follidol

- A broad spectrum, organophosphate compound pesticide used to control many

insects and mites and highly toxic by all routes

- Has a wide range of applications on many crops against numerous insect species

- Mechanism of action
o Act by interfering with the activities of cholinesterase, an enzyme that is
essential for the proper working of the nervous system of both humans and
insects

- Points of entry:
o Ingestion
o Dermal adsorption
 As with all organophosphates, parathion is readily absorbed through the
skin
 Skin which has come in contact with this material should be washed
immediately with soap and water and all contaminated clothing should
be removed
 Hyperkeratinization
 Thickening and roughening of the skin
 Skin contact with organophosphates may cause localized sweating and
involuntary muscle contractions
 Eye contact will cause pain, bleeding, tears, pupil constriction, and
blurred vision
o Inhalation
 The first effects are usually respiratory and may include bloody or runny
nose, coughing, chest discomfort, difficult or short breath, and wheezing
due to constriction or excess fluid in the bronchial tubes

23
- Persons with cardiovascular, liver or kidney diseases, glaucoma, or central nervous
system abnormalities may be at increased risk from exposure to parathion

- High environmental temperatures or exposure of the chemical to visible or UV light

may increase its toxicity

- Death may be caused by respiratory failure or cardiac arrest

Malathion

- Malathion as insecticide
o As an insecticide, it has relatively low human toxicity

- Malathion as topical for human use

24
 o Indication
 Treating head lice
 A pediculicide. It works by killing lice and their eggs
o Mechanism of action
 Acts via cholinesterase inhibition
 Exerts both lousicidal and ovicidal actions in vitro
o Administration
 This medication is for use on hair and scalp only
 Do not swallow
 Be careful to avoid getting malathion in your nose, ears, mouth, vagina
or eyes
 Protect eyes during application by keeping them tightly closed and
covered with a cloth or towel
 If the medication accidentally comes in contact with the eyes, flush them
with water to reduce irritation
 Apply onto dry hair and scalp
 Use enough medication to make the hair and scalp wet, especially the
back of the head and neck
 Allow the hair to air-dry, uncovered
 Wash hands after applying this medication
 Leave malathion on the hair and scalp for 8-12 hours
 Then shampoo and rinse well, especially the back of the head and neck
 Run a fine-toothed comb (nit comb) through your wet hair to remove the
dead lice and lice eggs
o Side effects
 Common
 Mild stinging or irritation of the skin and scalp
 Severe
 Severe allergic reactions (rash; hives; itching; difficulty breathing;
tightness in the chest; swelling of the mouth, face, lips or tongue)
 Burning of the skin or scalp
o Contraindication
 Do not use if the patient is an infant

Isoflurophate

- Also called diisopropyl fluorophosphate

- A parasympathomimetic drug irreversible anti-cholinesterase and has been used in

ophthalmology as a miotic agent in treatment of chronic glaucoma, as a miotic in
veterinary medicine, and as an experimental agent in neuroscience because of its
acetylcholinesterase inhibitory properties and ability to induce delayed peripheral
neuropathy

- Stable but undergoes hydrolysis when subjected to moisture, producing hydrofluoric

acid

25
Echothiophate

- Phospholine Iodide
o Indication
 Used in treating types of glaucoma
 Used for diagnosing and treating certain types of crossed eyes
o Mechanism of action
 A long-acting cholinesterase inhibitor for topical use which enhances the
effect of endogenously liberated acetylcholine in iris, ciliary muscle, and
other parasympathetically innervated structures of the eye
 Binds irreversibly to cholinesterase, and is long acting due to the slow
rate of hydrolysis by cholinesterase
 It causes miosis, increase in facility of outflow of aqueous humor, fall in
intraocular pressure, and potentiation of accommodation
o Administration
 Applied as eye drops
 Wash your hands first
 To avoid contamination, be careful not to touch the dropper to any
surface or let it touch the eye
 If contact lens are worn, remove them before using the eye drops
 Wait at least 15 minutes before replacing the contact lens
 Tilt your head back, look upward, and pull down the lower eyelid to make
a pouch
 Hold the dropper directly over the eye and place one drop into the pouch
 Let go of the eyelid and gently close your eyes
 Place one finger at the corner of the eye (near the nose and apply gentle
pressure for 1 to 2 minutes
 This will prevent the medication from draining out
 Try not to blink and do not rub the eye

26
  Repeat these steps for your other eye if so directed or if the dose is more
than 1 drop
 Remove extra solution around the eye with a tissue and wash your
hands to remove any medicine that may be on them
 Do not rinse the dropper
 Replace the dropper cap after each use
o Common side effects
 Temporary irritation of the eye
 Temporary burning sensation of the eye
 Temporary stinging of the eye
 Temporary blurred vision
 Eyelid muscle twitching
 Poor vision in dim light
 Headache
 Brow ache
o Contraindication
 Narrow-angle glaucoma
 Inflammation of the eye
 Succinylcholine
 Risk of severe breathing or heart problems may be increased
 Cholinesterase inhibitors
 Side effects of these drugs may be increased by echothiopate eye
drops
 Example is Pyridostigmine

Atropine

- Muscarinic antagonist
o Also called Muscarinic Receptor Antagonist (MRA)
o Agent that blocks the activity of the mAChRs

- Atropine Sulfate Injection

27
o Indication
 As an antisialogogue when reduction of secretions of the respiratory tract
are thought to be needed; its routine use as a preanesthetic agent is
discouraged
 To blunt the increased vagal tone (decreased pulse and blood pressure)
produced by intra-abdominal tract or ocular muscle traction, its routine
use to prevent such events is discouraged
 To temporarily increase heart rate or decrease AV-block until definitive
intervention can take place, when bradycardia or AV-block are judged to
be hemodynamically significant and thought to be due to excess vagal
tone
 As an antidote for inadvertent overdose of cholinergic drugs or for
cholinesterase poisoning such as from organphosphorus insecticides
 As an antidote for the “rapid type of mushroom poisoning due to the
presence of the alkaloid muscarine, in certain species of fungus such as
Amanita muscaria
 Top alleviate the muscarinic side effects of anticholinesterase dryugs
used for reversal of neuromuscular blockade
o Mechanism of action
 May be classified as the following:
 Anticholinergic
 Antiparasympathetic (Parasympatholytic)
 Antimuscarinic
 More precise indication
 Antagonizes the muscarine-like actions of acetylcholine and other
choline esters
 Inhibits the muscarinic actions of acetylcholine on structures innervated
by postganglionic cholinergic nerves, and on smooth muscles, which
respond to endogenous acetylcholine but are not so innervated
 As with other antimuscarinic agents, the major action of atropine is a
competitive or surmountable antagonism, which can be overcome by
increasing the concentration of acetylcholine at receptor sites of the
effector organ (e.g., by using anticholinesterase agents, which inhibit the
enzymatic destruction of acetylcholine)
 The receptors antagonized by atropine are the peripheral structures that
are stimulated or inhibited by muscarine, (i.e., exocrine glands and
smooth and cardiac muscle)
 Responses to postganglionic cholinergic nerve stimulation may also be
inhibited by atropine, but this occurs less readily than with responses to
injected (exogenous) choline esters
o Administration
 Usually given as injection at the doctor’s clinic or in the hospital

28
 o Side effects
 Serious
 An allergic reaction (swelling of lips, tongue or face, difficulty
breathing, closing of the throat or hives)
 An irregular or fast heart rate
 Rash or flushing
 Eye pain
 Less serious
 Headache, dizziness or lightheadedness
 Weakness or nervousness
 Blurred vision, large pupils or sensitivity of the eyes to bright light
 Nausea, bloating, heartburn or constipation
 Changes in taste
 Difficulty urinating
 Decreased sweating
 Nasal congestion, stuffiness or a dry mouth
o Contraindication
 Increase the risk of atropine’s side effects
 Antihistamines (e.g., diphenhydramine)
 Parkinson’s disease medicines(e.g., benzotropine)
 Tricyclic antidepressant (e.g., amitriptyline)

Scopolamine

- Transderm Scop
o Scopolamine
o Indication
 Used to relieve nausea, vomiting, and dizziness associated with motion
sickness and recovery from anesthesia and surgery

29
  May also be used in the treatment of parkinsonism, spastic muscle
states, irritable bowel syndrome, diverticulitis and other conditions
 Diverticulitis
 A common digestive disease which involves the formation of
pouches within the bowel wall
o Mechanism of action
 Scopolamine acts by interfering with the transmission of nerve by
acetylcholine in the parasympathetic nervous system (specifically the
vomiting center)
 Anticholinergic effect
 The vestibular part of the ear is very important for balance
 When a person who is susceptible to motion sickness experiences
motion, the vestibule sends a signal through nerves to the
vomiting center in the brain, and vomiting occurs
 Acetylcholine is a chemical that nerves use to transmit messages
to each other (a neurotransmitter)
 It is believed that scopolamine prevents communication between
the nerves of the vestibule and the vomiting center in the brain by
blocking the action of acetylcholine
o Administration
 May be administered by topical, transdermal and injection
 Patch administration
 Wash your hands with soap and water before and after applying a
patch. Do not touch your eyes until after you have washed your
hands
 Apply the patch right away after removing it from the protective
pouch. Do not cut into smaller pieces and do not touch the sticky
surface of the patch
 Apply the patch to a clean, dry, and intact skin area behind the
ear. Choose an area with little or no hair and free of scars, cuts, or
irritation
 Press the patch firmly in place with your fingertips to make sure
that the edges of the patch stick well
 The patch should stay in place even during showering, bathing, or
swimming. Apply a new patch behind the other ear if the first one
becomes too loose or falls off
 Remove the patch after 3 days. If treatment is to be continued for
more than 3 days, remove the first patch and apply a new one
behind the opposite ear
o Side effects
 Blurred vision
 Chest pain or discomfort
 Difficulty with urinating
 Dilation of the pupils

30
  Dizziness, faintness, or lightheadedness when getting up from a lying or
sitting position suddenly
 Eye pain
 Flushing or redness of the skin
 Mood or mental changes
 Muscle weakness
 Nausea or vomiting
 Rash
 Redness of the white part of the eyes
 Restlessness
 Seeing, hearing or feeling things that are not there
 Shortness of breath
 Slow or irregular heartbeat
 Sweating
 Unusual tiredness
 Unusually warm skin
o Contraindication
 Contraindicated in persons who are hypersensitive to the drug
scopolamine or to other belladonna alkaloids or to any ingredient or
component in the formulation or delivery system, or inpatients with
angle-closure (narrow angle glaucoma)

Ipratropium

- Chronic Obstructive Pulmonary Disease (COPD)

o A progressive disease that makes it hard to breathe
o Can cause coughing, that produces large amounts of mucus, wheezing,
shortness of breath, chest tightness and other symptoms
o SMOKING is the leading cause of COPD
o Causes of less airflow in COPD
 The airways and air sacs lose their elastic quality
 The walls between many of the air sacs are destroyed
 The walls of the airways become thick and inflamed
 The airways make more mucus than usual, which clog them

31
- Two forms
o Bronchitis (chronic)
 A respiratory disease in which the mucus membrane in the lungs’
bronchial passages becomes inflamed
 As the irritated membrane swells and grows thicker, it narrows or shuts
off the tiny airways in the lungs, resulting in coughing spells that may be
accompanied by phlegm and breathlessness
 Two forms
 Acute Bronchitis
o Lasting from 1 to 3 weeks
 Chronic Bronchitis
o Lasting at least months of the year for 2 years in a row
 SMOKING damages cilia, if the cilia are damaged debris, irritants and
excess mucus are not brushed out leading to increased chances of
chronic bronchitis. QUIT SMOKING!!!

32
 o Emphysema
 Air sacs are gradually damaged making breathing more and more
difficult over time
 The inner walls of the air sacs weaken and eventually rupture, creating
one larger air space instead of many small ones, this reduces the
surface area of the lungs and, in turn, the amount of oxygen that reaches
the bloodstream
 SMOKING is the leading cause of emphysema

- Rhinitis
o Also called Coryza
o Irritation and inflammation of the mucous membrane inside the nose
o Two types of
 Allergic
 The immune system mistakenly identifies a typical harmless
substance as an intruder
 Two types
o Seasonal allergic rhinitis
 Also called hay fever
 Most common cause is pollen and occurs at different
times of the year
o Perennial allergic rhinitis
 Causes include dried skin flakes, urine and saliva
found on pet dander, mold, droppings from dust mites
and cockroach particles and occurs year round
 Non-allergic
 The patient do not have allergies
 Usually affects adults and causes year-round symptoms,
especially runny nose and nasal congestion
 Immune system is not involved

- Rhinorrhea
o Also called Runny nose
o A condition in which the nasal cavity is filled with a significant amount of mucus
fluid

33
- Atrovent
o Indication
 Maintenance treatment of bronchospasm associated with COPD,
including chronic bronchitis and emphysema, used alone or in
combination with other bronchodilators (inhalation)
 Symptomatic relief of rhinorrhea associated with allergic and non-allergic
rhinitis and symptomatic relief of rhinorrhea associated with the common
cold
o Mechanism of action
 Antagonizes action of acetylcholine on bronchial smooth muscle in
lungs, causing bronchodilation
o Administration
 Aerosol/inhalation
 Priming applies, what is priming?
 2 inhalations 4 times daily, allow 1 to 2 minutes/s between
inhalation
 Must NOT exceed 12 inhalations in 24 hours
 Combivent
 Combined Ipratropium Bromide & Albuterol Sulfate
 Albuterol
o Relaxes the smooth muscles of all the airways
o Common side effects
 Bladder pain
 Bloody or cloudy urine
 Cough producing mucus
 Difficult, burning, or painful urination
 Difficulty with breathing
 Frequent urge to urinate
 Lower back or side pain
 Shortness of breath
 Tightness in the chest
 Wheezing
o Contraindication
 Increased intraocular pressure and precipitation or exacerbation of
angle-closure glaucoma may also occur due to inadvertent contact of the
eye with aerosolized or nebulized drug
 Worsening of urinary retention

Pirenzepine

- Stomach ulcers
o Also known as Gastric ulcers
o Open sores that develop on the lining of the stomach

- Symptoms of an ulcer
o A gnawing or burning pain in the middle or upper stomach between meals or at
night

34
 o Bloating
o Heartburn
o Nausea and vomiting

- Causes of ulcer
o Use of painkillers called nonsteroidal anti-inflammatory drugs (NSAIDs), such
as aspirin, naproxen, ibuprofen and many others
o Excess acid production from gastrinomas, tumors of the acid producing cells of
the stomach that increases acid outpout
 Zollinger-Ellison syndrome
 A condition in which there is increased production of the hormone
gastrin
 Most of the time, a small tumor (gastrinoma) in the pancreas or
small intestine produces extra gastrin in the blood
 Gastrin
o A peptide hormone that stimulates secretion of gastric acid
(HCl) by the parietal cells of the stomach and aids in gastric
motility
o Excessive drinking of alcohol
o Smoking or chewing tobacco
o Serious illness
o Radiation treatment to the are

- Pirenzepine Hydrochloride
o Indication
 For the treatment of peptic ulcer, gastric ulcer and duodenal ulcer as it
reduces gastric acid secretion and reduces muscle spasm
o Mechanism of action
 An M1 selective antagonist
 A muscarinic receptor antagonist and binds to the muscarinic
acetylcholine receptor
o Administration
 Should be taken on an empty stomach 30 minutes before meals
o Common side effects
 Dry mouth
 Blurred vision
o Contraindication
 Contraindicated in renal failure
 Enhanced effect when used with other drugs with antimuscarinic
properties and MAOIs, could be fatal

Pralidoxime

- Protopam
o Pralidoxime chloride

35
o Indication
 The principal indications are muscle weakness and respiratory
depression
 Muscle weakness
o In the control of over dosage by anticholinesterase drugs
used in the treatment of myasthenia gravis
 Respiratory depression
o In severe poisoning, respiratory depression may be due to
muscle weakness
o In the treatment of poisoning due to pesticides and
chemicals (e.g., nerve agents) of the organophosphate class
which have anticholinesterase activity
o Mechanism of action
 Organophosphates bind to the esteratic site of acetylcholinesterase,
which results initially in reversible inactivation of the enzyme
 Acetylcholinesterase inhibition causes acetylcholine to accumulate in
synapses, producing continuous stimulation of cholinergic fibers
throughout the nervous systems
 If given within 24 hours after organophosphate exposure, pralidoxime
reactivates the acetylcholinesterase by cleaving phosphate-ester bond
formed between the organophosphate and acetylcholinesterase
 Involves the nicotinic receptor

o Administration
 Administered Iv or IM
36
 o Common side effects
 Blurred or double vision
 Change in near or distance vision
 Difficult or rapid breathing
 Difficulty in focusing the eyes
 Difficulty with speaking
 Dizziness
 Fast, pounding, or irregular heartbeat or pulse
 Muscle stiffness or weakness
 Pain at the injection site after injection into a muscle
o Contraindication
 Barbiturates
 Poisoning with organophosphates sensitizes the medullary centers
to depression by barbiturates
 CNS depression-producing medications (Aminophylline, Caffeine,
Theophylline, etc.)
 Use of these medications may exacerbate the effects of
organophosphate poisoning
 Succinylcholine
 Metabolized by plasma cholinesterases, which are inhibited in
organophosphate poisoning or cholinesterase inhibitor overdose,
therefore, prolonged respiratory paralysis could occur
 Thiamine
 Concurrent administration of intravenous thiamine may delay initial
excretion of Pralidoxime, probably by competing at a common
renal excretory site

Mecamylamine

- The first orally available antihypertensive agent launched in the 1950s, rarely used
today for hypertension because of its widespread ganglionic side effects at
antihypertensive doses (25 – 90 mg/day)

- Mecamylamine Hydrochloride
o Indication
 Severe high blood pressure
o Mechanism of action
 Relaxes and dilates (widens) blood vessels so blood flows more freely
and at a lower pressure through dilated blood vessel, which helps lower
blood pressure
 A nicotinic acetylcholine receptor antagonist
o Administration
 May be taken with or without food
 It is important though to choose one way and take this medication the
same way with every dose

37
 o Common side effects
 Blurred vision
 Constipation (sometimes preceded by small, frequent liquid stools)
 Decreased sex drive
 Dizziness
 Dry mouth
 Enlarged pupils
 Impotence
 Inflammation of the tongue
 Lightheadedness
 Loss of appetite
 Nausea
 Urinary retention
 Vomiting
o Contraindication
 Antibiotics
 Sulfonamides
 Urinary alkalinizers
 The blood pressure lowering effects of this drug may be increased

Hexamethonium

- Formerly used to treat chronic hypertension of the peripheral nervous system

- Treatment has no specificity leading to discontinuing of the drug

- Inhaled hexamethonium, not an approved drug, is also believed to be responsible for

a death of one volunteer in a medical study

Trimethaphan

- Arfonad
o Trimethaphan Camsylate
o Indication
 Controlled hypotension
 Indicated for production of controlled hypotension during surgery
to reduce bleeding into the surgical field
 Hypertension
 Indicated for rapid reduction of blood pressure in the treatment of
hypertensive emergencies, especially in patients with acute
dissecting aneurysm, and in the emergency treatment of
pulmonary edema in patients with pulmonary hypertension
associated with systemic hypertension
o Mechanism of action
 Ganglionic blocking agent that prevents stimulation of postsynaptic
receptors by competing with acetylcholine for receptor sites

38
  Additional effects may include direct peripheral vasodilation and release
histamine
 Histamine
 An organic nitrogenous compound involved in local immune
responses as well as regulating physiological function in the GUT
and acting as a neurotransmitter
 Involved in the anti-inflammatory response
 Part of the immune response to foreign pathogens, it is produced
by basophils and by mast cells found in nearby connective tissues
 Increases the permeability of the capillaries to white blood cells
and some proteins, to allow them to engage in the infected tissues
 Trimethaphan’s hypotensive effect is due to reduction in sympathetic
tone and vasodilation and is primarily postural
o Administration
 Injection
o Common Side effects
 Anorexia, nausea and vomiting
 Constipation
 Cycloplegia and mydriasis
 Dryness of mouth
 Impotence
 Itching, urticarial
 Orthostatic hypotension
 Paralytic ileus
 Precipitation of angina
 Tachycardia
 Urinary retention (short term)
o Some contraindication
 Addison’s disease
 Allergies
 The drug liberates histamine and has been reported to cause a
histamine-like reaction along the vein where administered
 Urethral stricture
 Recent Myocardial Infarction
 Ischemia may be aggravated by hypotension

Epinephrine

- Adrenergic receptors
o Is this the same with the cholinergic receptors?
o Also called adrenoreceptors
o Mediates the action of epinephrine and related compounds
o Sympathetic neuroeffector junction
 Classical site of adrenergic receptors
 However, adrenergic receptors may exist on the cells of effector organs,
even in the absence of sympathetic innervation
39
 o Two types
 Alpha receptors
 When activated, generally produce excitatory responses of smooth
muscle in which they are located
 Subdivisions
o Alpha 1 receptors
 Sensitive to blockade by Prazosin
 Mainly postsynaptic
 Molecular biology classification (recent)
 Alpha 1A
 Alpha 1B
 Alpha 1D
o Alpha 2 receptors
 Sensitive to blocked of Yohimbine
 Found mainly presynaptically (recent evidence shows
postsynaptic as well) on sympathetic postganglionic
nerve terminals
 Action inhibits the release of NE
 Molecular biology classification (recent)
 Alpha 2A
 Alpha 2B
 Alpha 2C
 Beta receptors
 When activated, generally produce inhibitory responses of smooth
muscle in which they are located
 Isoproterenol
o Classical agonist of the beta receptor
 Propanolol
o Classical antagonist of the beta receptor
 Therapeutic classification
o Beta 1 receptors
 When activated, produce cardiac positive chrono- and
inotropic responses and lipolysis
 Chronotropic
 Influencing the rate of the heartbeat
 Inotropic
 Affecting the force of muscle contraction
o Beta 2 receptors
 When activated, produce bronchodilation, vasodilation
and uterine relaxation
o Beta 3 receptors
 When activated, produce lipolysis in adipose tissue
 Not well understood

- Adrenergic mechanisms

40
o Adrenaline or Noradrenaline are receptor ligands to either alpha1, alpha2 or
beta adrenergic receptors

 Alpha1 couples to Gq which results in increased intracellular calcium and

subsequent smooth muscle contraction
 Alpha2 couples to Gi, which causes a decrease in neurotransmitter
release, as well as decrease in cAMP activity and a resulting and smooth
muscle contraction
 Beta receptors couple to Gs, and increases intracellular cAMP activity
resulting in e.g., heart muscle contraction, smooth muscle relaxation and
glycogenolysis
o Illustration 1

o Illustration 2

41
42
- Also known as Adrenaline

- A hormone secreted by the medulla of the adrenal glands

- Strong emotions such as fear or anger cause epinephrine to be released into the
bloodstream, which causes an increase in heart rate, muscle strength, blood
pressure and sugar metabolism

- Found in small amounts in the body and is essential for maintaining cardiovascular
homeostasis because of its ability to divert blood to tissues under stress

- Causes “Flight or Fight response” preparing the body for strenuous activity

- The common dosage form

- Prefilled syringe
43
- EpiPen
o Epinephrine Injection
o Indication
 Used chiefly as a stimulant in cardiac arrest, as a vasoconstrictor in
shock, and as a bronchodilator and antispasmodic in bronchial asthma
o Mechanism of action
 Epinephrine is a direct-acting sympathomimetic drug that acts as an
agonist at alpha and beta-adrenergic receptors
 Sympathomimetic
 Stimulant compounds which mimic the effect of neurotransmitter
substances of the sympathetic nervous system
 It produces vasoconstriction to counteract the vasodilation and resulting
hypotension associated with anaphylaxis
 The bronchodilatory effects of epinephrine and its ability to reduce
mucosal edema relieve bronchoconstriction and improve respiratory
effort
 Epinephrine also down-regulates the release of histamine, tryptase, and
other inflammatory mediators from mast cells and basophils, improving
respiratory function and reducing the pruritus, urticaria, angioedema, and
gastrointestinal symptoms which occur after allergen exposure
o Administration
 IM injection
 May come in pre-filled syringe
 Must be injected as soon as there is suspicion of a serious allergic
reaction
 Epinephrine should be injected only in the middle of the outer side of the
thigh and can be injected through clothing if necessary in an emergency.
Should not be injected into buttocks or any other part of the body
 Helps treat serious allergic reaction but does not take the place of
medical treatment
44
 o Common Side effects
 Tachycardia
 Diaphoresis
 Difficulty breathing
 Nausea and vomiting
 Pallor
 Dizziness
 Weakness
 Tremor
 Headache
 Anxiety
o Contraindication
 Arrythmias and hypertension
 Digoxin
 Quinidine
 Diuretics
 Alpha and Beta-Adrenergic agonist
 Increased effects
 Antihistamine
 Flurazolidone
 Levothyroxine
 Methyldopa
 Reserpine
 Tricyclic antidepressants
 MAOIs

Norepinephrine

- Levophed
o Norepinephrine Bitartrate
o Indication
 For blood pressure control in certain acute hypotensive states
o Mechanism of action

45
  Functions as a peripheral vasoconstrictor by acting on alpha-adrenergic
receptors
 It is also an inotropic stimulator of the heart and dilator of coronary
arteries as a result of its activity at the beta-adrenergic receptor
o Administration
 Intravenous
o Serious side effects
 Pain, burning irritation, discoloration, or skin changes where the injection
is given
 Sudden numbness, weakness, or cold feeling anywhere in the body
 Slow or uneven heart rate
 Blue lips or fingernails, mottled skin
 Urinating less than usual or not at all
o Contraindication
 Hypotension
 Not given during hypotension except as an emergency measure to
maintain coronary and cerebral artery perfusion until blood volume
replacement therapy can be completed
 Mesenteric or peripheral vascular thrombosis
 Due to the risk of increasing ischemia and extending the area of
infarction
 Cyclopropane and Halothane
 Due to the risk of producing ventricular tachycardia or fibrillation

Isoproterenol

- Catecholamines
o Hormones made by the adrenal glands
o Released into the blood when a person is under physical or emotional stress
o Adrenal glands
 The glands on top of the kidneys
o Some Catecholamines
 Dopamine
 Norepinephrine
 Epinephrine

- Isuprel
o Isoproterenol Hydrochloride Injection

46
o Indication
 For mild or transient episodes of heart block that do not require electric
shock or pacemaker therapy
 Pacemaker
o A small device, about the size of a half dollar piece, that is
placed under the skin near the heart to help control
heartbeat
o Implanted as part of what’s often referred to as “cardiac
resynchronization therapy”
o Using the pacemaker is usually due to one of a group of
conditions called “arrhythmias”, in which the heart’s rhythm
is abnormal
 For serious episodes of heart block and Adams-Stokes attacks(except
when caused by ventricular tachycardia or fibrillation)
 Adams-Stokes attack
o Also called Stokes-Adams attacks, Morgagni, Morgagni-
Adams-Stokes and Spens’ syndrome

o Collapse without warning, associated with loss of

consciousness for a few seconds
 For use in cardiac arrest until electric shock or pacemaker therapy, the
treatment of choice, is available
 For bronchospasm occurring during anesthesia
 As an adjunct to fluid and electrolyte replacement therapy and the use of
other drugs and procedures in the treatment of hypovolemic and septic
shock, low cardiac output (hypoperfusion) states, congestive heart failure
and cardiogenic shock
 Types of shock
o Hypovolemic shock
 An emergency condition in which severe blood (1/5 or
more) and fluid loss make the heart unable to pump
enough blood to the body
 This type of shock can cause organs to stop working
47
  Causes
 Blood loss
o Bleeding from cuts
o Bleeding from other injuries
o Internal bleeding, such as in the GIT
 Loss of body fluids
o Burns
o Diarrhea
o Excessive perspiration
o Vomiting
o Septic shock
 A serious condition that occurs when a body-wide
infection leads to dangerously low blood pressure
 May be caused by bacteria, fungi and virus (rarely)
 Occurs most often in the very old and in the very
young
o Cardiogenic shock
 When the heart has been damaged so much that it is
unable to supply enough blood to the organs of the
body
 Most common causes are serious heart complications
o Anaphylactic shock
 Caused by an allergic reaction (not an indication of
Isuprel)
o Neurogenic shock
 Caused by a spinal cord injury (not an indication of
Isuprel)
 Congestive heart failure
o Occurs when heart muscle doesn’t pump blood as well as it
should

o May be caused by narrowed arteries in the heart (coronary

artery disease) or high blood pressure, which leave the
heart too weak or stiff to fill and pump efficiently
o Mechanism of action
 A potent nonselective beta-adrenergic agonist with very low affinity for
alpha-adrenergic receptors
 Intravenous infusion of isoproterenol lowers peripheral vascular
resistance, primarily in skeletal muscle but also in renal and mesenteric
vascular beds
 Diastolic pressure falls
 Renal blood flow is decreased in normotensive subjects but is increased
markedly in shock
 Normotensive
o Having normal blood pressure

48
  Systolic blood pressure may remain unchanged or rise, although mean
arterial pressure typically falls
 Cardiac output is increased because of the positive inotropic and
chronotropic effects of the drug in the face of diminished peripheral
vascular resistance
 Inotrope
o An agent that alters the force or energy of muscular
contractions
 Chronotrope
o An agent that change the heart rate
 The cardiac effects of isoproterenol may lead to palpitations, sinus
tachycardia, and more serious arrhythmias
 Large doses may cause myocardial necrosis in animals
 REMEMBER
 Isoproterenol relaxes all varieties of smooth muscle when the tone
is high, but this action is most pronounced on bronchial and
gastrointestinal smooth muscle
 It prevents or relieves bronchoconstriction, but tolerance to this
effect develops with overuse of the drug
o Administration
 Administered by the doctor via IV, IM, SC & Intracardiac
o Side effects
 CNS
 Nervousness
 Headache
 Dizziness
 Nausea
 Visual Blurring
 Cardiovascular
 Palpitations
 Angina

 Pulmonary edema
 Hypertension
 Hypotension
 Ventricular arrhythmias
 Tachycardia
o Heart beat that is too fast, more than 100 beats per minute
(BPM)
 Tachyarrhythmia
o Any disturbance of the heart rhythm in which the heart rate
is abnormally increased
 Respiratory
 Dyspnea
o Contraindication
 Tachyarrhythmia
49
  Heart block caused by digitalis intoxication
 Ventricular arrhythmias which require inotropic therapy
 Angina pectoris

Dobutamine

- A beta-1 agonist catecholamine that has cardiac stimulant action without evoking
vasoconstriction or tachycardia

- It is proposed as a cardiotonic after myocardial infarction or open heart surgery

- Dobutamine Injection
o Indication
 Heart failure caused by surgery or heart disease
o Mechanism of action
 An inotropic agent, what is an inotrope?

 Works by increasing the strength and force of the heartbeat, causing

more blood to circulate through the body
 Directly stimulates beta-1 receptors of the heart to increase myocardial
contractility and stroke volume, resulting in increased cardiac output
 Stroke volume
 The amount of blood pumped by the left ventricle of the heart in
one contraction
o Administration
 Administered as an injection
o Common side effects
 Headache
 Nausea
o Contraindication
 Cimetidine or methyldopa
50
  Increases side effects of dobutamine
 Catechol-O-methyltransferase (COMT) inhibitors or droxidopa
 Its side effects may be increased by dobutamine
 History of heart valve problems, an adrenal gland tumor, an increased
irregular heartbeat (tachyarrhythmia), or an enlarged left ventricle of the
heart due to narrowing of the aortic blood vessel (idiopathic hypertrophic
subaortic stenosis)

Dopamine

- A neurotransmitter that helps control the brain’s reward and pleasure centers

- A major transmitter in the extrapyramidal system of the brain

o Extrapyramidal system
 The part of the nervous system that includes the basal nuclei (substantia
nigra, subthalamic nucleus, etc.), part of the midbrain, and the
motorneurons of the spine

- It is derived from tyrosine and is the precursor to norepinephrine and epinephrine

- Parkinson’s disease
o Dopamine deficiency result

- People with low dopamine activity may be more prone to addiction

- Risk-takers
o Sensation seeking people that may have presence of a certain kind of
dopamine receptor

- Inotropin
o Dopamine Hydrochloride Injection, USP

51
o Indication
 Correction of hemodynamic imbalances present in the shock syndrome
due to myocardial infarctions, trauma, endotoxic septicemia, open heart
surgery, renal failure, and chronic cardiac decompensation as in
congestive heart failure
 Myocardial infarction
o The irreversible necrosis of heart muscle secondary to
prolonged ischemia
o Myocardial ischemia
 When blood flow to the heart muscle is decreased by
a partial or complete blockage of the heart’s arteries
(coronary arteries)
 The decrease in blood flow reduces the heart’s
oxygen supply
o Mechanism of action
 Dopamine is a precursor to norepinephrine in nonadrenergic nerves and
is also a neurotransmitter in certain areas of the CNS
 Dopamine produces positive chronotropic and inotropic effects on the
myocardium, resulting in increased heart rate and cardiac contractility
 This is accomplished directly by exerting an agonist action on beta-
adrenoceptors and indirectly by causing release of norepinephrine from
storage sites in sympathetic nerve endings
 In the brain, dopamine acts as an agonist to the five dopamine receptor
subtypes (D1, D2, D3, D4 & D5) – This is another story☻
o Administration
 IV

o Side effects
 Serious
 Chest pain
52
  Fast, slow or pounding heartbeats
 Painful or difficult urination, blood in urine
 Weakness, confusion, swelling in the feet or ankles, urinating less
than usual or not at all
 Weak or shallow breathing
 Feeling like passing out, even while lying down
 Burning, pain, or swelling around the IV needle
 Cold feeling, numbness, or blue-colored appearance in the hands
or feet
 Darkening or skin changes in the hands or feet
 Less serious
 Headache
 Feeling anxious
 Nausea and vomiting
 Chills
 Goosebumps
o Contraindication
 Should not be used in patients with pheochromocytoma
 Pheochromocytoma
o A rare tumor of the adrenal gland tissue
o It results in the release of too much epinephrine and
norepinephrine, hormones that control heart rate,
metabolism and blood pressure
 Should not be administered in the presence of uncorrected
tachyarrhythmias or ventricular fibrillation

Phenylephrine

- Sudafed PE
o Phenylephrine
o A decongestant that shrinks blood vessels in the nasal passages [dilated blood
vessels can cause nasal congestion (stuffy nose)]
o Used to treat nasal and sinus congestion or congestion of the tubes that drain
fluid from the inner ear (Eustachian tube)
o Eustachian tube
 A tube that links the nasopharynx to the middle ear

53
o Indication
 Used for the temporary relief of stuffy nose, sinus and ear symptoms
caused by common cold, flu, allergies or other breathing illnesses (e.g.,
sinusitis, bronchitis)
o Mechanism of action
 Works by decreasing swelling in the nose and ears, thereby lessening
discomfort and making it easier to breathe
 A sympathomimetic amine that acts predominantly on α-adrenergic
receptors
 IMPORTANT
 In general, α1-adrenergic receptors mediate contraction and
hypertrophic growth of smooth muscle cells
 Α1-receptors are 7-transmembrane domain receptors coupled to
G proteins, Gq/11
 Three α1-receptor subtypes, which share approximately 75%
homology in their transmembrane domains, have been identified:
α1A (chromosome 8), α1B (chromosome 5) and α1D (chromosome
20)
 Phenylephrine appears to act similarly on all three receptor
subtypes
 All three receptor subtypes appear to be involved in maintaining
vascular tone
 The α1A-receptor maintains basal vascular tone while the α 1B-
receptor mediates the vasocontrictory effects of exogenous α1-
agonists
 Activation of the α1-receptor activates Gq-proteins, which results in
intracellular stimulation of phospholipases C, A2 and D

54
  This results in mobilization of Ca2+ from intracellular stores,
activation of mitogen-activated kinase and PI3 kinase pathways
and subsequent vasoconstriction
 Phenylephrine produces its local and systemic actions by acting
on α1-adrenergic receptors peripheral vascular smooth muscle
 Stimulation of the α1-adrenergic receptors results in contraction
arteriolar smooth muscle in the periphery
 Phenylephrine decreases nasal congestion by acting on α 1-
adrenergic receptors in the arterioles of the nasal mucosa to
produce constriction; this leads to decreased edema and
increased drainage of the sinus cavities
o Administration
 Available in many dosage forms
 May be in the form of IV (dilute as ordered, this should be consumed
within 24 hours in a refrigerated condition and 4 hours at room
temperature)
o Common side effects
 Loss of appetite
 Warmth, tingling or redness under the skin
 Feeling restless or excited (especially in children)
 Insomnia
 Skin rash or itching
o Contraindication
 Do not take with MAOi, may cause fatal interaction

Methoxamine

- A direct-acting α-1 receptor agonist

- Causes a prolonged increase in blood pressure via its vasoconstricting action

- Used parenterally, but clinical applications are rare and limited to hypotensive states,
notably in general and spinal anesthesia

- Methoxamine Hydrochloride
o Indication
 Indicated for the treatment and management of hypotension
o Mechanism of action
 Acts through peripheral vasoconstriction by acting as a pure alpha-1
adrenergic receptor agonist, consequently increasing systemic blood
pressure (both systolic and diastolic)
o Administration
 Parenteral
o Side effects
 Bradycardia
 Decreased plasma volume

55
  Heart failure
 Severe hypertension
 Cerebrovascular accidents
o Contraindication
 Drug interactions are as follows:
 Halothane
 Methylergonovine
o Ergot alkaloids may cause a significant increase in blood
pressure when combined with peripheral or central
vasoconstrictors
o The mechanism is an additive or synergestic
vasoconstriction due to the alpha adrenergic agonist activity
of ergot alkaloids

Oxymetazoline

- A decongestant

- Relieves nasal congestion due to common cold, hay fever, other upper respiratory
tract allergies or sinus infection

- Afrin
o Oxymetazoline Hydrochloride
o Indication
 For treatment of nasal congestion and redness associated with minor
irritations of the eye
o Mechanism of action
 Works by shrinking swollen and congested nasal tissues (mucous
membranes) by constricting blood vessels
 This results in relief of congestion (stuffy feeling), improved drainage of
mucus and improved breathing through the nose
 Local application (e.g., nose drops and sprays) causes more intense and
rapid vasoconstriction than oral medicines
 Acts on alpha-adrenergic receptors in the arterioles of the conjunctiva
and nasal mucosa
56
 o Administration
 Nasal spray
o Side effects
 Tricyclic antidepressants (e.g., amitriptyline)
 The effectiveness of oxymetazoline solution may be decreased
 Cocaine, furazolidone, MAO inhibitors (e.g., phenelzine), or tricyclic
antidepressants (e.g., amitriptyline)
 The side effects, such as headache, fever or high blood pressure
may be increased
 Bromocriptine or cocaine
 The actions and side effects of these medicines may be increases
o Contraindication
 High blood pressure
 Enlarged prostrate
 Diabetes
 Overactive thyroid
 Heart disease

Clonidine

- Catapres
o Clonidine

o Indication
 Used to treat hypertension (high blood pressure)
o Mechanism of action
 Alpha-adrenergic agonist
 Also has some alpha-adrenergic antagonist effects
 Treats high blood pressure by stimulating α2-receptors in the brain which
decreases peripheral vascular resistance, lowering blood pressure

57
  A centrally-acting alpha adrenergic receptor agonist with more affinity for
alpha 2 than alpha 1
 It selectively stimulates presynaptic alpha 2 receptors in the brain that
monitor catecholamine levels in the blood
 These receptors close a negative feedback loop that begins with
descending sympathetic naerves from the brain that control the
production of catecholamines (adrenaline and noradrenaline) in the
adrenal medulla
 By fooling the brain into believing that catecholamine levels are higher
than they really are, clonidine causes the brain to reduce its signals to
the adrenal medulla, which in turn lowers catecholamine production and
blood levels
 The result is lowered heart rate and blood pressure
o Administration
 Usually in the form of tablets and TDDS
o Side effects
 Dizziness
 Lightheadedness
 Drowsiness
 Dry mouth
 Constipation
o Contraindication
 Heart disease or severe coronary artery disease
 Heart rhythm disorder, slow heartbeats
 Low blood pressure
 A history of heart attack or stroke
 Pheochromocytoma (tumor of the adrenal gland)
 Kidney disease

Ritodrine

- Yutopar
o Ritodrine Hydrochloride

58
o Indication
 Treatment and prophylaxis of premature labor
o Mechanism of action
 Beta-2 adrenergic agonist
 It binds to beta-2 adrenergic receptors on outer membrane of myometrial
cell, activates adenyl cyclase to increase the level of cAMP which
decreases intracellular calcium and leads to a decrease of uterine
contractions
o Administration
 IV
o Side effects
 Mostly related to its beta-adrenergic stimulating activity
o Contraindication
 May interact with the following medications
 Anesthetics
o May potentiate the hypotensive effects
 Parenteral diazoxide
 Magnesium sulfate
 Meperidine
 Sympathomimetic amines
o May be additive
 Beta-adrenergic antagonists
o Inhibit Ritoridine
 Corticosteroids
o May cause pulmonary edema
 Should not be given to the following medical conditions
 Pregnancy less than 20 weeks
 Antepartum hemorrhage which demands immediate delivery
 Eclampsia and severe preeclampsia
o Eclampsia
 Seizures (convulsions) in a pregnant woman
 These seizures are not related to an existing brain
condition
 Intra-uterine fetal death
 Chorioamnionitis
o Inflammation of the fetal membranes (amnion and chorion)
due to bacterial infection
 Maternal cardiac disease
 Pulmonary hypertension
 Maternal hyperthyroidism
 Uncontrolled maternal diabetes mellitus
 Pre-existing maternal medical conditions

59
Terbutaline

- Used to relieve and prevent bronchospasms caused by asthma, emphysema or

bronchitis

- Bricanyl
o Terbutaline Sulfate

o Indication
 A beta agonist
 Used to prevent and treat wheezing, shortness of breath, and chest
tightness caused by asthma, chronic bronchitis and emphysema
 Works by relaxing and opening the airways, making it easier to breathe
o Mechanism of action
 Adrenergic bronchodilator
 Acts by stimulating beta 2-adrenergic receptors in the lungs to relax
bronchial smooth muscle, thereby relieving bronchospasm
o Administration
 Comes in many dosage forms
 Can be in the form of a powder inhaler
o Side effects
 Catechol-O-methyltransferase (COMT) inhibitors, droxidopa, monoamine
oxidase inhibitors (MAOIs or tricyclic antidepressants
 Risk of side effects, such as life-threatening irregular heartbeat
may be increased
 Diuretics
 May increase risk of side effects
 Beta-blockers
 Because they may decrease terbutaline’s effectiveness
 Insulin
 Decrease effectiveness of terbutaline

60
 o Contraindication
 Pregnancy
 Heart disease, an irregular heartbeat, high blood pressure, an overactive
thyroid, diabetes, a history of seizures or an adrenal tumor

Albuterol

- A bronchodilators

- Also known as Salbutamol

- It works by relaxing and opening air passages to the lungs to make breathing easier

- Ventolin
o Albuterol (USAN) /Salbutamol (INN)
o Indication
 Used to prevent and treat wheezing, shortness of breath, coughing, and
chest tightness caused by lung diseases such as asthma and chronic
obstructive pulmonary disease (COPD)
 Albuterol inhalation aerosol is also used to prevent breathing difficulties
during exercise
o Mechanism of action
 Albuterol is a beta(2)-adrenergic agonist, it stimulates beta(2)-adrenergic
receptors
 Binding of albuterol to beta(2)-receptors in the lungs results in relaxation
of bronchial smooth muscles

61
 o Administration
 Administered by using an inhaler
o Side effects
 Serious
 Bronchospasm (wheezing, chest tightness, trouble breathing)
especially after starting a new canister of the medicine
 Chest pain and fast, pounding, or uneven heart beats
 Tremor, nervousness
 Low potassium (confusion, uneven heart rate, extreme thirst,
increased urination, leg discomfort, muscle weakness or limp
feeling)
 Dangerously high blood pressure (severe headache, blurred
vision, buzzing in the ears, anxiety, confusion, chest pain,
shortness of breath, uneven heartbeats, seizure)
 Less serious
 Headache, dizziness
 Sleep problems (insomnia)
 Cough, hoarseness, sore throat, runny or stuffy nose
 Mild nausea, vomiting
 Dry mouth and throat
 Muscle pain
 Diarrhea
o Contraindication
 Heart disease, high blood pressure or congestive heart failure
 A heart rhythm disorder
 A seizure disorder such as epilepsy
 Diabetes
 Overactive

Salmeterol

- Salmeterol is in a class of medications called long-acting beta agonists (LABAs)

62
- Serevent
o Salmeterol
o Indication
 Used to treat wheezing, shortness of breath, coughing, and chest
tightness caused by asthma and chronic obstructive pulmonary disease
 It also is used to prevent bronchospasm (breathing difficulties) during
exercise
o Mechanism of action
 It works by relaxing and opening air passages in the lungs, making it
easier to breathe
 Salmeterol’s long, lipophilic side chain binds to exosites near beta(2)-
receptors in the lungs and on bronchiolar smooth muscle, allowing the
active portion of the molecule to remain at the receptor site, continually
binding and releasing
 Beta(2)-receptor stimulation in the lung causes relaxation of bronchial
smooth muscle, bronchodilation and increased bronchial airflow
o Administration
 Powder through aerosol
o Side effects
 Hoarseness
 Throat irritation
 Headache
 Rapid heartbeat
 Nervousness
 Cough
 Dry mouth/throat
To relieve, suck on sugarless hard candy or ice chips, chew
(sugarless) gum, drink water or use a saliva substitute
 Upset stomach
o Contraindication
 Tell the doctor if the patient has heart problems, Salmeterol may cause a
condition that affects the heart rhythm (QT prolongation)

Ephedrine

63
- Ephedrine
o Ephedrine Sulfate Injection
o Indication
 Allergic disorders, such as bronchial asthma
o Mechanism of action
 A sympathomimetic amine
 Ephedrine increases post-synaptic noradrenergic receptor activity by
(weakly) directly activating post-synaptic α-receptors and β-receptors,
but the bulk of its effect comes from the pre-synaptic neuron being
unable to distinguish between real adrenaline or noradrenaline from
ephedrine
 The ephedrine, mixed with noradrenaline, is transported through the
noradrenaline reuptake complex and packaged (along with real
noradrenaline) into vesicles that reside at the terminal button of a nerve
cell
 Ephedrine’s action as an agonist at most major noradrenaline receptors
and its ability to increase the release of both dopamine and to a lesser
extent, serotonin by the same mechanism is presumed to have a major
role in its mechanism of action
o Administration
 Available in the following dosage forms: IV, capsule and powder
o Side effects
 Common side effects
 Dizziness  Loss of appetite
 Headache  Restlessness
 Nausea  Sleeplessness
 Nervousness  Stomach irritation
 Tremor
 Severe side effects
 Severe allergic reaction (rash; hives; difficulty breathing; tightness
in the chest; swelling of the mouth, face, lips or tongue)
 Difficulty urination
o Contraindication
 Do not take when currently taking MAOi or have taken it in the last 14
days
 High blood pressure, heart disease, an irregular heartbeat, thyroid
disease, diabetes or difficulty in urination due to enlargement of the
prostate gland or other severe heart problems
 The following may decrease effectivity of ephedrine
 Guanadrel
 Guanethidine
 Mecamylamine
 Methyldopa
 Reserpine

64
Pseudoephedrine

- A decongestant that shrinks blood vessels in the nasal passages

- Sudafed
o Pseudoephedrine
o Indication
 Temporarily relieves nasal congestion due to the common cold, hay
fever or other upper respiratory allergies
 Temporarily relieves sinus congestion and pressure
o Mechanism of action
 Pseudoephedrine acts directly on both alpha- and to a lesser degree,
beta-adrenergic receptors
 Through direct action on alpha-adrenergic receptors in the mucosa of the
respiratory tract, pseudoephedrine produces vasoconstriction
 Pseudoephedrine relaxes bronchial smooth muscle by stimulating beta2-
adrenergic receptors
o Administration
 Orally administered, ER is available
o Side effects
 Nausea
 Vomiting
 Trouble sleeping
 Dizziness
 Headache
 Nervousness
o Contraindication
 Chronic obstructive lung disease
 Closed angle glaucoma
 Chronic difficulty having a bowel movement
 High blood pressure
 Severe uncontrolled high blood pressure
 Severe diabetes of the arteries of the heary
 Stenosing peptic ulcer
 Stomach or intestine blockage
 Blockage of urinary bladder
 Enlarged prostate, cannot empty bladder
 Overactive thyroid gland diabetes

65
Cocaine

- Cocaine Hydrochloride
o Indication
 Introduction of local (topical) anesthesia of accessible mucous
membranes of the oral, laryngeal and nasal cavities
o Mechanism of action
 Cocaine produces anesthesia by inhibiting excitation of nerve endings or
by blocking conduction in peripheral nerves
 This is achieved by reversibly binding to and inactivating sodium
channels
 Sodium influx through these channels is necessary for the depolarization
of nerve cell membranes and subsequent propagation of impulses along
the course of the nerve
 Cocaine is the only local anesthetic with vasoconstrictive properties
 This is a result of its blockade of norepinephrine reuptake in the ANS
 Cocaine bids differentially to the dopamine, serotonin and
norepinephrine transport proteins and directly prevents the re-uptake of
dopamine, serotonin and norepinephrine into pre-synaptic neurons
 Its effect on dopamine levels is most responsible for the addictive
property of cocaine
o Administration
 Administered using cotton applicators or packs, instilled into a cavity, or
as a nasal spray
o Side effects
 CNS excitatory which may be nervousness, restlessness and excitement
o Contraindication
 Hypersensitivity to the drug

66
Tyramine

- Decarboxylated tyrosine, a sympathomimetic amine having an action in some

respects resembling that of epinephrine

- Tyramine
o Indication
 For temporary relief of symptoms related to tyramine sensitivity including
food cravings, muscle spasm, headache, high blood pressure, excessive
sweating, weight loss, fatigue, nervousness, agitation and vasodilation
o Mechanism of action
 An indirect sympathomimetic
 Tyramine does not directly activate adrenergic receptors, but it can serve
as a substrate for adrenergic uptake systems and monoamine oxidase
so it prolongs the actions of adrenergic transmitters
 It also provokes transmitter release from adrenergic terminals
o Administration
 1 to 10 drops under the tongue, 3 times a day or as directed by a health
professional
o Side effects
 Elevated blood pressure
 Heart rhythm problems
 Flushing
o Contraindication
 Tolerance may develop, more data needed

Amphetamine

- A stimulant and an appetite suppressant

- It stimulates the central nervous system (nerves and brain) by increasing the amount
of certain chemicals in the body
- Increases heart rate and blood pressure and decreases appetite, among other
effects
- Amphetamine
o Indication
 Used to treat narcolepsy and attention deficit disorder with hyperactivity
(ADHD)
o Mechanism of action
 A powerful CNS stimulant and sympathomimetic
 Amphetamine has multiple mechanisms of action including blocking
uptake of adrenergics and dopamine, stimulation of release of
monoamines and inhibiting monoamine oxidase
o Administration
 Oral
67
  Insufflation
 Intranasal administration
 Not used in the therapeutic setting
 Injection
 Rectal
o Side effects
 Loss of appetite  Headache
 Weight loss  Diarrhea
 Dry mouth  Fever
 Stomach upset/pain  Nervousness
 Nausea/vomiting  Trouble sleeping
 Dizziness
o Contraindication (Adderall)
 Advanced arteriosclerosis
 Symptomatic cardiovascular disease
 Moderate to severe hypertension
 Hyperthyroidism
 Known hypersensitivity or idiosyncrasy to the sympathomimetic amines
 Glaucoma
 Agitated states
 History of drug abuse
 During or within 14 days following the administration of monoamine
oxidase inhibitors (hypertensive crisis may result)

- Adderall
o Amphetamine and dextroamphetamine
o Dextroamphetamine
 Exact mechanism of action not understood
 Stimulates the release of norepinephrine from central adrenergic
receptors

68
Prazosin

- Minipress
o Prazosin Hydrochloride
o Indication
 High blood pressure
 Benign prostatic hyperplasia (BPH)
o Mechanism of action
 An alpha blocker
 Works by causing the blood vessels and the muscles around the urethra
(the tube leading out of the bladder) to relax
 This helps to lower blood pressure and to improve urinary symptoms
associated with enlargement of the prostate
o Administration
 Tablets
o Side effects
 Common
 Dizziness  Drowsiness
69
 Dry mouth  Lightheadedness
 Frequent urination  Nasal congestion
 Headache  Nausea
 Lack of energy  Weakness
 Severe
 Severe allergic reactions (rash; hives; itching; difficulty breathing;
tightness in the chest; swelling of the mouth, face, lips or tongue)
 Blurred vision
 Fainting
 Fast or irregular heartbeat
 Depression
 Severe or persistent dizziness
 Swelling of the hands or feet

o Contraindication
 Diuretics (e.g., furosemide, hydrochlorothiazide) or verapamil
 May increase the risk of prazosin’s side effects
 Beta-blockers (e.g., propranolol)
 Their actions and the risk of their side effects may be increased by
prazosin

Terazosin

- Hytrin
o Terazosin Hydrochloride
o Indication
 Benign prostatic hyperplasia
 High blood pressure
o Mechanism of action
 A non-selective alpha(1) blocker
 Post-synaptic alpha(1) blockade leads to
 Arterial and venous vasodilation, hypotension
 Smooth muscle relaxation of the prostate, bladder neck and the
urethra

70
  Alpha-blocker improve the dynamic component of subvesical
obstruction due to BPH
 Positive effect on the lipid metabolism by lowering cholesterol and
triglycerides
o Administration
 Capsule
 Tablet
o Side effects
 Priapism  Palpitations
 Postural hypotension  Nasal congestion
 Dizziness  Sleepiness
 Weakness  Decreased libido
 Fatigue  Impotence
 Headaches  Blurred vision
 Swelling of the legs
(edema)

o Contraindication
 Should be paused perioperatively for cataract surgery to prevent an
intraoperative floppy iris syndrome
 Hypotension, mechanical heart failure (valvular, pulmonary embolism,
pericarditis), CHF

Trimazosin

- Cardovar DB
o Trimazosin Hydrochloride
o Indication
 Hypertension
o Mechanism of action
 Adrenergic alpha-1 receptor antagonists
 Bind to and block the activation of adrenergic alpha-1 receptors
o Administration
 Administered orally

Doxazosin

71
- Cardura
o Doxazosin Mesylate
o Indication
 Hypertension
 Benign prostatic hyperplasia
o Mechanism of action
 Acts by inhibiting the postsynaptic alpha(1)-adrenoceptors on vascular
muscle
 This inhibits the vasoconstrictor effect of circulating and locally released
catecholamines (epinephrine and norepinephrine), resulting in peripheral
vasodilation
o Administration
 Oral dosage form

o Side effects
 More common
 Dizziness or lightheadedness
 Less common
 Blurred vision
 Confusion
 Dizziness, faintness or lightheadedness when getting up from a
lying down or sitting position
 Fainting (sudden)
 Fast and pounding heartbeat
 Irregular heartbeat
 Shortness of breath
 Sweating
 Swelling of feet or lower legs
o Contraindication
 Contraindicated in patients with a known sensitivity to quinazolines,
doxazosin or any of the inert ingredients

Phentolamine
72
- Phentolamine Mesylate
o Indication
 It is used in the treatment of hypertension and hypertensive
emergencies, pheochromocytoma, vasospasm of raynaud disease and
frostbite, clonidine withdrawal syndrome, impotence and peripheral
vascular disease
o Mechanism of action
 Alpha-adrenergic blocker
 A nonselective alpha-adrenergic antagonist
 Phentolamine produces its therapeutic actions by competitively blocking
alpha-adrenergic receptors (primarily excitatory responses of smooth
muscle and exocrine glands), leading to a muscle relaxation and a
widening of the blood vessels

 This widening of the blood vessels results in a lowering of blood

pressure
 The action of phentolamine on the alpha adrenergic receptors is
relatively transient and the blocking effect is incomplete
 The drug is more effective in antagonizing responses to circulating
epinephrine and/or norepinephrine than in antagonizing responses to
mediator released at the adrenergic nerve ending
 Phentolamine also stimulates β-adrenergic receptors and produces a
positive inotropic and chronotropic effect on the heart and increases
cardiac output
o Administration
 Solution
 Injectable
 Powder for solution
o Side effects
 Rare
 Dizziness
 Erection continuing for more than 4 hours or painful erection
 Less common
 Bruising or bleeding at place of injection

73
  Burning (mild) along penis
 Difficulty in ejaculating
 Swelling at place of injection
o Contraindication
 Myocardial infarction
 History of myocardial infarction
 Coronary insufficiency
 Angina
 Evidence suggestive to coronary artery disease

Phenoxybenzamine

- Dibenzyline / Fenoxene
o Indication
 High blood pressure and sweating caused by a certain kind of tumor
(pheochromocytoma)
o Mechanism of action
 An alpha blocker
 Works by relaxing blood vessels, causing blood pressure to decrease
o Administration
 Oral
o Side effects
 Epinephrine because severe low blood pressure may occur
 Levarterenol or reserpine because their effectiveness may be decreased
by phenoxybenzamine
o Contraindication
 Pregnancy, planning to become pregnant or are breast-feeding
 Problems with the blood vessels of the heart or brain, heart problems, an
irregular heartbeat, a lung or respiratory tract infection or kidney
problems
 History of cancer
 Taking any other medicine for blood pressure
74
Tolazoline

- Priscoline
o Tolazoline Hydrochloride
o Indication
 For treatment of pulmonary artery anomalies
o Mechanism of action
 Vasodilation by means of a direct effect on peripheral vascular smooth
muscle and indirect effects produced, in part, by release of endogenous
histamine
 Has moderate alpha-adrenergic blocking activity and has histamine
agonist activity

 Usually reduces pulmonary arterial pressure and vascular resistance

o Administration
 Comes in liquid preparation
o Side effects
 More frequent
 Gastrointestinal hemorrhage
 Hypochloremic alkalosis
 Systemic hypotension
 Acute renal failure, especially oliguria
 thrombocytopenia
 Less frequent
 Diarrhea or nausea and vomiting
 Increased pilomotor activity (goose flesh)
 Peripheral vasodilation (flushing)
 Tachycardia
o A reflex response to vasodilation and a result of direct
cardiac stimulation
 Rare
 Mydriasis
75
 o Contraindication
 Hypersensitivity to the products like most of the drugs ☻

Labetalol

- Trandate
o Labetalol Hydrochloride
o Indication
 Management of hypertension
o Mechanism of action
 Labetalol HCl combines both selective, competitive, alpha-1-adrenergic
blocking and nonselective, competitive, beta-adrenergic blocking activity
in a single substance

 In man, the ratios of alpha- to –beta blockade have been estimated to be

approximately 1:3 and 1:7 following oral and intravenous (IV
administration, respectively
 The principal physiologic action of labetalol is to competitively block
adrenergic stimulation of β-receptors within the myocardium (β1-
receptors) and within bronchial and vascular smooth muscle (β2-
receptors), and α1-receptors within vascular smooth muscle
 This causes a decrease in systemic arterial blood pressure and systemic
vascular resistance without a substantial reduction in resting heart rate,
cardiac output, or stroke volume, apparently because of its combined α-
and β-adrenergic blocking activity
o Administration
 Various dosage forms including oral administration
o Side effects
 Fatigue
 Dizziness
 Nausea
 Headache
 Diarrhea
76
  Edema
 Shortness of breath
o Contraindication
 Can mask early warning symptoms of hypoglycemia (low blood sugar)
such as tremors and increased heart rate which are the result of
activation of the adrenergic nervous system

Yohimbine

- Yohimbine
o Indication
 Indicated as a sympatholytic and mydriatic
 Impotence has been successfully treated with yohimbine in male patients
with vascular or diabetic origins and psychogenic origins

o Mechanism of action
 Yohimbine is a pre-synaptic alpha 2-adrenergic blocking agent
 The exact mechanism for its use in impotence has not been fully
elucidated
 However, yohimbine may exert its beneficial effect on erectile ability
through blockade of central alpha 2-adrenergic receptors producing an
increase in sympathetic drive secondary to an increase in
norepinephrine release and in firing rate of cells in the brain
noradrenergic nuclei
 Yohimbine-mediated norepinephrine release at the level of the corporeal
tissues may also be involved
 In addition, beneficial effects may involve other neurotransmitters such
as dopamine and serotonin and cholinergic receptors
o Administration
 Taken as solid dosage form
o Side effects
 Typical doses
 Stomach upset  Excitation
77
  Tremor  Sinus pain
 Sleep problems  Irritability
 Anxiety or agitation  Headache
 High blood  Frequent urination
pressure  Bloating
 Racing heart beat  Rash
 Dizziness  Nausea and
 Stomach problems vomiting
 Drooling
 High doses
 Difficulty breathing  Heart problems
 Paralysis  Death
 Very low blood
pressure
o Contraindication
 Pregnancy or breast-feeding
 Bleeding conditions
 Schizophrenia
 Prostate problems
 Post-traumatic stress disorder (PTSD)
 Liver disease
 Kidney disease
 High blood pressure or low blood pressure
 Chest pain or heart disease
 Anxiety
 Depression
 Diabetes
 Surgery

Propranolol

- Inderal
o Propanolol
o Indication
 Used to treat tremors, angina (chest pain), hypertension (high blood
pressure), heart rhythm disorders
 Used to treat or prevent heart attack
 Reduce the severity and frequency of migraine headaches

78
o Mechanism of action
 Beta blocker
 Propanolol competes with sympathomimetic neurotransmitters such as
catecholamines for binding at beta(1)-adrenergic receptors in the heart,
inhibiting sympathetic stimulation
 This results in a reduction in resting heart rate, cardiac output, systolic
and diastolic blood pressure and reflex orthostatic hypotension
 Orthostatic hypotension
o Also called postural hypotension
o A condition in which the blood pressure falls when one stand
up quickly, leaving that person feeling dizzy or lightheaded
o Administration
 Orally administered
o Side effects
 Dizziness  Stomach pain
 Lightheadedness  Vision changes
 Tiredness  Trouble sleeping
 Nausea and vomiting  Unusual dreams
o Contraindication
 Asthma
 Very slow heart beats that have caused you to faint
 Sick sinus syndrome
 A group of heart rhythm disorders that include
o Sinus bradycardia
 This occurs when the natural pacemaker of the heart
does not send out a signal telling the heart to beat
often enough

 The heart beat rate is slow

o Sinus pauses or arrest
 This occurs when the natural pacemaker of the heart
stops sending out signals telling to heart to beat for
periods of time
 People with these disorders may also have other abnormal heart
rhythms
o Supraventricular tachycardia
 This is a fast heart rate that starts in the upper
chambers of the heart (atria)
79
 o Bradycardia-tachycardia
 This is a pattern of alternating slow and fast heart
rhythms (sometimes called “tachybrady syndrome”)
 Atrioventricular block
 Also known as AV block
 Partial or complete interruption of impulse transmission from the
atria to the ventricles

Metoprolol

- Lopressor
o Metoprolol Tartrate

o Indication
 Used to treat angina and hypertension
 Also used to prevent heart attack
o Mechanism of action
 Competes with adrenergic neurotransmitters such as catecholamines for
binding at beta(1)-adrenergic receptors in the heart
 Beta(1)-receptor blockade results in a decrease in heart rate, cardiac
output and blood pressure
o Administration
 Orally administered

o Side effects
 Blurred vision
 Chest pain or discomfort
 Confusion
 Dizziness, faintness or lightheadedness when getting up suddenly from a
lying or sitting position
 Shortness of breath
 Slow or irregular heartbeat
 Sweating

80
  Unusual tiredness or weakness
o Contraindication
 Serious heart problem
 Heart block
 Sick sinus syndrome
 Slow heart rate
 Severe circulation problems
 Severe heart failure
 History of slow heart beats that caused fainting

Esmolol

- Brevibloc
o Esmolol Hydrochloride

o Indication
 Temporary control of heart rate and blood pressure
o Mechanism of action
 A beta-blocker
 Reducing the workload on the heart and helping the heart beat more
regularly
o Administration
 Intravenous solution

o Side effects
 Blurred vision
 Confusion
 Dizziness, faintness or lightheadedness when getting up from lying or
sitting position suddenly
 Increased sweating
 Unusual tiredness or weakness
o Contraindication
 Mibefradi (Posicor)
81
  A drug for the treatment of hypertension and chronic angina
pectoris
 Heart block
 Shock caused by serious heart problems
 Moderate to severe heart failure
 Certain types of irregular heartbeat (e.g., sick sinus syndrome)
 Very slow heart beat
 Pulmonary hypertension

Atenolol

- Tenormin
o Atenolol

o Indication
 Used to treat angina and hypertension (high blood pressure)
 Used to treat or prevent heart attack
o Mechanism of action
 A beta blocker
 Like metoprolol, atenolol competes with sympathomimetic
neurotransmitters such as catecholamines for binding at beta(1)-
adrenergic receptors in the heart and vascular smooth muscle, inhibiting
sympathetic stimulation
 This results in a reduction in resting heart rate, cardiac output, systolic
and diastolic blood pressure, and reflex orthostatic hypotension
 Higher doses of atenolol also competitively block beta(2) adrenergic
responses in the bronchial and vascular smooth muscles

o Administration
 Tablet
 IV
o Side effects
 Blurred vision
 Cold hands or feet
 Confusion
 Difficult or labored breathing
82
  Dizziness, faintness or lightheadedness when getting up from a lying or
sitting position suddenly
 Shortness of breath
 Sweating
 Tightness in chest
 Unusual tiredness or weakness
 Wheezing
o Contraindication
 Asthma, bronchitis, emphysema
 Diabetes
 Low blood pressure
 A heart problem such as heart block, sick sinus syndrome, slow heart
rate or CHF
 Depression
 Liver or kidney disease
 A thyroid disorder
 Myasthenia gravis
 Pheochromocytoma
 Problems with circulation (such as raynaud’s syndrome)
 Raynaud’s syndrome
o A rare disorder of the blood vessels, usually in the fingers
and toes
o It causes the blood vessels to narrow in cold times or when
the patient is feeling stressed
o When this happens, blood can’t get to the surface of the skin
and the affected areas turn white and blue
o When the blood flow returns, the skin turns red and throbs
or tingles
o In severe cases, loss of blood flow can cause sores or
tissue death
o Things that can be done when Raynaud’s attacks:
 Soaking hands in warm water at the first sign of attack
 Keeping your hands and feet warm I cold weather
 Avoiding triggers, such as certain medicines and
stress

Nadolol

- Corgard
o Nadolol
o Indication
 Long term management of angina
o Mechanism of action
83
  Like other beta-adrenergic antagonists, nadolol competes with
adrenergic neurotransmitters such as catecholamines for binding at
sympathetic receptor sites
 Like propranolol and timolol, nadolol binds at beta(1)-adrenergic
receptors in the heart and vascular smooth muscle, inhibiting the effects
of the catecholamines epinephrine and norepinephrine and decreasing
heart rate, cardiac output, and systolic and diastolic blood pressure
 It also blocks beta-2 adrenergic receptors located in bronchiole smooth
muscle, causing vasoconstriction
 By binding beta-2 receptors in the juxtaglomerular apparatus, nadolol
inhibits the production of renin, thereby inhibiting angiotensin II and
aldosterone production
 Nadolol therefore inhibits the vasoconstriction and water retention due to
angiotensin II and aldosterone, respectively

o Administration
 Oral tablet
 Compounding powder
o Side effects
 Blurred vision
 Chest pain or discomfort
 Confusion
 Dilated neck veins
 Dizziness, faintness, or lightheadedness when getting up from a lying or
sitting position suddenly
 Extreme fatigue
 Irregular breathing

 Lightheadedness, dizziness or fainting

 Paleness or cold feeling in fingertips and toes
 Shortness of breath
 Slow or irregular heartbeat
 Sweating
 Swelling of face, fingers, feet or lower legs
 Tingling or pain in fingers or toes when exposed to cold
84
  Unusual tiredness or weakness
 Weight gain
 Wheezing
o Contraindication
 Mibefradil
 Arbutamine
 A cardiac stimulant
 Very serious interaction

Timolol

- Timoptic
o Timolol Maleate Opthalmic Solution
o Indication
 Used to treat glaucoma
o Mechanism of action
 A beta blocker
 Works by decreasing the pressure in the eye
 Like propranolol and nadolol, timolol competes with adrenergic
neurotransmitters such as catecholamines for binding at beta(1)-
adrenergic receptors in the heart and vascular smooth muscle and
beta(2)-receptors in the bronchial and vascular smooth muscle
 Beta(1)-receptor blockade results in a decrease in resting and exercise
heart rate and cardiac output, a decrease in both systolic and diastolic
blood pressure, and possibly, a reduction in reflex orthostatic
hypotension

 Beta(2)-blockade results in an increase in peripheral vascular resistance

 The exact mechanism whereby timolol reduces ocular pressure is still
not known
 The most likely action is by decreasing the secretion of aqueous humor
o Administration
 Ophthalmic gel forming solution
85
  Opthalmic solution
o Side effects
 Severe
 Eye irritation
 Double vision
 Headache
 Depression
 Dizziness
 Nausea
 Serious
 Slow or irregular heartbeat
 Difficulty breathing
 Sudden weight gain
 Swelling of the feet or lower legs
 Fainting
o Contraindication
 Bronchial asthma
 History of bronchial asthma
 Severe chronic obstructive pulmonary disease
 Sinus bradycardia
 Second or third degree atrioventricular block
 Overt cardiac failure
 Cardiogenic shock

Pindolol

- Visken
o Pindolol
o Indication
 High blood pressure
o Mechanism of action
86
  Beta-adrenergic blocking agent
 Works by slowing down the heart and decreasing the amount of blood it
pumps out

 This helps to decrease blood pressure, helps the heart pump more
efficiently, and reduces the workload on the heart
 Pindolol non-selectively blocks beta-1 adrenergic receptors mainly in the
heart, inhibiting the effects of epinephrine and norepinephrine resulting
in a decrease in the heart rate and blood pressure
 By binding beta-2 receptors in the juxtaglomerular apparatus, pindolol
inhibits the production of renin, thereby inhibiting angiotensin II and
aldosterone production and therefore the vasoconstriction and water
retention due to angiotensin II and aldosterone respectively

o Administration
 Oral tablet
 Compounding powder
o Side effects
 More common
 Swelling of the face, fingers, feet or lower legs

 Less common
 Burning, crawling, itching, numbness, “pins and needles”, or
tingling feelings
 Chest pain
 Difficult or labored breathing
87
  Shortness of breath
 Tightness in chest
 Wheezing
o Contraindication
 Clonidine
 Stopping it or pindolol suddenly can lead to a rapid increase in
blood pressure
 Catecholamine-depleting medicines (e.g., reserpine), cimetidine, digoxin,
diltiazem, disopyramide, flecainide, ketanserin, mefloquine, mibefradil,
phenothiazines (e.g., thioridazine or verapamil
 Serious side effects such as very slow heart rate, evry low blood
pressure, fainting, severe dizziness or light-headedness when
standing may occur
 Indomethacin
 Decrease pindolol’s effectiveness
 Fingolimod, insulin, meglitinide antidiabetics (e.g., nateglinide) or
quinazolines (e.g., alfuzosin)
 The risk of the side effects of these drugs may be increased with
pindolol
 Sympathomimetics (e.g., albuterol) or theophylline
 Effectiveness may be decreased by pindolol
 Epinephrine
 Effectiveness may be decreased by pindolol
 Risk of side effects, such as high blood pressure and slow
heartbeat may be increased

Butoxamine

- Butoxamine Hydrochloride
o Indication
 No clinical use
 Used primarily in animal and tissue experiments to characterize beta-2
adrenergic receptors
 Example:
 “If the beta-2 receptor is completely blocked, but the given effect is
still present, the given effect is not a characteristic of beta-2
receptor”
o Mechanism of action
 A beta-2 selective adrenergic antagonist
o Administration
 May be administered via aerosol

Reserpine

- A rauwolfia alkaloid

- Serpasil
88
o Reserpine
o Indication
 Treatment of high blood pressure
 Sometimes used to treat agitation associated with certain mental
problems like schizophrenia

o Mechanism of action
 Works by decreasing the amounts of certain chemicals in the brain
(norepinephrine and serotonin) which helps to lower blood pressure and
decrease agitation in patients who have certain mental problems
 Reserpine’s mechanism of action is through inhibition of the ATP/Mg 2+
pump responsible for the sequestering (hidden) of neurotransmitters into
storage vesicles located in the presynaptic neuron
 The neurotransmitters that are not sequestered in the storage vesicles
are readily metabolized by MAO causing a reduction in catecholamine
o Administration
 Oral tablet
o Side effects
 An allergic reaction (difficulty breathing; closing of the throat; swelling of
the lips, tongue, or face; or hives)
 A very irregular hearbeat
 Heart failure (shortness of breath, swelling of ankles or legs, sudden
weight gain of 5 pounds or more)
 Uncontrollable hand, arm or leg movements
 Chest pain
o Contraindication
 Furazolidone or a MAOi (e.g., phenelzine)
 Side effects of reserpine may be increased

 Digoxin or quinidine
 The risk of irregular heartbeat may be increased
 Tricyclic antidepressant
 The effectiveness of reserpine may be decreased
89
  Isoproterenol or phenylephrine
 Side effects may be increased by reserpine
 Amphetamine or sympathomimetics (e.g., ephedrine)
 Effectiveness may be decreased by reserpine

Guanethidine

- Ismelin
o Guanethidine Monosulphate
o Indication
 For the treatment of moderate and severe hypertension, either alone or
as an adjunct, and for the treatment of renal hypertension
o Mechanism of action
 Adrenergic neuron blocking agent that reduces release of
catecholamines
 Acts at the sympathetic neuroeffector junction by inhibiting or interfering
with the release and/or distribution of norepinephrine, rather than acting
at the effector cell by inhibiting the association of norepinephrine with its
receptors
 It is taken up by norepinephrine transporters
 It becomes concentrated in NE transmitter vesicles, replacing NE in
these vesicles
 This leads to a gradual depletion of NE stores in the nerve endings
 Once inside the terminal it blocks the release of noradrenaline in
response to arrival of an action potential
 In contrast to ganglionic blocking agents, Guanethidine suppresses
equally the responses mediated by alpha- and beta-adrenergic receptors
but does not produce parasympathetic blockade

 Since sympathetic blockade results in modest decreases in peripheral

resistance and cardiac output, Guanethidine lowers blood pressure in
the supine position
 It further reduces blood pressure by decreasing the degree of
vasoconstriction that normally results from reflex sympathetic nervous

90
 activity upon assumption of the upright posture, thus reducing venous
return and cardiac output more
o Administration
 Oral tablet
o Side effects
 Diarrhea or increase in bowel movements
 Dizziness, lightheadedness, or fainting, especially when getting up from
a lying or sitting position
 Sexual problems in males
 Slow heartbeat
 Stuffy nose
 Unusual tiredness or weakness
o Contraindication
 Pheochromocytoma
 CHF
 Narrow-angle glaucoma
 Hypersensitivity

91
Cancer Therapy  Central mechanism:
CINV: Types of CINV - Chemotherapeutic agent activates
the chemoreceptor trigger zone
Chemotherapy Induced Nausea and Vomiting.
(CTZ).
 Acute
- Activated CTZ invokes release of
- Occurs within first 24 hours after various neurotransmitters, which
administration of cancer stimulate vomiting center.
chemotherapy
 Peripheral mechanism:
 Delayed
- Chemotherapeutic agent causes
- CINV that begins after first 24 hours irritation and damage to
gastrointestinal (GI) mucosa,
- May last for 120 hours
resulting in the release of
 Anticipatory neurotransmitters.

- Learned or conditioned response - Activated receptors send signals to

from poorly controlled nausea and vomiting center via vagal afferents.
vomiting associated with previous
CINV: patient-specific risk factors
chemotherapy
 Age <50 years
( Iniisip na mag cchemo nanaman)
 Women > men
 Breakthrough
 History of light alcohol use
- CINV that occurs despite prophylaxis
and requires rescue  History of vomiting with prior exposure
to chemotherapeutic agents
 Refractory
 Other risks
- Occurs during subsequent treatment
cycles when prophylaxis and/or - History of motion sickness
rescue has failed in previous cycles
- History of nausea or vomiting during
pregnancy
- History of anxiety
CINV: therapy-related risk factors

 High drug dose

 High emetogenicity of chemotherapy

drugs
NOTE: the predominant risk factor
(patientrelated or therapy-related) is the degree
of emetogenicity of the chemotherapeutic
agent
CINV: mechanisms
CINV: other causes
  Partial or complete bowel obstruction

 Vestibular Dysfunction

 Brain Metastases

 Electrolyte imbalance: hypercalcemia,

hyperglycemia, hyponatremia, uremia

 Concomitant drugs, including opiates

 Gastroparesis induced by a tumor or

chemotherapy (such as vincristine)

 Psychophysiologic factors, including

anxiety as well as anticipatory nausea
CINV: classes of drugs
and vomiting
 Serotonin (5-HT3) antagonists
CINV: emetogenic potentials
 NK-1 receptor antagonists

 Corticosteroids

 Dopamine antagonists

 Cannabinoids
CINV: 5HT3-antagonists
1st Generation Agents are therapeutically
equivalent: Dolasetron, Ondansetron,
Granisetron
1 st Generation oral and IV doses equally
effective
Second generation 5-HT3 antagonist:
Palonosetron

CINV: Aprepitant

 Selective antagonist of the binding of

Substance P to the neurokinin 1 (NK1)
receptor
- IV: Fosaprepitan
Principles of Care for Acute Highly
andModerately Emetic Settings
UNANIMOUS CONSENSUS: CATEGORY
EVIDENCE
 Use the lowest tested fully effective
dose.
 No schedule is better than a single dose
given before chemotherapy.
 The antiemetic efficacy and adverse
effects of serotonin antagonist agents
are comparable in controlled trials.
 Intravenous and oral formulations are
equally effective and safe.
 Always give dexamethasone with a 5-
HT3 antagonist before chemotherapy
CINV: guidelines
High Emetic Risk: 3 drug
- 5-HT3 antagonist
- Dexamethasone
- Aprepitant (or fosaprepitant)
Moderate Emetic Risk in women (receiving AC
regimen):
- 5-HT3 antagonist
- Dexamethasone
- Aprepitant (or fosaprepitant)
Moderate Emetic Risk (except AC):
 5-HT3 receptor antagonist +
 Dexamethasone
1
CINV: other situations
 Multiple-day chemotherapy regimens
 Breakthrough CINV
 Anticipatory CINV
 Delayed CINV
CINV: multiple-day regimens
 Increased risk for both acute and
delayed nausea and vomiting
 Difficult to recommend appropriate
antiemetics for each day since acute
and delayed may overlap after the initial
day of chemotherapy.
 Period of risk for delayed nausea and
vomiting also depends on the
emetogenic potential of the last
chemotherapy agent administered in the
regime
 A 5-HT3 receptor antagonist should be
administered prior to each day of
moderately or highly-emetogenic
chemotherapy.
 Dexamethasone should be administered
once daily either orally or IV for every
day of chemotherapy and for 2-3 days
post chemotherapy.
 Aprepitant may be used for multi-day
chemotherapy. Aprepitant 125 mg on
 day 1, then aprepitant 80 mg daily on more aggressive therapy and have
days 2 and 3 along with dexamethasone poorer emesis control than older
patients
CINV: breakthrough CINV
 The most effective way to treat is to
 Breakthrough emesis refers to vomiting
prevent CINV by using optimal
that occurs despite prophylactic
antiemetics during every cycle of
treatment and/or requires rescue.
therapy.
 Refractory emesis refers to emesis that
 Either:
occurs during subsequent treatment
cycles when antiemetic prophylaxis - Alprazolam PO 0.25 to 0.5 mg
and/or rescue have failed in earlier t.i.d. beginning on the night
cycles before treatment OR;

 Challenge - Breakthrough nausea and - Lorazepam 0.5-2 mg PO on the

vomiting represents a difficult situation night before and the morning of
as ongoing refractory nausea is hard to treatment.
revers
 Behavioral therapy
 Management : round the clock
CINV: delayed
administration over prn
 Challenge - Delayed emesis is 2.5 times
 Additional agents should be from a
more prevalent than acute emesis.
different drug class than initial therapy
(all are equal):  For moderately emetogenic
chemotherapy: =Delayed nausea
- dopamine antagonists,
exceeds acute nausea by 16%.
metoclopramide, haloperidol,
cannabinoids, corticosteroids, =Delayed emesis exceeds acute emesis
lorazepam by 15%

 Anti-secretory agents if patient has  For highly emetogenic chemotherapy:

dyspepsia
=Delayed nausea exceeds acute nausea
CINV: anticipatory by 27%.

 Anticipatory nausea and/or vomiting is =Delayed emesis exceeds acute emesis

the occurrence of nausea and/or by 38
vomiting before patients receive their
CINV: prognostic factors delayed CINV
chemotherapy treatment. Because it is a
conditioned response, it can only occur  Strongest predictor: occurrence of acute
after a negative past experience with nausea and vomiting
chemotherapy.
 ≤ 52 years
 Challenge - Anticipatory nausea and/or
 Women
vomiting occurs in 18% to 57% of
chemotherapy patients.  High expectation of nausea
 Younger patients may be more
susceptible as they generally receive
PAIN MANAGEMENT - Phantom limb pain
Causes of Cancer-Related Pain - Post-mastectomy syndrome

 Tumor / Mass effect - Post-thoracotomy syndrome

 Post-chemotherapy PAIN SCORING

 Post-radiation - Numerical rating scale ( 0- no

pain ; 10- worst pain )
 Post-surgical
- Categorical scale ( none (0) ; Mild
Types of cancer-related pains (1-3) ; moderate (4-6) ; Severe (7-
 Somatic 10)

- Tumor/Mass effect, Musculoskeletal, - Face pain rating scale

Dull or sharp, localized

 Visceral
- infiltration, compression, extension, or
stretching of the thoracic, abdominal, or
pelvic viscera
- pressure, deep, squeezing, not well-
localized
- Referred

 Neuropathic
- CA compressing or infiltrating Pharmacologic Management
nerves/nerve roots/blood supply to
 WHO Ladder
nerve, Nerve damage from treatments
 Non-opioid therapy / Co-analgesics
- Shooting, sharp, burning, “pins &
needles”  Opioids
- Ex: Cranial neuropathies, Post-herpetic
neuropathies, Brachial plexus
WHO LADDER
neuropathies, Post-radiation

 Others
Neuropathic Pain

 Chemotherapy-induced neuropathies
- Cisplatin, Oxaliplatin
- Paclitaxil, Thalidomide
- Vincristine, Vinblastine

 Surgical Neuropathies
  Corticosteroids

 Neuroleptics

 Alpha2 – agonists

 Benzodiazepines

 Antispasmodics

 Muscle relaxants

 Systemic local anesthetic

 Bone pain
STEP 1: Non-opioids – aspirin, non-steroidal
- Bisphosphonates
anti-inflammatory drugs (NSAIDs) or
paracetamol (MILD TO MODERATE PAIN) - Calcitonin

STEP 2: Mild opioids (e.g codeine), with or  Pain from malignant bowel obstruction
without non-opioids (MODERATE TO SEVERE
- Steroids
PAIN)
- Octreotide
STEP 3: Strong opioids (e.g. morphine), with or
without non- opioids (SEVERE PAIN) - Anticholinergics
Non-Opioids Opioids

 NSAIDS  Step 2 opioids

 Acetaminophen  Codeine, Oxycodone, tramadol,

hydrocodone
 Topicals
 Step 3 opioids
- Lidocaine, Capsaicin
 Oxycodone, morphine, dilaudid, fentanyl,
methadone
Opioids: equivalent dosing
Practice Points:

 Mild pain

 “ceiling” effect

 Start at lowest effective dose

 Review pt’s underlying medical illnesses

Adjuvants

 Antidepressants
- TCAs for neuropathic pain

 Anticonvulsants
Opioids: equivalent fentanyl patch dosing

Additional interventions: pain syndromes GCSF PROPHY

 Inflammation: NSAIDs European Organisation for Research and
 Bone pains (not emergency): NSAIDs Treatment ofCancer Patient Assessment
Algorithm to Decide ProphylacticGranulocyte
- If diffuse: bisphosphonates, Colony-stimulating Factor Usage
chemotherapy
STEP 1: Assess frequency of FN associated
 Neuropathic: with the planned chemotherapy regimen
- Antidepressants: TCAs, Venlafaxine, STEP 2: Assess factors that increase the
Duloxetine frequency/ risk of FN
- Anticonvulsants: gabapentin, STEP 3: Define the patient’s overall FN risk for
carbamazepine, pregabalin planned chemotherapy regimen
- Locally acting: lidocaine patch
GCSF Support
Neutropenia and Febrile Neutropenia

 Neutropenia:
- ANC (absolute neutrophil count)
<500 OR
- ANC < 1000 and expected to
decrease to ≤500 in the next 48 h

 Febrile Neutropenia (NF)

- Neutropenia + Oral Temp ≥ 38.3 C
single determination
- Neutropenia + Oral Temp ≥ 38
Cover 1h GCSF PROPHY - National Comprehensive
Cancer Network Guidelines –Decision Tree for
Primary Prophylaxis
 1. Evaluate  63/F
2. Assess risk  Breast Carcinoma St. III, Right breast
3. Intervene  S/P Neoadjuvant chemotherapy

 S/P – MRM Right

 On her Cycle 3 Adjuvant Chemotherapy-

Docetaxel

 During her last minutes of

chemotherapy...
- Patient complains of discomfort
on her (L) dorsal hand.
- Infusion of Docetaxel was
immediately discontinued .
- IV line removed, patient was sent
NCCN: GCSF secondary prophylaxis
home and was advised Cold
Compress

NNCN: Therapeutic GCSF  Patient was complaining of severe pain

on the extravasation area

 She was treated with the ff...

1) Oxycontine 10mg 1 tab BID
2) Pregabalin 75mg 1tab BID
3) Mefenamic Acid 500mg 1tab TID
4) Silver Sulfadiazine Cream (applied to
the affected area

EXTRAVASATION
Clinical case

 C.J.
 - Carboplatin
- Fluorouracil ( 5FU)
- Cisplatin*
- Gemcitabine
- Oxaliplatin
- Etoposide
- Docetaxel
- Irinotecan
Extravasations –
- Paclitaxel
 Refers to the escape of a chemotherapy
drug into the extravascular space, either - Topotecan
by leakage from a vessel or by direct - Carmustine
infiltration
- Thiotepa
 Local symptoms (ie, pain, erythema,
swelling) are usual - Bleomycin

- Change in the rate of drug - Cyclophosphamide

infusion or the absence of blood
return from the vascular catheter
may be the initial indicator that
extravasation has occurred
VESICANTS
IRRITANTS
 Capable of inducing a local
inflammatory reaction
 Can cause pain/ tenderness at the
injection site or along the vein, with or
without an inflammatory reaction
- Mitoxantrone
- Dacarbazine *
- BortezomibIfosfamide
- * Large vol. (>20ml) of conc. Drug
(>0.5mg/ml) may produce
necrosis
 Capable to induce formation of blisters
and/or cause tissue destruction
 Symptoms may be delayed for up to 6-
12 hours after drug extrasvastion
 Pruritusare common if without pain

 May have potential to cause soft tissue  May have severe necrosis with
ulcers only if a large amount of involvement of tendons and joints
concentrated drug solution is HIGH Vesicant potential
inadvertently extravasated
- ActinomycinD
 Short-term injury that does NOT lead to
tissue injury or necrosis - Vinblastine

IRRITANTS - Daunorubicin
 - Vincristine
- Doxorubicin
- Vindesine
- Epirubicine
- Vinorelbine
- Idarubicin
- Mitomycin C
Manifestations
 Within two to three days, increased
erythema, pain, brawny discoloration,
induration, dry desquamation, and/or
blistering may appear
 all volume extravasations, symptoms
may disappear over the next several
weeks.
 More extensive infiltrations, necrosis,
eschar formation, and ulceration with
raised, red, painful edges and a yellow
necrotic base may appear over several
weeks.
DID YOU KNOW...
 Extravasation recall phenomenon
 where previous sites of
extravasation of a vesicant drug
become inflamed upon re-
exposure of the patient to the
same drug administered at a
remote IV site.
 This phenomenon has been
reported with DOXORUBICIN,
EPIRUBICIN and PACLITAXE
How do we PREVENT
 Peripheral infusions of chemotherapy,
the vein selected should be large and
intact, with good blood return
established prior to starting the infusion.
 Sites with sclerosis, thrombosis, or scar
formation should be avoided, as should
limbs with impaired circulation.
 Controversial- most experts do not feel
that the avoidance of IV lines on the
ipsilateral side is necessary or beneficial
in a woman who has undergone
mastectomy for breast cancer, as long
as lymphedema is absent
 Taping of the entry site itself should be
avoided so that the area can be
examined.
 A clear dressing such as Tegaderm is
usually applied to cover the skin entry
site.
 The patency of the IV line should be
verified just prior to drug infusion by
flushing with 5 to 10 mL of isotonic
saline or a 5 percent dextrose solution.
How to MANAGE
1.Stop the infusion immediately.
2.Do not flush the line, and avoid applying
pressure to the extravasated site.
3.Elevate the affected extremity.
4.The catheter/needle should not be removed
immediately. Instead, it should be left in place
to attempt to aspirate fluid from the
extravasated area and to facilitate the
administration of an antidote to the local area,
if appropriate.
5.If an antidote will not be injected into the
extravasation site, the catheter/needle can be
removed after attempted aspiration of the
subcutaneous tissues.
6.Application of heat or cold 4.Dexrazoxane
6. If extravasation occurs from a central line, it 5.Corticosteroids
should be stopped if its rate decreases, or if
 Sodium thiosulfate is for extravasations
the patient complains of changes in sensation,
of : 1.Mechlorethamine
pain, burning, swelling at the central venous
catheter site, or in the ipsilateral chest. 2.Dacarbazine
7.The catheter/needle should not be removed 3.Cisplatin
immediately. Instead, it should be left in place
 Local injection of Hyaluronidase is for:
to attempt to aspirate fluid from the
extravasated area and to facilitate the 1.Vinca alkaloids
administration of an antidote to the local area,
if appropriate. 2.Paclitaxel

8.If an antidote will not be injected into the 3.Epipodophyllotoxins

extravasation site, the catheter/needle can be 4.Ifosfamide
removed after attempted aspiration of the
subcutaneous tissues.  Systemic administration of Dexrazoxane
is for:
9.If the patient has an implanted port, it should
be assessed for proper needle placement. The  Anthracycline extravasation
residual drug should be aspirated from the area ANTIDOTES
of suspected infiltration at the port pocket or at
the exit site of the tunneled catheter. If an  Corticosteroids — For anthracycline
antidote is indicated, it should be injected into extravasations, systemic, subcutaneous,
subcutaneous tissue along with local care. If and intradermal administration of
the antidote is administered intravenously, an corticosteroids at the extravasation site
adequate amount has to be instilled while have all been recommended, although
avoiding excess pressure on the central venous whether there is benefit for this approach is
catheter site. unclear.

10.If the patient has an implanted port, it has to  Corticosteroids may worsen the skin
be deaccessed after instilling the antidote damage from etoposide or vinca alkaloids,
and they are specifically contraindicated in
How to MANAGE these situations
 ICE or COLD packs is recommended for
extravasation of ALL vesicant & irritant
drugs except the vinca alkaloids
(vincristine, vinblastine, vinorelbine) and
epipodophyllotoxins such as etoposide
ANTIDOTES
1.Sodium thiosulfate
2.Hyaluronidase
3.Dimethylsulfoxide
Antihelminthic Drugs
Albendazole

 A broad spectrum oral anthelminthic

 Drug of choice for the treatment of

hydatid disease and cysticercosis

 Also used in the treatment of pinworm

and hookworm infections, ascariasis,
trichuriasis and strongyloides

 Adverse effects include mild and

transient epigastric distress, diarrhea,
headache, nausea, dizziness, lassitude,
and insomnia
Pharmacology

 After oral administration, it is

eratically absorbed (increased
with fatty meal) and then rapidly
undergoes first-pass metabolism
in the liver to the active
metabolite albendazole sulfoxide

 Thought to act against

nematodes by inhibiting
microtubule synthesis
  Also has larvicidal effects in  A drug of choice in the treatment of
hydatid disease, cysticercosis, filariasis, loiasis, and tropical eosinophilia
ascariasis, and hookworm
 Has been replaced by ivermectin for the
infection, and ovicidal effects in
treatment of onchocerciasis
ascariasis, ancylostomiasis, and
trichuriasis  Adverse effects are generally mild and
transient, include headache, malaise,
Clinical Uses
anorexia, weakness, nausea, vomiting, and
 Ascariasis, trichuriasis and hookworm and dizziness
pinworm infections
o Pharmacology
 For adults and children older
 Immobilizes microfilariae and
than 2 years with ascariasis and
alters their surface structure,
pinworm
displacing them from tissues and
making them more susceptible to
destruction by host defense
Infections, the treatment for ascariasis is a
mechanisms
single dose of 400 mg orally (repeated for 2-3
days for heavy infections and in 2 weeks for
pinworm infections)

 Hydatid disease
o Clinical Uses
 The treatment of choice for
 Wuchereria bancrofti, Brugia
medical therapy and is a useful
malayl, Brugia timori and Loa loa
adjunct to surgical removal or
aspiration of cysts  The drug of choice for treatment of
infections with these parasites because
 Neurocyticercosis
of its efficacy and lack of serious
 Controversial use since toxicity
antihelminthic therapy is not
 Microfilariae all species are rapidly killed:
clearly superior to therapy with
adult parasites are killed more slowly,
corticosteroids
often requiring several courses of
Bithionol treatment

 Alternative to triclabendazole for the Doxycycline

treatment of fascioliesis (sheep liver fluke)
 Has recently been shown to have
and an alternative to praziquantel for the
significant microfilaricidal activity
treatment of paragonimiasis
against Wuchereria bancrofti,
 Reaches peak blood levels in 4-8 hours and suggesting better activity than any other
excretion is mainly through the kidneys available drug against adult worms

 Adverse effects include mild diarrhea,  Activity is also seen against

abdominal cramps, anorexia, nausea, onchocerciasis o Acts indirectly, by
vomiting, dizziness, and headache killing Wolbachia, an intracellular
bacterial symbiont of filarial parasites
Diethylcarbamazine Citrate
  It may prove to be an important drug for treatments have led to major reductions
filariasis, both for treatment of active in disease transmissions
disease and in mass chemotherapy
 Strongyloidiasis
campaigns
- In immunosuppressed patients with
Ivermectin
disseminated infection, repeated
 Drug of choice in strongyloidiasis and treatment is often needed, and cure may
onchocerciasis not be possible. In this case,
suppressive therapy like once monthly
 Also an alternative drug for a number of
may be helpful
other helminthic infections
Mebendazole
 In strongyloidiasis treatment, infrequent
adverse effects include fatigue,  Has wide spectrum of antihelminthic
dizziness, nausea, vomiting, abdominal activity and a low incidence of adverse
pain, and rashes effects

 In onchocerciasis treatment, adverse  Adverse effects include mild nausea,

effects are principally from the killing of vomiting, diarrhea, and abdominal pain
microfilariae and can include fever, have been reported infrequently
headache, dizziness, somnolence,
o Pharmacology
weakness, rash, Increased pruritus,
diarrhea, joint and muscle pains,  Probably acts by inhibiting
hypotension, tachycardia lymphadenitis, microtubule synthesis, the parent
lymphagitis, and peripheral edema drug appears to be the active form

o Pharmacology  Efficacy of the drug varies with

gastrointestinal transit time, with
 Appears to paralyze nematodes
intensity of infection, and perhaps
and arthropods by intensifying v-
with the strain of parasite
aminobutyric
 The drug kills hookworm, ascaris,
and trichuris eggs
acid (GABA)-mediated transmission of signals
o Clinical Uses
in pempheral nerves
 Indicated for use ascariasis,
 In onchocerciasis, ivermectin is
trichuriasis. hookwarm and pinworm
microfilaricidal
infections, and certain other
 It does not effectively kill adult helminthic infections
worms but block the release of
 It can be taken before or after meals;
microfilariae for some months
the tablets should be chewed before
after therapy
swallowing
o Clinical Uses
Metrifonate (Trichlorfon)
 Onchocerciasis
 A safe, low-cost alternative drug for the
- Ivermectin plays a key role in treatment of Schistosoma haematobium
onchocerciasis control. Annual mass infections
  it is not active against Schistosoma
mansani or Schistosoma japonicum
 Adverse effects include nausea and
vomiting, diarrhea, abdominal pain,
branchospasm,
 headache, sweating, fatigue, weakness,
dizziness, and vertigo
o Pharmacology
 Mode of action is thought to be
cholinesterase inhibition
 This inhibition temporanly paralyzes
adult worms, resulting in their shift
from be bladder venous plexus to
small arterioles of the lungs, where
they are killed
o Clinical uses
 Also effective as a prophylactic agent
when given monthly to children in highly
endemic area, and it has been used in
mass treatment programs
Niclosamide
 A second-line drug for the treatment of
most tapeworm infections
 Adverse effects include nausea,
vomiting, diarrhea, and abdominal
discomfort
o Pharmacology
 Adult worms (but not ova) are rapidly
killed, presumably dure to inhibition of
oxidative phosphorylation or stimulation
of ATPase activity
o Clinical Uses
 Taenia soginata (beef tapeworm],
Taenia solium (pork tapeworm), and
Diphyllobothrium latum (fish tapeworm)
 Intestinal fluke infections
- Can be used as an alternative drug in the
treatment of Fasciolopsis buski
Heterophyes heterophyes, and Metogonimus
yokogawai
Oxamniquine
 An alternative to praziquantel for the
treatment of S. mansoni infections
 It has also been used extensively for
mass treatment
 Adverse effects: Central nervous
system symptoms (dizziness, headache,
drowsiness) are most common; nausea
and vomiting, diarrhea, colic, pruritus
and urticarial also occur
o Pharmacology
 Active against both mature and
immature stages of S. mansoni but
does not appear to be cercaricidal
 The mechanism of action is unknown
 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 the mesenteric
vessels but cease to lay eggs
o Clinical uses
 Safe and effective in all stages of S.
mansoni disease, including advanced
hepatosplenomegaly
 The drug is generally less effective in
children, who require higher doses than
adults
 It is better tolerated with food
Piperazine
 Causes paralysis of ascaris by blocking
 acetylcholine at the myoneural junction:  Clonorchiasis, opisthorchiasis, and
live worms are expelled by peristalsis paragonimiasis
 Mild adverse effects include nausea,  Taeniasis and diphyllobothriasis
vomiting, diarrhea, abdominal pain,
 Neurocysticercosis
dizziness, and headache
 Albendazole is now the
preferred drug, but when it is
not appropriate or available,
praziquantel has similar
efficacy
Praziquantel
 Indications for praziquantel
 Effective treatment of schistosome are similar to albendazole
infections of all species and most other
 Hymenolepis nana
trematode and cestode infcetions,
including cysticercosis  Praziquantel is the drug of choice
for H. nana infections and the
 Most common adverse effects include
first drug to be highly effective
nausea, vomiting, abdominal pain, loose
stolls, pruritus, urticarial, arthralgia,
myalgia and lower grade fever
 Hydatid disease
o Pharmacology
 Praziquantel kills protascoleces
 Appears to increase the permeability but does not affect the germinal
of trematode and cestode cell membrane
membranes to calcium, resulting in
 Praziquantel is being evaluated
paralysis. Dislodgement, and death
as an adjunct with albendazole
 In schistosome infections of pre- and postsurgery
experimental animals, praziquantel is
 In addition to its direct action
effective against adult worms and
praziquantel enhances the
immature stages, and it has a
plasma concentration of
prophylactic effect against cercarial
albendazole
infection
Pyrantel Pamoate
o Clinical Uses
 A broad-spectrum antihelminthic highly
 Tablets are taken with liquid after a
effective for the treatment of pinworm,
meal; they should be swallowed without
ascaris and Trichostrongylus orientalis
chewing because their bitter taste can
infections.
induce retching and vomiting
 Adverse effects include susea, vomiting,
 Schistosomiasis
diarrhea, abdominal cramps, dizziness,
 Praziquantel is the drug of drowsiness, headache, insomnia, rash,
choice for all forms of fever. And weakness
schistosomiasis
o Pharmacology
  Effective against mature and
immature forms of susceptible
helminths within the intestinal tract
but not against migratory stages in
the tissues or against ova

 The drug is a neuromuscular

blocking agent that causes release
of acetylcholine and inhibition of
cholinesterase; this results in
paralysis of worms, followed by
expulsion
Thiabendazole Roundworms  nematodes  albendazole,
mebendazole
 Alternative to ivermectin or albendazole
for the treatment of strongyloidiasis and Flukes  trematodes  praziquantel
cutaneous larva migrans Tapeworms  cestodes  praziquantel or
niclosamide
 Common adverse effects include
dizziness, anorexia, nausea, and
vomiting
o Pharmacology

 The mechanism of action is probably

the same as that of other
benzimidazoles (inhibition of
microtubule synthesis)

 The drug has ovicidal effects against

some parasites
Cancer Therapy  Central mechanism:
CINV: Types of CINV - Chemotherapeutic agent activates
the chemoreceptor trigger zone
Chemotherapy Induced Nausea and Vomiting.
(CTZ).
 Acute
- Activated CTZ invokes release of
- Occurs within first 24 hours after various neurotransmitters, which
administration of cancer stimulate vomiting center.
chemotherapy
 Peripheral mechanism:
 Delayed
- Chemotherapeutic agent causes
- CINV that begins after first 24 hours irritation and damage to
gastrointestinal (GI) mucosa,
- May last for 120 hours
resulting in the release of
 Anticipatory neurotransmitters.

- Learned or conditioned response - Activated receptors send signals to

from poorly controlled nausea and vomiting center via vagal afferents.
vomiting associated with previous
CINV: patient-specific risk factors
chemotherapy
 Age <50 years
( Iniisip na mag cchemo nanaman)
 Women > men
 Breakthrough
 History of light alcohol use
- CINV that occurs despite prophylaxis
and requires rescue  History of vomiting with prior exposure
to chemotherapeutic agents
 Refractory
 Other risks
- Occurs during subsequent treatment
cycles when prophylaxis and/or - History of motion sickness
rescue has failed in previous cycles
- History of nausea or vomiting during
pregnancy
- History of anxiety
CINV: therapy-related risk factors

 High drug dose

 High emetogenicity of chemotherapy

drugs
NOTE: the predominant risk factor
(patientrelated or therapy-related) is the degree
of emetogenicity of the chemotherapeutic
agent
CINV: mechanisms
CINV: other causes
  Partial or complete bowel obstruction

 Vestibular Dysfunction

 Brain Metastases

 Electrolyte imbalance: hypercalcemia,

hyperglycemia, hyponatremia, uremia

 Concomitant drugs, including opiates

 Gastroparesis induced by a tumor or

chemotherapy (such as vincristine)

 Psychophysiologic factors, including

anxiety as well as anticipatory nausea
CINV: classes of drugs
and vomiting
 Serotonin (5-HT3) antagonists
CINV: emetogenic potentials
 NK-1 receptor antagonists

 Corticosteroids

 Dopamine antagonists

 Cannabinoids
CINV: 5HT3-antagonists
1st Generation Agents are therapeutically
equivalent: Dolasetron, Ondansetron,
Granisetron
1 st Generation oral and IV doses equally
effective
Second generation 5-HT3 antagonist:
Palonosetron

CINV: Aprepitant

 Selective antagonist of the binding of

Substance P to the neurokinin 1 (NK1)
receptor
- IV: Fosaprepitan
Principles of Care for Acute Highly
andModerately Emetic Settings
UNANIMOUS CONSENSUS: CATEGORY
EVIDENCE
 Use the lowest tested fully effective
dose.
 No schedule is better than a single dose
given before chemotherapy.
 The antiemetic efficacy and adverse
effects of serotonin antagonist agents
are comparable in controlled trials.
 Intravenous and oral formulations are
equally effective and safe.
 Always give dexamethasone with a 5-
HT3 antagonist before chemotherapy
CINV: guidelines
High Emetic Risk: 3 drug
- 5-HT3 antagonist
- Dexamethasone
- Aprepitant (or fosaprepitant)
Moderate Emetic Risk in women (receiving AC
regimen):
- 5-HT3 antagonist
- Dexamethasone
- Aprepitant (or fosaprepitant)
Moderate Emetic Risk (except AC):
 5-HT3 receptor antagonist +
 Dexamethasone
1
CINV: other situations
 Multiple-day chemotherapy regimens
 Breakthrough CINV
 Anticipatory CINV
 Delayed CINV
CINV: multiple-day regimens
 Increased risk for both acute and
delayed nausea and vomiting
 Difficult to recommend appropriate
antiemetics for each day since acute
and delayed may overlap after the initial
day of chemotherapy.
 Period of risk for delayed nausea and
vomiting also depends on the
emetogenic potential of the last
chemotherapy agent administered in the
regime
 A 5-HT3 receptor antagonist should be
administered prior to each day of
moderately or highly-emetogenic
chemotherapy.
 Dexamethasone should be administered
once daily either orally or IV for every
day of chemotherapy and for 2-3 days
post chemotherapy.
 Aprepitant may be used for multi-day
chemotherapy. Aprepitant 125 mg on
 day 1, then aprepitant 80 mg daily on more aggressive therapy and have
days 2 and 3 along with dexamethasone poorer emesis control than older
patients
CINV: breakthrough CINV
 The most effective way to treat is to
 Breakthrough emesis refers to vomiting
prevent CINV by using optimal
that occurs despite prophylactic
antiemetics during every cycle of
treatment and/or requires rescue.
therapy.
 Refractory emesis refers to emesis that
 Either:
occurs during subsequent treatment
cycles when antiemetic prophylaxis - Alprazolam PO 0.25 to 0.5 mg
and/or rescue have failed in earlier t.i.d. beginning on the night
cycles before treatment OR;

 Challenge - Breakthrough nausea and - Lorazepam 0.5-2 mg PO on the

vomiting represents a difficult situation night before and the morning of
as ongoing refractory nausea is hard to treatment.
revers
 Behavioral therapy
 Management : round the clock
CINV: delayed
administration over prn
 Challenge - Delayed emesis is 2.5 times
 Additional agents should be from a
more prevalent than acute emesis.
different drug class than initial therapy
(all are equal):  For moderately emetogenic
chemotherapy: =Delayed nausea
- dopamine antagonists,
exceeds acute nausea by 16%.
metoclopramide, haloperidol,
cannabinoids, corticosteroids, =Delayed emesis exceeds acute emesis
lorazepam by 15%

 Anti-secretory agents if patient has  For highly emetogenic chemotherapy:

dyspepsia
=Delayed nausea exceeds acute nausea
CINV: anticipatory by 27%.

 Anticipatory nausea and/or vomiting is =Delayed emesis exceeds acute emesis

the occurrence of nausea and/or by 38
vomiting before patients receive their
CINV: prognostic factors delayed CINV
chemotherapy treatment. Because it is a
conditioned response, it can only occur  Strongest predictor: occurrence of acute
after a negative past experience with nausea and vomiting
chemotherapy.
 ≤ 52 years
 Challenge - Anticipatory nausea and/or
 Women
vomiting occurs in 18% to 57% of
chemotherapy patients.  High expectation of nausea
 Younger patients may be more
susceptible as they generally receive
  Corticosteroids

 Neuroleptics

 Alpha2 – agonists

 Benzodiazepines

 Antispasmodics

 Muscle relaxants

 Systemic local anesthetic

 Bone pain
STEP 1: Non-opioids – aspirin, non-steroidal
- Bisphosphonates
anti-inflammatory drugs (NSAIDs) or
paracetamol (MILD TO MODERATE PAIN) - Calcitonin

STEP 2: Mild opioids (e.g codeine), with or  Pain from malignant bowel obstruction
without non-opioids (MODERATE TO SEVERE
- Steroids
PAIN)
- Octreotide
STEP 3: Strong opioids (e.g. morphine), with or
without non- opioids (SEVERE PAIN) - Anticholinergics
Non-Opioids Opioids

 NSAIDS  Step 2 opioids

 Acetaminophen  Codeine, Oxycodone, tramadol,

hydrocodone
 Topicals
 Step 3 opioids
- Lidocaine, Capsaicin
 Oxycodone, morphine, dilaudid, fentanyl,
methadone
Opioids: equivalent dosing
Practice Points:

 Mild pain

 “ceiling” effect

 Start at lowest effective dose

 Review pt’s underlying medical illnesses

Adjuvants

 Antidepressants
- TCAs for neuropathic pain

 Anticonvulsants
Opioids: equivalent fentanyl patch dosing

Additional interventions: pain syndromes GCSF PROPHY

 Inflammation: NSAIDs European Organisation for Research and
 Bone pains (not emergency): NSAIDs Treatment ofCancer Patient Assessment
Algorithm to Decide ProphylacticGranulocyte
- If diffuse: bisphosphonates, Colony-stimulating Factor Usage
chemotherapy
STEP 1: Assess frequency of FN associated
 Neuropathic: with the planned chemotherapy regimen
- Antidepressants: TCAs, Venlafaxine, STEP 2: Assess factors that increase the
Duloxetine frequency/ risk of FN
- Anticonvulsants: gabapentin, STEP 3: Define the patient’s overall FN risk for
carbamazepine, pregabalin planned chemotherapy regimen
- Locally acting: lidocaine patch
GCSF Support
Neutropenia and Febrile Neutropenia

 Neutropenia:
- ANC (absolute neutrophil count)
<500 OR
- ANC < 1000 and expected to
decrease to ≤500 in the next 48 h

 Febrile Neutropenia (NF)

- Neutropenia + Oral Temp ≥ 38.3 C
single determination
- Neutropenia + Oral Temp ≥ 38
Cover 1h GCSF PROPHY - National Comprehensive
Cancer Network Guidelines –Decision Tree for
Primary Prophylaxis
 1. Evaluate  63/F
2. Assess risk  Breast Carcinoma St. III, Right breast
3. Intervene  S/P Neoadjuvant chemotherapy

 S/P – MRM Right

 On her Cycle 3 Adjuvant Chemotherapy-

Docetaxel

 During her last minutes of

chemotherapy...
- Patient complains of discomfort
on her (L) dorsal hand.
- Infusion of Docetaxel was
immediately discontinued .
- IV line removed, patient was sent
NCCN: GCSF secondary prophylaxis
home and was advised Cold
Compress

NNCN: Therapeutic GCSF  Patient was complaining of severe pain

on the extravasation area

 She was treated with the ff...

1) Oxycontine 10mg 1 tab BID
2) Pregabalin 75mg 1tab BID
3) Mefenamic Acid 500mg 1tab TID
4) Silver Sulfadiazine Cream (applied to
the affected area

EXTRAVASATION
Clinical case

 C.J.
 - Carboplatin
- Fluorouracil ( 5FU)
- Cisplatin*
- Gemcitabine
- Oxaliplatin
- Etoposide
- Docetaxel
- Irinotecan
Extravasations –
- Paclitaxel
 Refers to the escape of a chemotherapy
drug into the extravascular space, either - Topotecan
by leakage from a vessel or by direct - Carmustine
infiltration
- Thiotepa
 Local symptoms (ie, pain, erythema,
swelling) are usual - Bleomycin

- Change in the rate of drug - Cyclophosphamide

infusion or the absence of blood
return from the vascular catheter
may be the initial indicator that
extravasation has occurred
VESICANTS
IRRITANTS
 Capable of inducing a local
inflammatory reaction
 Can cause pain/ tenderness at the
injection site or along the vein, with or
without an inflammatory reaction
- Mitoxantrone
- Dacarbazine *
- BortezomibIfosfamide
- * Large vol. (>20ml) of conc. Drug
(>0.5mg/ml) may produce
necrosis
 Capable to induce formation of blisters
and/or cause tissue destruction
 Symptoms may be delayed for up to 6-
12 hours after drug extrasvastion
 Pruritusare common if without pain

 May have potential to cause soft tissue  May have severe necrosis with
ulcers only if a large amount of involvement of tendons and joints
concentrated drug solution is HIGH Vesicant potential
inadvertently extravasated
- ActinomycinD
 Short-term injury that does NOT lead to
tissue injury or necrosis - Vinblastine

IRRITANTS - Daunorubicin
 - Vincristine
- Doxorubicin
- Vindesine
- Epirubicine
- Vinorelbine
- Idarubicin
- Mitomycin C
Manifestations
 Within two to three days, increased
erythema, pain, brawny discoloration,
induration, dry desquamation, and/or
blistering may appear
 all volume extravasations, symptoms
may disappear over the next several
weeks.
 More extensive infiltrations, necrosis,
eschar formation, and ulceration with
raised, red, painful edges and a yellow
necrotic base may appear over several
weeks.
DID YOU KNOW...
 Extravasation recall phenomenon
 where previous sites of
extravasation of a vesicant drug
become inflamed upon re-
exposure of the patient to the
same drug administered at a
remote IV site.
 This phenomenon has been
reported with DOXORUBICIN,
EPIRUBICIN and PACLITAXE
How do we PREVENT
 Peripheral infusions of chemotherapy,
the vein selected should be large and
intact, with good blood return
established prior to starting the infusion.
 Sites with sclerosis, thrombosis, or scar
formation should be avoided, as should
limbs with impaired circulation.
 Controversial- most experts do not feel
that the avoidance of IV lines on the
ipsilateral side is necessary or beneficial
in a woman who has undergone
mastectomy for breast cancer, as long
as lymphedema is absent
 Taping of the entry site itself should be
avoided so that the area can be
examined.
 A clear dressing such as Tegaderm is
usually applied to cover the skin entry
site.
 The patency of the IV line should be
verified just prior to drug infusion by
flushing with 5 to 10 mL of isotonic
saline or a 5 percent dextrose solution.
How to MANAGE
1.Stop the infusion immediately.
2.Do not flush the line, and avoid applying
pressure to the extravasated site.
3.Elevate the affected extremity.
4.The catheter/needle should not be removed
immediately. Instead, it should be left in place
to attempt to aspirate fluid from the
extravasated area and to facilitate the
administration of an antidote to the local area,
if appropriate.
5.If an antidote will not be injected into the
extravasation site, the catheter/needle can be
removed after attempted aspiration of the
subcutaneous tissues.
6.Application of heat or cold 4.Dexrazoxane
6. If extravasation occurs from a central line, it 5.Corticosteroids
should be stopped if its rate decreases, or if
 Sodium thiosulfate is for extravasations
the patient complains of changes in sensation,
of : 1.Mechlorethamine
pain, burning, swelling at the central venous
catheter site, or in the ipsilateral chest. 2.Dacarbazine
7.The catheter/needle should not be removed 3.Cisplatin
immediately. Instead, it should be left in place
 Local injection of Hyaluronidase is for:
to attempt to aspirate fluid from the
extravasated area and to facilitate the 1.Vinca alkaloids
administration of an antidote to the local area,
if appropriate. 2.Paclitaxel

8.If an antidote will not be injected into the 3.Epipodophyllotoxins

extravasation site, the catheter/needle can be 4.Ifosfamide
removed after attempted aspiration of the
subcutaneous tissues.  Systemic administration of Dexrazoxane
is for:
9.If the patient has an implanted port, it should
be assessed for proper needle placement. The  Anthracycline extravasation
residual drug should be aspirated from the area ANTIDOTES
of suspected infiltration at the port pocket or at
the exit site of the tunneled catheter. If an  Corticosteroids — For anthracycline
antidote is indicated, it should be injected into extravasations, systemic, subcutaneous,
subcutaneous tissue along with local care. If and intradermal administration of
the antidote is administered intravenously, an corticosteroids at the extravasation site
adequate amount has to be instilled while have all been recommended, although
avoiding excess pressure on the central venous whether there is benefit for this approach is
catheter site. unclear.

10.If the patient has an implanted port, it has to  Corticosteroids may worsen the skin
be deaccessed after instilling the antidote damage from etoposide or vinca alkaloids,
and they are specifically contraindicated in
How to MANAGE these situations
 ICE or COLD packs is recommended for
extravasation of ALL vesicant & irritant
drugs except the vinca alkaloids
(vincristine, vinblastine, vinorelbine) and
epipodophyllotoxins such as etoposide
ANTIDOTES
1.Sodium thiosulfate
2.Hyaluronidase
3.Dimethylsulfoxide
Antihelminthic Drugs
Albendazole

 A broad spectrum oral anthelminthic

 Drug of choice for the treatment of

hydatid disease and cysticercosis

 Also used in the treatment of pinworm

and hookworm infections, ascariasis,
trichuriasis and strongyloides

 Adverse effects include mild and

transient epigastric distress, diarrhea,
headache, nausea, dizziness, lassitude,
and insomnia
Pharmacology

 After oral administration, it is

eratically absorbed (increased
with fatty meal) and then rapidly
undergoes first-pass metabolism
in the liver to the active
metabolite albendazole sulfoxide

 Thought to act against

nematodes by inhibiting
microtubule synthesis
  Also has larvicidal effects in  A drug of choice in the treatment of
hydatid disease, cysticercosis, filariasis, loiasis, and tropical eosinophilia
ascariasis, and hookworm
 Has been replaced by ivermectin for the
infection, and ovicidal effects in
treatment of onchocerciasis
ascariasis, ancylostomiasis, and
trichuriasis  Adverse effects are generally mild and
transient, include headache, malaise,
Clinical Uses
anorexia, weakness, nausea, vomiting, and
 Ascariasis, trichuriasis and hookworm and dizziness
pinworm infections
o Pharmacology
 For adults and children older
 Immobilizes microfilariae and
than 2 years with ascariasis and
alters their surface structure,
pinworm
displacing them from tissues and
making them more susceptible to
destruction by host defense
Infections, the treatment for ascariasis is a
mechanisms
single dose of 400 mg orally (repeated for 2-3
days for heavy infections and in 2 weeks for
pinworm infections)

 Hydatid disease
o Clinical Uses
 The treatment of choice for
 Wuchereria bancrofti, Brugia
medical therapy and is a useful
malayl, Brugia timori and Loa loa
adjunct to surgical removal or
aspiration of cysts  The drug of choice for treatment of
infections with these parasites because
 Neurocyticercosis
of its efficacy and lack of serious
 Controversial use since toxicity
antihelminthic therapy is not
 Microfilariae all species are rapidly killed:
clearly superior to therapy with
adult parasites are killed more slowly,
corticosteroids
often requiring several courses of
Bithionol treatment

 Alternative to triclabendazole for the Doxycycline

treatment of fascioliesis (sheep liver fluke)
 Has recently been shown to have
and an alternative to praziquantel for the
significant microfilaricidal activity
treatment of paragonimiasis
against Wuchereria bancrofti,
 Reaches peak blood levels in 4-8 hours and suggesting better activity than any other
excretion is mainly through the kidneys available drug against adult worms

 Adverse effects include mild diarrhea,  Activity is also seen against

abdominal cramps, anorexia, nausea, onchocerciasis o Acts indirectly, by
vomiting, dizziness, and headache killing Wolbachia, an intracellular
bacterial symbiont of filarial parasites
Diethylcarbamazine Citrate
  It may prove to be an important drug for treatments have led to major reductions
filariasis, both for treatment of active in disease transmissions
disease and in mass chemotherapy
 Strongyloidiasis
campaigns
- In immunosuppressed patients with
Ivermectin
disseminated infection, repeated
 Drug of choice in strongyloidiasis and treatment is often needed, and cure may
onchocerciasis not be possible. In this case,
suppressive therapy like once monthly
 Also an alternative drug for a number of
may be helpful
other helminthic infections
Mebendazole
 In strongyloidiasis treatment, infrequent
adverse effects include fatigue,  Has wide spectrum of antihelminthic
dizziness, nausea, vomiting, abdominal activity and a low incidence of adverse
pain, and rashes effects

 In onchocerciasis treatment, adverse  Adverse effects include mild nausea,

effects are principally from the killing of vomiting, diarrhea, and abdominal pain
microfilariae and can include fever, have been reported infrequently
headache, dizziness, somnolence,
o Pharmacology
weakness, rash, Increased pruritus,
diarrhea, joint and muscle pains,  Probably acts by inhibiting
hypotension, tachycardia lymphadenitis, microtubule synthesis, the parent
lymphagitis, and peripheral edema drug appears to be the active form

o Pharmacology  Efficacy of the drug varies with

gastrointestinal transit time, with
 Appears to paralyze nematodes
intensity of infection, and perhaps
and arthropods by intensifying v-
with the strain of parasite
aminobutyric
 The drug kills hookworm, ascaris,
and trichuris eggs
acid (GABA)-mediated transmission of signals
o Clinical Uses
in pempheral nerves
 Indicated for use ascariasis,
 In onchocerciasis, ivermectin is
trichuriasis. hookwarm and pinworm
microfilaricidal
infections, and certain other
 It does not effectively kill adult helminthic infections
worms but block the release of
 It can be taken before or after meals;
microfilariae for some months
the tablets should be chewed before
after therapy
swallowing
o Clinical Uses
Metrifonate (Trichlorfon)
 Onchocerciasis
 A safe, low-cost alternative drug for the
- Ivermectin plays a key role in treatment of Schistosoma haematobium
onchocerciasis control. Annual mass infections
  it is not active against Schistosoma
mansani or Schistosoma japonicum
 Adverse effects include nausea and
vomiting, diarrhea, abdominal pain,
branchospasm,
 headache, sweating, fatigue, weakness,
dizziness, and vertigo
o Pharmacology
 Mode of action is thought to be
cholinesterase inhibition
 This inhibition temporanly paralyzes
adult worms, resulting in their shift
from be bladder venous plexus to
small arterioles of the lungs, where
they are killed
o Clinical uses
 Also effective as a prophylactic agent
when given monthly to children in highly
endemic area, and it has been used in
mass treatment programs
Niclosamide
 A second-line drug for the treatment of
most tapeworm infections
 Adverse effects include nausea,
vomiting, diarrhea, and abdominal
discomfort
o Pharmacology
 Adult worms (but not ova) are rapidly
killed, presumably dure to inhibition of
oxidative phosphorylation or stimulation
of ATPase activity
o Clinical Uses
 Taenia soginata (beef tapeworm],
Taenia solium (pork tapeworm), and
Diphyllobothrium latum (fish tapeworm)
 Intestinal fluke infections
- Can be used as an alternative drug in the
treatment of Fasciolopsis buski
Heterophyes heterophyes, and Metogonimus
yokogawai
Oxamniquine
 An alternative to praziquantel for the
treatment of S. mansoni infections
 It has also been used extensively for
mass treatment
 Adverse effects: Central nervous
system symptoms (dizziness, headache,
drowsiness) are most common; nausea
and vomiting, diarrhea, colic, pruritus
and urticarial also occur
o Pharmacology
 Active against both mature and
immature stages of S. mansoni but
does not appear to be cercaricidal
 The mechanism of action is unknown
 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 the mesenteric
vessels but cease to lay eggs
o Clinical uses
 Safe and effective in all stages of S.
mansoni disease, including advanced
hepatosplenomegaly
 The drug is generally less effective in
children, who require higher doses than
adults
 It is better tolerated with food
Piperazine
 Causes paralysis of ascaris by blocking
 acetylcholine at the myoneural junction:  Clonorchiasis, opisthorchiasis, and
live worms are expelled by peristalsis paragonimiasis
 Mild adverse effects include nausea,  Taeniasis and diphyllobothriasis
vomiting, diarrhea, abdominal pain,
 Neurocysticercosis
dizziness, and headache
 Albendazole is now the
preferred drug, but when it is
not appropriate or available,
praziquantel has similar
efficacy
Praziquantel
 Indications for praziquantel
 Effective treatment of schistosome are similar to albendazole
infections of all species and most other
 Hymenolepis nana
trematode and cestode infcetions,
including cysticercosis  Praziquantel is the drug of choice
for H. nana infections and the
 Most common adverse effects include
first drug to be highly effective
nausea, vomiting, abdominal pain, loose
stolls, pruritus, urticarial, arthralgia,
myalgia and lower grade fever
 Hydatid disease
o Pharmacology
 Praziquantel kills protascoleces
 Appears to increase the permeability but does not affect the germinal
of trematode and cestode cell membrane
membranes to calcium, resulting in
 Praziquantel is being evaluated
paralysis. Dislodgement, and death
as an adjunct with albendazole
 In schistosome infections of pre- and postsurgery
experimental animals, praziquantel is
 In addition to its direct action
effective against adult worms and
praziquantel enhances the
immature stages, and it has a
plasma concentration of
prophylactic effect against cercarial
albendazole
infection
Pyrantel Pamoate
o Clinical Uses
 A broad-spectrum antihelminthic highly
 Tablets are taken with liquid after a
effective for the treatment of pinworm,
meal; they should be swallowed without
ascaris and Trichostrongylus orientalis
chewing because their bitter taste can
infections.
induce retching and vomiting
 Adverse effects include susea, vomiting,
 Schistosomiasis
diarrhea, abdominal cramps, dizziness,
 Praziquantel is the drug of drowsiness, headache, insomnia, rash,
choice for all forms of fever. And weakness
schistosomiasis
o Pharmacology
  Effective against mature and
immature forms of susceptible
helminths within the intestinal tract
but not against migratory stages in
the tissues or against ova

 The drug is a neuromuscular

blocking agent that causes release
of acetylcholine and inhibition of
cholinesterase; this results in
paralysis of worms, followed by
expulsion
Thiabendazole Roundworms  nematodes  albendazole,
mebendazole
 Alternative to ivermectin or albendazole
for the treatment of strongyloidiasis and Flukes  trematodes  praziquantel
cutaneous larva migrans Tapeworms  cestodes  praziquantel or
niclosamide
 Common adverse effects include
dizziness, anorexia, nausea, and
vomiting
o Pharmacology

 The mechanism of action is probably

the same as that of other
benzimidazoles (inhibition of
microtubule synthesis)

 The drug has ovicidal effects against

some parasites
 1

TOXICOLOGY

- Occupaonal-environmental toxicologist
o Assess and idenfy hazards associated with chemicals used in the workplace or
introduced into the human environment
o De&ne and carry-out surveillance programs
o Works with occupaonal hygienist, cer&ed safety professionals and occupaonal
health nurses

- Occupaonal toxicology
o Deals with chemicals found in workplace
o Idenfy agents of concern, idenfy the acute and chronic diseases that they cause,
de&ne the condions which they may be used safely and prevent absorpon of harmful
amounts of these chemicals
o PEL (permissible exposure limits)
o TLV (threshold limit values)
o Occupaonal safety and health administraon
 Promulgates standards for speci&c materials of parcular toxicity

- Environmental toxicology
o Air, soil and water
o Includes ADL (acceptable daily intake)

- Ecotoxicology
o Concerned with toxic e/ects of chemical and physical agents on populaons and
communies of living organisms within de&ned ecosystems

- Hazard
o The ability of a chemical agent to cause injury in a given situaon or se2ng; the
condions of use and exposure and primary consideraons

- Risk
o De&ned as the expected frequency of the occurrence of an undesirable e/ect arising
from exposure to a chemical or physical agent

- Routes of exposure
o Industrial
 Inhalaon is the major route of entry
o Ingeson
o Dermal

- Acute exposure
o Single or mulple exposure that occur over a brief period from seconds to 1-2 days
o Example is accidental discharge
o Cyanide is detoxi&ed by rhodanese (a mitochondrial enzyme in humans) in small
amounts to relavely nontoxic thiocyanate but enzyme is overwhelmed in large
amounts

- Chronic exposure
o Single or mulple exposures over a longer period of me
o Example is repeve handling of a chemical

- Bioaccumulaon
o May be lipophilic and accumulate in body fat where ssue residues are slowly released
over me

- Biomagni&caon
o When toxicant is incorporated into the food chain and one species feeds on other and
concentrates chemicals in organisms higher on the food chain

Air Pollutants

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- Five major substances accounng for 98% air polluon

o 52% Carbon monoxide
o 14% Sulfur oxides
o 14% Hydrocarbons
o 14% Nitrogen oxides
o 4% Ozone breakdown product and parculate maAers

- Carbon monoxide
o Colorless, tasteless, odorless and non-irritang gas, a by-product of incomplete
combuson
o Carboxyhemoglobin
 Product when CO combines ghtly but reversibly with the oxygen-binding sites
of hemoglobin and has an aBnity for hemoglobin that is about 220 mes that of
oxygen
 Replaces oxyhemoglobin
 Clinical e/ects
 Hypoxia
o A/ects brain, heart and kidneys
 Psychomotor impairment
 Headache and ghtness in the temporal area
 Confusion and loss of bvisual acuity
 Tachycardia, tachypnea, syncope and coma
 Deep coma, convulsions and respiratory failure
o Treatment
 Remove from source of CO immediately
 Respiraon maintained and high Dow of concentrated oxygen
 Not too high oxygen though as it may be toxic and may develop acute
respiratory distress syndrome, treatment with oxygen for a short period of me
 At recovery, neuropsychological and motor dysfuncon should be checked

- Sulfur dioxide
o Colorless irritant gas generated primarily by the combuson of sulfur-containing fossil
fuels
o Inhalaon of SO2 causes bronchial constricon; parasympathec reDexes and altered
smooth muscle tone appear to be involved
o Acute irritant asthma
 Intoxicaon of the eyes, nose and throat, reDex bronchoconstricon and
increased bronchial secreons
o Treatment
 Directed to treat irritaon of the respiratory tract and asthma

- Nitrogen oxides
o Nitrogen dioxide (NO2)
 A brownish irritant gas somemes associated with &res
 Miners regularly exposed to diesel equipment exhaust leading to serious
respiratory distress syndrome
 A relavely insoluble deep long irritant, capable of producing pulmonary edema
and acute adult respiratory distress (ARDS)
 Type I alveolar cells → recovery
 Type I and II alveolar cells → alveolar collapse
 Signs and symptoms
 Irritaon of eyes and nose, cough, mucoid and frothing sputum
producon, dyspnea and chest pain
 Treatment
 Adequate oxygenaon and alveolar venlaon
 Bronchodilators, sedaves and anbiocs may also be employed

o Ozone
 Bluish irritant gas found in the earths athmosphere where it is an important
absorbent of UV at high altude at ground level, it is an important pollutant
 Causes upper respiratory tract irritaon in mild exposure
 Severe exposure cause deep lung irritaon with pulmonary edema
 Treatment

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 Management for deep lung irritaon and noncardiogenic pulmonary

edema that have resulted in ARDS

Solvents

- Halogenated aliphac hydrocarbons

o Carbon tetrachloride
 Carcinogen
 Removed from workplace
o Chloroform
 Carcinogen
 Industrial degreasing and cleaning agent
o Trichloroethylene
 Carcinogen
 Removed from workplace
 Industrial degreasing and cleaning agent
o Tetrachloroethylene
 Likely carcinogen
 Industrial degreasing and cleaning agent
o 1,1,1-trichloroethane (Methylchloroform) DCM
 Neurotoxin
o Freons
 Related but limited due to ozone layer damage
o Mechanism of acon
 CNS depression, liver injury, kidney injury and some degree of cardiotoxicity
 Chronic exposure leads to neurotoxicity with impaired memory and peripheral
neuropathy
o Treatment
 Management depends on organ system involved

- Aromac hydrocarbons
o Benzene
 Solvent and used in intermediate synthesis of severe chemicals
 5 ppm limit to skin exposure (0.1 ppm suggested as blood cancers sll occur)
 Causes bone marrow injury (aplasc anemia, leukopenia, pancytopenia and
thrombocytopenia as well as leukemia)
 Benzene is a clastogen (breaks chromosomes)
o Toluene (methylbenzene)
 CNS depressant, skin and eye irritant
 Fetotoxic
 8000 ppm → severe fague and ataxia
 10,000 ppm → rapid loss of consciousness
o Xylene (dimethylbenzene)
 CNS depressant and a skin irritant

Pescides

- Organochloride pescides
o DDT (chlorpenothane) and its analogues
o Benzene hexachlorides
o Cyclodienes
o Toxaphenes

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o Mechanism of acon
 Interfere with inacvaon of the sodium channel in excitable membranes and
cause rapid repeve &ring in most neurons
 Calcium transport is inhibited
 CNS smulaon (tremor, 1st manifestaon)
 Links with tescular cancer and non-hodgkins lymphoma
o Once adsorbed, not readily desorb

- Organophosphorus pescides

o Absorbed in plants and exerts its e/ect on the insects that feed on the plant
o Based on compounds as somarin and sarin which are war gases
o Absorbed in skin and respiratory and GITs
o Mechanism of acon
 Inhibion of acetylcholinesterase through phosphorylaon

- Carbamate pescides
o Mechanism of acon
 Inhibit acetylcholinesterase by carbamylaon of the esterac site

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 Weak binding
 Dissociaon minutes to hours and clinical e/ects are shorter
 Management similar to organophosphates

- Botanical pescides
o Nicone
 Absorbed in skin as free alkaloid and not salt
 Treatment
 Maintennace of vital signs and suppression of convulsions
o Rotenone
 GIT irritaon, conjuncvis, dermas, pharyngis and rhinis
 Treatment is symptomac
o Pyrethrum (pyrethrin I, II, Cinarin I, II, jasmolin I and II)
 CNS excitaon and convulsions
 Tetanic paralysis
 Treatment is symptomac

- Herbicides
o Chlorophenoxy Herbicides
 Generates dimethylnitrosane (N-nitrosodimethylamine; NDMA)
 2,4-dichlorophenoxyacec acid (2,4-D)
 2,4,5-trichlorophenoxyacec acid
 Low acute human toxicity
 2,4-D in large doses cause coma and generalized muscle hypotonia
 Linked to non-hodgkin’s lymphoma
o Glyphosate
 Most widely used herbicide in the world
 Nonselecve so damages the plant as well in high content
 Used as herbicides for GMOs (which are glyphosate resistant)
 Eye and skin irritant
 Ingeson leads to esophageal erosion
 Treatment is symptomac
o Biphenyl herbicides
 Paraquat is the most common
 Mechanism of acon is single electron reducon of the herbicide to free radical
species
 Causes lung edema, alveolis and progressive &brosis. It probably inhibits
superoxide dismutase, resulng in intracellular free-radical oxygen toxicity
 Adsorbents are given (acvated charcoal, fullers earth)
 Gastric lavage not recommended as it may promote aspiraon from stomach to
lungs

Environmental Pollutants

- Polychlorinated and polybrominated biphenyls

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o PCBs
o Used for insulaon, &re retardancy, etc.
o Manufactured in large quanes before
o Biomagni&caon
o Yosho disease
 Cooking oil in Japan contaminated with PCBs

- Polychlorinated dibenzo-p-dioxins (PCDDs) or Dioxin

o By products of combuson process
o Heangs at 600°C like lightning strikes or electrical &res in PCB transformers
o Wasng syndrome
 Severe weight loss accompanied by reducon of muscle mass and adipose ssue

- PerDuorinated compounds
o Coolant in air condioning systems; ar&cial oxygen-carrying substances in experimental
clinical studies and heat-, strain- and sck-resistant coangs for cookware, fabrics and
other materials
o TeDon
 PerDourinated substances
o Proliferators of breast cancer cells and other cancers
o Polymer fume fever
 Also called TeDon Du
 Caused by pyrolysis of PFOA
 Welders are prone to this due to cadmium vaporizaon

- Asbestos
o Asbestosis
 Progressive &brolyc lung disease
o Lung cancer
o Mesothelioma
o Asbestos and cigareAe smoking increases the incidence of lung cancer
o Sll used with good environmental control

Metals

- Classic includes arsenic, lead and mercury

- New problems with beryllium, cadmium, manganese and uranium

- Beryllium
o Light alkaline metal that confers special properes on the alloys and ceramics in which
it is incorporated
o Used in computer compounds, nuclear weapons and dental appliances (beryllium
disease in densts)
o Chronic beryllium disease
 Progressive pulmonary &brosis
 Skin disease
o Mechanism of acon is accumulaon of an autoimmune aAack on the skin and lungs

- Cadmium
o Transion metal used in the industry
o Manufacture of baAeries, pigments, low-melng point electric materials; in solder; in
television phosphorus; and in plang operaons
o Semiconductor and plasc stabilizer
o Inhalaon and ingeson
o Cadmium fume fever
 When cadmium containing materials are vaporized by the heat torches or
cu2ng implements, the &ne dust and fumes released produce this acute
respiratory disorder
 Common in welders (shaking chills, cough, fever and malaise)

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PERINATAL & PEDIATRIC PHARMACOLOGY

Pharmacokinecs

- Factors a"ecng placental drug transfer and drug e"ects on the fetus include the following
o Physicochemical properes of the drug
o The rate at which the drug crosses the placenta and the amount of drug reaching the
fetus
o The duraon of exposure to the drug
o Distribuon characteriscs in di"erent fetal ssues
o The stage of placental and fetal development at the me of exposure to the drug
o The e"ects of drugs used in combinaon

- Lipid solubility
o Passage across placenta is dependent on lipid solubility and the degree of drug
ionizaon
o Salicylates which is almost completely ionized at physiologic pH crosses the placenta
rapidly because the small amount of salicylate that is not ionized is highly lipid-soluble

- Molecular size
o 250-500 MW → can easily cross placenta
o 500-1000 MW → cross more di5cultly
o 1000> → cross very poorly

- Placental transporters
o Example is P-glycoprotein transporter encoded by the MDRI gene pumps back into the
maternal circulaon a variety of drugs, including cancer drugs like vinblasne and
doxorubicin

- Protein-binding
o A"ects rate of transfer and the amount transferred
o Very lipid-soluble drugs will not be a"ected greatly by protein binding
o Di"erenal protein binding is also important since some drugs exhibit greater protein
binding in maternal plasma than in fetal plasma because of a lower binding a5nity of
fetal proteins

- Placental and fetal drug metabolism

o Two mechanisms that help protect the fetus from drugs in the maternal circulaon
 Placenta itself plays a role both as a semipermeable barrier and as a site of
metabolism of some drugs passing through it
 Drugs that have crossed the placenta enter the fetal circulaon via the umbilical
vein about 40-60% of umbilical venous blood <ow enters the fetal liver; the
remainder bypasses the liver and enters the general fetal circulaon. A drug
that enters the liver may be parally metabolized there before it enters the fetal
circulaon

Pharmacodynamic

- Matenal drug acons

o Drug a"ects on the reproducve ssues may be altered – breast, uterus, etc.
o Drug e"ects on other maternal ssues (heart, lungs, kidneys, CNS, etc.) are not changed
signiBcantly by pregnancy, although the physiologic context (cardiac output, renal blood
<ow, etc.) may be altered requiring drugs

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- Therapeuc drug acons in fetus

o Corcosteroids are used to smulate fetal lung maturaon when pretrerm birth is
expected
o Phenobarbital when given to pregnant women near term, can induce fetal hepac
enzymes responsible for the glucorunidaon of bilirubin, and the incidence of jaundice
is lower in newborns when mothers are given phenobarbital than when phenobarbital is
not used
o Anarrythmic drugs have also been given to mothers for treatment of fetal cardiac
arrhythmias – digoxin, <ecainamide, procainamide, verapamil, etc.)
o Maternal useof zidovudine decreases by 2/3s transmission of HIV from the mother to
the fetus and use of combinaons of 3 anretroviral agents can eliminate fetal infecon
almost enrely

- Predictable toxic drug acons in the fetus

o Use of opioids by mother give dependence to fetus and newborn shown by the
neonatal withdrawal symptoms
o ACE inhibitors result in irreversible renal damage in fetus
o Diethylslbestrol gives adenocarcinoma of vagina to the fetuses exposed aHer their
puberty (delayed e"ect)

- Teratogenic drug acons

o Thalidomide causes phocomelia
o Vitamin A analogs (isotrenoin and etrenate) are potenal teratogens
o Folic acid supplementaon during pregnancy reduce neural tube defects like spina biBda
o Chronic high alcohol consumpon during 1 st and 2nd trimester of pregnancy lead to fetal
alcohol syndrome

- Teratogen
o Result in a characterisc set of malformaons, indicang selecvity for certain target
organs
o Exert its e"ects at a parcular stage of fetal development, e.g., during the limited me
period of organogenesis of the target organs
o Show a dose-dependent incidence

- Teratogenic drugs

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- FDA system in teratogenic potenal

- Counseling pregnant women on teratogenic risk

o The baseline teratogenic risk in pregnancy (risk of a neonatal abnormality in the absence
of any known teratogenic exposure) is about 3%
o Cannot stop medicaon immediately – morbidity in women who disconnued selecve
serotonin reuptake inhibitor therapy for depression in pregnancy

Drug Therapy in Infants and Children

- Drug absorpon
o Same in adults
o Unique factors that in<uence drug absorpon
 Blood <ow at the site of administraon
 Physiologic condions that might reduce blood <ow to injecon afrea
(IM and SC)
o Cardiovascular shock
o Vasoconstricon due to sympathomimec agents
o Heart failure

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 IM has diminished peripheral perfusion so absorpon becomes irregular

and di5cult to predict, because the drug may remain in the muscle and
be absorbed more slowly than expected
 Example is cardiac glycosides, aminoglycosides, anbiocs and
anconvulsants
 Gastrointesnal funcon
 Drugs that are parally or totally inacvated by the low pH of gastric
contents should not be administered orally
 Peristalsis is slow and irregular so amount of drug absorbed is
unpredictable
 Gastrointesnal enzymes are low

- Drug distribuon
o High water content in body 70-75% than adult which is 50-60%
o More diuresis
o Protein binding of drugs is reduced in neonates (diazepam, phenytoin, ampicillin and
phenobarbital) which may result in toxicity
o Greater permeability in blood brain barrier so bilirubin may enter brain and cause
kernicterus

- Drug metabolism
o Decrease ability to metabolize drugs
o Many drugs have slow clearance rates and prolonged eliminaon half-lives
o Phenobarbital
 Can induce early maturaon of fetal hepac enzymes when mother is taking it

- Drug excreon
o Lower Bltraon rate, only 30-40% of the adult value

- Drug use in lactaon

o It is important to remember that formula feeding is associated with higher morbidity
and mortality in all socioeconomic group
o If there is really a need to take drugs, take medicaons 30-60 minutes aHer nursing and
3-4 hours before feeding

- Drugs used in lactaon and possible e"ects to the infant

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Pharmacology and Therapeucs II Lecture Notes

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GERIATRIC PHARMACOLOGY

- 65 is elderly but most authori!es consider 75

- Many disease at this age

- Caloric restric!on prolong life span in animals as seen in mice

- Me(ormin and rapamycin increase life span alone and appear to have synergis!c e*ects when
given together

Pharmacologic Changes Associated with Aging

- Pharmacokine!c changes
o Absorp!on
 Li-le evidence of changes
 Indirect causes: altered nutri!onal habits, greater consump!on of
nonprescrip!on drugs and changes in gastric emptying (older diabe!cs)
o Distribu!on
 Decrease in serum albumin, which binds to many drugs, especially weak acids
 There may be a concurrent increase in serum alpha acid glycoprotein, a protein
that binds many basic drugs
 So, ra!o of bound to free drug may be signi4cantly altered

o Metabolism
 Drugs that metabolize more slowly in the elderly

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 Decline of liver’s ability to recover from injury with age so cau!on in dosing with
drugs cleared primarily by the liver
o Elimina!on
 Age related decline in renal func!on should be considered
 Decline in crea!nine clearance occurs in about 2/3 of the popula!on
o Cockcro;-Gault formula for ages 40-80 (adults require allowance for reduced renal
clearance)
 12- or 24-hour crea!nine clearance determina!on is needed (standard)

(140-Age) X (weight in kg)

Es!mated crea!nine clearance (mL/min) = -----------------------------------------------------
72 X Serum crea!nine in mg/dL

- Pharmacodynamic changes
o Clinical studies have supported the idea that the elderly are more sensi!ve to some
seda!ve-hypno!cs and analgesics
o Temperature regula!on is impaired and hypothermia is poorly tolerated by the elderly
o Certain homeosta!c control mechanisms appear to be blunted in the elderly

Major Drug Groups

- CNS
o Seda!ve –hypno!cs
 Vary in their sensi!vity
 Reduced elimina!on
 Toxici!es include ataxia and other stability impairments leading to increase falls
and fractures
o Analgesics
 Sensi!ve to respiratory e*ects of these agents due to age-related respiratory
decline
o An!psycho!c and an!depressant drugs
 Phenothiazines and haloperidol
 Common for adult schizophrenia
 Also in delirium, demen!a, agita!on, comba!veness and paranoid
syndrome
 On theory, these drugs may worsen memory impairment
o Alzheimer’s disease
 Progressive memory impairment, demen!a and cogni!ve dysfunc!on leading to
completely vegeta!ve state then death

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- Cardiovascular
o Blood pressure, esp. systolic that increases with age
o Same treatment protocol as anybody with hypertension
o Beta blockers are poten!ally hazardous in pa!ents with obstruc!ve airway disease
o Every pa!ent receiving an!-HPN drugs should be checked regularly for orthosta!c
hypotension because of the danger of cerebral ischemia and falls
o Posi!ve inotropic agents
 Heart failure
 Toxic e*ects of digoxin, some geriatrics are more suscep!ble to arrhythmic
o An!arrhythmic agents
 Challenging because of lack of good hemodynamic reserve, frequency of
electrolyte disturbances and increase prevalence of signi4cant coronary disease
 Clearances of quinidine and procainamide decreases
 Disopyramide avoided cause voiding problems in men and heart failure

- An!microbial therapy
o Due to reduc!on of host defense
o Altered T-lymphocyte func!on
o Preven!ve immuniza!ons should be maintained – inHuenza annually, tetanus every 10
years and pneumococcal and zoster vaccine once

- An!-inHammatory drugs
o Osteoarthri!s and rheumatoid drug therapy are the same
o NSAID
 Use with care because of toxici!es, may cause irreversible renal damage

- Opthalmic

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o Glaucoma is common
o AMS (age-related macular disease)
 Common cause of blindness in developed countries
 AMD may be due to smoking

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DERMATOLOGIC PHARMACOLOGY

- Major variables that determine pharmacologic response to drugs applied to the skin include:
o Regional varia'on in drug penetra'on
 For example, the scrotum, face, axilla, and scalp are far more permeable than
the forearm and may require less drug for equivalent e.ect
o Concentra'on gradient
 Increasing the concentra'on gradient increases the mass of drug transferred
per unit 'me, just as in the case of di.usion across other barriers
 Thus, resistance to topical cor'costeroids can some'mes be overcome by use of
higher concentra'ons of drug
o Dosing schedule
 Because of its physical proper'es, the skin acts as a reservoir for many drugs
 As a result, the “local half-life” may be long enough to permit once-daily
applica'on of drugs with short systemic half-lives
 For example, once-daily applica'on of cor'costeroids appears to be just as
e.ec've as mul'ple applica'ons in many condi'ons
o Vehicles and occlusion
 An appropriate vehicle maximizes the ability of the drug to penetrate the outer
layers of the skin
 In addi'on, through their physical proper'es (moistening or drying e.ects),
vehicles may themselves have important therapeu'c e.ects
 Occlusion (applica'on of a plas'c wrap to hold the drug and its vehicle in close
contact with the skin) is extremely e.ec've in maximizing e7cacy

An'bacterial Agents

- Topical an'bacterial prepara'ons

o Bacitracin and gramicidin
 Bacitracin
 Pep'de an'bio'cs, ac've against gram posi've organisms such as
streptococci, pneumococci, and staphylococci
 In addi'on, most anaerobic cocci, neisseriae, tetanus bacilli, and
diphtheria bacilli are sensi've
 Bacitracin is compounded in an ointment base alone or in combina'on
with neomycin, polymyxin , or both
 Microbial resistance may develop following prolonged use

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 Gramicidin
 Available only for topical use, in combina'on with other an'bio'cs such
as neomycin, polymixin, bacitracin, and nysta'n
o Mupirocin
 Pseudomonic acid A
 Most gram-posi've aerobic bacteria, including methicillin-resistant S. aureus
(MRSA) are resistant
 E.ec've in the treatment of impe'go caused by S. aureus and group A beta
hemoly'c streptococci
o Retapamulin
 A semisynthe'c pleromu'lin deriva've e.ec've in the treatment of
uncomplicated super:cial skin infec'on caused by group A beta hemoly'c
streptococci and S. aureus, excluding MRSA
o Polymyxin B sulfate
 A pep'de an'bio'c e.ec've against gram-nega've organisms, including
Pseudomonas aeruginosa, Escherichia coli, Enterobacter, and klebsiella
 Total daily dose applied to denuded skin or open wounds should not exceed 200
mg in order to reduce the likelihood of neurotoxicity and nephrotoxicity
o Neomycin and gentamycin
 Are aminoglycoside an'bio'cs ac've against gram-nega've organisms,
including E coli, proteus, klebsiella, and Enterobacter
 Gentamicin generally shows greater ac'vity against P. aeruginosa than
neomycin
 Gentamicin is also more ac've against staphylococci and group A beta
hemoly'c streptococci
o Topical an'bio'c in acne
 Clindamycin
 Has in vitro ac'vity against Propionibacterium acnes
 The hydroalcoholic vehicle and foam formula'on (Evoclin) may cause
drying and irrita'on of the skin, with complaints of burning and s'nging
 Erythromycin
 Mechanism of ac'on of topical erythromycin in in>ammatory acne
vulgaris is unknown\one of the possible complica'ons of topical therapy
is the development of an'bio'c-resistant strains of organisms, including
staphylococci
 Metronidazole
 Topical metronidazole is e.ec've in the treatment of rosaceae
 The drug may act as an an'-in>ammatory agent by direct e.ect on
neutrophil cellular func'on
 Oral metronidazole has been shown to be a carcinogen in suscep'ble
rodent species, and topical use during pregnancy and by nursing
mothers and children is therefore not recommended
 Sodium sulfacetamide
 Several combina'on with sulfur for the treatment of acne vulgaris and
acne rosacea
 The nechanism of ac'on is thought to be inhibi'on of P acnes by
compe''ve inhibi'on of p-aminobenzoic acid u'liza'on
 Approximately 4% of topically applied sulfacetamide is absorbed
percutaneously, and its use is therefore contraindicated in pa'ents
having a known hypersensi'vity to sulfonamides
 Dapsone
 For the treatment of acne vulgaris
 Adverse local side e.ects include mild dryness, redness, oiliness, and
skin peeling

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 Applica'on of dapsone gel followed by benzoyl peroxide may result in a

temporary yellow discolora'on of the skin and hair

An'fungal Agents

- Topical an'fungal prepara'ons

o Topical azole deriva'ves
 Ac'vity against dermatophytes (epidermophyton, microsporum, and
Trichophyton) and yeasts, including Candida albicans and Pityrosporum
orbiculare
 Miconazole
 Available for topical applica'on as cream or lo'on and as vaginal cream
or suppositories for use in vulvovaginal candidiasis
 Clotrimazole
 Available for topical applica'on to the skin as a cream or lo'on and as
vaginal cream and tablets for use in vulvovaginal candidiasis
 Econazole
 Available as a cream for topical applica'on
 Oxiconazole
 Available as cream and lo'on for topical use
 Ketoconazole
 Available as a cream for topical treatment of dermatophytosis and
candidiasis and as a shampoo or foam for the treatment of seborrheic
derma''s
 Sulconazole
 Available as a cream or solu'on
 Sertaconazole
 Available as cream
 Adverse local reac'ons to the imidazoles may include s'nging, pruritus,
erythema, and local irrita'on
o Ciclopirox olamine
 A synthe'c broad-spectrum an'myco'c agent with inhibitory ac'vity against
dermatophytes, candida species, and P. orbiculare
 Appear to inhibit the uptake of precursors of macromolecular synthesis; the site
of ac'on is probably the fungal cell membrane
 Topical 8% has been approved for the treatment of mild to moderate
onchomycosis of :ngernails and toenails
 Although well tolerated with minimal side e.ects, the overall cure rates in
clinical trials are less than 12%
o Allylamines: NaFi:ne and terbina:ne
 Highly ac've against dermatophytes but less ac've against yeast
 The ac'vity derives from selec've inhibi'on of squalene epoxidase, a key
enzyme for the synthesis of ergosterol
 Adverse reac'ons include local irrita'on, burning sensa'on, and erythema
 Contact with mucous membranes should be avoided
o Butena:ne
 Inhibits the epoxida'on of squalene, thus blocking the synthesis of ergosterol,
an essen'al component of fungal cell membranes
 Treatment for super:cial dermatophytosis
o TolnaFate
 Synthe'c an'fungal compound that is e.ec've topically against dermatophyte
infec'ons caused by epidermophyton, microsporum, and Trichophyton
 It is also ac've against P. orbiculare but not against candida
o Nysta'n and Amphotericin B
 Useful in the topical therapy of C. albicans infec'ons but ine.ec've against
dermatophytes

Pharmacology and Therapeucs II Lecture Notes

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 4

 Nysta'n
 Limited to topical treatment for cutaneous and mucosal candida
infec'ons because of its narrow spectrum and negligible absorp'on
from the gastrointes'nal tract following oral administra'on
 Amphotericin B
 Has a broader an'fungal spectrum and is used intravenously in the
treatment of many systemic mycoses and to a lesser extent in the
treatment of cutaneous candida infec'ons
- Oral an'fungal agents
o Oral azole deriva'ves
 Azole deriva'ves currently available for oral treatment of candida and
dermatophytre infec'ons include >uconazole and itraconazole
 Fluconazole and itraconazole are e.ec've in the therapy of cutaneous
infec'ons caused by epidermophyton, microsporum, and Trichophyton species
as well as candida
 Tinea versicolor is responsive to short courses of oral azoles
 Administra'on of the oral azoles with midazolam, trizolam, or HMG-CoA
inhibitors is contraindicated
o Griseofulvin
 E.ec've orally against dermatophyte infec'ons caused by epidermophyton,
microsporum, and Trichophyton
 It is ine.ec've against Candida and P. orbiculare
 Most e.ec've in trea'ng 'nea infec'ons of the scalp and glabrous (nonhairy)
skin
 Ad verse e.ects seen with griseofulvin therapy include headaches, nausea,
vomi'ng, diarrhea, photosensi'vity, peripheral neuri's, and occasionally
confusion
o Terbina:ne
 Treatment of oncomycosis
 Pa'ents receiving terbina:ne for onchomycosis should be monitored closely
with periodic laboratory evalua'ons for possible hepa'c dysfunc'on

Topical An'viral Agents

- Acyclovir, valacyclovir, penciclovir and famciclovir

o Synthe'c guanine analogs with inhibitory ac'vity against members of the herpesvirus
family, including herpes simplex types 1 and 2
o Adverse local reac'ons to acyclovir and penciclovir may include pruritus and mild pain
with transient s'nging or burning

Immunomodulators

- Imiquimod
o Available as 5% cream for the treatment of external genital and perianal warts in adults,
ac'nic keratosis on the face and scalp, and biopsy-proven primary basal cell carcinomas
on the trunk, neck and extremi'es
o The mechanism of its ac'on is thought to be related to its ability to s'mulate periphera;l
mononuclear cells to release interferon alpha and to s'mulate macrophages to produce
interleukins -1, -6, and -8 and tumor necrosis factor-α (TNF-α)

- Tacrolimus and pimecrolimus

o Macrolide immunosuppressants that have been shown to be of signi:cant bene:t in the
treatment of atopic derma''s
o Both agents inhibit T-lymphocyte ac'va'on and prevent the release of in>ammatory
cytokines and mediators from mast cells in vitro aFer s'mula'on by an'gen-IgE
complexes

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 5

o Adverse e.ects include burning sensa'on in the applied area that inmproves with
con'nued use
o A black box warning regarding the long-term safety of topoical tacrolimus and
pimecrolimus because of animal tumorigenicity data

Ectoparasi'cides

- Permethrin
o Toxic to Pediculus humanus, Pthirus pubis, and Sarcoptes scabiei
o Adverse reac'ons to permethrin include transient burning, s'nging, and pruritus

- Spinosad
o Approved for the topical treatment of head lice in pa'ents 4 years of age and older
o Toxic to P humanus with no appreciable absorp'on from topical applica'on
o Recommended that the 0.9% suspension be applied to the hair and scalp for 10 minutes
and then rinsed out
o A repeat treatment may be applied 1 week later if live lice are present

- Ivermec'n
o Approved for the treatment of head lice in pa'ents 6 months of age and older
o Toxic to P. humanus, resul'ng in paralysis and death of the parasite
o Lo'on should be applied to the hair and scalp for 10 minutes
o For single use only and should not be repeated without health care provider
recommenda'on

- Lindane (hexachlorocyclohexane)
o Available as a 1% shampoo or lo'on
o For pediculosis capi's or pubis, 30 mL of shampoo is applied to dry hair on the scalp or
genital area for 4 minutes and then rinsed o.
o No addi'onal applica'on is indicated unless living lice are present 1 week aFer
treatment

- Crotamiton
o N-ethyl-o-crotonotoluidide
o A scabicide with some an'pruri'c proper'es
o An e.ec've agent that can be used a an alterna've to lindane
o Allergic contact derma''s and primary irrita'on may occur, necessita'ng
discon'nuance of therapy
o Applica'on to acutely in>amed skin or to the eyes or mucous membranes should be
avoided

- Sulfur
o Non-irrita'ng, it has an unpleasant odor, is staining, and is thus disagreeable to use
o The usual formula'on is 5% precipitated sulfur in petrolatum

- Malathion
o An organophisphate cholinesterase inhibitor that is hydrolyzed and inac'vated by
plasma carboxylesterases much faster in humans than in insects, thereby providing a
therapeu'c advantage in trea'ng pediculosis

- Benzyl alcohol
o Available as a 5% lo'on for the treatment of head lice in pa'ents older than 6 months
o Eye irrita'on and allergic contact derma''s have been reported

Agents A.ec'ng Pigmenta'on

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 6

- Hydroquinone, monobenzone and mequinol

o Used to reduce hyperpigmenta'on of the skin
o Topical hydroquinone and mequinol usually result in temporary lightening, whereas
monibenzen e causes irreversible depigmenta'on
o The mechanism of ac'on of these compounds appears to involve inhibi'on of the
enzyme tyrosinase, thus interfering with the biosynthesis of melanin
o In addi'on, monobenzene may be toxic to melanocytes, resul'ng in permanent loss of
these cells

- Trioxsalen and methoxsalen

o Psoralens used ofr the repigmenta'on of depigmented macules of vi'ligo
o Psoralens must be photoac'vated by lng-wavelength ultraviolet light in the range of
320-400 nm (ultraviolet A [UVA]) to produce a bene:cial e.ect
o Psoralens intercalate with DNA and, wit subsequent UVA irradia'on, cyclobutane
adducts are formed with pyrimidine bases
o Both monofunc'onal and bifunc'onal adducts may be formed, the laNer causing
interstrand cross-links
o These DNA photoproducts may inhibit DNA synthesis
o The major long-term risks of psoralen photochemotherapy are cataracts and skin cancer

Sunscreens

- Topical medica'ons useful in protec'ng against sunlight contain either chemical compounds
that absorb ultraviolet light, called sunscreens, or opaque materials such as 'tanium dioxide
that re>ect light, called sunshades

- The three classes of chemical compounds most commonly used in sunscreens are p-
aminobenzoic acid (PABA) and its esters, the benzophenones, and the dibenzoylmethanes

- Most sunscreen prepara'ons are designed to absorb ultraviolet light in the ultraviolet B (UVB)
wavelength range from 280 to 320 nm, which is the range responsible for most of the erythema
and sunburn associated with sun exposure and tanning

- The sun protec'on factor (SPF) of a given sunscreen is a measure of its e.ec'veness in
absorbing erythrogenic ultraviolet light

- It is determined by measuring the minimal erythema dose with and without the sunscreen in a
group of normal people

- The ra'o of the minimal erythema dose with sunscreen to the minimal erythema dose without
sunscreen is the SPF

Acne Prepara'ons

- Re'noic acid and deriva'ves

o Also known as tre'noin or all-trans re'noic acid
o The acid form of vitamin A
o It is an e.ec've topical treatment for acne vulgaris

- Isotre'noin
o A synthe'c re'noid currently restricted to the oral treatment of severe cys'c acne that
is recalcitrant to standard therapies
o Common adverse e.ects resemble hypervitaminosis A and include dryness and itching
of the skin and mucous membranes
o Teratogenicity is a signi:cant risk in pa'ents taking isotre'noin; therefore, women of
childbearing poten'al must use an e.ec've form of contracep'on for at least 1 month

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 7

before, throughout isotre'noin therapy, and for one or more menstrual cycles following
discon'nuance of treatment
o A nega've serum pregnancy test must be obtained within 2 weeks before star'ng
therapy in these pa'ents, and therapy should be ini'ated only on the second or third
day of the next normal menstrual period
o Adapalene
 A deriva've of naphthoic acid that resembles re'noic acid in structure and
e.ects
 Less irrita'ng than tre'noin and is most e.ec've in pa'ents with mild to
moderate acne vulgaris
 Also available in a :xed-dose combina'on gel with benzyl peroxide
o Tazarotene
 Acetylenic re'noid
 For the treatment of mild to moderately severe facial acne
 Topical tazarotene should be used by women of childbearing age only aFer
contracep've counseling
 It is recommended that it should not be used by pregnant women

- Benzoyl peroxide
o An e.ec've topical agent in the treatment of acne vulgaris
o Has been postulated that the mechanism of ac'on of benzoyl peroxide in acne is related
to its an'microbial ac'vity against P acnes and to its peeling and comedoly'c e.ects

- Azelaic acid
o A straight chain saturated dicarboxylic acid that is e.ec've in the treatment of acne
vulgaris

- Brimonidine
o Is alpha-2 adrenergic agonist indicated for the topical treatment of persistent facial
erythema of rosacea in adults 18 years of age or older

Drugs for Psoriasis

- Acitre'n
o A metabolite of the aroma'c re'noid etre'nate, is quite e.ec've in the treatment of
psoriasis, especialliy pustular forms
o Adverse e.ects aNributable to acitre'n therapy are similar to those seen with
isotre'noin and resemble hypervitaminosis

- Tazarotene
o A topical acetylenic re'noid prodrug that is hydrolyzed to its ac've form by an esterase
o The ac've metabolite. Tazarotenic acid, binds to re'noic acid receptors, resul'ng in
modi:ed gene expression
o Poten'a'on of photosensi'zing medica'on may occur, and pa'ents should be
cau'oned to minimize sunlight exposure and to use sunscreens and protec've clothing

- Calcipotriene and calcitriol

o A synthe'c vitamin D3 deriva've that is e.ec've in the treatment of plaque-type
psoriasis vulgaris of moderate severity
o Adverse e.ects include burning, itching and mild irrita'on

- Biologic agents
o Alefacept

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 8

 An immunosuppressive dimeric fusion protein that consists of extracellular CD2-

binding por'on of the human leukocyte func'on an'gen-3 linked to the Fc
por'on of human IgG1
 Interferes with lymphocyte ac'va'on, which plays a role in the pathophysiology
of psoriasis, and causes a reduc'on in subsets of CD2 T lymphocytes and
circula'ng total CD4 and CD8 T-lymphocyte counts
 Because of the possibility of an increased risk of malignancy, it should not be
administered to pa'ents with a history of systemic malignancy
o TNF inhibitors: Etanercept, in>iximab, and adalimumab
 Etanercept
 A dimeric fusion protein consis'ng of the extracellular ligand-binding
por'on of the human TNF receptor linked to the Fc por'on of human
IgG1
 Binds selec'vely to TNF-α and –β and blocks interac'on with cell
surface TNF receptors that play a role in the in>ammatory process of
plaque psoriasis
 In>iximab
 A chimeric IgG1 monoclonal an'body composed of human constant and
murine variable regions
 Binds to the soluble and transmembrane forms of TNF-α and inhibits
binding of TNF-α with its receptors
 Adalimumab
 A recombinant IgG1 monoclonal an'body that binds speci:cally to TNF-
α and blocks its interac'on with cell surface TNF receptors
o Ustekinumab
 A human IgG1κ monoclonal an'body that binds with high a7nity and speci:city
to interleukin (IL)-12 and IL-23 cytokines inhibi'ng TH1 and TH17 cell-mediated
responses, which are involved in the pathogenesis of psoriasis
o Fumaric acid esters
 The mechanism of ac'on of dimethyl fumarate in psoriasis may be due to
immunodilatory e.ects on lymphocytes and kera'nocytes resul'ng in a shiF
away from a psoria'c cytokine pro:le

An'-in>ammatory Agents

- Topical cor'costeroids
o The remarkable e7cacy of topical cor'costeroids in the treatment of in>ammatory
dermatoses was noted soon aFer the introduc'on of hydrocor'sone in 1952

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 9

- Tar compounds
o Tar prepara'ons are used mainly in the treatment of psoriasis, derma''s,a nd lichen
simplex chronicus

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 10

Keratoly'c & Destruc've Agents

- Salicylic acid
o A keratoly'c agent
o The drug may solubilize cell surface proteins that keep the stratum corneum intact,
thereby resul'ng in desquama'on of kerato'c debris
o It is advisable to limit both the total amount of salicylic acid applied and the frequency
of applica'on

- Propylene glycol
o Used extensively in topical prepara'ons because it is an excellent vehicle for organiuc
compounds
o Has been used alone as a keratoly'c agent
o An e.ec've keratoly'c agent for the removal of hyperkerato'c debris
o It is also e.ec've humectant and increases the water content of the stratum corneum

- Urea
o Compa'ble cream vehicle or ointment base has a soFening and moisturizing e.ect on
the stratum corneum
o It has the ability to make creams and lo'ons feel less greasy, and this has been u'lized
in dermatologic prepara'ons to decrease the oily feel of a prepara'on that otherwise
might feel unpleasant
o Also keratoly'c
o The mechanism of ac'on appears to involve altera'ons in prekera'n and kera'n
leading to increased solubiliza'on

- Podophyllum resin and podo:lox

o And alcoholic extract of Podophyllum peltatum, commonly known as mandrake root or
mayapple
o Used in the treatment of condyloma acuminate and other verrucae
o It is a mixture of podophyllotoxin, α and β peta'n, desoxypodophyllotoxin,
dehyfropodophyllotoxin, and other compounds

- Sinecatechins
o A prescrip'on botanical drug product of a par'ally puri:ed frac'on of the water extract
of green tea leaves from Camellia sinensis containing a mixture of catechins
o Indicated for the topical treatment of external genital and perianal warts in
immunocompetent pa'ents 18 years and older

- Fluorouracil
o A >uorinated pyrimidine an'metabolite that resembles uracil, with a >uorine atom
subs'tuted for the 5-methyl group
o Used topically for the treatment of mul'ple ac'nic keratosis

- Ingenol mebutate
o Derived from the sap of the Euphorbia peplus plant and has recently been approve dfor
the treatment of ac'nic keratosis
o Local skin reac'ons are to be expected with crus'ng, swelling, vesicula'on, and possible
ulcera'on
o Cau'on must be taken to prevent eye exposure
o Pa'ents must wash their hands well aFer applying the gel and avoid transfer of the drug
to the periocular area during and aFer applica'on

- Nonsteroidal an'-in>ammatory drugs

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 11

o A topical 3% gel formula'on of the nonsteri=oidal an'-in>ammatpry drug diclofenac has

shown moderate e.ec'veness in the treatment of keratosis

- Aminolevulinic acid
o An endogenous precursor of photosensi'zing porphyrin metabolites
o When exogenous ALA is provided to the cell through topical applica'ons,
protoporphyrin IX (PpIX) accumulates in the cell
o When exposed to light of appropriate wavelength and energy, the accumulated PpIX
produces a photodynamic reac'on resul'ng in the forma'on of cytotoxic superoxide
and hydroxyl radicals

An'pruri'c Agents

- Doxepin
o Topical doxepin hydrochloride 5% cream may provide signi:cant an'pruri'c ac'vity
when u'lized in the treatment of pruritus associated with atopic derma''s or lichen
simplex chronicus

- Pramoxine
o A topical anesthe'c that can provide temporary relief from pruritus associated with mild
eczematous dermatoses

An'seborrhea Agents

Trichogenic & An'trichigenic Agents

- Minoxidil
o E.ec've in reversing the progressive miniaturiza'on of terminal scalp hairs associated
with androgenic alopecia
o Possible systemic e.ects on blood pressure, should be monitored in pa'ents with
cardiac disease

- Finasteride
o 5α-reductase inhibitor that blocks the conversion of testosterone to
dihydrotestosterone, the androgen responsible for androgenic alopecia in gene'cally
predisposed men
o Reported adverse e.ects include decreased libido, ejacula'on disorders, and erec'le
dysfunc'on, which resolve in most men who remain on therapy and in all men who
discon'nue :nasteride

- Bimatoprost
o A prostaglandin analog that is available as a 0.03% ophthalmic solu'on to treat
hypotrichosis of the eyelashes

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 12

o Side e.ects include pruritus, conjunc'val hyperemia, skin pigmenta'on, and erythema
of the eyelids

- E>ornithine
o An irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limi'ng
step in the biosynthesis of polyamines
o Hair growth was observed to return to pretreatment levels 8 weeks aFer
discon'nua'on
o Local adverse e.ects include s'nging, burning and folliculi's

Agents for Melanoma

- Braf inhibitors: Vemurafenib, Dabrafenib and trame'nib

o Indicated for the treatment of unresectable or metasta'c melanoma witrh BRAF
muta'ons as detected by an FDA-approved test
o Vemurafenib and dabrafenib increase the risk for new primary cutaneous malignancies
including squamous cell carcinoma, keratoacanthoma, and new primary melanoma
o Trame'nib use is associated with a de:ned risk of cardiomyopathy
o All BRAF inhibitors are associated with serious hypersensi'vity reac'ons, including
severe dermatologic reac'ons as well as ophthalmologic complica'ons

- Ipilimumab
o A cytotoxic T-lymphocyte an'gen 4 (CTLA-4) blocker an'body recently approved for the
treatment of unresectable or metasta'c melanoma

- Pegylated interferon
o Recently approved for adjuvant therapy of stage III node-posi've melanoma pa'ents

Other neoplas'c Agents

- Alitre'noin
o Topical formula'on of 9-cis-re'noic acid which is approved for the treatment of
cutaneous lesions in pa'ents with AIDS-related kaposi’s sarcoma

- Bexarotene
o A member of a subclass of re'noids that selec'vely binds and ac'vates re'noid X
receptor subtypes

- Vismodegib
o The :rst hedgehog pathway inhibitor available for the oral treatment of metasta'c basal
cell carcinoma or locally advanced basal cell carcinoma in adults who are not candidates
for surgery or radia'on

- Vorinostat and romidepsin

o Histone deacetylase inibitors that are approved for the treatment of cutaneous T-cell
lymphoma in pa'ents with progressive, persistent, or recurrent disease aFer prior
systemic therapy

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
 13

Pharmacology and Therapeucs II Lecture Notes

Romeo C. Ongpoy, Jr.
CARDIOVASCULAR-
RENAL DRUGS
1st Topic

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
 AGENDA
 Antihypertensive Agents
 Vasodilators and the Treatment of Angina Pectoris

 Drugs Used in Heart Failure

 Agents Used in Cardiac Arrythmias

 OTHER DRUGS
 Diuretic Agents
 Medications that Affect Angiotensin Action

 Antihyperlipidemic Drugs (to be discussed under blood,

inflammation and gout)

 Managing Coagulopathy (to be discussed under blood,

inflammation and gout)

  ANTIHYPERTENSIVE AGENTS

ANTIHYPERTENSIVE AGENTS
 High blood pressure (HBP) or hypertension means
high pressure (tension) in the arteries

 Arteries are vessels that carry blood from the

pumping heart to all the tissues and organs of the
body
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VASODILATORS & THE TREATMENT OF ANGINA PECTORIS

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DRUGS USED IN HEART FAILURE

 Congestive heart failure (CHF) is a condition in which
the heart's function as a pump is inadequate to deliver
oxygen rich blood to the body.
 Congestive heart failure can be caused by:
 Diseases that weaken the heart muscle,

 Diseases that cause stiffening of the heart muscles, or

 Diseases that increase oxygen demand by the body

tissue beyond the capability of the heart to deliver

adequate oxygen-rich blood.
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AGENTS USED IN CARDIAC ARRHYTHMIAS

 An irregular heartbeat is an arrhythmia (also called
dysrhythmia). Heart rates can also be irregular.
 A normal heart rate is 50 to 100 beats per minute.
Arrhythmias and abnormal heart rates don't
necessarily occur together.
 Arrhythmias can occur with a normal heart rate, or
with heart rates that are slow (called
bradyarrhythmias -- less than 50 beats per minute).
 Arrhythmias can also occur with rapid heart rates
(called tachyarrhythmias -- faster than 100 beats
per minute).
 Arrhythmias may be caused by many different factors,
including:
 Coronary artery disease.

 Electrolyte imbalances in your blood (such as sodium

or potassium).
 Changes in your heart muscle.

 Injury from a heart attack.

 Healing process after heart surgery.

 Irregular heart rhythms can also occur in "normal,

healthy" hearts.
 Example of arrhythmia is Atrial Fibrillation…
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DIURETIC AGENTS
 Diuretic:
 Anything that promotes the formation of urine by the

kidney.
 (The word "diuretic" comes from a combination of

the Greek "dia-", thoroughly + "ourein", to urinate =

to urinate thoroughly).
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DRUGS THAT INTERFERE WITH THE ACTION OF ANGIOTENSIN

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RESPIRATORY DRUGS
2nd Topic

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
 AGENDA
 Cold Medications
 Asthma Drugs
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 Colds or acute coryza
 This is a very common occurrence, usually resulting from
either rhino- or adenovirus infections, which produce
symptoms of a runny nose (rhinorrhoea), sneezing and
pyrexia.
 The common cold is often referred to as “flu-like” illness
but it should be noted that influenza is an entirely different
and more serious infection.
 Infants may have around 12 colds per year and adults can
expect to have 1-2 per year.
 Colds are self-limiting with a typical course of 1 week
 However, there are a number of complications, including
sinusitis, otitis media and secondary chest infections
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 Treatment of a cold
 Treatment of the cold is generally directed at
symptomatic relief
 The mainstay of treatment should be regular
ibuprofen and/or paracetamol to reduce the
increased temperature.
 Additional simple measures include steam
inhalation, which appears to hydrate the airways
and promote the removal of mucus
 Zinc lozenges have been advocated for reducing
the length of colds but there is no evidence to
support this
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 Asthma is simply airway hyperreactivity (twitchy
airways, reactive airways) in the absence of other
lung disease.
 The manifestations of chronic airway
inflammation include cough, especially nocturnal;
wheeze, especially with colds; and shortness of
breath that limits activities.
 If there is no evidence of other lung disease such
as cystic fibrosis, bronchiolitis, foreign body
aspiration or pertussis, assume asthma and initiate
management
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 Same MoA, Clinical use and side effects…
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 Vague words:
 Rehydration aggressive
 Abbreviations
 MDI = metered dose inhaler
 Preparations
 Preparations
ENDOCRINE DRUGS
4th Topic

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
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 Hypothalamic and pituitary hormones
 Glucocorticoids and mineralocorticoids
 Thyroid drugs
 Medications affecting calcium levels
 Medications for managing diabetes
 Drugs affecting reproductive hormones
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Antimycobacteri
al
 An Antimycobacterial is a type of
drug used to treat mycobacterial
infections
 Types:

1. Tuberculosis treatments
2. Leprostatic agents
 Tuberculosis
 Itis a common, and in many cases
lethal, infectious disease caused by
various strains of mycobacteria,
usually Mycobacterium tuberculosis.
 Tuberculosis
usually attacks the lungs
but can also a ect other parts of the
body.
 Tuberculosis
 Itis spread through the air when
people who have an active MTB
infection.
 Cough, sneeze, or otherwise transmit
their saliva through the air.
Symptoms:

 Chestpain, coughing up blood, and a

productive, prolonged cough for more
than three weeks.
 Symptomatic symptoms include fever,
chills, night sweats, appetite loss,
weight loss, pallor, and fatigue.
First-Line Medications:
 All )rst-line anti-tuberculous drug names
have a standard three-letter and a single-
letter abbreviation:
-Ethambutol (EMB or E),
-Isoniazid (INH or H),
-Pyrazinamide (PZA or Z),
-Rifampicin (RMP or R),
-Streptomycin
Isoniazid
Mechanism of Action:
 Bacteriostatic at low conc. &
Bactericidal at high conc. Especially
against actively growing bacteria
 Inhibits synthesis of mycolic acid is an
essential components of mycobacterial
cell wall.
 Readily absorbed from GIT.
Mechanism of Action:
 Di use into all body 5uids and tissues.
 Penetrates caseous material and
macrophages, so it is e ective against
intra and extracellular organisms.
 Metabolized in liver by acetylation
 Excreted mainly in urine.
Clinical Uses:
 Mycobacterial infections (it is
recommended to be given with pyridoxine
to avoid neuropathy).
 Latent tuberculosis in patients with
positive tuberculin skin test
 Prophylaxis against active TB in
individuals who are in great risk as very
young or immunocompromised
individuals.
Side E ects:
 Peripheral neuritis
 Optic neuritis
 Allergic reactions (fever, skin rash,
systemic lupus erythematosus)
 Hepatitis
 Gastric upset
Side E ects:
 Haemolytic anaemia
 Enzyme inhibitor
 CNS toxicity
Ethambutol
Mechanism of Action:
 Inhibits mycobacterial cell wall synthesis
by inhibiting arabinosyl transferase.
 Bacteriostatic
 Active against intra & extracellular bacilli.
 Well absorbed from GUT.
 20% excreted in feces and 50% in urine in
unchanged form.
 Crosses BBB in meningitis.
Clinical Uses:
 Used only in mycobacterial infections.
Side E ects:
 Retrobulbar (optic) neuritis causing loss
of visual acuity and red-green color
blindness.
 It is relatively contraindicated in
children.
 GIT upset
 Hyperuricemia
Second-Line Medications:
 Indication of 2nd line treatment:
-Resistance to the drugs of 1st line.
-Failure of clinical response.
-Increase of risky e ects.
-When the patient is not tolerating the
drugs in the )rst line of treatment.
First-Line Medications:
 Ethionamide
 Capreoycin
 Amikacin
 Cipro5oxacin & Levo5oxacin
 Rifapentine
 Aminosalicylic acid
Ethionamide
Mechanism of Action:
 Asisoniazid blocks synthesis of
mycolic acid.
 Available only in oral form.
 Metabolized by the liver, excreted
by kidney.
Mechanism of Action:
 It is poorly tolerated because of:
-Intense gastric irritation
-Neurologic symptoms
-Hepatotoxicity
Clinical Uses:
 Used in TB and leprosy.
 Leprosy
 Lepros or Hansen’s disease (HD) is a
chronic disease caused by the bacteria
Mycobacterium leprae and
Mycobacterium lepromatosis.
 Granulomatous disease of the peripheral
nerves and mucosa of the upper
respiratory tract; skin lesions are the
primary external sign.
 Leprosy
 Secondary infections, in turn, can
result in tissue loss causing )ngers
and toes to become shortened and
deformed, as cartilage is absorbed
into the body.
 Usually spread from person to person
in respiratory droplets.
Drugs Used in Leprosy:
 Dapsone
 Clofazimine
Dapsone
Mechanism of Action:
 Inhibits folate synthesis.
-Well absorbed orally, widely distributed
-Half-life 1-2 days, tends to be retained
in skin, muscle, liver and kidney.
-Excreted into bile and reabsorbed in
the intestine.
-Excreted in urine as acetylated.
-It is well tolerated.
Clinical Uses:
 Tuberculoid leprosy
 Lepromatous leprosy in combination
with Rifampin & Clofamazine
 To prevent & treat Pneumocystis
pneumonia in AIDS cause by
Pneumocystis jiroveci (Pneumocystis
carinii).
Side E ects:
 Haemolytic anaemia
 Methemoglobinemia
 Gastrointestinal intolerance
 Fever, pruritus, rashes
 Erythema nodosum leprosum
Clofazimine
Mechanism of Action:
 It is a phenazine dye
 Unknown mechanism of action, may be
DNA binding
 Anti-in5ammatory e ect
 Absorption from the GUT is variable
 Given orally, once daily
Mechanism of Action:
 Excreted mainly in feces
 Stored mainly in reticuloendothelial
tissues and skin
 Half-life 2 months
 Delayed onset of action (6 weeks)
Clinical Uses:
 Multidrug resistance TB
 Lepromatous leprosy
 Tuberculoid leprosy in:
-patients intolerant to sulfones
 Dapsone-resistant bacilli
 Chronic skin ulcers caused by M.
ulcerans
Side E ects:
 Skin discoloration ranging from red-
brown to black
 Gastrointestinal intolerance
 Red color urine
 Eosinophilic enteritis
ANTIMYCOBACTERIAL AGENTS John Paul Andrie V. Feranil, BSP4-2

Pharmacokinetics,
Drug MoA Effects Clinical applications
Toxicities, Interactions
Isoniazid Inhibits synthesis of mycolic acid, Bactericidal activity against First-line agent for TB, treatment P: Oral, IV. Hepatic clearance
an essential component of susceptible strains of M. of latent infections. Less effective (T1/2 is 1h)
mycobacterial cell walls. tuberculosis. against other mycobacteria. T: Hepatotoxic, peripheral
neuropathy (reversed by intake
or pyridoxine)
I: Reduces phenytoin levels
Rifampicin Inhibits DNA-dependent RNA Bactericidal activity against First-line agent for TB, atypical P: Oral, IV. Hepatic clearance
polymerase, thereby blocking susceptible bacterial and mycobacterial infections, (T1/2 is 3.5h)
production of RNA. mycobacteria. Resistance rapidly eradication of meningococcal T: Turns body fluids to color
emerges when used as a single colonization and staphylococcal orange. Rashes, nephritis,
drug in the treatment of active infections. thrombocytopenia, cholestasis,
infection. flu-like syndrome.
I: Potent CYP450 inducer.
Pyrazinamide Not fully understood. It is Bacteriostatic activity against Sterilizing agent for the first 2 P: Oral. Hepatic clearance (T1/2
converted to the active susceptible strains of M. months of therapy. Allows total is 9h). Metabolites are renally
pyrazinoic acid under acidic tuberculosis. May be bactericidal duration of therapy to be cleared so use 3 doses weekly if
conditions in macrophage against actively dividing shortened to 6 months. creatinine clearance <30mL/min
lysosomes. organisms. T: Hepatotoxic, hyperuricemia
I:
Ethambutol Inhibits mycobacterial arabinosyl Bacteriostatic activity against Given in four-drug initial P: Oral. Mixed clearance (T1/3 is
transferases, which are involved susceptible mycobacteria. combination therapy for TB until 4h) dose must be reduced in
in the polymerization reaction of drug sensitivities are known. Also renal failure.
arabinoglycan, an essential used for atypical mycobacterial T: Retrobulbar neuritis.
component of the mycobacterial infections. I:
cell wall.
Streptomycin Prevents bacterial protein Bactericidal activity against Used in TB when an injectable P: IM, IV. Renal clearance (T1/2
synthesis by binding to the susceptible mycobacteria. drug is needed and in treatment is 2.5h). administered daily
ribosomal subunit. of drug-resistant strains. initially, then twice per week.
T: Nephrotoxic, ototoxic.
I:
ANTIFUNGAL AGENTS
Pharmacokinetics,
Drug MoA Effects Clinical applications
Toxicities, Interactions
POLYENE MACROLIDE
Amphotericin B Forms pores in fungal Loss of intracellular contents Localized and systemic P: Oral but not absorbed. IV for
membranes (which contain through pores is fungicidal. candidemia, Cryptococcus, systemic use. Intrathecal for
ergosterol) but not in mammalian Broad spectrum of action Histoplasma, Blastomyces, fungal meningitis. Topical for
(cholesterol-containing) Coccidioides, Aspergillus. ocular and bladder infections.
membranes. T: Infusion reactions.
I: Additive with other renal toxic
drugs.
PYRIMIDINE ANALOG
Flucytosine Interferes with DNA and RNA Synergistic with amphotericin. Cryptococcus and P: Oral. Renal excretion.
synthesis selectively in fungi. Systemic toxicity in host due to chromoblastomycosis infections. T: Myelosuppression.
DNA and RNA effects. I:
AZOLES
Ketoconazole Blocks fungal P450 enzymes Poorly selective, also interferes Broad spectrum but toxicity P: Oral, Topical.
and interferes with ergosterol with mammalian P450 function. restricts use to topical therapy. T:
synthesis. I: Interferes with steroid hormone
synthesis and phase 1 drug
metabolism

P: Oral, IV. Duration of 1-2 days.

Itraconazole Same as ketoconazole Much more selective than Broad spectrum: Candida, Poor entry into CNS.
ketoconazole. Cryptococcus, blastomycosis, T: Low toxicity
coccidioidomycosis, I:
histoplasmosis
ECHINOCANDINS
Capsofungin Blocks β-glucan synthase Prevents synthesis of fungal cell Fungicidal Candida sp, also used P: IV only. Duration of 11-15h.
wall. in aspergillosis T: Minor GI effects, flushing.
I: Increases cyclosporine levels
(avoid combination)
ALLYLAMINE
Terbinafine Inhibits epoxidation of squalene Reduces ergosterol, prevents Mucocutaneous fungal P: Oral. Duration of days.
in fungi. Increased levels are synthesis of fungal cell infections. T: GI upset, headache,
toxic to fungi. membrane. hepatotoxicity.
I: No reports of interaction.
 ANTIBIOTICS

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
 Outline
 Introduction

 Antibiotic policies

 Antibiotics

 Antimycobacterial agents

 Antifungal
 Outline
 Antiviral

 Antiprotozoal

 Cancer chemotherapy

 Resistance

 Renal failure

 Drug interactions
 Introduction to the history of
antibiotics
 Antisepsis (local chemotherapy):
 any application to a surface, even of something
capable of exerting a systemic effect
 Described best as an antiseptic or it’s use for
antisepsis rather than a chemotherapeutic agent
 Eras of chemotherapy
 Alkaloids

 Synthetic compounds

 Antibiotics
 Alkaloids
 Dated from 1619, researches were from South
America
 First record is derived of the successful treatment
of malaria with an extract of cinchona bark (Peru)
 Efficacy of ipecacuanha root in amebic dysentery
 Other extracts in this era: emetine and quinine
were the only chemotherapy known to man
 Synthetic compounds
 Researches came from Germany
 Discovery of salvarsan by Ehrlich in 1909
 Germanin for trypanosomiasis and other drugs
effective in protozoal infections
 Prontosil (sulfonamide, sulfonamido-chyrosidin)
was discovered in 1935
 Synthetic compounds in the treatment of
tuberculosis
 Sulfonamides
 Prontosil (sulfonamido-chrysoidin)
 First synthesized by Klarer & Mietzsch in 1932
 One of a series of azo dyes examined by Domagk
for possible effects on hemolytic streptococcal
infection
 Colebrook and Kenny (1936) demonstrated the
efficacy in puerperal fever in England
 Sulfonamides
 Prontosil (sulfonamido-chrysoidin)
 No antibacterial action in vitro
 Antibiotic property is due to the liberation from it
in the body of sulfanilamide
 Pharmaceutical companies worldwide was soon
making this drug and at one time it was on the
market under at least 70 different proprietary
names (Sulfapyridine  sulfathiazole 
sulfadiazine)
 Antibiotics
 Definition:
 Substances produced by microorganisms
antagonistic to the growth or life of others in high
dilution (the last clause being necessary to exclude
such metabolic products as organic acids,
hydrogen peroxide and alcohol)
Antibiotic Policies
General & specific advantages of an
antibiotic policy
 Knowledge
 General
 Promotes awareness of benefits, risks and cost of
prescribing
 Facilitates educational and training programs within the

health care setting

 Reduces the impact of aggressive marketing by the

pharmaceutical industry
 Encourages rational choice between drugs based on

analysis of pharmacology, clinical efficacy, safety and

cost
General & specific advantages of an
antibiotic policy
 Knowledge
 Specific
 Provides education about local epidemiology of
pathogens and their susceptibility to antimicrobials
 Promotes awareness of the importance of infection

control
General & specific advantages of an
antibiotic policy
 Attitudes
 General
 Acceptance by clinicians of the importance of setting
standards of care and prescribing
 Acceptance of peer review and audit of prescribing
General & specific advantages of an
antibiotic policy
 Attitudes
 Specific to antimicrobials
 Recognition of the complex issues underlying
antimicrobial therapy
 Recognition of the importance of the special expertise

required for full evaluation of antimicrobial

chemotherapy:
 Diagnostic microbiology
 Epidemiology and infection control
 Clinical diagnosis and recognition of other diseases mimicking
infection
 Pharmacokinetics and pharmacodynamics
General & specific advantages of an
antibiotic policy
 Behavior
 General
 Increased compliance with guidelines and treatment
policies
 Reduction of medical practice variation

 Specific
 Improved liaison between clinicians, pharmacists,
microbiologists and the infection control team
General & specific advantages of an
antibiotic policy
 Outcome
 General
 Improved efficiency of prescribing by increasing
sensitivity (patients who can benefit receive treatment)
and specificity (treatment is not prescribed to patients
who will not benefit)
 Improved clinical outcome

 Reduces medico-legal liability

General & specific advantages of an
antibiotic policy
 Outcome
 Specific to antimicrobials
 Limit emergence and spread of drug-resistant strains
 Practical advantages of limiting the
range of antimicrobials prescribed
 A prescribed antibiotic by a doctor has
implications for nurses, pharmacists &
microbiologists:
 limiting the range of drugs used allows the team to
become familiar with the necessary processes
 having common policies within and between
departments reduces the need for time-consuming
retraining of staff as they move between clinical units
 Staff will find it easier to comply with policies which
cover a limited range of drugs.
Cost
Cost
Cost
Quality and safety of prescribing
 Iatrogenic disease due to prescribing errors
 Risk of drug reactions is non-linearly related
to the number of prescribed drugs
 If the number of drugs which a patient is
prescribed is increased from 3 to 6, the risk of
adverse effects is more than doubled
Quality and safety of prescribing
 Prescribing drugs which do not benefit the
patients exposes them to unnecessary risk.
 Study of Ponge et al. showed that 26% of all
adverse drug reactions in a hospital were due
to drugs prescribed unnecessarily
Quality and safety of prescribing
 Administering drugs by IV is more hazardous
than oral administration
 Assessment of the quality of prescribing must
therefore consider several elements, including
the risks and benefits of introducing another
drug and of IV vs. oral administration.
Quality and safety of prescribing
 Appropriate or inappropriate treatment?
 Inappropriate prescribing is associated with increased
costs of care, and prescribing errors may just be a
marker for a generally poor quality of care.
 Others:
 Inappropriate dose
 Antimicrobial not needed
 Serum level not measured
 More effective drug available
 Less expensive drug available
 Toxicity
Quality and safety of prescribing
 Monitoring of community prescribing is difficult
particularly where drugs are available OTC.
 Unregulated availability of antibiotics from
pharmacies in developing countries is a problem
that remains a problem in the Philippines
 Compounding this is the fact that antibiotic
prescribing and antibiotic resistance are growing
in countries where antibiotics are only available
by prescription from doctors
Implementation of antibiotic policies
 The first aim: CHANGE MEDICAL
PRACTICE
 Secondary aims:
 Reduce drug costs
 Improve quality of prescribing
 Limiting drug resistance

The success of a policy at achieving these secondary

aims cannot be assessed unless it has achieved or
maintained a specified standard of practice.
 Methods for implementation of antibiotic policies
(Re-education strategies)

Target Strategy Outcome

Reduce use of specific drug Mailed information Transient effect,

Unsuccessful

Substitution of specific Drug bulletin Successful

drugs

Compliance with formulary Issuing formulary without Unsuccessful

feedback
 Methods for implementation of antibiotic policies
(Persuasive strategies)

Target Strategy Outcome

Reduction in costs of IV Feedback of costs to Unsuccessful
antibiotics individual with peer
comparison
Promote use of cheaper Educational advertising Successful
alternative agents campaign using posters
Improve antibiotic dosing Structured educational Successful
for parenteral antibiotics order form
Reduction in IV antibiotic Information about cost- Successful
costs added to microbiology
form
Reduction in IV antibiotic Guidelines for switching Successful
costs from IV to oral dosing
 Methods for implementation of antibiotic policies
(Facilitative strategies)
Target Strategy Outcome
Substitution of specific Computerized feedback of Successful
drugs potential cost savings
Reduce use of specific Mailed information with Successful
drugs feedback at interview

Academic detailing
Compliance with formulary Regular feedback to Successful
individual prescribers
Reduce costs of surgical Educational marketing Successful
prophylaxis
Identification of Individual tailored Successful
educational needs for 10 instruction packets
most commonly prescribed
drugs
 Methods for implementation of antibiotic policies
(Power or restrictive strategies)
Target Strategy Outcome
Controlled use of Automatic stop orders for Successful
expensive broad-spectrum specific drugs
parenteral drugs
Prior approval of Successful
ID/microbiologist
Required ID consultation Successful
prior to prescription
Written justification by Transiently successful
clinician
Prescribing of injectable Guidelines posted to non- Successful
antibiotics complying doctors and
reimbursement denied for
non-compliance
 Policies – the who, what, why and
how
 Who develops the policies?
 How is the policy presented?
 Is the effect of the policy sustained?
 How restrictive should antibiotic policies be?
 How should compliance with policies be
monitored?
 Including more than just drug choice in an
antibiotic policy
 Including more than just drug
choice in an antibiotic policy
 Route of administration, dose, duration of
treatment
 Is there a need for antibiotic prescribing?
 Spend less time talking about which antibiotic
to use and more time debating the need for any
antibiotic at all
 Do antibiotic policies achieve their
secondary aims?
 Evidence that antibiotic policies reduce health-
care costs

 Do antibiotic policies improve the quality of

prescribing?

 Do antibiotic policies control resistance?

 Benefit/cost ratios for studies of drug
utilization review
Target for Cost of Estimated savings Benefit-cost ratio
utilization review intervention and achieved by the
monitoring to review program
measure change
in practice
Cephalexin, $100/doctor/yr Average dec 1:1
dextropropoxyphene $105/doctor/yr
& vasodilators
Antibiotics for sore $50/month ($4200 $10,560/case of 2.5:1
throat for a total of 7 yrs) acute RF avoided
Antibiotics for sore $1/prescription ~$! Reduction in 1:1
throat audited average charges per
patient
All drugs in a $924 over 9 Estimated savings 44:1
hospital-affiliated months ($153 for in the final month
clinic set up and of the program
$75/mon running $3259
cost)
 Evidence in support of a link between antimicrobial
prescribing and the prevalence of drug-resistant strains of
bacteria, with some of the potential confounding variables
which could mean that it is wrong to interpret the association
as simple cause and effect

Supporting evidence Potential confounding variables

In the preantibiotic era pneumococci and There have been many other changes
other streptococci were common causes of which may account for these observations
nosocomial infection. In the antibiotic era (case mix, new medical technology)
they have been replaced by organisms
such as Pseudomonas aeruginosa. In
general, antimicrobial resistance is more
prevalent in bacterial strains causing
nosocomial infection than in organisms
from community-acquired cases.
Patients with resistant organisms are more Antibiotic use may just be marker for
likely to have received prior antibiotic patients who are more ill
therapy than are controls
 Evidence in support of a link between antimicrobial prescribing and the
prevalence of drug-resistant strains of bacteria, with some of the potential
confounding variables which could mean that it is wrong to interpret the
association as simple cause and effect

Supporting evidence Potential confounding variables

Concurrent variation between
antimicrobial utilization and resistance has
been noted for both increases and
decreases in these two factors
There is a dose-response relationship
between antimicrobial prescribing and the
probability of infection with drug-resistant
strains which operates at several different
levels (individual patient, ward unit,
hospital, country)
Other reports document decreased
prevalence of antimicrobial resistance
without a corresponding decrease in
antimicrobial use. It is difficult to
separate control of antimicrobial
prescribing from other infection-control
measures which are used in the context of
an outbreak of nosocomial infection with
drug-resistant strains
The association may be because of
differences in underlying disease and/or
aspects of management other than
antimicrobial therapy
 Evidence in support of a link between antimicrobial
prescribing and the prevalence of drug-resistant strains of
bacteria, with some of the potential confounding variables
which could mean that it is wrong to interpret the
association as simple cause and effect
Supporting evidence Potential confounding variables

Interruption of transmission of resistant It is virtually impossible to separate the

organisms (e.g., barrier isolation effects of these two measures, which are
techniques) and control of antimicrobial almost always implemented concurrently.
prescribing are the only two measures
which have been shown to be successful
in limiting the prevalence of drug
resistant bacteria
 ANTIBIOTICS
Antifungal, Antiviral & Antiprotozoal

Romeo C. Ongpoy, Jr. MSc RPh CPS

Pharmacology II
ANTIFUNGAL
 Background
 Dramatic increase in incidence and severity of
fungal infections in recent years is due to the
driving force of advances in surgery, cancer
treatment, and critical care accompanied by
increases in the use of broad-spectrum
antibiotics and the HIV-epidemic.
 Systemic antifungal drugs for
systemic infections
 Amphotericin B
 Flucytosine
 Azoles
 1. Ketoconazole
 2. Itraconazole
 3. Fluconazole
 4. Voriconazole
 Echinocandins (e.g, Caspofungin, micafungin,
anidulafungin)
Amphotericin B
 MOA
 Selective in fungicidal effect because it exploits
the difference in lipid composition of fungal and
mammalian cell membranes
 Ergosterol, a cell membrane sterol is found in the
cell membrane of fungi, whereas the predominant
sterol of bacteria and human cells is cholesterol.
 AMPB binds to ergosterol and alters the
permeability of the cells by forming AMPB-
associated pores in the cell membrane
 MOA
 The pore allows the leakage of intracellular ions
and macromolecules, eventually leading to cell
death.
 Some binding to human membrane sterols occurs,
probably accounting for the drug’s prominent
toxicity.
 Mechanism of resistance
 If ergosterol binding is impaired
 Decreasing the membrane concentration of ergosterol
 Modifying the sterol target molecule to reduce its

affinity for the drug

 Antifungal activity
 Broadest spectrum of activity
 Candida albicans, Cryptococcus neoformans,
Histoplasma capsulatum, Blastomyces
dermatitides, Coccidiodes immitis, Aspergillus
fumigatus, Pseudallescheria boydii, Candida
lusitaniae
 Adverse reactions
 A. infusion-related toxicity
 Fever, chills, muscles spasms, vomiting, headache, and
hypotension.
 Ameliorated by slowing down the infusion rate or

decreasing the daily dose

 B. cumulative toxicity
 Renal damage is the most significant toxic reaction
 Renal impairment occurs in nearly all patients treated

with clinically significant doses of amphotericin.

Flucytosine
 MOA
 Taken up by fungal cells via the enzyme cytosine
permease
 Converted intracellulary first to 5-FU then to 5-
fluorodexoyuridine monophosphate (FdUMP) and
fluorouridine triphosphate (FUTP), which inhibit
DNA and RNA synthesis, respectively
 Human cells are unable to convert the parent drug
to its active metabolite
 MOA
 Synergy with AMPB is related to enhanced
penetration of the flucytosine through
amphotericin-damaged fungal cell membranes
 In vitro synergy with azole drugs has also been
seen, although the mechanism is unknown
 Mechanism of resistance
 Mediated through altered metabolism of
flucytosine and develops rapidly in the course of
flucytosine monotherapy
 Clinical use
 Restricted to Cryptococcus neoformans, some
candida species and the dematiaceous molds that
cause chromoblastomycosis
 Not used as single agent
 Confined to combination therapy:
 + AMPB for cryptococcal meningitis
 + itraconazole for chromoblastomycosis
 Adverse effects
 Metabolism to the toxic antineoplastic compound
fluorouracil
 Bone marrow toxicity with anemia, leukopenia and
thrombocytopenia are the most common
 Altered liver enzymes
 Toxic enterocolitis
 Narrow therapeutic window with increased
toxicity at higher doses
Azoles
 MOA
 Reduction of ergosterol synthesis by inhibition of
fungal cytochrome P450 enzyme
 Greater affinity for fungal than for human
cytochrome P450 enzymes
 Imidazoles have less specificity than triazoles
accounting for the higher drug interactions and
side effects
 Echinocandins
 Large cyclic peptides linked to long-chain
fatty acid
 Caspofungin, micafungin, and anidulafungin
 Available only in IV form
 Dosage adjustments are required in the
presence of severe hepatic insufficienty
 Anidulafungin has a half-life of 24-48 hrs
 MOA
 Act at the level of the fungal cell wall by inhibiting
the synthesis of β(1-3)glucan. This results in
disruption of the fungal cell wall and cell death.
 Adverse effects
 Well tolerated with minor GI side effects and flushing
reported infrequently
 Elevated liver enzymes with caspofungin in
combination with cyclosporine
 Micafungin has been shown to increase levels of
nifedipine, caspofungin and sirolimus
 Anidulafungin does not seem to have significant drug
interactions but histamine release may occur during
IV infusion
 Systemic antifungal drugs for
mucocutaneous infections
 1. Griseofulvin
 Very insoluble fungistatic drug
 Its only use is in the systemic treatment of
dermatophytosis
 Absorption is best with fatty meal
 2. Terbinafine
 Synthetic allylamine that is fungicidal
 Treatment of dermatophytoses especially
onychomycosis
 Systemic antifungal drugs for
mucocutaneous infections
 1. Griseofulvin
 MOA: deposits in newly forming skin where it
binds to keratin, protecting the skin from new
infection
 2. Terbinafine
 MOA: inhibits the fungal enzyme squalene
epoxidase leading to accumulation of the sterol
squalene which is toxic to the organism
 Topical antifungal therapy
 1. Nystatin

 2. Topical azoles
 Clotrimazole
 Miconazole

 3. Topical allylamines
 Terbinafine
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ANTIVIRAL
 Biology of viruses
 Obligate intracellular parasites
 Replication depends primarily on synthetic
processes of the host cell
 Antiviral therapy to be effective should:
 1. block viral entry into or exit from the cell
 2. active inside the host cell
 Agents to treat HSV and VZV
infections
 Acyclovir
 Valacyclovir
 Famciclovir
 Penciclovir
 Docosanol
 Trifluridine
MOA of antiherpes agents
 Docosanol
 Saturated 22-C aliphatic alcohol that inhibits
fusion between the plasma membrane and the HSV
envelope, thereby preventing viral entry into cells
and subsequent viral replication.
 Topically as 10% cream for recurrent orolabial
herpes
 Trifluridine
 Fluorinated pyrimidine nucleoside that inhibits viral
DNA synthesis in HSV-1, HSV-2, vaccinia, and some
adenoviruses
 It is phosphorylated intracellularly to its active form
by host cell enzymes and then competes with
thymidine triphosphate for incorporation by the viral
DNA polymerase
 Available as 1% solution for keratoconjunctivitis and
recurrent epithelial keratitis due to HSV-1 and HSV-2
 Agents to treat CMV infections
 Ganciclovir
 Valganciclovir
 Foscarnet
 Cidofovir
 CMV infections occur primarily in the setting
of advanced immunosuppression and are
typically due to reactivation of latent infection
 Dissemination of infection results in end-organ
disease – retinitis, colitis, esophagitis, CNS
disease and pneumonitis.
 Reactivation after organ transplantation is
clinically prevalent
 Availability of oral valganciclovir and
ganciclovir intraocular implant has decreased
the use of IV gancicloir, IV foscarnet, and IV
cidofovir in the treatment of end-organ CMV
disease.
 Oral valganciclovir has replaced oral
ganciclovir because of its lower pill burden
 Valganciclovir (Valcyte)
 L-valyl ester prodrug of ganciclovir that exists as a
mixture of 2 diastereomers
 After oral administration, both diastereomers are
rapidly hydrolyzed to ganciclovir by intestinal and
hepatic esterases
 Well absorbed and rapidly metabolized in the
intestines and liver to ganciclovir; no other
metabolites are detected
 Valganciclovir (Valcyte)
 Absolute oral bioavailability is 60%
 Recommended that it be taken with food
 2 tabs of 450 mg preparation = 5mg/kg daily of IV
ganciclovir and 1.65 times that of oral ganciclovir
 Plasma protein binding <2%
 Major route of elimination is renal (through GFR and
active tubular secretion)
 Indicated for the treatment of CMV retinitis in patients
with AIDS and for the prevention of CMV disease in
high-risk kidney, heart and kidney-pancreas transplant
patients
 Foscarnet
 Phosphonoformic acid is an inorganic pyrophosphate
compound that inhibits viral DNA polymerase, RNA
polymerase, and HIV reserve transcriptase directly
without requiring activation by phosporylation
 Available in IV form; poor oral bioavailability and GI
intolerance
 Mean plasma half-life is 3-6.8h, but up to 30%
foscarnet may be deposited in bone, with a half-live of
several months
 Cidofovir
 Cytosine nucleotide analog
 Phosporylation of cidofovir to the active
diphosphate is independent of viral enzymes
 After phosphorylation, cidofovir acts both as a
potent inhibitor of and as an alternative substrate
for viral DNA polymerase, competitively
inhibiting DNA synthesis and becoming
incorporated into the viral DNA chain
 Cidofovir
 Terminal half-life ~2.6hr but active metabolite
cidofovir diphosphate has a prolonged intracellular
half-life of 17-65 hrs, thus allowing widely spaced
administration
 A separate metabolite, cidofovir phosphocoline,
has a half-life of at least 87 hrs and may serve as
an intracellular reservoir of active drug
 CSF penetration is poor
 Standard of treatment for HIV
 Combination therapy with maximally
efficacious and potent agents will reduce viral
replication to the lowest possible level and
decrease the likelihood of emergence of
resistance
 HAART – highly active anti-retroviral therapy
 Combination of 3-4 antiretroviral drugs has
become the standard of care
 Antiretroviral agents
 1. Nucleoside & nucleotide reverse
transcriptase inhibitors
 2. Nonnucleoside reverse transcriptase
inhibitors
 3. Protease inhibitors
 4. Fusion inhibitors - Enfuvirtide
 NRTIs
 Act by competitive inhibition of HIV-1 reverse
transcriptase and can also be incorporated into
the growing viral DNA chain to cause its
termination
 Each requires intracytoplasmic activation via
phosphorylation by cellular enyzmes to the
triphosphate form. Most have activity against
HIV-2 and HIV-1.
 NRTIs
 Associated with mitochondrial toxicity due to
inhibition of mitochondrial DNA polymerase
gamma and they can increase the risk of lactic
acidosis with hepatic steatosis, which may be
fatal, as well as disorders of lipid metabolism
 Should be suspended in the setting of rapidly
increased ALT/AST, progressive hepatomegaly
and metabolic acidosis of unknown cause
 NRTIs
 Abacavir
 Didanosine
 Emtricitabine
 Lamivudine
 Stavudine
 Tenofovir
 Zalcitabine
 Zidovudine
 NNRTIs
 Bind directly to HIV-1 reverse transcriptase
resulting in blockade of RNA- and DNA-
dependent DNA polymerase
 The binding site of NNRTIs is near to but
distinct from that of NRTIs.
 Neither compete with nucleoside triphosphates
nor require phosphorylation to be active
 NNRTIs
 NNRTI resistance occurs rapidly with
monotherapy and can be due to a single
mutation (eg., K103N)
 K103N and Y181C mutations confer
resistance across the entire class of NNRTIs,
whereas L100I, Y188C, and G190A confer
resistance to both nevirapine and efavirenz.
 Protease Inhibitors
 Amprenavir
 Atazanavir
 Fosamprenvair
 Indinavir
 Lopinavir/Ritonavir
 Nelfinavir
 Ritonavir
 Saquinavir
 Tipranavir
 Protease Inhibitors
 During the late stage of the HIV growth cycle, the
Gag and Gag-Pol gene products are translated
into polyproteins, and these become immature
budding particles
 Protease is responsible for cleaving these
precursor molecules to produce the final structural
proteins of the mature virion core. By preventing
cleavage of the Gag-Pol polyprotein, PIs result in
the production of immature, noninfectious viral
particles.
 Protease Inhibitors
 Specific genotypic alterations that confer
phenotypic resistance are common with PIs, thus
contraindicating monotherapy
 Syndrome of redistribution and accumulation of
body fat resulting in central obesity, dorsocervical
fat enlargement (buffalo hump), peripheral and
facial wasting, breast enlargement, and
cushingoid appearance has been observed in
patients receiving antiretroviral therapy.
 Protease Inhibitors
 Increase in TG and LDL levels, glucose
intolerance and insulin resistance
 Increase spontaneous bleeding in patients with
hemophilia A or B
 All PIs are substrates and inhibitors of CYP3A4,
with ritonavir having the most pronounced
inhibitory effect and saquinavir the least.
 Very large drug-drug interactions with other
antiretroviral agents and other commonly used
drugs.
 Lopinavir/Ritonavir
 100/400 licensed combination in which
subtherapeutic doses of ritonavir inhibit the
CYP3A-mediated metabolism of lopinavir, thereby
resulting in increased exposure to lopinavir
 This combination, ritonavir is acting as a
pharmacokinetic enhancer rather than an
antiretroviral agent
 Improved patient compliance due to reduced pill
burden
 Fusion inhibitors
 Enfuvirtide (formerly called T-20)
 First representative of fusion inhibitors that blocks
entry into the cells
 Synthetic 36-amino-acid peptide, binds to the gp41
subunit of the viral envelope glycoprotein,
preventing the conformational changes required
for the fusion of the viral and cellular membranes
 Administered by injection
 Fusion inhibitors
 Enfuvirtide (formerly called T-20)
 Metabolism appears to be by proteolytic
hydrolysis without involvement of the CYP450
system
 Elimination half-life ~4hrs
 Lacks cross-resistance to other currently approved
antiretroviral drug classes
Antihepatitis agents
 Interferon alfa
 Interferons are host cytokines that exert complex
antiviral, immunomodulatory, and antiproliferative
activities
 IFN-alfa appears to function by induction of
intracellular signals following binding to specific cell
membrane receptors, resulting in inhibition of viral
penetration, translation, transcription, protein
processing, maturation, and release as well as
increased expression of major histocompatibility
complex antigens, enhanced phagocytic activity of
macrophages, and augmentation of the proliferation
and survival of cytotoxic T cells.
 Treatment of hepatitis B virus
infection
 Lamivudine
 Adefovir dipivoxil
 Entecavir
The most common efficacy end points in clinical trials
of hepB virus infection are seroconversion from
HBeAg+ to negative and suppression of HBV DNA to
undetectable levels. These end points are correlated
with improvement in necroinflammatory disease, a
decreased risk of hepatocellular carcinoma and
cirrhosis, and decreased need for liver
transplantation.
 Lamivudine (3TC)
 Cytosine analog with in vitro activity against HIV1
that is synergistic with many antiretroviral nucleoside
analogs (zidovudine and stavudine) and HBV
 Oral bioavailability >80% and is not food dependent
 More prolonged intracellular half life in HBV cell
lines (17-19 hrs) than HIV-infected cell lines (10.5-
15.5 hrs) allows for lower doses and less frequent
administration
 Lamivudine (3TC)
 Inhibits HBV DNA polymerase and HIV reserve
transcriptase by competing with deoxycytidine
triphosphate for incorporation into the viral DNA
resulting in chain termination
 Seroconversion of HBeAg from + to – occurs ~ 17% of
patients and is durable at 3 years in ~70% of responders.
 Chronic therapy with lamivudine in patients with
hepatitis may be limited by the emergence of resistant
HBV isolates
 Adefovir dipivoxil
 Initially and abortively approved for treatment of
HIV infection, gained approval at lower and less
toxic doses for HBV infection
 Diester prodrug of adefovir (acyclic phosphonated
adenine nucleotide analog)
 Oral bioavailability ~ 59% and unaffected by
meals
 Termination half-life ~ 7.5 hrs and excreted by a
combination of glomerular filtration and active
tubular secretion
 Treatment of Hepatitis C
infection
 Ribavirin
 Investigational agents (valopicitabine, isatoribine,
viramidine, monoclonal antibodies)
Primary goal of treatment in patient with HCV infection
is viral eradication. In clinical trials, the primary
efficacy end point is typically achievement of
sustained viral response (SVR), defined as the
absence of detectable viremia for 6 months after
completion of therapy.
 Ribavirin
 Guanosine analog that is phosphorylated
intracellularly by host cell enzymes
 It appears to interfere with the synthesis of
guanosine triphosphate to inhibit capping of viral
messenger RNA and to inhibit the viral RNA-
dependent polymerase of certain viruses
 Inhibits the replication of a wide variety of viruses
including: Influenza A and B, paraninfluenza,
RSV, paramyxoviruses, HCV and HIV-1
 Ribavirin
 Oral bioavailability ~64% and increases with high-
fat meals and decreases with antacid
 Elimination is primarily renal
 Higher doses (>11mg/kg) and longer duration of
ribavirin therapy + interferon alfa improves
response
 Dose dependent hemolytic anemia occurs in 10-
20% of patients
 Ribavirin
 Adverse effects:
 Depression, fatigue, irritability, rash, cough, insomnia,
nausea and pruritus
 Teratogenic and embryotoxic in animals as well as
mutagenic in mammalian cells
 Anti-influenza agents
 Amantadine and Rimantadine

 Zanamavir and Oseltamivir

 Influenza virus strains
 Classified by:
 A. core protein – A, B or C
 B. species of origin – avian or swine
 C. geographic site of location
 Influenza virus strains
 Influenza A
 Only strain that causes pandemics
 Classified into 16H (hemagglutinin) and 9N
(neuraminidase) known subtypes based on surface
proteins
 Current influenza A subtypes that are circulating
among people worldwide include H1N1, H1N2,
and H3N2.
 Amantadine and Rimantadine
 Cyclic amines of the amantadine family that block the M2
proton ion channel of the virus particle and inhibit
uncoating of the viral RNA within infected host cells, thus
preventing its replication
 Effective against influenza A only
 Rimantadine is 4-10x more active than amantadine in vitro
 CNS toxicity may be due to alteration of dopamine
neurotransmission (less with rimantadine than amantadine)
 Zanamavir and Oseltamivir
 Neuraminidase inhibitors, analogs of sialic acid
 Interfere with release of progeny influenza virus
from infected to new host cells, halting the spread
of infection within the respiratory tract
 Have activity against both influenza A and B
 Early administration is crucial because replication
of influenza virus peaks at 24072 hrs after onset of
illness.
 Zanamavir
 Inhalation device
 10-20% of the active reaches the lung while the
remainder is in the oropharynx
 Concentration of the drug in the respiratory tract
~1000x the 50% inhibitory concentration for
neuraminidase
 AEs: cough, bronchospasm, reversible decrease in
pulmonary function, transient nasal and throat
discomfort
 Oseltamivir
 Orally administered prodrug that is activated by
hepatic esterases and widely distributed throughout
the body
 75mg bid x treatment and 75 mg OD for
prevention
 Half life is 6-10 hrs
 AEs: headache, fatigue, and diarrhea and more
common with prophylactic use
 Other antiviral agents
 Interferons
 Ribavirin (aerosolized inhalation for RSV
infections in high risk patients)
 Palivizumab (prevention of RSV infection in high
risk infants and children)
 Imiquimod (immune response modifier as topical
treatment of external genital and perianal warts as
5% cream and washed off 6-10 hrs after
application)
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ANTIPROTOZOAL
 Parasite life cycle
 Plasmodium falciparum, P malariae, P ovale,
P vivax
 Understanding of the parasite life cycle is
important in the management of malaria
infection (treatment and prophylaxis)
 Antimalarial drug classification
 Tissue schizonticides – drugs that eliminate
developing or dormant liver forms
 Blood schizonticides – drugs that act on
erythrocytic parasites
 Gametocides – drugs that kill sexual stages
and prevent transmission to mosquitoes
Treatment of malaria
 Chloroquine
 Drug of choice for both treatment and
chemoprophylaxis of malaria since 1940s
 Remains the drug of choice in the treatment of
sensitive P falciparum and other species of human
malaria parasites
 Semi-synthetic 4-aminoquinoline formulated as
the phosphate salt for oral use
 Chloroquine
 Rapidly and almost completely absorbed from GIT
 Maximum plasma concentration ~3hrs and rapidly
distributed to tissues
 Vd is large (100-1000L/kg) and is slowly released
from tissues and metabolized
 Principally excreted in urine with initial half-life of
3-5 days but a longer terminal elimination half-life
of 1-2 months.
 Chloroquine
 Antimalarial action
 Highly effective blood schizonticide
 Moderately effective against gametocytes of vivax,

ovale and malariae but NOT falciparum

 Not active against liver stage parasites
 Chloroquine
 Mechanism of action and resistance
 Probably acts by concentrating in parasite food
vacuoles, preventing the polymerization of the
hemoglobin breakdown product, heme, into hemozoin,
and thus eliciting parasite toxicity due to the buildup of
free heme
 Resistance is common to falciparum strains

 Mutations in a putative transporter, PfCRT

 Reversed by verapamil, desimipramine, and chlorpheniramine
(clinical value is not established)
 Chloroquine
 Clinical uses
 A. Treatment
 Drug of choice in treatment of nonfalciparum and sensitive
falciparum malaria
 Rapidly terminates fever (24-48h) and clears parasitemia (48-
72hr) due to sensitive parasites
 Does not eliminate dormant liver forms of vivax and ovale,
and for that reason primaquine must be added for the radical
cure of these species
 Chloroquine
 Clinical uses
 B. Chemoprophylaxis
 Preferred chemoprophylactic agent in malarious regions
without resistant falciparum strains.
 Eradication of vivax and ovale requires a course of primaquine
to clear hepatic stages
 C. Amebic liver abscess
 Reaches high liver concentrations and may be used for amebic
abscesses that fail initial therapy with metronidazole
 Chloroquine
 Adverse effects
 Nausea, vomiting abdominal pain, headache, anorexia,
malaise, blurring of vision, urticaria
 G6PD patients may have hemolysis

 Others” impaired hearing, confusion, psychosis,

seizures, agranulocytosis, exfoliative dermatitis,

alopecia, hair bleaching, hypotension, ECG changes
 Best avoid parental administration unless no oral is

available or the route cannot be given.

 Amodiaquine
 Closely related to chloroquine wth same MOA and
resistance
 Low cost, limited toxicity and effectiveness vs
chloroquine-resistant strains of faliciparum in
some areas
 AE: agranulocytosis, aplastic anemia and
hepatotoxicity
 Chemoprophylaxis is best avoided with this
because of increased toxicity with long-term use
 Quinine and quinidine
 Remain first-line therapies for falciparum,
especially severe disease, although toxicity may
complicate therapy
 Quinidine is the dextrorotatory stereoisomer of
quinine
 After oral administration, quinine is rapidly
absorbed, reaches peak plasma levels in 1-3 hr, and
is widely distributed in body tissues.
 Quinine and quinidine
 PK is dependent among populations with
individuals having malaria having higher plasma
levels vs healthy controls, but toxicity is not
increased, apparently because of increased protein
binding
 Half life of quinine is longer with severe malaria
(18hrs) vs healthy controls (11hrs)
 Quinidine has a shorter half life than quinine
 Quinine is primarily metabolized in liver & renal
elimination occurs
 Quinine and quinidine
 Clinical use:
 A. Antimalarial action
 Rapidly acting, highly effective blood schizonticide vs all
malaria parasites
 Gametocidal vs viva and ovale but not falciparum
 Not active against liver stage parasites
 MOA is unknown
 B. Resistance
 Increasing in vivo resistance from most areas of southeast Asia
especially Thailand
 Quinine and quinidine
 Clinical use:
 C. Parenteral treatment of severe falciparum malaria
 Cardiac toxicity hence should be administered under cardiac monitoring
 D. Oral treatment of falciparum malaria
 Uncomplicated malaria
 Include doxycycline or clindamycin to shorter quinine’s duration of use
(to 3 days) and decrease toxcity
 E. Malarial chemoprophylaxis
 Not generally used
 F. Babesiosis
 First line in combination with clindamycin for Babesia microti
 Quinine and quinidine
 Adverse effects:
 Tinnitus, headache, nausea, dizziness, flushing, and visual
disturbances (constellation called cinchonism)
 Mild symptoms do not warrant discontinuation of the drug

 With prolonged therapy: marked visual and auditory

abnormalities, vomiting, diarrhea, and abdominal pain

 Blackwater fever is a rare severe illness that includes marked

hemolysis and hemoglobinuria in the setting of quinine

therapy for malaria. Appears to be due to a hypersensitivity
reaction to the drug although its pathogenesis is uncertain.
 Quinine and quinidine
 Adverse effects:
 Severe hypotension can follow too rapid IV infusions of
quinine or quinidine. ECG abnormalities (QT
prolongation) are fairly common with IV quinidine, but
dangerous arrhythmias are uncommon when the drug is
administered appropriately in a monitored setting.
 Mefloquine
 Synthetic 4-quinoline methanol that is chemically
related to quinine
 Orally administered only because of severe local
irritation with parenteral use
 Well absorbed and peak plasma reached in 18 hrs
 Highly protein-bound, extensively distributed in
tissues, and eliminated slowly, allowing a single
dose treatment regimen
 Mefloquine
 Terminal elimination half-life ~20 days (allowing
weekly dosing for chemoprophylaxis)
 Steady state levels reached over a number of
weeks
 Blood schinzonticidal activity vs falciparum and
vivax but not active hepatic stages or gametocytes
 MOA is unknown
 Mefloquine
 Clinical uses:
 1. Effective chemoprophylaxis vs falciparum, but add
primaquine for eradication of vivax and ovale
 2. Effective for treatment of most falciparum malaria.

Not recommended for severe or complicated malaria.

 Mefloquine
 Adverse effects:
 Nausea, vomiting, dizziness, sleep and behavioral
disturbances, epigastric pain, diarrhea, abdominal pain,
headache, rash, seizures, psychosis
 Leukocytosis, thrombocytopenia, increase in

aminotransferases
 Primaquine
 Synthetic 8-aminoquinoline
 Well absorbed orally, peak plasma levels in 1-2
hrs, plasma half life ~3-8hrs
 Widely distributed to tissues, but only a small
amount is bound there
 Rapidly metabolized and excreted in urine
 Three major metabolites appear to have less
antimalarial activity but more potential for
inducing hemolysis than the parent compound
 Primaquine
 Active against hepatic stages of all human malaria
parasites
 The only available agent active against the
dormant hypnozoite stages of vivax and ovale
 Gametocidal against all malarial species
 Acts against erythrocytic stage parasites, but this
activity is too weak to play an important role
 Primaquine
 Clinical uses:
 1. Therapy (radical cure) of acute vivax and ovale
malaria
 2. terminal prophylaxis of vivax and ovale malaria

 3. Chemoprophylaxis of malaria

 4. Gametocidal action

 5. Pneumocytis jiroveci infection

 Together with clindamycin as treatment of mild to moderate

pneumocystosis
 Primaquine
 Adverse effects:
 Well tolerated generally
 Nausea, epigastric pain, abdominal cramps, and

headache (more common with higher doses and when

taken on an empty stomach)
 Serious: agranulocytosis, leukopenia, leukocytosis,

cardiac arrhythmias, hemolysis, methemoglobinemia

(esp in patients with G6PD)
 Atovaquone
 Hydroxynaphthoquinone was initially developed
as an antimalarial and as a component of Malarone
 Given orally
 Bioavailability is low and erratic but absorption is
increased by fatty food
 Most of the dug is eliminated unchanged in feces
 MOA: appears to disrupt mitochondrial electron
transport in plasmodia
 Inhibitors of folate synthesis
 Pyrimethamine
 2,4 dipyrimidine related to TMP
 Peak plasma in 2-6 hrs after oral dose, bound to
plasma proteins, elimination half-life 3.5 days
 Proguanil
 Biguanide derivative
 Peak plasma level about 5 hrs after oral dose,
elimination half-life 16 hrs
 Inhibitors of folate synthesis
 Pyrimethamine is extensively metabolized
before excretion
 Fansidar (Sulfadoxine 500 mg/Pyrimethamine 25
mg/tab) is well absorbed; peak plasma in 2-8hrs
and average half-life of sulfadoxine ~170 hrs.
 Proguanil is a prodrug; only its triazine
metabolite (cycloguanil) is active
 Inhibitors of folate synthesis
 Clinical uses
 1. Chemoprophylaxis
 2. Treatment of chloroquinine-resistant falciparum
malaria
 3. Presumptive treatment of falciparum malaria
 4. Toxoplasmosis
 Sulfadiazine + pyrimethamine
 5. Pneumocystosis
 Antibiotics
NONE OF THEM SHOULD BE USED AS SINGLE
AGENTS IN THE TREATMENT OF MALARIA
BEAUSE THEIR ACTION IS MUCH SLOWER
THAN STANDARD ANTIMALARIALS

 Tetracycline and doxycycline

 Clindamycin
 Azithromycin
 Fluoroquinolones
 Halofantrine and Lumefantrine
 Halofantrine hydrochloride
 Phenanthrene-methanol related to quinine
 Effective vs the erythrocytic (but not to other) stages of

all malaria species

 Oral absorption is variable and enhanced with food

intake (DO NOT GIVE WITH FOOD)

 Plasma levels peak 16 hrs and half-life ~4days

 Excretion mainly in feces

 MOA is unknown
 Halofantrine and Lumefantrine
 Halofantrine hydrochloride
 Rapidly effective against most chloroquine-resistant
straine of falciparum, but its use is limited by irregular
absorption and cardiac toxicity
 Cross resistance with mefloquine may occur

 Drug is contraindicated in patients with cardiac

conduction defects and should not be used in those who

have recently taken mefloquine
 Halofantrine and Lumefantrine
 Lumefantrine
 Aryl alcohol related to halofantrine
 Available in some countries as a fixed-dose

combination with artemether as Coartem

 Half life of lumefantrine (in combination form) is 4.5 hr

 Oral absorption is highly variable and improved when

taken with food

 Expensive and requires twice daily dosing
 Artemisinin and its derivatives
 Artemesinin (qinghaosu)
 Sesquiterpene lactone endoperoxide (active
component of an herbal medicine used in China as
an antipyretic for 2 centuries)
 Two analogs have been synthesized:
 1. Artesunate (water-soluble) – oral, IV, IM, and rectal
administration
 2. Artemether (lipid-soluble) – oral, IM and rectal

administration
 Artemisinin and its derivatives
 Artemesinin (qinghaosu)
 Rapidly absorbed with peak plasma in 1-2 hrs and half-lives
1-3 hrs after oral administration
 Rapidly metabolized to the active metabolite
dihydroartemisinin
 Rapidly acting blood schizonticides against all malaria
parasites
 No effect on hepatic stages
 Resistance is not yet a problem but isolated cases of
decreased in vitro susceptibility to artemether has been
described
 Artemisinin and its derivatives
 Artemesinin (qinghaosu)
 They are the only drugs reliably effective against
quinine-resistant strains
 Efficacy is limited by short plasma half-lives
 Recrudescence rates are unacceptably high after
short-course therapy
 1. best used with another drug (eg., + mefloquine, as
FDC with lumefantrine, + amodiaquine, + sulfadoxine
pyrimethamine)
 2. should not be used as chemoprophylaxis
 Artemisinin and its derivatives
 Artemesinin (qinghaosu)
 Better tolerated than most antimalarials
 AEs: nausea, vomiting, diarrhea
 Should be avoided in pregnancy because of
teratogenicity in animal studies
Treatment of amebiasis
 Metronidazole
 Nitroimidazole
 Drug of choice in the treatment of extraluminal
amebiasis (kills trophozoites but not cysts of E.
histolytica and effectively eradicates intestinal and
extraintestinal tissue infections)
 Tinidazole has similar activity and better toxicity
profile than metronidazole and offers simpler
dosing regimens
 Metronidazole
 Readily absorbed and permeate all tissues by
simple diffusion
 Intracellular concentrations rapidly approach
extracellular levels
 Peak plasma in 1-3hr
 Protein binding of both drugs is low (10-20%);
half-life of unchanged drug is 7.5hr for
metronidazole and 12-14hr for tinidazole
 Metabolites excreted in urine
 Metronidazole
 MOA:
 Nitro group of metronidazole is chemically reduced in
anaerobic bacteria and sensitive protozoans
 Reactive reduction products appear to be responsible for

antimicrobial activity
 Metronidazole
 Clinical uses:
 1. Amebiasis
 2. Giardiasis

 3. Trichomoniasis
 Metronidazole
 Adverse effects and cautions:
 Nausea, headache, dry mouth, or a metallic taste in the mouth
occurs commonly
 Others: vomiting, diarrhea, insomnia, weakness, dizziness,

thrush, dysuria, dark urine, vertigo, paresthesias and

neutropenia
 GI irritiation when taken on an empty stomach

 Use with caution in patients with CNS disease

 Reported to potentiate the anticoagulant effect of coumarin-

type anticoagulants
 Phenytoin and phenobarbital may accelerate drug elimination
 Metronidazole
 Adverse effects and cautions:
 Cimetidine may decrease plasma clearance
 Metronidazole and its metabolites are mutagenic in

bacteria
 Chronic administration of large doses are tumorigenic

in mice
 Best avoided in pregnant or nursing women
 Iodoquinol
 Halogenated hyroxyquinoline
 Effective luminal amebicide commonly used with
metronidazole to treat amebic infections
 90% of the drug is retained in intestines and excreted
in feces, remainder enters the circulation and has a
half life 11-14hr and excreted in urine as
glucuronides
 Effective vs organisms in bowel lumen but not
against trophozoites in intestinal wall or
extraintestinal tissues
 Iodoquinol
 Should be taken with meals to limit GI toxicity
 Use with caution in patients with optic neuropathy,
renal or thyroid disease, or nonamebic hepatic disease
 Discontinue if it produces persistent diarrhea or signs
of iodine toxicity (dermatitis, utricaria, pruritus,
fever)
 Contraindicated in patients with intolerance to iodine
 Diloxanide furoate
 Dichloroacetamide derivative
 Effective luminal amebicide but not active vs tissue
trophozoites
 In the gut, diloxanide furoate is split into diloxanide and
furoic acid
 ~90% of diloxanide rapidly absorbed then conjugated to
form glucuronide which is excreted promptly in urine
 The unabsorbed diloxanide is the active amebic
substance
 Paromomycin sulfate
 Aminoglycoside antibiotic that is not significantly
absorbed from the GIT
 Used only as a luminal amebicide and no effect
against extraintestinal amebic infections
 Slowly excreted unchanged by GFR
 Avoid in patients with renal disease and use with
caution in persons with GI ulcerations
 Emetine and dehydroemetine
 Alkaloid derived from ipecac and dehydroemetine,
a synthetic analog are effective against tissue
trophozoites of E histolytica
 Limited to unusual circumstances in which severe
amebiasis warrant effective therapy and
metronidazole cannot be used
 Use only for 3-5days (to relieve severe symptoms)
 Parenterally administered
Other antiprotozoal
drugs
 Pentamidine
 Aromatic diamidine formulated as an isethionate salt
 Administered only parenterally
 Drug leaves the circulation rapidly with initial half-
life ~6hrs, but bound avidly by tissues
 Accumulates and is eliminated very slowly with
terminal elimination half-life about 12 days.
 Drug detected in urine 6 or more weeks after
treatment
 Pentamidine
 Only trace amounts in CNS thus not effective in
CNS African trypanosomiasis
 Inhaled as nebulized powder for prevention of
pneumocystosis
 Absorption into the systemic circulation after
inhalation appears to be minimal
 MOA is unknown
 Pentamidine
 Clinical uses:
 1. Pneumocystosis
 As alternative to cotrimoxazole
 2. African trypanosomiasis (Sleeping sickness)
 As alternative to suramin or together with suramin
 3. Leishmaniasis
 As alternative to sodium stibogluconate
 Sodium Stibogluconate
 Suramin
 Melarsoprol
 Nitazoxanide
 Eflornithine
 Nifurtimox
 Benznidazole
 Amphotericin
 Miltefosine
Anthelmintic drugs
 Albendazole
 Broad spectrum oral anthelmintic
 Drug of choice for treatment to hydatid disease
and cysticercosis
 Used in the treatment of pinworm and hookworm
infections, ascariasis, trichuriasis and
strongyloidiasis
 Albendazole
 Benzimidazole carbamate
 Erratically absorbed (increased with fatty meal)
then rapidly undergoes first-pass metabolism in the
liver to the active metabolite albendazole sulfoxide
 Reaches variable maximum plasma concentration
3 hrs after 400 mg dose and plasma half life ~8-
12hrs
 Albendazole
 The sulfoxide is mostly protein bound, distributes
well to tissues and enters bile, CSF and hydatid
cysts
 Metabolites are excreted in urine
 MOA: inhibit microtubule synthesis; larvicidal
effects in hydatid disease, cysticercosis, ascariasis,
and hookworm infection and ovicidal in ascariasis
ancylostomiasis and trichuriasis
 Mebendazole
 Synthetic benzimidazole with wide spectrum of
anthelmintic activity and low incidence of adverse effects
 Less than 10% is orally absorbed; absorbed drug ins
>90% protein bound and rapidly converted to inactive
metabolites (primarily during its first pass in the liver);
half life 2-6hrs
 Excreted mostly in urine, principally as decarboxylated
derivatives
 Absorption is increased if the drug is ingested with fatty
meal
 Praziquantel
 Effective in the treatment of schistosome
infections of all species and most other trematode
and cestode infections, including cysticerdosis
 Synthetic isoquinoline-pyrazine derivative
 Rapidly absorbed with oral bioavailability ~80%;
peak serum in 1-3hrs after a therapeutic dose; CSF
concentrations 14-20% of plasma concentration;
80% of the drug is bound to plasma proteins
 Praziquantel
 Most of the drug is rapidly metabolized to inactive
mono- and polyhydroxylated products after a first
pass in the liver; half life 0.8-1.5 hrs; excretion
mainly by kidney (60-80%) and bile (15-35%)
 Plasma concentration increases when drug is taken
with high-carbohydrate meal or with cimetidine
 Praziquantel
 Clinical uses:
 1. schistosomiasis
 2. clonorchiasis, opisthorchiasis, and paragonimiasis

 3. taenaisis and diphlyllobotriasis

 4. neurocysticercosis

 5. H. nana

 6. hydatid disease
 Praziquantel
 Adverse reactions, contraindications, & cautions:
 Most frequent: headache, dizziness, drowsiness,
lassitude
 Several days after starting the drug, low-grade fever,

pruritus and skin rashes (macular and urticarial)

sometimes associated with worsened eosinophilia may
occur probably due to the release of proteins from dying
worms rather than direct drug toxicity
 Contraindicated in ocular cysticercosis and safety in

children <4 y/o is unclear

 Pyrantel pamoate
 Tetrahydropyrimidine derivative
 Poorly absorbed from GI and active mainly against
luminal organisms
 Peak plasma in 1-3hr with over half of the
administered dose recovered unchanged in feces
 MOA: neuromuscular blocking agent that causes
release of acetylcholine and inhibition of
cholinesterase resulting in paralysis and expulsion of
worms
 Piperazine
 Alternative for the treatment of ascariasis with
cure rates >90% when taken for 2 days but it is not
recommended for other helminth infections
 Available as hexahydrate and as a variety of salts
 Readily absorbed, and maximum plasma levels
reached in 2-4hrs; most of the drug is excreted
unchanged in urine in 2-6hrs and excretion
complete within 24 hrs
 Piperazine
 MOA: paralysis of ascaris by blocking acetylcholine at
myoneural junction; unable to maintain their position in
th ehost, liver worms are expelled by normal peristalsis
 Adverse events: nausea vomiting, diarrhea, abdominal
pain, dizziness, and headache
 Should not be given to women during pregnancy,
patients with impaired renal or hepatic function or to
those with a history of epilepsy or chronic neurologic
disease
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BLOOD, INFLAMMATION &
GOUT DRUGS
3rd Topic

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
 AGENDA
 Drugs used to treat inflammation
 Agents used in hyperlipidemia
 Drugs used in disorders of coagulation
 r
 Inflammation
 Occurs when tissues are injured by bacteria, trauma,
toxins, heat, or any other cause
 The damaged cells release chemicals including

histamine, bradykinin, and prostaglandins

 These chemicals cause blood vessels to leak fluid into

the tissues, causing swelling

 This helps isolate the foreign substance from further

contact with body tissues

 Inflammation
 The chemicals also attract white blood cells called
phagocytes that "eat" microorganisms and dead or
damaged cells
 This process is called phagocytosis

 Phagocytes eventually die

 Pus is formed from a collection of dead tissue, dead

bacteria, and live and dead phagocytes

 Gout
 A disease that results from an overload of uric acid

in the body
 This overload of uric acid leads to the formation of

tiny crystals of urate that deposit in tissues of the

body, especially the joints
 When crystals form in the joints, it causes recurring

attacks of joint inflammation

 Hyperuricemia
 Elevated blood uric acid levels
"While hyperuricemia may indicate an increased risk
of gout, the relationship between hyperuricemia
and gout is unclear. Many patients with
hyperuricemia do not develop gout, while some
patients with repeated gout attacks have normal or
low blood uric acid levels. Among the male
population in the United States, approximately ten
percent have hyperuricemia. However, only a
small portion of those with hyperuricemia will
actually develop gout."
 Drugs for inflammation
 PGE analog
1
 Alprostadil
 Misoprostol

 PGE analog
2
 Dinoprostone
 Epoprostenol

 Drugs for gout

 Indomethacin

 Colchicine

 Allopurinol

 Probenecid

 Sulfinpyrazone

 Febuxostat
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 Gout
algorithm
 Hyperuricemia algorithm
 Pain
 Pain is an unpleasant feeling that is conveyed to the
brain by sensory neurons
 The discomfort signals actual or potential injury to the

body
 However, pain is more than a sensation, or the physical

awareness of pain; it also includes perception, the

subjective interpretation of the discomfort
 Perception gives information on the pain's location,

intensity, and something about its nature

 The various conscious and unconscious responses to

both sensation and perception, including the emotional

response, add further definition to the overall concept of
pain
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 Algorithm
 Hyperlipidemia
 Hyperlipidemia is an excess of fatty substances called lipids,

largely cholesterol and triglycerides, in the blood

 It is also called hyperlipoproteinemia because these fatty

substances travel in the blood attached to proteins. This is the

only way that these fatty substances can remain dissolved
while in circulation.
 Hyperlipidemia, in general, can be divided into two

subcategories:
 Hypercholesterolemia, in which there is a high level of

cholesterol
 Hypertriglyceridemia, in which there is a high level of

triglycerides, the most common form of fat

 r
 Ezetimibe (Zetia)
 Use: Primary hypercholesterolemia
 Adverse reaction: Diarrhea, back pain, sinusitis,
dizziness, abdominal pain, arthralgia, coughing,
fatigue
 Dosage regimen: 10mg/day orally
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 Coagulopathy
 Any disorder of blood coagulation

 A condition in which the blood’s ability to clot is

impaired. This condition can cause prolonged or

excessive bleeding, which may occur spontaneously
or following an injury or medical and dental
procedures
 Treatment of coagulopathy depends on the

underlying cause. Options include an infusion of

fresh frozen plasma to provide the body with
necessary clotting factors
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 ANTIBIOTICS
Antimicrobial & Antimycobacterial agents

Romeo C. Ongpoy, Jr. MSc RPh

Pharmacology II
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Antibiotic Mechanisms of Action
Summary of Penicillins
Classification of Penicillins
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Classification of Cephalosporins
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Effectiveness of Cephalosporins Against G- & G+ Organisms
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30s Antibacterial Agents
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50s Antibacterial Agents
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Macrolide & Chloramphenicol Toxicities
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Antimycobaterial Agents
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 LONG QUIZ_PHARMA
1. Other agents that can enter the cell through d. Bithional
specialized transmembrane carrier protiens that e. Piperazine
facilitate the passage of large molecules 8. Muscarinic receptor of the smooth muscle
a. Active transport a. M1
b. Passive transport b. M2
c. Endocytosis c. M3
d. Facilitated diffusion d. M4
e. Pinocytosis e. M5
2. Which is NOT true of the inhalation route of drug 9. This is the general term for the route of
administration? administration for drugs given by injection
a. Does not cause irritation a. Topical
b. Variable systemic distribution b. Enteral
c. Rapid absorption c. Rectal
d. Ideal for treating lung disease, as drug is d. Sublingual
essentially exerting a local effect e. Parenteral
e. Ideal for drugs that can be administered as an 10. This is a shock caused by a spinal cord injury
aerosol a. Neurogenic shock
3. Cellular energy is used to move the drug from an b. Septic shock
area of low concentration to one of high c. Cardiogenic shock
concentration d. Hypovolemic shock
a. Passive transport e. Anaphylactic shock
b. Active transport 11. The trade name of Acetylcholine Chloride
c. Facilitated diffusion Intraocular Injection is?
d. Endocytosis and exocytosis a. Bethanechol
e. Pinocytosis b. Levophed
4. Which is an agonist for M1,M2, M3 and Nn c. Miochol E
receptors? d. Hexamethonium
a. Oxotremorine e. Parathion
b. Methacholine 12. Muscarinic receptor of the heart
c. Carbamycholine a. M1
d. Atropine b. M5
e. Muscarine c. M2
5. Which is a beta-2 adrenergic antagonist? d. M4
a. Clonidine e. M3
b. Dopamine 13. Which is an alpha antagonist?
c. Labetalol a. Timolol
d. Prazosin b. Phentolamine
e. Butoxamine c. Oxymetazoline
6. The trade name of Oxymetazoline is? d. Propanolol
a. Afrin e. Isoproterenol
b. Parathion 14. The trade name of Trimethapan is?
c. Tolazoline a. Bethanechol
d. Bethanechol b. Arfonad
e. Atropine c. Hexamethonium
7. Which antihelminthic drug causes paralysis of ascaris d. Parathion
by blocking acetylcholine at the myoneural junction? e. Soman
a. Albendazole 15. This is also known as adrenaline
b. Thiabendazole a. Dopamine
c. Oxamniquine b. Lopressor
 LONG QUIZ_PHARMA
c. Salbutamol e. Not well accepted in adults
d. Norepinephrine 23. When taking a heparin with alcohol, bleeding
e. Epinephrine increases
16. Which is the drug of choice for all forms of a. Cumulative drug effect
schistosomiasis? b. Additive drug reaction
a. Praziquantel c. Synergistic drug reaction
b. Niclosamide d. Antagonistic drug reaction
c. Bithional e. Adverse event
d. Oxamniquine 24. What do you call the study of adverse effects of
e. Thiabendazole chemicals on living organisms?
17. Which is the drug of choice for the treatment of a. Pharmacoepidemiology
filariasis, loiasis and tropical eosinophilia? b. Pharmaceutical biotechnology
a. Thiabendazole c. Pharmacology
b. Albendazole d. Toxicology
c. Oxamniquine e. Pharmacovigilance
d. Piperazine 25. Which is NOT true of the subcutaneous drug
e. Diethylcarbamazine citrate administration?
18. Which is an alpha antagonist? a. Can only be used for relatively small volumes of
a. Propanolol injection
b. Isoproterenol b. Rapid absorption
c. Atenolol c. Easy to administer
d. Timolol d. May be used to deliver depot injections, where
e. Phenoxybenzamine the active compound of a drug is released
19. Which antihelminthic has a mechanism of action n consistently over time
that is cholinesterase inhibition and indicated for e. There is potential tissue irritation
Schistosoma mansoni and Schistosoma japonicum? 26. Which acts indirectly by killing Wolbachia?
a. Bithional a. Oxamniquine
b. Albendazole b. Doxycycline
c. Oxamniquine c. Piperazine
d. Thiabendazole d. Ivermectin
e. Trichlorfon e. Albendazole
20. Which is the drug of choice for cysticercosis? 27. This name is given to a drug before it becomes
a. Thiabendazole official and may be used in all countries and all
b. Bithional manufacturers
c. Piperazine a. Trade name
d. Oxamniquine b. Nonproprietary name
e. Albendazole c. Brand name
21. Which is a beta-1 adrenergic antagonist? d. Chemical name
a. Labetalol e. Official name
b. Clonidine 28. Drugs classified in the US for diseases affecting
c. Prazosin fewer than 200,000 individuals
d. Albuterol a. Prescription drugs
e. Atenolol b. OTC drugs
22. Which is not a characteristic of administering drug c. Orphan drug
through the rectal route? d. Nonprescription drugs
a. Avoids first-pass metabolism e. Controlled substances
b. Tolerated well in children 29. Which is the most non-specific of the following
c. Irritation of the rectal mucosa is common cholinergic agonists?
d. Relatively painless a. Muscarine
 LONG QUIZ_PHARMA
b. Acetylcholine d. Labetalol
c. DMPP e. Dopamine
d. N-methylatropine 37. Which is NOT true of the transdermal route?
e. Nicotine a. May cause irritation
30. This is a shock caused by blood loss b. Controlled release preparations may be used
a. Neurogenic shock via this mode of application
b. Hypovolemic shock c. Painful
c. Septic shock d. Rate of absorption varies
d. Anaphylactic shock e. Can achieve systemic affects
e. Cardiogenic shock 38. Drug conjugations happen in which
31. The trade name of Norepinephrine bitartrate is? pharmacokinetic phase?
a. Atropine a. Administration
b. Levophed b. Distribution
c. Parathion c. Liberation
d. Enlon d. Excretion
e. Bethanechol e. Metabolism
32. Occurs when one drug interferes with the action of 39. The trade name of Isoproterenol is?
another, causing neutralization or a decrease in the a. Levophed
effect of one drug b. Hexamethonium
a. Antagonistic drug reaction c. Isuprel
b. Additive drug reaction d. Arfonad
c. Cumulative drug effect e. Parathion
d. Adverse event 40. Cells engulf the drug particle (the cell forms a
e. Synergistic drug reaction vesicle to transport the drug into the inner cell)
33. This is a substance that is capable of causing the a. Active transport
illness or death of a living organism when b. Pinocytosis
introduced or absorbed c. Facilitated diffusion
a. Poison d. Exocytosis
b. Generic drug e. Endocytosis
c. Drug 41. Which of the following is not part of the peripheral
d. Medicine nervous system?
e. Adjuvant a. Touch
34. Diclofenac sodium is which of the following? b. Smooth muscle
a. Chemical name c. Spinal cord
b. Brand name d. Nerves
c. Nonproprietary name e. Internal senses
d. Trade name 42. This is a shock caused by an allergic reaction
e. Scientific name a. Anaphylactic shock
35. Which adrenergic receptor thickens salivary b. Cardiogenic shock
secretion? c. Septic shock
a. Beta-3 d. Hypovolemic shock
b. Beta-2 e. Neurogenic shock
c. Alpha-1 43. Tuseran Forte is which of the following?
d. Beta-1 a. Scientific name
e. Alpha-2 b. Official name
36. Which is a beta-2 adrenergic agonist? c. Brand name
a. Clonidine d. Chemical name
b. Prazosin e. Generic name
c. Terbutaline
 LONG QUIZ_PHARMA
44. Which enteral route administration is most useful
for small amount of drug?
a. Oral
b. Inhalation
c. Rectal
d. Topical
e. Buccal
45. The trade name of Carbachol is?
a. Isopto
b. Parathion
c. Bethanechol
d. Miochol E
e. Levophed
46. The trade name of Pralidoxime is?
a. Atropine
b. Protopam
c. EpiPen
d. Bethanechol
e. Soman
47. Which is the alternative to praziquantel for the
treatment of Schistosoma mansoni infection?
a. Thiabendazole
b. Oxamniquine
c. Diethyl carbamazine
d. Ivermectin
e. Praziquantel
48. The trade name of Sersapil is?
a. Reserpine
b. Levophed
c. Clonidine
d. Sudafed
e. Prazosin
49. Which is replaced by ivermectin for the treatment
of onchocerciasis?
a. Ivermectin
b. Thiabendazole
c. Praziquantel
d. Doxycycline
e. Diethyl carbamazine
50. Which is the drug of choice for cysticercosis?
a. Piperazine
b. Oxamniquine
c. Bithional
d. Albendazole
e. Thiabendazole
 PHARMA LONG QUIZ MIDTERM 7. Milk of magnesia, a commonly used
osmotic laxative is also known as?
1. Which is an expectorant?
a. Docusate
a. Colace
b. Magnesium hydroxide
b. Dulcolax
c. Lactulose
c. Mucinex
d. Sorbitol
d. Krosyl
e. Mineral oil
e. Citrucel

8. Which is a vaccine that does not have a

2. Which vaccine is administered to all age
booster dose?
65 and above because of the increased
a. Human papillomavirus
risk of disease concerned and its
b. Meningococcal conjugate vaccine
complications?
c. Pneumococcal polysaccharide vaccine
a. Influenza, live attenuated
d. Poliovirus vaccine, inactivated
b. Pneumococcal polysaccharide vaccine
e. Influenza, live attenuated
c. Rabies vaccine
d. Hepatitis A
e. Pneumococcal conjugate
9. Which increases Theophylline
metabolism?
a. Ticlopidine
3. Which antihelminthic has a mechanism of
b. Smoking
action that is cholinesterase inhibition and
c. Zileuton
indicated for Schistosoma mansoni and
d. Tacrine
Schistosoma japonicum?
e. Diltiazem
a. Albendazole
b. Thiabendazole
c. Trichlorfon
10. Which is NOT a patient demographic?
d. Bithional
a. Occupation
e. Oxamniquine
b. Gender
c. Height
d. Race
4. Which is replaced by ivermectin for the
e. Age
treatment of onchocerciasis?
a. Praziquantel
b. Doxycycline
11. This follow-up status is when progress is
c. Thiabendazole
being made in achieving goals?
d. Ivermectin
a. Failure
e. Diethyl carbamazine
b. Expired
c. Worsened
d. Improved
5. This follow-up status is when therapeutic
e. Unimproved
goals and achieved for the acute
condition and that therapy should be
discontinued
12. When the condition is refractory to the
a. Expired
drug product being used, it will result to
b. Resolved
which of the following?
c. Worsened
a. Need for additional therapy
d. Improved
b. Adverse drug reaction
c. Dosage too low
d. Noncompliance
6. Which uses a live virus in a vaccine?
e. Ineffective drug
a. Rabies vaccine
b. Influenza, live attenuated vaccine
c. Hepatitis A vaccine
13. Which is the alternative to praziquantel for
d. Meningococcal conjugate vaccine
the treatment of Shistosoma mansoni
e. Pneumococcal conjugate vaccine
infection
a. Ivermectin
b. Oxamniquine
 c. Diethyl carbamazine 20. This dermatologic drug inhibits the
d. Thiabendazole epoxidation of squalene, thus blocking
e. Praziquantel the synthesis of ergosterol
a. Cyclophosphamide
b. Butenafine
14. The booster dose of Tetanus-diptheria c. Canakinumab
vaccine is given at what schedule? d. Xylene
a. Every 5 yrs e. Gramicidin
b. None, one time administration
c. Annually
d. Every 3 yrs 21. This dermatologic drug is effective in the
e. Every 10 yrs treatment of impetigo caused by the S.
aureus and group A beta hemolytic
streptococci
15. Used as treatment for acne vulgaris, its a. Dapsone
adverse effects include mild dryness, b. Mupirocin
redness, oiliness, and skin peeling c. Gramicidin
a. Permethrin d. Butenafine
b. Dapsone e. Permethrin
c. Alefacept
d. Gramicidin
e. Butenafine 22. Which drug gives good response in
coronary stent cell proliferation which is
usually impregnated in the stent?
16. Which is not true about mebendazole? a. Capromab pendetide
a. It has broad spectrum b. Tetracycline
b. It has been replaced by ivermectin c. Rhogam
c. It is chewed before swallowing d. Sirolimus
d. It is used against trichuriasis e. Thalidomide
e. It causes mild abdominal pain in some
patients
23. Which is usually administered intranasal?
a. Hepatitis A vaccine
17. Which vaccine is administered at one dose b. Rabies vaccine
in primary immunization? c. MMR vaccine
a. Meningococcal conjugate vaccine d. Influenza, live attenuated vaccine
b. Human papillomavirus e. Pneumococcal conjugate vaccine
c. Rabies vaccine
d. Influenza, live attenuated
e. Poliovirus vaccine, inactivated 24. Which is the drug of choice for
onchocerciasis?
a. Oxamniquine
18. Which is the drug of choice for b. Mebendazole
onchocerciasis? c. Piperazine
a. Mebendazole d. Ivermectin
b. Trichlorfon e. Albendazole
c. Albendazole
d. Piperazine
e. Ivermectin 25. This dermatologic drug is for typical use
only, it is antibacterial and usually used
with neomycin, polymixin, bacitracin and
19. Which is the alternative to praziquantel nystatin
for the treatment of Schistosoma a. Miconazole
mansoni infection? b. Permethrin
a. Ivermectin c. Dapsone
b. Oxamniquine d. Butenafine
c. Thiabendazole e. Gramicidin
d. Diethyl carbamazine
e. Praziquantel
26. Which is the drug of choice for the d. Fluvoxamine
treatment of filariasis, loiasis and tropical e. Fluorouracil
eosinophilia?
a. Diethylcarbamazine citrate
b. Thiabendazole 33. Which is use as a topical cream or lotion
c. Albendazole and as vaginal cream or suppository for
d. Piperazine use in vulvovaginal candidiasis?
a. Permethrin
b. Dapsone
27. Varicella vaccine is usually administered in c. Gramicidin
what route? d. Miconazole
a. Intranasal e. Butenafine
b. Intradermal
c. Intramuscular
d. Oral 34. Which is not an antacid?
e. Subcutaneous a. Magnesium hydroxide
b. Mylanta
c. Tums
28. Which is a stimulant laxative of d. Aleve (Analgesics and antipyretics)
anthraquinone derivative? e. Milk of magnesia
a. Both b and c
b. Both a and b (cascara and aloe)
c. Aloe 35. Yellow fever vaccine is usually
d. Cascara administered in what route?
e. Docusate a. Oral
b. Intramuscular
c. Intradermal
29. Which is the drug of choice for the d. Intranasal
treatment of filariasis, loiasis and tropical e. Subcutaneous
eosinophilia?
a. Diethylcarbamazine citrate
b. Piperazine 36. Which drug paralyzes nematodes and
c. Albendazole arthropods by intensifying
d. Thiabendazole GABA-mediated transmission of signals in
peripheral nerves?
a. Piperazine
30. Which is replaced by ivermectin for the b. Mebendazole
treatment of onchocerciasis? c. Trichlorfon
a. Diethyl carbamazine d. Ivermectin
b. Ivermectin
c. Praziquantel
d. Doxycycline 37. The treatment of disease through the
e. Thiabendazole administration of drugs
a. Pharmacoepidemiology
b. Pharmacotherapy
31. Which is not an antifungal vaginal c. Posology
preparation? d. Pharmacology
a. Lamisil e. Pharmacovigilance
b. Vagistat
c. Gyne-Lotrimin
d. Lotrimin 38. Which is a safe alternative drug for the
e. Monistat treatment of Schistosoma haematobium
infections?
a. Ceftriaxone
32. Which does not increase phenytoin b. Albendazole
plasma concentration? c. Trichlorfon (metrifonate)
a. Capecitabine d. Doxycycline
b. Bosentan e. Ivermectin
c. Felbamate
39. Which vaccine is administered to all
children and adults born after 1956?
45. Which is not true of praziquantel?
a. Pneumococcal conjugate vaccine
a. It causes microtubule damage to the
b. MMR vaccine
cell of helminths
c. Influenza, live attenuated vaccine
b. It is the drug of choice for
d. Rabies vaccine
neurocysticercosis
e. Hepatitis A vaccine
c. The tablets are not chewable
d. Used in Taenia saginata and
Diphyllobothrium latum (Niclosamide)
40. Which is the most common therapeutic
e. Used in hydatid disease
drug monitoring assay?
a. TLC
b. TDx
46. The type of agent in Zoster vaccine is
c. Radioimmunoassay
which of the following?
d. HPLC
a. Inactivated virus
e. EMIT
b. Live virus
c. Bacterial polysaccharide
d. Toxoid
41. This dermatologic drug is available as
e. Live bacteria
cream for topical treatment of
dermatophytosis and candidiasis and as
shampoo or foam for the treatment of
47. Which acts indirectly by killing Wolbachia?
seborrheic dermatitis
a. Piperazine
a. Canakinumab
b. Doxycycline
b. Butenafine
c. Oxamniquine
c. Dapsone
d. Albendazole
d. Ketoconazole
e. Ivermectin
e. Gramicidin

48. Which is highly effective for the treatment

42. Which is the drug of choice for H. nana
of pinworm, ascaris and Trichostrongylus
infections and the first drug to be highly
orientalis?
effective for the said helminth?
a. Thiabendazole
a. Oxamniquine
b. Pyrantel pamoate
b. Pyrantel pamoate
c. Praziquantel
c. Diethyl carbamazine citrate
d. Diethyl carbamazine
d. Thiabendazole
e. Ivermectin
e. Praziquantel

49. Which antiangiogenic drug is the first and

43. Inappropriate dosage form will result to
second line treatment of metastatic
which of the following?
colorectal cancer?
a. Dosage too low
a. Bevacizumab
b. Adverse drug reaction
b. Sirolimus
c. Noncompliance
c. Capromab pendetide
d. Ineffective drug
d. Thalidomide
e. Need for additional therapy
e. Rhogam

44. Which is alternative to ivermectin or

50. Average difference of the individual values
albendazole for the treatment of
from the mean, this statistical method is
strongyloidiasis and cutaneous larva
very much useful in clinical pharmacy
migrans?
a. Standard deviation
a. Bithional
b. Coefficient of variation
b. Albendazole
c. Range
c. Oxamniquine
d. ANOVA
d. 5-FU
e. Average
e. Thiabendazole
 FINAL QUIZ- PHARMA

1. Plant alkaloid that acts on mitotic spindle 10. Alters cell membrane permeability:
a. Amsacrine a. Griseofulvin
b. Tamoxifine b. Amantadine
c. Vincristine c. Ketocronazole
d. Narfarelin d. Flucytosine
2. Side-effects include systemic compensation, large 11. Which is an expectorant?
degree of cross tolerance between organic nitrates a. Codeine
and headache b. Oxymetazoline
a. Amly nitrate c. Guaifenesin
b. Inderal d. Phenylehrine
c. Lidocaine e. carbetapentane
d. Quinidine 12. Respiratory symptoms of anaphylactic shock, except
e. Diltiazem a. Wheezing
3. An antitumor antibiotic: b. Bronchospasm
a. Methotrexate - antineoplastic agent c. Cough
b. Paclitael - anti-cancer d. Pruritus
c. Mitoxantrone - antineoplastic antibiotic e. Dyspnea
d. Dactinomycin 13. Drugs that damage the DNA:
4. Azole a. Methotrexate
a. Nystatin b. Etoposide
b. Naftifine c. Paclitaxel
c. Griseofulvin d. Rituximab
d. Miconazole 14. Tricyclic amines:
5. Which is not a side effect of codeine? a. Vidarabine
a. Nausea and vomiting b. Interferon-alfa
b. Increases mucous production c. Ribavirin
c. Confusion d. Amantadine
d. Highly additive 15. Competitive inhibitor of tyrosine hydroxylase is the
e. Bitter taste MoA of which drug?
6. Which prevents formation of leukotrienes? a. Hylotel
a. Nedocromil b. Prazosin
b. Tilade c. Ismelin
c. Montelukast d. Hytrin
d. Zafrilukast e. Demser
e. Zileuton – (not sure, Zileuton is a leukotriene 16. Drugs that damage the DNA
synthesis inhibitor. It prevents the body from a. Irinotecan
making leukotrienes) b. Cyclophosphamide
7. Antifolate: c. Methotrexate
a. Pentamidine d. Paclitaxel
b. Primaquine 17. One of a series of azo dyes examined by domagk for
c. Tmp-smz possible effects on hemolytic streptococcal
d. Pryrimethamine infection:
8. Which is a bronchodilator in COPD? a. Synthetic compounds
a. Flovent b. Alkaloids
b. Vancenase c. Melatonin
c. Atrovent d. Sulfonamides
d. Fluticasone 18. Protease inhibitor:
e. Uniphyl a. Rimantadine
9. Which is a mast cell degranulation inhibitor? b. Amprenavir
a. Singulair c. Stavudine
b. Tilade d. Delavirdine
c. Zyflo 19. Antagonists:
d. Zileuton a. Estrogens
e. Accolate b. Vinblastine
c. Letrozole
 FINAL QUIZ- PHARMA

d. Topotecan 30. Factors influencing drug response

20. Topoisomerase inhibitors: a. All of the above
a. Goserelin b. Sex
b. Irinotecan c. Route of administration
c. Dacarbazine d. Weight
d. Cisplatin e. Age
21. Pyrophosphate derivative: 31. Antimetabolites
a. Ritonavir a. Topotecan
b. Ribavirin b. Flutamide
c. Nevirapine c. Indinavir
d. Foscarnet d. Mercaptopurine
22. Ventolin is also known as? 32. Penicillin derivative
a. Zyflo a. Griseofulvin
b. Isoethramine b. Naftifine
c. Isuprel c. Itraconazole
d. Albuterol d. Amphotericin B
e. Alupent 33. NNRTIs:
23. Amebiases agents: a. Efaviernz
a. TMP-SMZ b. Acyclovir
b. Diloxanide furoate c. Foscarnet
c. Mefloquine d. Indinavir
d. Sulfadoxine 34. Which drug has the ff. Side effects:
24. nucleoside RTIs: Bronchoconstriction, hypertension, bradcardia and
a. Rimantadine sexual dysfunction?
b. Amprenavir a. Minoxidil
c. Didanosine b. Coreg
d. Delaviridine c. Toporol
25. Which is used for hypertension, angina and d. Cardizem
alopecia? e. Isoptin
a. Capoten 35. Trypanosomiasis agent:
b. Enalapril a. Pentamidine
c. Loniten b. Amantadine
d. Lasix c. Flucytosine
26. Antimalarial agents: d. Griseofulvin
a. Cisplatin 36. Which is a methly xanthine?
b. Antifolates a. Isoetharine
c. Metranidazole b. Singlair
d. Mefloquine c. Zyflo
27. Which drug has side-effects of severe diarrhea. EPS d. Theophylline
and allergic reactions? e. Singulair
a. Metyrosine 37. Which drug is as effective as methydopa but requires
b. Serpasil smaller doses?
c. Ismelin a. Guanabenz
d. Guanedrel b. Catapres
e. Rogitine c. Wytensin
28. Plant alkaloid that acts on mitotic spindle: d. Inversine
a. Narfarelin e. Phenoxybezamine
b. Tamoxifen 38. Which is not a brand name of theophylline?
c. Vinblastine a. Uniphyl
d. Doxorubicin b. SLo-phyllin
29. Pyrimidine analog: c. Theo-dur
a. Terbinafine d. Theo-24
b. Flucytosine e. Serevent
c. Nystatine
d. Naftifine
 FINAL QUIZ- PHARMA

39. Renal malignancy seen in children, it is associated 48. Used for stable, unstable and variant angina
with hemihypertrophy of the body: supraventricular arrythmias, hypertension and
a. Non-hodgkin’s lymphoma ventricular rate control in atrial fibrillation.
b. Neuroblastoma a. Propanolol
c. Multiple myeloma b. Apresoline
d. Wilm’s tumor c. Adaral
40. Which is a leukotriene receptor antagonist? d. Verapamil
a. Tilade e. Inderal
b. Zyflo 49. Which is not a topical decongestant?
c. Singulair a. Afrin
d. Zleuton b. Sudafed
e. Nedocromil c. Naphazoline
41. nucleoside analogs: d. Phenylephrine
a. Nevirapine e. Privine
b. Ritonazir 50. Naphazoline is classified as which of the ff?
c. Foscarnet a. Opiate
d. Valacyclovir b. Systemic, direct and indirect adrenergic agonist
42. Group of malignancies stemming from fetal or c. Antihistamine
placental tissue: d. Topical alpha agonist
a. Neuroblastoma e. Centrally acting antitussive
b. Gestational trophoblastic neoplasms
c. Non-hodgkin’s lymphoma
d. Multiple myeloma
43. An alkaloid for amebic dysentery:
a. Alkaloids
b. Protonsil
c. Germanin
d. Ipecacuanha root
44. Antimalarial agents:
a. Quinine
b. Antifolates
c. Amantadine
d. Metronidazole
45. Which drug class reduces congestion or swelling?
a. Decongestant
b. Expectorant
c. Carminative
d. Antitussive
e. Antihistamine
46. Glycoproteins:
a. Saquinavir
b. Ribavirin
c. Trifluridine
d. Interferon- beta
47. Allylamine:
a. Flucytosine
b. Bleomycin
c. Clotrimazole
d. Naftifine