Implications Of Changing Renal Function on Creatinine and Drug Dosing

Creatinine clearance should be calculated and documented for all patients with impaired renal
function for dosage adjustment.
The half-life of creatinine is substantially prolonged in renal patients when their renal function
decreases below normal.
From pharmacokinetic analysis, the time required to reach a new steady-state serum creatinine
level after the onset of renal failure is highly dependent upon the degree of renal insufficiency.
Inappropriate drug dose adjustments are associated with patients having intermediate renal
insufficiency and co-morbid conditions. inappropriate dosing in patients with renal impaired
patients can cause toxicity or ineffective therapy.
In older patients, the impact is great due to they are at a higher risk of developing advanced
disease and related adverse drug events.
This is caused by an age-related decline in renal function and the use of complex medications to
treat their co-morbid conditions.
Inappropriate dosing in patients with impaired renal patients can affect patient's clinical
outcomes, and quality of life as well as contribute to unnecessary healthcare costs.
Therefore, correctly adjusting the drug dosage in renal dysfunction contributes to fewer adverse
drug effects, decreases the therapeutic costs, decreases the duration of hospital stay and mortality
as well as maintains therapeutic effectiveness.
Individualized therapeutic regimens that optimize desired outcomes and reduce adverse events
are necessary.

What is the impact of the following on drug levels and dosing:

Cirrhosis

Several pathophysiological changes that may occur in cirrhosis and the consequence of these
changes on PK parameters.

These changes could lead to decreased plasma levels of medicines, for example due to
diminished prodrug activation or disrupted enterohepatic recycling.

However, PK alterations in patients with cirrhosis most frequently result in increased exposure to
medicines. The extent of these increases depends on both drug and patient characteristics.

PK parameters may be affected by cirrhosis. Hepatic drug clearance depends on three factors: (1)
hepatic blood flow, (2) the hepatocytes’ ability to metabolize a medicine (intrahepatic clearance),
and (3) the fraction of unbound medicine.
The hepatic extraction ratio (EH) is the fraction of drug cleared from the blood during a single
passage through the liver. Medicines are classified by their hepatic extraction ratio into: high
(EH>0.7), intermediate (EH: 0.3–07), and low (EH<0.3) extraction drugs.

For drugs with a high EH, the liver is very efficient in clearing the medicine from the blood.
Therefore, hepatic blood flow is the factor limiting hepatic clearance (‘flow-limited’).

These medicines usually undergo substantial first-pass metabolism when orally administered in
healthy patients.

However, in patients with cirrhosis, pathophysiological changes that affect blood flow, such as
the development of portosystemic shunts, can have a large influence on circulating drug plasma
levels.

An example of this is the medicine naltrexone, which has a bioavailability of 5–40% in healthy
individuals. Exposure to naltrexone is approximately fivefold higher in compensated and tenfold
higher in decompensated cirrhosis compared to healthy controls, likely explained by a
diminished first-pass effect.

The liver is less efficient in clearing medicines from the blood for drugs with a low EH.
Therefore, drug clearance is predominantly influenced by intrinsic hepatic clearance and the free
fraction of the medicine (‘capacity-limited).

These medicines are sensitive to changes in plasma protein binding (if highly protein bound) and
reduced metabolic enzyme activity.

Examples of low EH medicines include proton pump inhibitors (PPIs), lansoprazole and
pantoprazole. Exposure to both medicines is largely increased in patients with cirrhosis, which
results from a decrease of CYP2C19 enzyme activity in cirrhosis.

Finally, hepatic clearance of medicines with an intermediate EH depends on all three factors (i.e.
hepatic blood flow, hepatic metabolic activity and a fraction of unbound medicine).

An example of such a medicine is paroxetine. In patients with cirrhosis, a doubled exposure to

paroxetine has been seen after multiple-dosing

o Protein binding
Drugs can form reversible bonds with various proteins in the body. Of all the proteins with which
drugs can bind, plasma albumin is the most important.
Like other proteins, albumin is a large molecule. Because of its size, albumin is too large to leave
the bloodstream. Even though a drug can bind albumin, only some molecules will be bound at
any moment.
The percentage of drug molecules that are bound is determined by the strength of the attraction
between albumin and the drug.
For example, the attraction between albumin and the anticoagulant warfarin is strong, causing
nearly all (99%) of the warfarin molecules in plasma to be bound, leaving only 1% free.
On the other hand, the attraction between the antibiotic gentamicin and albumin is relatively
weak; less than 10% of the gentamicin molecules in plasma are bound, leaving more than 90%
free.
An important consequence of protein binding is restriction of drug distribution. Because albumin
is too large to leave the bloodstream, drug molecules that are bound to albumin cannot leave
either.
This prevents bound molecules from reaching their sites of action or undergo metabolism or
excretion until the drug–protein bond is broken so that the drug is free to leave the circulation.
In addition to restricting drug distribution, protein binding can be a source of drug interactions.
Each molecule of albumin has only a few sites to which drug molecules can bind. Because the
number of binding sites is limited, drugs with the ability to bind albumin will compete with one
another for those sites.
Thus, one drug can displace another from albumin, causing the free concentration of the
displaced drug to rise, thus increasing the intensity of drug responses. If plasma drug levels rise
sufficiently, toxicity can result.
o Drug interactions
A drug interaction occurs when another substance alters a drug's efficacy, effects, or safety.
These are usually the result of interactions with other drugs, food, or supplements.
1. Drug–Drug Interactions
Drug–drug interactions can occur whenever a patient takes two or more drugs. Some interactions
are both intended and desired, as when we combine drugs to treat hypertension. In contrast, some
interactions are both unintended and undesired.
Consequences of Drug–Drug Interactions
When two drugs interact, there are three possible outcomes: (1) one drug may intensify the
effects of the other, (2) one drug may reduce the effects of the other, or (3) the combination may
produce a new response not seen with either drug alone.
Intensification of Effects
When one drug intensifies, or potentiates, the effects of the other, this type of interaction is often
termed potentiative. Potentiative interactions may be beneficial or detrimental.
Reduction of Effects
Interactions that result in reduced drug effects are often termed inhibitory. As with potentiative
interactions, inhibitory interactions can be beneficial or detrimental. Inhibitory interactions that
reduce toxicity are beneficial. Conversely, inhibitory interactions that reduce therapeutic effects
are detrimental.
Creation of a Unique Response
Rarely, the combination of two drugs produces a new response not seen with either agent alone.
To illustrate, let's consider the combination of alcohol with disulfiram (Antabuse)], a drug used
to treat alcohol use disorder. When alcohol and disulfiram are combined, a host of unpleasant
and dangerous responses can result; however, these effects do not occur when disulfiram or
alcohol is used alone.
Drug interactions can affect all four of the basic pharmacokinetic processes. That is, when two
drugs are taken together, one may alter the absorption, distribution, metabolism, or excretion of
the other.
Altered absorption.
There are several mechanisms by which one drug can alter the absorption of another.
• By elevating gastric pH, antacids can decrease the ionization of
basic drugs in the stomach, increasing the ability of basic drugs to
cross membranes and be absorbed. Antacids have the opposite
effect on acidic drugs.
• Laxatives can reduce the absorption of other oral drugs by
accelerating their passage through the intestine.
• Drugs that depress peristalsis (e.g., morphine, atropine) prolong
drug transit time in the intestine, thereby increasing the time for
absorption.
• Drugs that induce vomiting can decrease the absorption of oral
drugs.
• Orally administered adsorbent drugs that do not undergo
absorption (e.g., cholestyramine) can adsorb other drugs onto
themselves, thereby preventing the absorption of the other drugs into
the blood.
Drugs that reduce regional blood flow can reduce absorption of other drugs from that region. For
example, when epinephrine is injected together with a local anesthetic, the epinephrine causes
local vasoconstriction, thereby reducing regional blood flow and delaying absorption of the
anesthetic.
Altered distribution.
There are two principal mechanisms by which one drug can alter the distribution of another: (1)
competition for protein binding and (2) alteration of extracellular pH.

Competition for protein binding.

When two drugs bind to the same site on plasma albumin, coadministration of those drugs
produces competition for binding. As a result, binding of one or both agents is reduced, causing
plasma levels of free drug to rise.

In theory, the increase in free drug can intensify effects. However, because the newly freed drug
usually undergoes rapid elimination, the increase in plasma levels of free drug is rarely sustained
or significant unless the patient has liver problems that interfere with drug metabolism or has
renal problems that interfere with drug excretion.

Alteration of extracellular pH.

A drug with the ability to change extracellular pH can alter the distribution of other drugs. For
example, if a drug were to increase extracellular pH, that drug would increase the ionization of
acidic drugs in extracellular fluids (i.e., plasma and interstitial fluid).
Thus, acidic drugs would be drawn from within cells (where the pH was less than that of the
extracellular fluid) into the extracellular space. Hence the alteration in pH would change drug
distribution.

The ability of drugs to alter pH and thereby alter the distribution of other drugs can be put to
practical use in the management of poisoning. For example, symptoms of aspirin toxicity can be
reduced with sodium bicarbonate, a drug that elevates extracellular pH.

By increasing the pH outside cells, bicarbonate causes aspirin to move from intracellular sites
into the interstitial fluid and plasma, thereby minimizing injury to cells.

Altered metabolism.
Altered metabolism is one of the most important—and complex—mechanisms drugs interact.
Some drugs increase the metabolism of other drugs, and some drugs decrease the metabolism of
other drugs.
Drugs that increase the metabolism of other drugs do so by inducing synthesis of hepatic drug-
metabolizing enzymes. Drugs that decrease the metabolism of other drugs do so by inhibiting
those enzymes.
Conclusively, drug interactions have the potential to affect the outcome of therapy. As a result of
drug–drug interactions, the intensity of responses may be increased or reduced. Interactions that
increase therapeutic effects or reduce toxicity are desirable. Conversely, interactions that reduce
therapeutic effects or increase toxicity are detrimental.
Interactions are especially important for drugs that have a narrow therapeutic range. An
interaction that produces a modest increase in drug levels can cause toxicity for these agents.
Conversely, an interaction that produces a modest decrease in drug levels can cause therapeutic
failure.

Although many important interactions have been documented, many more are yet to be
identified. Therefore, if a patient develops unusual symptoms, it is wise to suspect that a drug
interaction may be the cause— especially because yet another drug might be given to control the
new symptoms.
2. Drug–Food Interactions
Coadministration with food can significantly alter the efficacy and safety of some drugs. The
primary mechanisms are by decreased or increased absorption and altered metabolism.

Decreased Absorption

Food frequently decreases the rate of drug absorption and occasionally decreases the extent of
absorption. Reducing the rate of absorption merely delays the onset of effects; peak effects are
not lowered.

In contrast, reducing the extent of absorption reduces the intensity of peak responses.
The interaction between calcium-containing foods and tetracycline antibiotics
is a classic example of food reducing drug absorption. Tetracyclines bind with calcium to form
an insoluble and nonabsorbable complex.

Hence, if tetracyclines are administered with milk products or calcium supplements, absorption
is reduced and antibacterial effects may be lost.

High-fiber foods can reduce absorption of some drugs. For example, absorption of digoxin
(Lanoxin), used for cardiac disorders, is reduced significantly by wheat bran, rolled oats, and
sunflower seeds. This reduced absorption can result in therapeutic failure.

Increased Absorption
With some drugs, food increases the extent of absorption. When this occurs, peak effects are
heightened. For example, a high-calorie meal more than doubles the absorption of saquinavir
(Invirase), a drug for HIV infection. If saqu inavir is taken without food, absorption may be
insufficient for antiviral activity.
Many drugs cause stomach upset when taken without food. If food does not significantly reduce
their absorption, then these drugs should be administered with meals.
However, if food does reduce their absorption, then we have a difficult choice: we can administer
them with food and thereby reduce stomach upset but also reduce absorption, or we can
administer them without food and thereby improve absorption but also increase stomach upset.
Unfortunately, the correct choice is not obvious. The best solution, when possible, may be to
select an alternative drug that does not upset the stomach.
3. Drug–Supplement Interactions
Dietary supplements (herbal medicines and other nonconventional remedies) create the potential
for frequent and significant interactions with conventional drugs.
Of greatest concern are interactions that reduce beneficial responses to conventional drugs and
interactions that increase toxicity.
These interactions occur through the same pharmacokinetic and pharmacodynamic mechanisms
by which conventional drugs interact with each other.
o Half-life
Drug half-life is defined as the time required for the amount of drug in the body to decrease by
50%. A few drugs have half-lives that are extremely short— on the order of minutes or less.
In contrast, the half-lives of some drugs exceed 1 week. The half-life of a drug determines the
dosing interval (i.e., how much time separates each dose).
For drugs with a short half-life, the dosing interval must be correspondingly short. If a long
dosing interval is used, drug levels will fall to less than the MEC between doses, and therapeutic
effects will be lost. Conversely, if a drug has a long half-life, a long time can separate doses
without loss of benefits.
When a patient ceases drug use, the combination of metabolism and excretion will cause the
amount of drug in the body to decline.
The half-life of a drug is an index of just how rapidly that decline occurs for most drugs. The
concept of half-life does not apply to the elimination of all drugs.
A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of
how much is present.
4. Different Routes of Administration And Dosage Forms And Some Of The
Challenges And Benefits Associated With These Routes And Forms
The route by which a drug is administered significantly affects both the onset and the intensity of
effects. The four routes of administration are Intravenous (IV), Intermuscular, Subcuteneous
(subQ) and Oral (PO). Their properties are discussed in the table below.

5. When Is It OK To Crush (Or Not Crush) Certain Dosage Forms And Why
Cushing oral solid dosage forms (OSDFs) is widespread among healthcare providers and patients
for increasing dose flexibility, making tablet parts easier to swallow, or allowing medication cost
savings.
However, this practice may be dangerous because some formulations and classes of drugs are
unsuitable for crushing or splitting and may cause significant problems, especially in drugs with
low therapeutic indices.
 Crushing refers to converting tablets into powder using suitable pharmacy tools such as mortar
and pestle. These may provide several advantages. It is ok to crush OSDFs for various reasons,
such as:
(i) providing the patient with the desired dose when the product is not available at the
required strength, e.g. hydrochlorothiazide: the available dose is 25mg and the drug is
commonly used in doses of 12.5mg, thus the patient needs to split the tablet to receive
the smaller dose. Another example is converting atenolol tablets into capsules with
the desired filling weight. This practice is useful for children or older persons;
(ii) slowing the titration of the medication to start therapy with the lowest possible doses
and then starting to increase the dose until reaching the desired dose to enable
toleration of the drug and reduce the incidence of side effects of certain drugs, e.g.
with beta-blockers such as metoprolol used post myocardial infarction, patients
cannot tolerate full doses of 50mg and instead are given 12.5mg, then the dose will be
increased. The lowest dose available is 50mg, which necessitates the tablet being split
into quarters to give the wanted dose. Another example of the benefit of splitting a
tablet in slow titration is patients who are taking anticoagulation therapy with
warfarin: patients require frequent dose changes to stay at an appropriate level of
anticoagulation. Instead of purchasing more than one strength, patients resort to
purchasing one strength and splitting the tablets to adjust the dose as required
(iii) reducing medication costs;
(iv) making the swallowing of large tablets easier;
(v) providing medication dose flexibility.
Crushing tablets is also an acceptable method of medication administration for patients with
swallowing problems due to the large size of the capsules or due to a bad taste or the number
of tablets to be administered, and crushing tablets and mixing them with food is considered a
convenient method of administration to individuals with memory loss or confusion.
However, altering the design of dosage forms may cause a change in the pharmacokinetic
and pharmacological effects of drugs. It is, therefore, not ok to crush some dosage forms for
the following reasons.
i. Crushing creates hazards for pharmacists: crushing teratogenic drugs or carcinogenic
drugs such as valganciclovir or methotrexate exposes pharmacists to risks via the
aerosolization of powder, in a similar way to some hormones, corticosteroids,
mycophenolate and many other drugs.
ii. Powder dust is one of the major factors that must be controlled during the
manufacturing of OSDFs since this factor is responsible of cross-contamination and
may cause serious hazards to operators.
iii. Crushing OSDFs may hurt drug stability; an example is nifedipine-coated tablets, as
this drug is very light-sensitive when crushed.
iv. Proton-pump inhibitors such as omeprazole and pantoprazole are enteric coated. This
coat protects them from the acidic environment of the stomach. This permits them to
 reach unchanged the site of absorption. The effect of the drug coating will be
removed by crushing it, which will decrease the drug’s effect in the small intestine.
v. Changes in bioavailability are another problem associated with crushing OSDFs.
These changes may be very significant for drugs with a narrow therapeutic window
such as carbamazepine or digoxin.
vi. One of the major disadvantages of sustained-release tablets is due to the rupture of
this design (coat or matrix), which cause the release of the content in the
gastrointestinal tract (GIT), causing toxic levels of the active pharmaceutical
ingredients.
vii. For drugs that have a problem with their taste, such as ciprofloxacin, clarithromycin
and sertraline, a coating is utilized to hide their unpleasant bitter or anaesthetic taste.
Crushing drugs with a bitter taste may lead patients to reject taking drugs unless
mixed with suitable food or drink.
Which routes of administration have the fastest and slowest rates of absorption?
Fastest: Intravenous (IV)
Slowest: Oral (PO)
Relative Onset, Monitoring And Appropriate Use Of Various Dosage Forms

o Patches (ie; fentanyl, rivastigmine)

The fentanyl transdermal system (Duragesic) consists of a fentanyl-containing patch that is
applied to the skin of the upper torso.

The drug is slowly released from the patch and absorbed through the skin, reaching effective
levels in 24 hours. Levels remain steady for another 48 hours, after which the patch should be
replaced.

If a new patch is not applied, effects will nonetheless persist for several hours, owing to
continued absorption of residual fentanyl remaining in the skin.

Transdermal fentanyl is indicated only for persistent severe pain in patients who are already
opioid tolerant. Use in nontolerant patients can cause fatal respiratory depression.

The patch should not be used in children younger than 2 years or in anyone younger than 18
years who weighs less than 110 pounds. Also, the patch should not be used for postoperative
pain, intermittent pain, or pain that responds to a less powerful analgesic.

Understand the mechanism of action, side effects, appropriate use and contraindications
for the classes of drugs and individual drugs listed below. Also, know the key patient
education points including cautions, expected effects, and appropriate use (with food,
empty stomach, etc.).
Loperamide
Loperamide (Imodium, others) is a structural analog of meperidine. The drug is employed to
treat diarrhea and reduce the volume of discharge from ileostomies.
Benefits derive from suppressing bowel motility and from suppressing fluid secretion into the
intestinal lumen. The drug is poorly absorbed and does not readily cross the blood–brain barrier.
Very large oral doses do not elicit morphine-like subjective effects.
Loperamide has little or no potential for abuse and is not regulated under the CSA. The drug is
supplied in 2-mg capsules, in 2- mg tablets, and in two liquid formulations (1 mg/5 mL and 1 
mg/7.5 mL
Diphenoxylate HCl With Atropine Sulfate
Diphenoxylate/atropine combination is a medication used in the management and treatment of
diarrhea. It is in the antimotility class of drugs.

Indications

Diphenoxylate is an active ingredient of commonly available antimotility agents. Its indication is

for the treatment of diarrhea in adults and children 13 years or older or as add-on therapy in
managing acute non-infectious diarrhea.

These conditions include diarrhea-predominant-irritable bowel syndrome, ulcerative colitis, and

Crohn disease, which have not responded to other medications. It is mainly used in a short-term
course only but is a possible therapeutic consideration for chronic diarrhea.

Long-term use requires the close supervision of a physician as its prolonged use may lead to
dependence.

Mechanism of Action

Diphenoxylate is an opioid agonist that acts on the presynaptic opioid receptors (predominantly
mu receptors) in the enteric nervous system. 

The enteric nervous system is comprised of two components: the myenteric plexus and
submucosal plexus.

The myenteric plexus lies between the circular and longitudinal smooth muscles of the bowel
wall and controls segmental contractions, i.e., peristaltic movements of the gut. The submucosal
plexus controls the secretions of fluid and electrolytes in the lumen of the intestine.
By acting on the presynaptic opioid receptors, it blocks the release of acetylcholine in the
synaptic cleft and hence inhibits the motility and secretory action of the enteric nervous system.

This action leads to a decrease in segmental contractions and prolongation of gastrointestinal

transit time. Diphenoxylate reduces the epithelial secretion of fluid and electrolytes and enhances
active absorption by mild action on delta receptors.

It does not have analgesic effects of morphine at standard doses, but it can lead to CNS effects,
like euphoria, at higher doses. 

The drug can have misuse potential if used for a prolonged time and classified as a Schedule II
drug under the Food and Drug Administration when used alone.

Atropine is added in a fixed dose of 0.025 mg; it is a competitive inhibitor of acetylcholine

receptors to prevent patients from misusing diphenoxylate. Atropine produces anticholinergic
side effects like nausea/bloating/tachycardia/dryness of mouth/eyes when ingested at higher
doses.

These adverse effects are unpleasant for the patient and discourage overdosing. The combination
medication is Schedule V.

Administration

Diphenoxylate hydrochloride/atropine sulfate combination is available as the fixed-dose

composition of 2.5 mg/0.025 mg. Diphenoxylate/atropine is available in both tablet and liquid
preparation.

Only the liquid preparation can be administered to children, not tablets. A maximum of eight
tablets, i.e., 20 mg of diphenoxylate, can be administered in 24 hours.

The dose is the same for children between 13 to 17 years. There is not enough evidence available
specifying the safety of diphenoxylate/atropine in children <13 yrs. However, the drug is
contraindicated in children < 6yrs due to severe complications.

Using medicine in quantities of more than 20 mg is associated with symptoms related to toxicity.

 The initial dose of 20 mg can be administered for the initial control of symptoms and then
reduced to a lower maintenance dose as per individual requirements. 

Clinical improvement after administration usually occurs within 48 hours. If there is no

improvement seen within ten days of maximum dosing, further drug administration is unlikely to
make a difference.
The preparation of diphenoxylate hydrochloride is insoluble in commonly available aqueous
media. This property precludes the self-administration of the drug.

A dose of 100 to 300 mg/day, or the equivalent of 40 to 120 tablets, administered over 50 to 70
days, can produce opioid withdrawal symptoms if the patient stops the drug abruptly.

Adverse Effects

Children: Diphenoxylate/atropine can cause respiratory and CNS depression in children <6

years.
Toxicity: At higher doses, it can present with anticholinergic side effects like hyperthermia,
tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes, confusion,
headache, or opioid side effects like respiratory depression.
Electrolyte imbalance: The drug can worsen dehydration and electrolyte imbalance in patients
with pre-existing electrolyte imbalance. Therefore, the electrolyte imbalance needs correction
before the administration of the drug.
Gastrointestinal complications:  Diphenoxylate/atropine can precipitate GI complications,
including sepsis and prolonged diarrhea when administered in patients with infectious
diarrhea. This effect is because of the prolongation of GI transit time and decreased GI motility,
which leads to bacterial overgrowth and release of enterotoxins into the bloodstream, creating a
septic shock-like picture.
Toxic Megacolon: This drug can precipitate toxic Megacolon in patients with acute ulcerative
colitis. Due to decreased motility, the physiological secretions might accumulate in the bowel
leading to distension. The colon is already fragile in ulcerative colitis and is prone to rupture.
Drug Interactions: Diphenoxylate crosses the blood-brain barrier and causes central side effects
like depression,  sedation/drowsiness, numbness of extremities, euphoria, malaise/lethargy,
confusion,  dizziness, restlessness, headache, hallucination. Therefore its use requires caution in
patients already taking drugs with CNS activity such as barbiturates, benzodiazepines,
antipsychotics, antihistamines, or MAO inhibitors.
Allergic reactions: Patients can develop allergic reactions like anaphylaxis, urticaria,
angioneurotic edema,  swelling of the gums, pruritus. Clinicians should not administer the drug
to patients with previous episodes of an allergic reaction.
Rare: As its main action is on the enteric nervous system, higher doses can cause paralytic ileus,
pancreatitis.

The adverse effects listed above have been organized based on severity and not on frequency.

Contraindications
1. Patients who have known hypersensitivity to diphenoxylate or atropine.
 2. Patients with obstructive jaundice. Due to mu receptor agonism, diphenoxylate leads to
constriction of the sphincter of Oddi, which leads to the worsening of symptoms of
obstructive disease.
3. Children <6 yrs should not be administered diphenoxylate/atropine tablets owing to the
high risk of severe CNS/respiratory depression.
4. Diarrhea associated with pseudomembranous colitis (Clostridium difficile) or
enterotoxin-producing bacteria due to the risk of gastrointestinal complications like sepsis
and prolonged/worsened diarrhea.
Cautions
1. Patients with electrolyte imbalance as the drug decrease GI motility, potentially leading
to fluid retention and aggravating electrolyte imbalance & dehydration.
2. Patients with advanced hepatorenal disease, which can precipitate hepatic coma.
3. Other CNS depressants - Diphenoxylate/atropine can potentiate CNS depression when
used with other drugs like
barbiturates/benzodiazepines/tranquilizers/anxiolytics/antipsychotics/general
anesthetics/alcohol.
4. Patients with infectious diarrhea - Diphenoxylate/atropine can lead to gastrointestinal
complications like sepsis/ prolonged or worsening diarrhea by decreasing GI motility and
enhancing bacterial overgrowth and release of enterotoxins. These organisms include
toxigenic E.coli/Salmonella/Shigella/Clostridium difficile induced pseudomembranous
colitis
5. Patients with acute ulcerative colitis are at risk of developing toxic megacolon. Therefore
the drug has to be withdrawn if any signs of abdominal distension appear. 
6. In theory, the administration of diphenoxylate/atropine in patients taking monoamine
oxidase inhibitors can precipitate hypertensive crisis. This effect occurs as the chemical
structure of diphenoxylate hydrochloride is similar to meperidine hydrochloride.

Monitoring

Diphenoxylate is a Schedule V controlled substance classified by the Food and Drug

Administration and has minimal abuse potential. 

Monitoring is essential in patients who require a long-term course of the medication.

Diphenoxylate's chemical structure is similar to meperidine, which is a potent opioid analgesic.
This property is linked to dependence with prolonged use of diphenoxylate/atropine
and requires clinician supervision. 

Close monitoring is essential in patients with diarrhea associated with ulcerative colitis as this
medication increases the risk of toxic megacolon. Any symptom suggestive of toxic megacolon
like abdominal distension/decreased bowel sounds should prompt withdrawal of the drug.

This drug is withheld in patients with diarrhea associated with electrolyte imbalance until it's
corrected as it can precipitate dehydration. The initial and maximum dosage administered in 24
hours is 20 mg, i.e., eight tablets. 

Clinicians should monitor for symptoms of overdose in patients receiving higher doses of
diphenoxylate/atropine, which can present as mild dryness of mucous membranes or severe such
as respiratory and CNS depression.

Toxicity

Overdose can be life-threatening. The presentation can be delayed for up to 30 hours since the
drug decreases gastric emptying and hence takes time to reach toxic levels in the blood. 

Symptoms vary from anticholinergic to opioid toxidromes, like respiratory depression,

tachypnea, coma, delirium, lethargy, hyperthermia, tachycardia, dryness of mucous membranes,
mydriasis or miosis, encephalopathy, seizures.

The respiratory depression might correlate with the accumulation of difenoxin, which is an active
metabolite of diphenoxylate. The recommended treatment for toxicity is naloxone if the patient
exhibits respiratory depression.

Considerations may be given for gastric lavage and administration of activated charcoal if
indicated.

Close monitoring for 24 hours is advisable in significant overdose or those with concerning
symptoms. Naloxone is a pure mu (opioid) receptor antagonist which reverses the opioid toxicity
effects caused by diphenoxylate toxicity.
Recurrent episodes of respiratory depression require repeated doses of naloxone or infusion.

Laxatives
Laxatives can be highly beneficial when employed for valid indications. By
softening the stool, laxatives can reduce the painful elimination that can be
associated with episiotomy and with hemorrhoids and other anorectal lesions. In
patients with cardiovascular diseases.

Bulk-forming agents have the same effect on bowel function as dietary fiber. After ingestion,
these agents, which are nondigestible and nonabsorbable, swell in water to form a viscous
solution or gel, thereby softening the fecal mass and increasing its bulk.
Fecal volume may be further enlarged by the growth of colonic bacteria, which can utilize these
materials as nutrients. Transit through the intestine is hastened because swelling of the fecal mass
stretches the intestinal wall, thereby stimulating peristalsis.
Bulk-forming laxatives are preferred agents for the temporary treatment of constipation. Also,
they are widely used in patients with diverticulosis and irritable bowel syndrome.
In addition, by altering fecal consistency, they can provide symptomatic relief of diarrhea and
can reduce discomfort and inconvenience for patients with an ileostomy or colostomy
 5. Therapy for various gastrointestinal disorders including antiemetics, ulcers,
irritable bowel syndrome, Crohn’s ulcerative colitis (ie; alosetron, PPIs like
omeprazole, Mesalamine, ranitidine, etc.)
Antiemetics
Several types of receptors are involved in the emetic response. Important among these are
receptors for serotonin, glucocorticoids, substance P, neurokinin-1, dopamine, acetylcholine, and
histamine.
Many antiemetics, including ondansetron (Zofran), dexamethasone, aprepitant (Emend),
prochlorperazine, and dimenhydrinate, act by blocking (or activating) one or more of these
receptors.
Ulcers
Ulcers result from four causes:
• Increased secretion of acid and pepsin
• Decreased production of cytoprotective mucus and bicarbonate
• Decreased submucosal blood flow
• The direct irritant action of aspirin on the gastric mucosa
Direct injury to the stomach is most likely with aspirin preparations that dissolve slowly: owing
to slow dissolution, particulate aspirin becomes entrapped in folds of the stomach wall, causing
prolonged exposure to high concentrations of the drug.

Because aspirin-induced ulcers are often asymptomatic, perforation and upper GI hemorrhage
can occur without premonitory signs. (Hemorrhage is due in part to erosion of the stomach wall
and in part to suppression of platelet aggregation.

Prophylaxis with a proton pump inhibitor (PPI) is recommended for patients at risk, including
those with a history of peptic ulcers, those taking glucocorticoids, and older adults. PPIs (e.g.,
omeprazole, lansoprazole) reduce ulcer generation by suppressing production of gastric acid.

In addition to PPIs, other drugs that may be considered include histamine-2 receptor antagonists
(H2RAs) and misoprostol. COX-2 inhibitors may also be tried instead of traditional NSAIDs
because they are thought to produce fewer GI side effects.

Because many ulcers are caused by infection with Helicobacter pylori, the panel recommends
that patients with ulcer histories undergo testing and treatment for H. pylori before starting long-
term aspirin use.

Irritable bowel syndrome

IBS is a GI disorder characterized by crampy abdominal pain—sometimes
severe—occurring in association with diarrhea, constipation, or both.
Formally, IBS is defined by the Rome IV criteria as the presence, for at least 12 weeks in the
previous year, of abdominal pain or discomfort that cannot be explained by structural or
chemical abnormalities and that has at least two of the following features:

• Pain related to defecation.

• Onset associated with a change in frequency of stool.
• Onset of pain associated with a change in stool consistency
(from normal to loose, watery, or pellet-like).
IBS has four major forms, characterized as follows:
• Abdominal pain in association with diarrhea (diarrheapredominant IBS; IBS-D)
• Abdominal pain in association with constipation (constipationpredominant IBS; IBS-C)
• Abdominal pain in association with alternating episodes of
diarrhea and constipation (mixed IBS; IBS-M)
• Abdominal pain in association with episodes of diarrhea and/or
constipation that do not fit well into the other categories and thus
unclassified (IBS-U).

Two groups of drugs are used for treatment: nonspecific drugs and drugs specific for IBS. Both
groups are discussed next.
Nonspecific Drugs
Four groups of drugs—antispasmodics (e.g., hyoscyamine and dicyclomine), bulk-forming
agents (e.g., psyllium and polycarbophil), antidiarrheals (e.g., loperamide), and tricyclic
antidepressants (TCAs)—have been employed for years to provide symptomatic relief.
For some patients, symptoms can be relieved with antibiotics or an acid suppressant.

Therapeutic Goal: Decrease in IBS symptoms, including diarrhea, constipation, and abdominal
pain.
Baseline Data: Baseline symptoms, including duration and prior treatments as well as defecation
patterns.
Monitoring: Laboratory monitoring not needed. Identifying High-Risk Patients: Women
taking alosetron must enroll in a risk-management program for treatment.
Evaluating Therapeutic Effects: Evaluate for decrease in abdominal pain, increase in bowel
movements in patients with IBS-C, and decrease in amount or increase in quality of bowel
movements in patients with IBS-D.
Minimizing Adverse Effects: Patients who develop constipation or signs of ischemic colitis
(rectal bleeding, bloody diarrhea, and new or worsening abdominal pain) should immediately
inform the prescriber.
Crohn’s ulcerative colitis
Crohn disease is characterized by transmural inflammation and usually affects the terminal ileum
but can also affect all other parts of the GI tract.

Ulcerative colitis is characterized by inflammation of the mucosa and submucosa of the colon
and rectum. Five types of drugs are employed: 5-aminosalicylates (e.g., sulfasalazine),
glucocorticoids (e.g., hydrocortisone), immunosuppressants (e.g., azathioprine),
immunomodulators (e.g., infliximab), and antibiotics (e.g., metronidazole).

None of these drugs are curative; at best, drugs may control the disease process. Patients
frequently require therapy with more than one agent.
Cough is a complex reflex involving the CNS, the peripheral nervous system, and the muscles of
respiration. The cough reflex can be initiated by irritation of the bronchial mucosa as well as by
stimuli arising at sites distant from the respiratory tract.
Cough is often beneficial, serving to remove foreign matter and excess secretions from the
bronchial tree.

Not all cough, however, is useful. When cough is nonproductive, creates discomfort, or deprives
patients of comfort or sleep, cough suppressant medication is appropriate.

The most common use of cough medicines is suppression of nonproductive cough associated
with the common cold and other upper respiratory infections.

Antitussives are drugs that suppress cough. Some agents act within the CNS; others act
peripherally. The antitussives fall into two major groups: opioid antitussives and nonopioid
antitussives.

Interestingly, although the major antitussives—codeine, dextromethorphan, and

diphenhydramine—are clearly effective against chronic nonproductive cough and experimentally
induced cough, there is no good evidence that these drugs can suppress cough associated with the
common cold.

Cardiac Medications – Digoxin (understand toxicity, dosing, use), Statins, Colestipol,

Nitroglycerin, DDAVP
a. Digoxin toxicity, dosing, use

Digoxin is a medication used to manage and treat heart failure and certain arrhythmias. It is in
the cardiac glycoside class of drugs. Digoxin is beneficial in patients with systolic heart failure,
better known as heart failure with reduced ejection fraction (HFrEF), with an ejection fraction
below 40%.

It is used for rate control in atrial fibrillation or atrial flutter when conventional therapies have
not achieved the heart rate goal.

Digoxin should not be administered in cases of pre-excitation caused by accessory pathways, as

digoxin induces AV blockade and may trigger ventricular tachyarrythmias. It is ineffective in
states of high sympathetic activity.

Beta-blockers are preferable in such cases. Supraventricular tachycardias that are not rate
controlled by traditional therapies may benefit from digoxin.

Digoxin has two principal mechanisms of action, which are selectively employed depending on
the indication:

Positive Ionotropic: It increases the force of contraction of the heart by reversibly inhibiting the
activity of the myocardial Na-K ATPase pump, an enzyme that controls the movement of ions
into the heart.
Digoxin induces an increase in intracellular sodium that will drive an influx of calcium in the
heart and cause an increase in contractility. Cardiac output increases with a subsequent decrease
in ventricular filling pressures.
AV Node Inhibition: Digoxin has vagomimetic effects on the AV node. By stimulating the
parasympathetic nervous system, it slows electrical conduction in the atrioventricular node,
therefore, decreasing the heart rate.
The rise in calcium levels leads to prolongation of phase 4 and phase 0 of the cardiac action
potential, thus increasing the AV node's refractory period. Slower conduction through the AV
node carries a decreased ventricular response.
It is best to administer digoxin intravenously to achieve rapid digitalization. No more than 2 ml
of the drug should be injected at the same site. The injection should be made deep into the
muscle, and the overlying area massaged post-injection.
Intravenous injections are metabolized more efficiently than intramuscular injections and are the
preferred route, as only about 80% of the drug is absorbed in intra-muscular injections as
compared to intravenous dosing. There is a risk of local irritation or myonecrosis.
Digoxin toxicity is clinically relevant as it can lead to fatal cardiac arrhythmias. The estimated
frequency is at about 0.8 to 4% of patients on steady digoxin therapy.
The rate of toxicity increases as serum digoxin concentration reaches over 2.0 ng/ml. However,
toxicity can also occur at lower levels, especially in the setting of other risk factors such as low
body weight, advanced age, decreased renal function, and hypokalemia.
b. Statins
Statins are the most widely prescribed and evidence-based lipid-lowering drug in the world for
lowering LDL-c and reducing cardiovascular morbidity and mortality, both in primary and
secondary prevention. Recent statistics demonstrate increasing statin use in adults aged ≥40
years and in patients with elevated atherosclerotic CVD risk.
Statin toxicity or intolerance most commonly presents as SAMSs. Other side effects of statin
therapy, which can be more serious, include new-onset type 2 diabetes mellitus, neurological and
neurocognitive effects, hepatotoxicity, renal toxicity, and other conditions
It is important to consider all of the clinical manifestations of statin toxicity and intolerance,
which can significantly impact adherence to therapy and subsequent cardiovascular risk.
Mechanistically, statin toxicity is thought to arise because of HMG-CoA reductase inhibition
effects, direct cellular and subcellular effects, or a combination of both. Other possible causes
include genetic factors, drug-drug interactions, vitamin D status, and other metabolic or immune
effects. Regardless of the mechanistic pathway, the end result is a change in drug bioavailability
and activity, which can lead to nonadherence and intolerance
c. Colestipol
Colestipol is an FDA-approved antihyperlipidemic drug used for the treatment of primary
hypercholesterolemia. It is used as adjunctive therapy to dietary modifications and exercise.

Daily doses of 4 to 16 grams are associated with a 12 to 24% reduction in low-density

lipoprotein cholesterol (LDL-C) levels. It may also reduce the risk of coronary artery disease.

Colestipol is also used off-label to treat cholestatic pruritus and irritable bowel syndrome.

Colestipol has been successfully used to treat digoxin toxicity in patients taking this drug.

Colestipol interrupts the enterohepatic circulation of digoxin and increases its fecal excretion.

One case report by Payne et al. reported a reduced half-life of elimination of 55 hours compared
to a predicted half-life of elimination of 85 hours

Colestipol tablets are recommended in doses of 2 grams to 16 grams per day. Therapy should be
initiated at a dose of 2 grams per day. 

Colestipol powdered suspension is recommended in doses of one packet to six packets per day.
One packet contains 5 grams of colestipol.

As it is not systemically absorbed, colestipol does not cause severe side effects; therefore, it is
very safe to prescribe to patients. No reports of toxicity associated with colestipol therapy have
been reported other than the adverse events described above.

Patients often report poor tolerability to colestipol due to its many gastrointestinal adverse effects
and decreased palatability. Therefore, healthcare providers should consider this
and modify treatment accordingly, such as offering a different formulation of the drug.

d. Nitroglycerin
Nitroglycerin, a vasodilator, is typically used to treat anginal chest discomfort.
The FDA currently approves it for the acute prophylaxis of angina pectoris owing to coronary
artery disease (CAD) as well as the acute alleviation of an episode.

It is also used for the treatment of hypertensive urgency/emergency, coronary artery spasm,
cocaine-related angina, and congestive heart failure (CHF)

Most frequently, nitroglycerin is given as a tablet to be swallowed sublingually. There are three
different doses: 0.3 mg, 0.4 mg, and 0.6 mg. Every five minutes until relief is noticed, repeat the
dose. After three doses, if anginal pain still exists, immediate medical intervention is necessary.
Within 1 to 3 minutes after administration, vasodilatory effects start to show up, peaking in 5
minutes. The liver is where nitroglycerin is primarily metabolized, and its half-life is typically 2
to 3 minutes.

Nitroglycerin overdose toxicity is primarily caused by an augmented vasodilatory reaction. In

these patients, it is normal to anticipate hypotension, venous pooling, increased vasodilation, and
decreased cardiac output.

Also possible are compensatory effects like tachycardia and palpitations. In addition to
unpleasant headaches, vasodilation and venous pooling can increase the volume of blood in the
cranial space, raising intracranial pressures and triggering other symptoms like confusion, fever,
vertigo, nausea, and vomiting.

The symptoms will worsen as intracranial pressure rises, finally resulting in dyspnea caused by
decreased respiratory effort, heart block, bradycardia, paralysis, seizures, coma, and death.

Blood pressure medications

a. Calcium channel blockers

Calcium channel blockers (CCBs) are drugs that prevent calcium ions from entering cells.
These agents have their greatest effects on the heart and blood vessels.

CCBs are used widely to treat hypertension, angina pectoris, and cardiac dysrhythmias.
Although they are helpful, there has been controversy about the safety of CCBs, especially in
patients with hypertension and diabetes.

They exist in two categories:

Nondihydropyridine: Agent That Affects the Heart and Blood Vessels (Verapamil)
Dihydropyridine: Agent That Acts Mainly on Blood Vessels (Nifedipine).

Verapamil blocks calcium channels in blood vessels and in the heart. Major indications are
angina pectoris, essential hypertension, and cardiac dysrhythmias.

By blocking calcium channels in the heart and blood vessels, verapamil has five direct effects:
• Blockade at peripheral arterioles causes dilation and thereby
reduces arterial pressure.
• Blockade at arteries and arterioles of the heart increases
coronary perfusion.
• Blockade at the SA node reduces heart rate.
• Blockade at the AV node decreases AV nodal conduction.
• Blockade in the myocardium decreases force of contraction

Verapamil may be administered orally or intravenously. The drug is well absorbed after oral
administration but undergoes extensive metabolism on its first pass through the liver.
Consequently only about 20% of an oral dose reaches the systemic circulation. Effects begin 30
minutes after dosing and peak within 5 hours.

Elimination is primarily by hepatic metabolism. Because the drug is eliminated by the liver,
doses must be reduced substantially in patients with hepatic impairment.
b. ACE inhibitors
The ACE inhibitors have established roles in the treatment of hypertension, heart failure, and
diabetic nephropathy; in addition, these drugs are indicated for myocardial infarction (MI) and
prevention of cardiovascular events in patients at risk.

ACE inhibitors produce their beneficial effects and adverse effects by (1) reducing levels of
angiotensin II (through inhibition of ACE) and (2) increasing levels of bradykinin (through
inhibition of kinase II).

By reducing levels of angiotensin II, ACE inhibitors can dilate blood vessels (primarily arterioles
and to a lesser extent veins), reduce blood volume (through effects on the kidney), and,
importantly, prevent or reverse pathologic changes in the heart and blood vessels mediated by
angiotensin II and aldosterone.

Nearly all ACE inhibitors are administered orally. The only exception is enalaprilat (the active
form of enalapril), which is given intravenously.

Except for captopril and moexipril, all oral ACE inhibitors can be administered with food.

With the exception of captopril, all ACE inhibitors have prolonged half-lives and hence can be
administered just once or twice a day. Captopril is administered two or three times a day.

With the exception of lisinopril, all ACE inhibitors are prodrugs that must undergo conversion to
their active form in the small intestine and liver. Lisinopril is active as given.

All ACE inhibitors are excreted by the kidneys. As a result, nearly all can accumulate to
dangerous levels in patients with kidney disease and hence dosages must be reduced in these
patients. Only one agent—fosinopril—does not require a dosage reduction.
 c. Diuretics
Diuretics have two major applications: in the treatment of hypertension and the mobilization of
edematous fluid associated with heart failure, cirrhosis, or kidney disease.

In addition, because of their ability to maintain urine flow, diuretics are used to prevent renal
failure.

There are four major categories of diuretic drugs: (1) loop diuretics (e.g., furosemide); (2)
thiazide diuretics (e.g., hydrochlorothiazide); (3) osmotic diuretics (e.g., mannitol); and (4)
potassium-sparing diuretics.

The last group, the potassium-sparing agents, can be subdivided into aldosterone antagonists
(e.g., spironolactone) and nonaldosterone antagonists (e.g., triamterene).
In addition to the four major categories of diuretics, there is a fifth group: the carbonic
anhydrase inhibitors.

Most diuretics share the same basic mechanism of action: blockade of sodium and chloride
reabsorption.

By blocking the reabsorption of these prominent solutes, diuretics create osmotic pressure within
the nephron, which prevents the passive reabsorption of water.

Hence diuretics cause water and solutes to be retained within the nephron and thereby promote
the excretion of both.

With oral administration, diuresis begins in 60 minutes and persists for 8 hours. Oral therapy is
used when rapid onset is not required. Furosemide undergoes hepatic metabolism followed by
renal excretion.

Diuresis begins about 2 hours after oral administration. Effects peak within 4 to 6 hours and may
persist up to 12 hours. Most of the drug is excreted unchanged in the urine.

d. Beta Blockers
Beta-blockers, as a class of drugs, are primarily used to treat cardiovascular diseases and other
conditions.

Beta-blockers are indicated and have FDA approval for the treatment of tachycardia,
hypertension, myocardial infarction, congestive heart failure, cardiac arrhythmias, coronary
artery disease, hyperthyroidism, essential tremor, aortic dissection, portal hypertension,
glaucoma, migraine prophylaxis, and other conditions. They are also used to treat less common
conditions such as long QT syndrome and hypertrophic obstructive cardiomyopathy. 

Beta-blockers are available for administration in three primary forms: oral, intravenous, and
ophthalmic, and the route of administration often depends on the acuity of the illness (parenteral
use in arrhythmias), disease type (topical use in glaucoma), and chronicity of the disease. 
Beta-blockers are available in oral, intravenous, or ophthalmic forms and are also injectable
intramuscularly.
Dosages are available in various ranges, depending on the specific medication. Outpatient
prescriptions may include once-a-day dosing for longer-acting beta-blockers, such as metoprolol
succinate. However, most beta blockers are often dosed at least twice per day.
Certain beta-blockers, such as propranolol, with a half-life of approximately 4 hours, are dosed
up to 3 or 4 times a day, depending on the indication and dose.
e. Nitroprussides
Nitroprusside is a direct-acting vasodilator that relaxes smooth muscle of arterioles and veins.
Curiously, although nitroprusside is an effective arteriolar dilator, reflex tachycardia is minimal.
Nitroprusside can trigger retention of sodium and water; furosemide can help counteract this
effect
f. Other Diuretics
Spironolactone is a potassium-sparing diuretic that works by blocking the action of aldosterone
in the kidneys. It is used to treat hypertension and edema due to heart failure.
Furosemide is a loop diuretic that works by blocking the reabsorption of sodium and chloride in
the ascending loop of Henle in the kidneys. It is used to treat hypertension and edema due to
heart failure, liver failure, and renal disease.
Hydrochlorothiazide is a thiazide diuretic that works by blocking the reabsorption of sodium
and chloride in the distal convoluted tubule in the kidneys. It is used to treat hypertension and
edema due to heart failure.

The mechanism of action for each class of diuretics is different. The mechanism of action for
thiazide diuretics is blocking the reabsorption of sodium and chloride in the distal convoluted
tubule in the kidneys.

The mechanism of action for loop diuretics is blocking the reabsorption of sodium and chloride
in the ascending loop of Henle in the kidneys.
The mechanism of action for potassium-sparing diuretics is blocking the action of aldosterone in
the kidneys.

The mechanism of action for carbonic anhydrase inhibitors is inhibiting carbonic anhydrase in
the proximal convoluted tubule in the kidneys. 

The mechanism of action for osmotic diuretics is increasing osmotic pressure in the glomerular
filtrate.

The side effects for each drug can vary but common side effects include electrolyte imbalances
such as hypokalemia (low potassium), hyponatremia (low sodium), hyperkalemia (high
potassium), hyperuricemia (high uric acid), hyperglycemia (high blood sugar), hypomagnesemia
(low magnesium), hypocalcemia (low calcium), metabolic alkalosis (increased pH), metabolic
acidosis (decreased pH), dehydration, dizziness, headache, fatigue, muscle cramps, nausea,
vomiting, diarrhea.

Albuterol
Albuterol (Proventil, Ventolin, VoSpire, others) is a drug of choice in the treatment of asthma. It
can reduce airway resistance in asthma by causing β2- mediated bronchodilation.

Because albuterol is relatively selective for β2 receptors, it produces much less activation of
cardiac β1 receptors than does isoproterenol.

Two oral β2 agonists—albuterol and terbutaline—are approved for long-term control of asthma.
Dosing is 3 or 4 times a day

Exceeding recommended doses because doing so may cause undesired cardiac stimulation

Albuterol is associated with rare congenital anomalies. Albuterol also may decrease uterine
contractility

LABAs

Three single-agent inhaled LABAs are approved for treatment of asthma: salmeterol (Serevent
Diskus), formoterol (Foradil Aerolizer), and arformoterol (Brovana), the (R,R)-enantiomer of
formoterol.

Vilanterol, another LABA, is available only in combination with a glucocorticoid

(fluticasone/vilanterol [Breo Ellipta] and umeclidinium/vilanterol [Anoro Ellipta]).

LABAs have a long duration of action and thus are suited for long-term control. Dosing is every
12 hours.
If supplemental bronchodilation is needed between doses, a SABA should be used. As discussed
previously, LABAs are not first-choice agents for longterm control, and they should not be used
alone.

Rather, they should always be combined with an inhaled glucocorticoid, preferably in the same
inhaler device.

Although salmeterol is usually inhaled twice daily (every 12 hours), with continuous use, more
frequent dosing may be needed because benefits seem to persist for a shorter time as the duration
of treatment increases.

Asthma drugs
a. Theophylline
Theophylline (Theo-24, Theochron, Elixophyllin, Theolair , Uniphyl ) is the principal
methylxanthine employed in asthma.

Benefits derive primarily from bronchodilation. Theophylline has a narrow therapeutic range, so
dosage must be carefully controlled.

The drug is usually administered by mouth but may also be administered intravenously.

Theophylline produces bronchodilation by relaxing smooth muscle of the bronchi. Although the
mechanism of bronchodilation has not been firmly established, the most probable is blockade of
receptors for adenosine.

Oral theophylline is used for maintenance therapy of chronic stable asthma. Although less
effective than β2 agonists, theophylline has a longer duration of action (when administered in a
sustained-release formulation).

With regular use, theophylline can decrease the frequency and severity of asthma attacks.
Because its effects are prolonged, theophylline may be most appropriate for patients who
experience nocturnal attacks.

IV theophylline has been used in emergencies. However, the drug is no more effective than β2
agonists and glucocorticoids and is clearly more dangerous.

Oral theophylline is available in sustained-release formulations and as an elixir.

Absorption from sustained-release preparations is slow, but the resulting plasma levels are stable,
being free of the wide fluctuations associated with the immediate-release products.

Absorption from some sustained-release preparations can be affected by food.

Theophylline is metabolized in the liver. Rates of metabolism are affected by multiple factors—
age, disease, drugs—and show wide individual variation. As a result, the plasma half-life of
theophylline varies considerably among patients.
Smoking either tobacco or marijuana accelerates metabolism and decreases the half-life

Warn patients that, if a dose is missed, the following dose should not be doubled.
Instruct patients to swallow enteric-coated and sustained-release
formulations intact, without crushing or chewing.

Warn patients against consuming caffeine-containing beverages (e.g., coffee, many soft drinks)
and other sources of caffeine. Explain that caffeine can intensify adverse effects while decreasing
theophylline breakdown.

Instruct patients to call the clinic if they start to develop symptoms of nausea, vomiting,
abdominal discomfort, diarrhea, insomnia, restlessness, or palpitations, because these may
signify theophylline toxicity.

Warn patients that smoking tobacco or marijuana can increase theophylline clearance, resulting
in ineffective dosing.

b. Zafirlukast
Zafirlukast (Accolate) was the first representative of a unique group of
antiinflammatory agents, the LTRAs. The drug is approved for maintenance therapy of chronic
asthma in adults and children 5 years and older.

Benefits derive in part from reduced infiltration of inflammatory cells, resulting in decreased
bronchoconstriction.

Zafirlukast is administered orally, and absorption is rapid. Food reduces absorption by 40%;
therefore the drug should be administered at least 1 hour before meals or 2 hours after.

Zafirlukast undergoes hepatic metabolism followed by fecal excretion. The half-life is

approximately 10 hours but may be as long as 20 hours in older adults.

The most common side effects of zafirlukast are headache and gastrointestinal (GI) disturbances,
both of which are infrequent. Arthralgia and myalgia may also occur.

Like zileuton, zafirlukast can cause depression, suicidal thinking, hallucinations, and other
neuropsychiatric effects.

A few patients have developed Churg-Strauss syndrome, a potentially fatal disorder

characterized by weight loss, flulike symptoms, and pulmonary vasculitis (blood vessel
inflammation).

Zafirlukast inhibits several isoenzymes of cytochrome P450 and can suppress metabolism of
other drugs, causing their levels to rise.

Concurrent use can raise serum theophylline to toxic levels. Theophylline levels should be
closely monitored, especially when zafirlukast is started or stopped.
Zafirlukast can also raise levels of warfarin and thus may cause bleeding.

c. Steroids

Steroids a.k.a Androgens are hormones that promote expression of male secondary sex
characteristics.

Although approved by the FDA only for management of testosterone deficiency due to
hypogonadism, they continue to be used off label and illicitly for other purposes
The androgens used clinically fall into two basic groups: (1) testosterone and testosterone esters
and (2) 17-α-alkylated compounds (noted for their hepatotoxicity)

FDA approves testosterone for use in patients with confirmed testosterone deficiency due to
hypogonadism.

However, FDA emphasizes that lowered testosterone due to aging did not meet the criteria for
hypogonadism.

Hypogonadism is a condition in which the testes fail to produce adequate amounts of

testosterone.

Male hypogonadism may be hereditary, or it may result from other causes, including pituitary
failure, hypothalamic failure, and primary dysfunction of the testes.
Other instances when testosterone therapy is administered include in cachexia, in delayed
puberty and in menopausal women.

Virilization is the most common complication of androgen therapy.

When taken in high doses by women, androgens can cause acne, deepening of the voice,
proliferation of facial and body hair, male-pattern baldness, increased libido, clitoral
enlargement, and menstrual irregularities.

Clitoral growth, hair loss, and lowering of the voice may be irreversible.

Masculinization can also occur if taken by children (e.g., for sports performance enhancement).
Boys may experience growth of pubic hair, penile enlargement, increased frequency of erections,
and even priapism (persistent erection).

In girls, growth of pubic hair and clitoral enlargement may occur.

To prevent irreversible masculinization, androgens must be discontinued when virilizing effects
first appear.

Gout and arthritis therapies

Gout is a rheumatic disease associated with severe joint pain due to uric acid crystals.

Gout is a recurrent inflammatory disorder characterized by hyperuricemia (high blood levels of

uric acid) and episodes of severe joint pain, typically in the large toe.

Hyperuricemia—defined as a blood uric acid above 7 mg/dL in men or 6 mg/dL in women—can

occur through two mechanisms: (1) excessive production of uric acid and (2) impaired renal
excretion of uric acid
Drugs to manage inflammation can significantly reduce pain.

Drugs to decrease uric acid levels by blocking its synthesis or enhancing its excretion can help to
prevent future episodes, but they can also cause harm
For acute gouty arthritis, NSAIDs are considered agents of first choice. Compared with
colchicine, NSAIDs are better tolerated and their effects are more predictable.

Benefits derive from suppressing inflammation. Treatment should start as soon as possible after
symptom onset.

Most patients experience marked relief within 24 hours; swelling subsides over the next few
days. Adverse effects of NSAIDs include gastrointestinal (GI) ulceration, impaired renal
function, fluid retention, and increased risk for cardiovascular events.

Six drugs—allopurinol, febuxostat, lesinurad, probenecid, pegloticase, and rasburicasea—are

used to reduce uric acid levels.
Three mechanisms are involved:

Allopurinol and febuxostat inhibit uric acid formation.

Probenecid and lesinurad accelerate uric acid excretion.

Pegloticase and rasburicase convert uric acid to allantoin, a compound that is readily excreted by
the kidney.

These drugs lack antiinflammatory and analgesic actions, so they are not useful against an acute
gouty attack.

a. Allopurinol

Allopurinol (Zyloprim) is the current drug of choice for chronic tophaceous gout.

By reducing blood uric acid levels, allopurinol prevents the formation of new tophi and causes
regression of tophi that have already formed, thereby allowing joint function to improve.

Allopurinol is generally well tolerated. Mild side effects include GI reactions (nausea, vomiting,
diarrhea, and abdominal discomfort) and neurologic effects (drowsiness, headache, and metallic
taste).
Prolonged use (more than 3 years) may lead to the formation of cataracts.
Serious but less common adverse effects include bone marrow suppression, hepatotoxicity, and
hypersensitivity.

The most serious toxicity is a rare but potentially fatal hypersensitivity syndrome characterized
by rash, fever, eosinophilia, and dysfunction of the liver and kidneys.

b. Etanercept
Etanercept suppresses inflammation by inhibiting TNF. Etanercept is indicated for patients with
moderately to severely active RA.

In clinical trials, the drug was slightly superior to methotrexate at delaying the progression of
joint damage, and it suppressed signs and symptoms of RA more rapidly.

In addition to RA, etanercept is approved for ankylosing spondylitis, plaque psoriasis, psoriatic
arthritis, and juvenile idiopathic arthritis

Children and adolescents taking TNF inhibitors have developed lymphoma and other
malignancies.

Injection-site reactions—itching, erythema, swelling, pain—occur in 37% of patients but usually

subside in a few days. Other mild but less common reactions include headache, rhinitis,
dizziness, cough, and abdominal pain.
Etanercept increases the risk for several serious adverse effects. These include serious infections,
severe allergic reactions, heart failure, cancer, hematologic disorders, liver injury, and central
nervous system (CNS) demyelinating disorders.

c. Methotrexate
Methotrexate is also approved for management of severe psoriasis after other treatments have
been tried and found to be ineffective.

Methotrexate, under the brand name Xatmep, is approved for the treatment of some cases of
acute lymphoblastic leukemia and the management of polyarticular juvenile idiopathic arthritis
in pediatric patients who do not respond adequately to other therapy.
Major toxicities of methotrexate are hepatic fibrosis, bone marrow suppression, GI ulceration,
and pneumonitis.

To reduce GI and hepatic toxicity, supplementing dosing with folic acid (at least 5 mg/wk) is
recommended.

Supplemental folic acid enters the cell passively and does not compete with methotrexate.
Periodic tests of liver and kidney function are mandatory, as are complete blood cell and platelet
counts.

Methotrexate can cause fetal death and congenital abnormalities and therefore is contraindicated
during pregnancy.

Also, patients using methotrexate for RA may have a reduced life expectancy owing to increased
deaths from cardiovascular disease, infection, and certain cancers (melanoma, lung cancer, and
non-Hodgkin lymphoma)

Agents for hyperthyroid and hypothyroid disease

a. Levothyroxine (Synthroid)

Levothyroxine is a synthetic preparation of thyroxine, a naturally occurring thyroid hormone.

The structure of levothyroxine is identical to that of the natural hormone.

Levothyroxine is the drug of choice for most patients who require thyroid hormone replacement

Absorption of oral levothyroxine is reduced by food. Accordingly, to minimize variability in

blood levels, levothyroxine should be taken on an empty stomach in the morning, at least 30 to
60 minutes before breakfast.

Levothyroxine is indicated for all forms of hypothyroidism, regardless of cause.

The drug is used for congenital hypothyroidism, myxedema coma, simple goiter, and primary
hypothyroidism in adults and children.
In addition, levothyroxine is used to maintain proper levels of thyroid hormones after thyroid
surgery, irradiation, and treatment with antithyroid drugs.

When administered in appropriate dosage, levothyroxine rarely causes adverse effects.

With an acute overdose, thyrotoxicosis may result. Signs and symptoms include tachycardia,
angina, tremor, nervousness, insomnia, hyperthermia, heat intolerance, and sweating.

The patient should be informed about these signs and instructed to notify the prescriber if they
develop.

Chronic overdosage is associated with accelerated bone loss and increased risk for atrial
fibrillation, especially in older adults. Loss of bone increases the risk for fractures.

b. Methimazole
Methimazole (Tapazole) is a first-line drug for hyperthyroidism. Benefits derive from inhibiting
thyroid hormone synthesis.

Methimazole is safer and more convenient than PTU and hence is preferred for most patients—
except women who are pregnant or breastfeeding, and perhaps patients who are in thyrotoxic
crisis.

Therapeutic effects result from blocking synthesis of thyroid hormones. Two mechanisms are
involved.

First, methimazole prevents the oxidation of iodide, thereby inhibiting incorporation of iodine
into tyrosine.

Second, methimazole prevents iodinated tyrosines from coupling. Both effects result from
inhibiting peroxidase, the enzyme that catalyzes both reactions.

Methimazole is well absorbed after oral dosing. Binding to plasma proteins is minimal

Methimazole has four applications in hyperthyroidism:

• It can be used as the sole form of therapy for Graves disease.
• It can be used as an adjunct to radiation therapy until the effects of radiation become manifest.
• It can be given to suppress thyroid hormone synthesis in
preparation for thyroid gland surgery (subtotal thyroidectomy).
• It can be given to patients experiencing thyrotoxic crisis.
Methimazole is generally well tolerated but should be avoided by women who are pregnant or
breastfeeding.

Agranulocytosis is the most dangerous toxicity. The reaction is rare (approximately 3 cases per
10,000 patients) and usually develops during the first 2 months of therapy.
Sore throat and fever may be the earliest indications, and patients should be instructed to report
these immediately

Multiple sclerosis therapies

a. Dantrium or Dantrolene

Dantrolene can relieve spasticity associated with multiple sclerosis, cerebral palsy, and spinal
cord injury.

It is also used to manage muscle contraction and rigidity associated with malignant
hyperthermia.

Unfortunately, because dantrolene suppresses spasticity by causing a generalized reduction in the

ability of skeletal muscle to contract, treatment may be associated with a significant reduction in
strength.

Patients should be informed about possible depressant effects (drowsiness, dizziness,

lightheadedness, fatigue), and advise them to avoid driving and other hazardous activities if
significant impairment occurs.

Inform patients about signs of liver dysfunction too (e.g., jaundice, abdominal pain, malaise),
and instruct them to seek medical attention if these develop.

Warn patients to avoid central nervous system depressants too (e.g., alcohol, benzodiazepines,
opioids, antihistamines) because these drugs will intensify depressant effects of dantrolene.

Dose-related liver damage is the most serious adverse effect. The incidence is 1 in 1000. Deaths
have occurred.

Hepatotoxicity is most common in women older than 35 years. By contrast, liver injury is rare in
children younger than 10 years.

To reduce the risk for liver damage, liver function tests (LFTs) should be performed at baseline
and periodically thereafter.

b. Baclofen
Baclofen is helpful in relieving spasm related to multiple sclerosis and some spinal cord injuries.

It is not approved for management of spasticity related to cerebral palsy, stroke, Parkinson
disease, or Huntington chorea.

Baclofen acts within the spinal cord to suppress hyperactive reflexes involved in regulation of
muscle movement.

The precise mechanism of reflex attenuation is unknown.

Because baclofen is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid
(GABA), it may act by mimicking the actions of GABA on spinal neurons.

Baclofen has no direct effects on skeletal muscle. The drug decreases flexor and extensor spasms
and suppresses resistance to passive movement.

These actions reduce the discomfort of spasticity and allow increased performance. Because
baclofen has no direct muscle relaxant action, it does not decrease muscle strength.

For this reason, baclofen is preferred to dantrolene, a direct-acting muscle relaxer, when
spasticity is associated with significant muscle weakness.

The most common side effects involve the CNS and gastrointestinal tract. Approximately 10% of
patients taking baclofen develop hypotension.

Baclofen is a CNS depressant and hence frequently causes drowsiness, dizziness, weakness, and
fatigue

CNS depression can be minimized with doses that are small initially and then gradually
increased.
Patients should be cautioned to avoid alcohol and other CNS depressants because baclofen will
potentiate the depressant actions of these drugs.

Overdose can produce coma and respiratory depression. Because there is no antidote to baclofen
overdose, treatment for overdose is supportive and should be started immediately.

Antiepileptics
a. Phenytoin

Phenytoin (Dilantin, Phenytek) is the most widely used antiseizure drug, despite having tricky
kinetics and troublesome side effects.

The drug is active against partial seizures as well as primary generalized tonic-clonic seizures.

Phenytoin is of historical importance in that it was the first drug to suppress seizures without
depressing the entire CNS.

At the concentrations achieved clinically, phenytoin causes selective inhibition of sodium

channels.

Specifically, the drug slows recovery of sodium channels from the inactive state back to the
active state.

As a result, entry of sodium into neurons is inhibited, and hence action potentials are suppressed.

Blockade of sodium entry is limited to neurons that are hyperactive.

As a result, the drug suppresses activity of seizure-generating neurons while leaving healthy
neurons unaffected.

The capacity of the liver to metabolize phenytoin is limited. Doses of phenytoin needed to
produce therapeutic effects are only slightly smaller than the doses needed to saturate the hepatic
enzymes that metabolize phenytoin.

Consequently, if phenytoin is administered in doses only slightly greater than those needed for
therapeutic effects, the liver's capacity to metabolize the drug will be overwhelmed, causing
plasma levels of phenytoin to rise dramatically.

Phenytoin can be used to treat all major forms of epilepsy except absence seizures.
The drug is especially effective against tonic-clonic seizures, and phenytoin is a drug of choice
for treating these seizures in adults and older children.
Carbamazepine is preferred to phenytoin for treating tonic-clonic seizures in young children.

Although phenytoin can be used to treat simple and complex partial seizures, the drug is less
effective against these seizures than against tonic-clonic seizures.
Phenytoin can be administered by intravenous (IV) injection to treat generalized convulsive SE,
but other drugs are preferred.

Manifestations of excessive dosage include sedation, ataxia (staggering gait), diplopia (double
vision), and cognitive impairment
 b. Diazepam
Diazepam (Diastat, Valium) is a member of the benzodiazepine family.

Like baclofen, diazepam acts in the CNS to suppress spasticity. Beneficial effects appear to
result from mimicking the actions of GABA at receptors in the spinal cord and brain.

Diazepam does not affect skeletal muscle directly.

Because diazepam has no direct effects on muscle strength, the drug is preferred to dantrolene
when muscle strength is marginal.

Sedation is common when treating spasticity. To minimize sedation, initial doses should be low

c. Ethosuximide
Ethosuximide suppresses neurons in the thalamus that are responsible for generating absence
seizures.

The specific mechanism is inhibition of lowthreshold calcium currents, known as T currents.

Ethosuximide does not block sodium channels and does not enhance GABA-mediated neuronal
inhibition.

Ethosuximide (Zarontin) is the drug of choice for absence seizures, the only indication it has.

Absence seizures are eliminated in 60% of patients, and, in newly diagnosed patients, practical
control is achieved in 80% to 90% of cases.

Ethosuximide is generally devoid of significant adverse effects and interactions.

During initial treatment, it may cause drowsiness, dizziness, and lethargy. These diminish with
continued use.

Nausea and vomiting may occur and can be reduced by administering the drug with food.

Rare but serious reactions include systemic lupus erythematosus, leukopenia, aplastic anemia,
and SJS.

Osteoporosis drugs

a. Calcitonin
Calcitonin has two principal actions: (1) it inhibits the activity of osteoclasts and thus decreases
bone resorption, and (2) it inhibits tubular resorption of calcium, thereby increasing calcium
excretion.

As a result of decreasing bone turnover, calcitonin decreases alkaline phosphatase in blood and
increases hydroxyproline in urine.
Calicitonin has three indications. It is used to treat (1) postmenopausal osteoporosis, (2) Paget
disease, and (3) hypercalcemia.

Calcitonin, given by nasal spray or injection, is indicated for treatment of established

postmenopausal osteoporosis—but not for prevention.

Benefits derive from suppressing bone resorption. Unfortunately, these benefits subside within 1
or 2 years after the drug is discontinued.

The treatment program should include supplemental calcium and adequate intake of vitamin D.

With intranasal dosing, nasal dryness and irritation are the most common complaints.

After parenteral (IM, subcutaneous [subQ]) administration, about 10% of patients experience
nausea, which diminishes with time.

An additional 10% have inflammatory reactions at the injection site. Flushing of the face and
hands may also occur.

Patients should be taught how to inject calcitonin subcutaneously. Instruct them to rotate sites of
injection.

Pain drugs
a. Opoids
An opioid is any drug, natural or synthetic, that has actions similar to those of morphine.
The term opiate is more specific and applies only to compounds present in opium (e.g.,
morphine, codeine).

Morphine is the prototype of the strong opioid analgesics and remains the standard by which
newer opioids are measured.

Morphine has multiple pharmacologic effects, including analgesia, sedation, euphoria,

respiratory depression, cough suppression, and suppression of bowel motility.

Morphine has multiple pharmacologic actions. In addition to relieving pain, the drug causes
drowsiness and mental clouding, reduces anxiety, and creates a sense of well-being.

Through actions in the CNS and periphery, morphine can cause respiratory depression,
constipation, urinary retention, orthostatic hypotension, emesis, miosis, cough suppression, and
biliary colic.

With prolonged use, the drug produces tolerance and physical dependence

The drug is more effective against constant, dull pain than against sharp, intermittent pain.

However, sharp pain can even be relieved by large doses.

The ability of morphine to cause mental clouding, sedation, euphoria, and anxiety reduction can
contribute to relief of pain.

Respiratory depression is the most serious adverse effect. At equianalgesic doses, all of the pure
opioid agonists depress respiration to the same extent.

Death after an overdose is almost always from respiratory arrest. Opioids depress respiration
primarily through activation of µ receptors, although activation of κ receptors also contributes.

The time course of respiratory depression begins up to 90 minutes after PO ingestion.

Opioid medications can cause respiratory arrest in both opioid-naïve and opioid-tolerant patients.

Monitor for respiratory depression, especially during new-onset therapy or after escalation of
dose

Opioids promote constipation through actions in the CNS and gastrointestinal (GI) tract.

Opioid agonists lower blood pressure by blunting the baroreceptor reflex and by dilating
peripheral arterioles and veins.

Peripheral vasodilation results primarily from morphine-induced release of histamine

Morphine can cause urinary hesitancy and urinary retention

Morphine promotes nausea and vomiting through direct stimulation of the chemoreceptor trigger
zone of the medulla.

When administered to relieve pain, morphine is likely to cause drowsiness and some mental
clouding.

Opioid-induced neurotoxicity can cause delirium, agitation, myoclonus, hyperalgesia, and other
symptoms.

Opioid overdose produces a classic triad of signs: coma, respiratory depression, and pinpoint
pupils.

b. Acetaminophen

Acetaminophen has analgesic and antipyretic properties equivalent to those of aspirin. However,
in contrast to aspirin and the other NSAIDs, acetaminophen is devoid of clinically useful
antiinflammatory and antirheumatic actions.

In addition, acetaminophen does not suppress platelet aggregation, does not cause gastric
ulceration, and does not decrease renal blood flow or cause renal impairment. However,
acetaminophen overdose can cause severe liver injury.

Whereas aspirin can inhibit cyclooxygenase in both the CNS and the periphery, inhibition by
acetaminophen is limited to the CNS; acetaminophen has only minimal effects on
cyclooxygenase at peripheral sites.

By decreasing prostaglandin synthesis in the CNS, acetaminophen is able to reduce fever and
pain.

The inability to inhibit prostaglandin synthesis outside the CNS may explain the absence of
antiinflammatory effects, gastric ulceration, and adverse effects on the kidneys and platelets.

Acetaminophen is readily absorbed after oral dosing and undergoes wide distribution.

Most of each dose is metabolized by the liver, and the metabolites are excreted in the urine.

The plasma half-life is approximately 2 hours.

Acetaminophen can be metabolized by two pathways; one is major and the other minor

At therapeutic doses, practically all of the drug is converted to nontoxic metabolites through the
major pathway.

Only a small fraction is converted into the toxic metabolite through the minor pathway.

Furthermore, under normal conditions, the toxic metabolite undergoes rapid conversion to a
nontoxic form; glutathione is required for the conversion
Orlistat
Orlistat (Alli, Xenical) is a novel drug approved for promoting and maintaining weight loss in
obese patients aged 12 years and older.

Unlike most other weightloss drugs, which act in the brain to curb appetite, orlistat acts in the
gastrointestinal (GI) tract to reduce the absorption of fat.

Specifically, the drug acts in the stomach and small intestine to cause irreversible inhibition of
gastric and pancreatic lipases, enzymes that break down triglycerides into monoglycerides, and
free fatty acids.

If triglycerides are not broken down, they cannot be absorbed. In patients taking orlistat,
absorption of dietary fat is reduced by about 30%.

Patients must adopt a reduced-calorie diet in which 30% of calories come from fat.

Orlistat undergoes less than 1% absorption; hence systemic effects are absent. In contrast, GI
effects are common.

Approximately 20% to 30% of patients experience oily rectal leakage, flatulence with discharge,
fecal urgency, and fatty or oily stools. Another 10% experience increased defecation and fecal
incontinence.

All of these are the result of reduced fat absorption, and all can be minimized by reducing fat
intake.

Orlistat has been associated with rare cases of severe liver damage. Signs and symptoms include
itching, vomiting, jaundice, anorexia, fatigue, dark urine, and light-colored stools.

Adrenergic agonists
a. Anticoagulants
Anticoagulants are drugs that reduce the formation of fibrin. Two basic mechanisms are
involved.

One anticoagulant—warfarin—inhibits the synthesis of clotting factors, including factor X and

thrombin. All other anticoagulants inhibit the activity of clotting factors: factor Xa, thrombin, or
both.

Anticoagulants are in three pharmacologic classes—vitamin K antagonists, direct factor Xa

inhibitors, and direct thrombin inhibitors.

Heparin and all other anticoagulants pose a risk for spinal or epidural hematoma in patients
undergoing spinal puncture or spinal or epidural anesthesia.

Pressure on the spinal cord caused by the bleed can result in prolonged or permanent paralysis
 b. Anesthetics
Isoflurane
Isoflurane is a volatile anesthetic approved by the Federal Drug Administration (FDA) for the
induction and maintenance of general anesthesia.

Induction and maintenance of general anesthesia are achieved through various sites of action.

The most likely of these sites include inhibition of neurotransmitter-gated ion channels such as
GABA, glycine, and N-methyl-d-aspartate (NMDA) receptors in the central nervous system
(CNS).
 Inhibition of these receptors helps to produce the amnesia and sedation needed for adequate
surgical conditions.

Volatile anesthetics in general also have sites of action within the spinal cord that contribute to
skeletal muscle relaxation through inhibition of NMDA-type glutamate and glycine receptors.

Isoflurane affects the respiratory system by causing a large decrease in tidal volumes with a
minimal increase in respiratory rate leading to an overall decrease in minute ventilation. The
decrease in minute ventilation causes an increased PaCO2.
At concentrations greater than 1 MAC, isoflurane causes an increase in cerebral blood flow and
intracranial pressure. Although blood flow is increased, the cerebral metabolic rate is decreased,
and concentrations of 2 MAC can produce an electrically silent electroencephalogram.
Isoflurane also produces a dose-dependent decrease in renal and hepatic blood flow with no
clinical effect on renal or hepatic function.
c. Dementia medications
Dementia occurs in 40% of PD patients. The AAN guidelines recommend considering treatment
with two drugs: donepezil and rivastigmine.
In patients with PD, these drugs can produce a modest improvement in cognitive function
without causing significant worsening of motor symptoms, even though these drugs increase
availability of acetylcholine at central synapses.
Four drugs are approved for treating AD dementia. Three of the drugs— donepezil, galantamine,
and rivastigmine—are cholinesterase inhibitors. The fourth drug—memantine—blocks neuronal
receptors for N-methyl-D-aspartate (NMDA).
Treatment of dementia with these drugs can yield improvement that is statistically significant but
clinically marginal.
Donepezil (Aricept) is indicated for mild, moderate, or severe AD. The drug causes reversible
inhibition of AChE—but is more selective for the form of AChE found in the brain than that
found in the periphery.

Like other cholinesterase inhibitors, donepezil does not affect the underlying disease process.

Donepezil is well absorbed after oral administration and undergoes metabolism by hepatic
CYP2D6 and CYP3A4 isoenzymes.

Elimination is mainly in the urine and partly in the bile. Donepezil is highly protein bound and
has a prolonged plasma half-life (about 60 hours).

Unlike donepezil, which causes reversible inhibition of AChE, rivastigmine causes irreversible
inhibition.

As with other cholinesterase inhibitors, the benefits in AD are modest.

Like other cholinesterase inhibitors, rivastigmine can cause peripheral cholinergic side effects.

d. Antihyperlipemics

Antihyperlipidemic Drugs lower serum levels of cholesterol and various lipids. They are also
called as lipid-lowering agents; these drugs provide effective treatment for hyperlipidemia
(increased lipid level in the blood).

The incidence of coronary artery disease (CAD), the most common cause of death among adults,
is higher in people with hyperlipidemia.
High level of lipids and triglyceride is associated with metabolic syndrome consist
of insulin resistance, abdominal obesity, hypertension, and proinflammatory and prothrombotic
state

The medications include Bile Acid Sequestrants, HMG-CoA Reductase Inhibitors, Cholesterol
Absorption Inhibitor, Fibrates and Vitamin B

Terminology

Efficacy - Efficacy, or maximal efficacy, is an index of the maximal response a drug can
produce. The efficacy of a drug is indicated by the height of its dose–response curve. Efficacy is
an important quality in a drug.

Pharmacokinetics - Pharmacokinetics is the study of drug movement throughout the body.

There are four basic pharmacokinetic processes: absorption, distribution, metabolism, and
excretion.
Absorption is the drug's movement from its site of administration into the blood.
Distribution is the drug's movement from the blood to the interstitial space of tissues and from
there into cells.
Metabolism (biotransformation) is the enzymatically mediated alteration of drug structure.
Excretion is the movement of drugs and their metabolites out of the body. The combination of
metabolism and excretion is called elimination

Pharmacodynamics: Pharmacodynamics is the study of the biochemical and physiologic effects

of drugs on the body and the molecular mechanisms by which those effects are produced.

Drug tolerance: Tolerance is a decreased responsiveness to a drug as a result of repeated drug

administration. There are three categories of drug tolerance:

a. pharmacodynamic tolerance refers to the familiar type of tolerance associated with long-
term administration of drugs such as morphine and heroin. Pharmacodynamic tolerance is
the result of adaptive processes that occur in response to chronic receptor occupation
b. Metabolic tolerance is defined as tolerance resulting from accelerated drug metabolism.
This form of tolerance is brought about by the ability of certain drugs (e.g., barbiturates)
to induce the synthesis of hepatic drug-metabolizing enzymes, thereby causing rates of
drug metabolism to increase. Because of increased metabolism, dosage must be increased
to maintain therapeutic drug levels.
c. Tachyphylaxis is a reduction in drug responsiveness brought on by repeated dosing over a
short time. This is unlike pharmacodynamic tolerance and metabolic tolerance, which
take days or longer to develop. Transdermal nitroglycerin provides a good example of
tachyphylaxis. When nitroglycerin is administered using a transdermal patch, effects are
lost in less than 24 hours if the patch is left in place around the clock.
Addiction: Addiction is a complex but treatable disease that affects brain function and behavior

Dependence: Physical dependence is a state in which abrupt discontinuation of drug use will
precipitate a withdrawal syndrome

Withdrawal: Abrupt discontinuation of medication

First pass effect: The first pass effect is a phenomenon in which a drug gets metabolized at a
specific location in the body that results in a reduced concentration of the active drug upon
reaching its site of action or the systemic circulation. The first pass effect is often associated with
the liver, as this is a major site of drug metabolism. However, the first pass effect can also occur
in the lungs, vasculature, gastrointestinal tract, and other metabolically active tissues in the body.
This effect can become augmented by various factors such as plasma protein concentrations,
enzymatic activity, and gastrointestinal motility.

Idiosyncratic response: Idiosyncratic drug reactions may be defined as adverse effects that
cannot be explained by the known mechanisms of action of the offending agent, do not occur at
any dose in most patients, and develop mostly unpredictably in susceptible individuals only.
These reactions are generally thought to account for up to 10% of all adverse drug reactions.

Medication Reconciliation: Medication reconciliation is the process of comparing a list of all

medications that a patient is currently taking with a list of new medications that are about to be
provided. Reconciliation is conducted whenever a patient undergoes a transition in care in which
new medications may be ordered or existing orders may be changed.

Polypharmacy: Treatment with multiple drugs

Which drug classes produce withdrawal if stopped abruptly?

- Clonidine
- Beta blockers such as propranolol
- serotonin-norepinephrine reuptake inhibitors (SNRIs)
- selective serotonin reuptake inhibitors (SSRIs)
- corticosteroids
- Opioids
- muscle relaxants

Which drugs/meds have EPS symptoms?

Extrapyramidal side effects (EPS), commonly referred to as drug-induced movement disorders
are among the most common adverse drug effects patients experience from dopamine-receptor
blocking agents. First-generation antipsychotics commonly caused extrapyramidal symptoms.
With second-generation antipsychotics, side effects tend to occur at lower rates.

Appropriate Use of Herbal Therapies

Herbal medicines are generally sold as food supplements, but a common regulatory framework
does not exist in different countries. As a result, information on clinical indications for their use,
efficacy, and safety are influenced by the traditional experience available in each place.

The Dietary Supplement Health and Education Act (DSHEA) of 1994, any herb, botanical and
natural concentrate, metabolite and constituent of extract, is classified as a dietary supplement.
Dietary supplements do not need approval from the Food and Drug Administration (FDA) before
they are marketed.

Under DSHEA, herbal medicines, which are classified as dietary supplements, are presumed
safe, and the FDA does not have the authority to require them to be approved for safety and
efficacy before they enter the market, which is the case for drugs.

This means that the manufacturer of the herbal medicine is responsible for determining that the
dietary supplements manufactured or distributed are indeed safe and that any representations or
claims made about them are sustained by adequate evidence to show that they are not false or
misleading.

All domestic and foreign companies that manufacture package labels or hold dietary supplements
must follow the FDA’s current good manufacturing practice (GMP) regulations, which outline
procedures for ensuring the quality of supplements intended for sale.

Cultural competence

Cultural competence, cultural humility, and patient-centered care are all concepts that endeavor
to detail essential components of a health care system that is sensitive to patient diversity,
individual choice, and doctor–patient connection.

A culturally competent health care workforce highlights five components: cultural awareness,
knowledge, skill, desire, and encounters.

Cultural humility focuses on identifying one’s own implicit biases, self-understanding, and
interpersonal sensitivity and cultivating an appreciation for the multifaceted components of each
individual (culture, gender, sexual identity, race and ethnicity, religion, lifestyle, etc.), which
promotes patient-centered approaches to treatment.

How can adverse drug events be minimized?

Given the risks of drug and diet interactions as well as individual differences in drug metabolism,
physicians should expect and be mindful that patients will likely experience ADEs from at least 1
of their prescribed medications.

Preventing, identifying, and addressing ADEs from prescribed medications will require
systematic rethinking and redesign of how medications are prescribed, monitored, and
discontinued, particularly medications for chronic conditions.
The most effective interventions for preventing ADEs will require greater involvement and
integration of pharmacists, meaningful implementation and use of medication reconciliation, and
the inclusion of patients and their caregivers.

Overcoming the insidious and pervasive diffusion of responsibility within the current health care
system must be a key component in preventing, identifying, and addressing ADEs from
prescribed medications.

Why do drugs require clinical study and FDA approval?

FDA approval of a drug means that data on the drug’s effects have been reviewed by CDER, and
the drug is determined to provide benefits that outweigh its known and potential risks for the
intended population. The drug approval process takes place within a structured framework that
includes:

 Analysis of the target condition and available treatments

 Assessment of benefits and risks from clinical data
 Strategies for managing risks

Common Teaspoon, Tablespoon, And Milliliter Conversions

DEA schedules and examples of therapies in each scheduled class (1-5). What are the
special prescribing restrictions for these various classes?
Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted
medical use and a high potential for abuse. Some examples of Schedule I drugs are: heroin,
lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine
(ecstasy), methaqualone, and peyote.

Schedule II drugs, substances, or chemicals are defined as drugs with a high potential for abuse,
with use potentially leading to severe psychological or physical dependence. These drugs are
also considered dangerous. Some examples of Schedule II drugs are: combination products with
less than 15 milligrams of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine,
methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin),
fentanyl, Dexedrine, Adderall, and Ritalin

Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low
potential for physical and psychological dependence. Schedule III drugs abuse potential is less
than Schedule I and Schedule II drugs but more than Schedule IV. Some examples of Schedule
III drugs are: products containing less than 90 milligrams of codeine per dosage unit (Tylenol
with codeine), ketamine, anabolic steroids, testosterone

Schedule IV drugs, substances, or chemicals are defined as drugs with a low potential for abuse
and low risk of dependence. Some examples of Schedule IV drugs are: Xanax, Soma, Darvon,
Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol

Schedule V drugs, substances, or chemicals are defined as drugs with lower potential for abuse
than Schedule IV and consist of preparations containing limited quantities of certain narcotics.
Schedule V drugs are generally used for antidiarrheal, antitussive, and analgesic purposes. Some
examples of Schedule V drugs are: cough preparations with less than 200 milligrams of codeine
or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin

Which medications should be taken with food? Which on an empty stomach?

Taken without food:

- Some Antibiotics
- Iron
- Statins
- Thyroid replacements
- Bisphosphonates
- Proton Pump Inhibitors
- Bethanechol Captopril
- Digoxin
- Sucralfate
Taken with food
- aspirin
- non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and ibuprofen
- steroids, such as prednisolone and dexamethasone
- HIV medicine ritonavir
- Medicines for diabetes
What is the purpose of the MedWatch Program

MedWatch receives reports from the public and when appropriate, publishes safety alerts for
FDA-regulated products such as:

 Prescription and over-the-counter medicines

 Biologics such as blood components, blood/plasma derivatives and gene therapies.
 Medical devices such as hearing aids breast pumps, and pacemakers.
 Combination products such as pre-filled drug syringe, metered-dose inhalers and nasal
spray.
 Special nutritional products such as dietary supplements, medical foods and infant
formulas.
 Cosmetics such as moisturizers, makeup, shampoos, hair dyes and tattoos.
 Food such as beverages and ingredients added to foods.

Symptoms and treatment of drug intoxication from cocaine, opioids, marijuana

Opioid intoxication may have a varied presentation. From a neurologic perspective, opioids can
cause euphoria, agitation, drowsiness, delirium, and miotic (“pinpoint”) pupils.
 Other acute signs and symptoms from heroin use may include nausea, vomiting, constipation,
xerostomia, pruritis, diaphoresis, and urinary retention.

Opioid overdose may lead to respiratory depression and stupor.

Treatment of overdose includes use of the opioid antagonist, naloxone, which can be
administered repeatedly as needed by intranasal, parenteral, and pulmonary routes.

For respiratory depression, ventilatory support is necessary and orotracheal intubation may also
provide protection against a major complication of opioid overdose, aspiration

These are some of the signs and symptoms of cocaine intoxication:

 Euphoria and excitement
 Jumbled speech, sometimes about bad things that might happen
 Extreme confusion and anxiety
 Restlessness and agitation
 Muscle tremors, often in the face and fingers
 Dilated pupils that don’t contract even when a light is shined into the eyes
 Rapid or irregular heartbeat
 Increased blood pressure
 Pallor or bluish-colored skin
 Lightheadedness
 Nausea and vomiting
 Fever
 Sweating 
  Lack of awareness of surroundings
 Loss of bladder control
 Rapid or restricted breathing

There are currently no medications that have been approved for the treatment of cocaine
addiction, but there are several behavioral interventions that can be effective. Some of these
include:

 Contingency managment (CM): This approach uses positive reinforcement to motivate

people to stay drug-free. For example, people can earn points that can be exchanged for
prizes such as restaurant gift certificates, gym memberships, movie tickets, and other
incentives.
 Cognitive behavioral therapy (CBT): This approach focuses on the thoughts and
behaviors that contribute to cocaine use. CBT helps people develop coping skills that
help support long-term recovery and abstinence. 
 Therapeutic communities: These are drug-free residential treatment centers where
people learn to change their behaviors as they recover from drug use. Such facilities often
involve an extended stay that includes supportive services and vocational rehabilitation to
improve long-term outcomes.

Marijuana intoxication is the euphoria, relaxation, and sometimes undesirable side effects that
can occur when people use marijuana.

The ability to perform complex tasks may be adversely affected. Many users report excessive
appetite after marijuana use

Treatment of marijuana intoxication is usually unnecessary; for patients experiencing

significant discomfort, treatment is supportive.

Patients with cannabinoid hyperemesis syndrome may require IV fluids and antiemetics
(anecdotal reports suggest haloperidol and topical capsaicin are effective).

The definitive treatment of cannabinoid hyperemesis syndrome is the cessation of marijuana

use.

Management of abuse typically consists of behavioral therapy in an outpatient drug treatment

program.

Appropriate use of reversal agents for digoxin, opioids, etc

Naloxone is an opioid antagonist medication used to block or reverse the effects of opioid drugs,
particularly within the setting of drug overdoses which are rapidly becoming a leading cause of
death worldwide
When taken in large quantities, opioid medications such
as morphine, hydromorphone, methadone, heroin, or fentanyl are capable of causing life-
threatening symptoms such as respiratory depression, reduced heart rate, slurred speech,
drowsiness, and constricted pupils.

 If untreated, this can progress to vomiting, absent pulse and breathing, loss of consciousness,
and even death.

 Naloxone is indicated for the rapid reversal of these symptoms of central nervous system
depression in opioid overdose.

 It's important to note that naloxone only works on opioid receptors within the body, and is
therefore not capable of reversing the effects of non-opioid medications such as stimulants
like methamphetamine or cocaine, or benzodiazepines like lorazepam or diazepam.

Thiamine prevents/treats Wernicke encephalopathy, a disorder caused by thiamine deficiency in

people who abuse alcohol 

Deferoxamine binds to free iron, and it is the antidote for iron poisoning. Deferoxamine is used if
the serum iron level is > 400-500 mcg/dL or when a patient has signs/symptoms of severe iron
poisoning. Deferoxamine is given IV; the dose is weight-based

Digoxin-specific antibodies, aka FAB fragments, bind free digoxin and are used to treat patients
who have signs of serious digoxin poisoning, e.g., hyperkalemia, life-threatening arrhythmias, or
an elevated digoxin level, or children who have ingested > 4 mg and adults who have ingested >
10 mg.

Digoxin-specific antibodies are given IV. Calculate the dose by using the steady-state digoxin
level or by the amount of digoxin ingested 

Glucagon is used to treat beta-blocker and calcium channel blocker overdose. Glucagon bypasses
beta receptors in the heart and increases heart rate, cardiac contractility, and cardiac conduction

Hydroxocobalamin combines with cyanide, and it is the preferred antidote for acute cyanide
poisoning and for cyanide poisoning that occurs during smoke inhalation

Lipid emulsion therapy, aka lipid rescue, is used to treat cardiotoxicity caused by local
anesthetics, and occasionally it has been successful for treating poisoning caused by
antidepressants, beta-blockers, calcium channel blockers, cocaine, and other drugs

Physostigmine is an acetylcholinesterase inhibitor, and it is used to diagnose and treat severe

anticholinergic poisoning