Chapter 28: Drugs for Obesity Flashcards
ANOREXIANTS
Diethylpropion TENUATE
Phentermine ADIPEX-P
LIPASE INHIBITORS
Orlistat ALLI, XENICAL
SEROTONIN AGONISTS
Lorcaserin BELVIQ
COMBINATION DRUGS
Phentermine/Topiramate QSYMIA
ANOREXIANTS (APPETITE SUPPRESSANTS)
Phentermine [FEN-ter-meen] and diethylpropion [dye-eth-ill-PROE-peeon]
are considered appetite suppressants.
A. Mechanism of action: Phentermine exerts its pharmacologic action
by increasing the release of norepinephrine and dopamine from the
nerve terminals and by inhibiting reuptake of these neurotransmitters,
thereby increasing levels of neurotransmitters in the brain. The
increase in norepinephrine signals a “fight-or-flight” response by the
body, which, in turn, decreases appetite. Diethylpropion has similar effects on norepinephrine. Tolerance to the weight loss effect of these
agents develops
within weeks, and weight loss typically plateaus. An
increase in the dosage generally does not result in further weight
loss, and discontinuation of the drug is usually recommended once
the plateau is reached.
B. Pharmacokinetics: Limited information is available regarding the
pharmacokinetics of phentermine. The duration of activity is dependent
on the formulation, and the primary route of excretion is via
the kidneys. Diethylpropion is rapidly absorbed and undergoes
extensive first-pass metabolism. Many of the metabolites are active.
Diethylpropion and its metabolites are excreted mainly via the kidneys.
The half-life of the metabolites is 4 to 8 hours.
C. Adverse effects: All of the anorexiants are classified as controlled
substances due to the potential for dependence or abuse. Dry mouth,
headache, insomnia, and constipation are common adverse effects.
Heart rate and blood pressure may be increased with these agents.
Therefore, these drugs should be avoided in patients with a history of
uncontrolled hypertension, cardiovascular disease, arrhythmias, heart
failure, or stroke. Concomitant use of anorexiants with monoamine oxidase
inhibitors (MAOIs) or other sympathomimetics should be avoided.
LIPASE INHIBITORS
Orlistat [OR-lih-stat] is currently the only available agent in a class of
antiobesity drugs known as lipase inhibitors. It is indicated for weight loss
or weight maintenance. The clinical utility of orlistat is limited by gastrointestinal
adverse effects.
A. Mechanism of action: Orlistat is a pentanoic acid ester that
inhibits gastric and pancreatic lipases, thus decreasing the breakdown
of dietary fat into smaller molecules that can be absorbed.
Administration of orlistat decreases fat absorption by about 30%. The
loss of calories from decreased absorption of fat is the main cause
of weight loss. However, adverse gastrointestinal effects associated
with the drug may also contribute to an overall decreased intake of
food. Figure 28.2 shows the effects of orlistat treatment.
B. Pharmacokinetics: Orlistat is administered orally with each meal
that contains fat. It has minimal systemic absorption and is mainly
excreted in the feces. No dosage adjustments are required in patients
with renal or hepatic dysfunction.
C. Adverse effects: The most common adverse effects associated with
orlistat are gastrointestinal symptoms, such as oily spotting, flatulence
with discharge, fecal urgency, and increased defecation. These
effects may be minimized through a low-fat diet and the use of concomitant
cholestyramine. Pancreatitis and liver injury have occurred
rarely in people taking orlistat. Orlistat is contraindicated in pregnancy
and in patients with chronic malabsorption syndrome or cholestasis.
The drug also interferes with the absorption of fat-soluble vitamins and
β-carotene. Thus, patients should be advised to take a multivitamin
supplement that contains vitamins A, D, E, and K and also β-carotene.
The vitamin supplement should not be taken within 2 hours of orlistat. Orlistat can also interfere with the absorption of other medications,
such as amiodarone, cyclosporine, and levothyroxine, and clinical
response to these medications should be monitored if orlistat is initiated.
The dose of levothyroxine should be separated from orlistat by at
least 4 hours
SEROTONIN AGONISTS
Lorcaserin [lor-KAS-er-in] is a newer serotonin agonist, with selectivity
for the 2C serotonin receptor (5-HT2C). It is used for chronic weight management.
Previous serotonin agonists used for weight loss were pulled
from the market following an increase in potentially fatal adverse effects,
including valvular heart disease. It is believed that valvulopathy, which
may lead to pulmonary hypertension, is linked to 5-HT2B receptors.
A. Mechanism of action: Lorcaserin selectively activates 5-HT2C receptors,
which are almost exclusively found in the central nervous system.
This activation, in turn, stimulates pro-opiomelanocortin neurons,
which activate melanocortin receptors, thereby causing a decrease
in appetite (Figure 28.3). If a patient does not lose at least 5% of their
body weight after 12 weeks of use, the drug should be discontinued.
B. Pharmacokinetics: Lorcaserin is extensively metabolized in the
liver to two inactive metabolites that are then eliminated in the urine.
Lorcaserin has not been studied for use in severe hepatic impairment
and is not recommended in severe renal impairment.
C. Adverse effects: The most common adverse effects observed with lorcaserin
are nausea, headache, dry mouth, dizziness, constipation, and
lethargy. Although rare, mood changes and suicidal ideation can occur.
The development of life-threatening serotonin syndrome or neuroleptic
malignant syndrome has been reported with the use of serotonin
agonists. Therefore, patients should be monitored for the emergence
of these conditions while on lorcaserin. Because of the increased risk
of serotonin syndrome, concomitant use of lorcaserin with selective
serotonin reuptake inhibitors, serotonin–norepinephrine reuptake
inhibitors, MAOIs, or other serotonergic drugs should be avoided. As
mentioned above, valvulopathy has been associated with the use of
5-HT2B receptor agonists. Although the incidence of valvulopathy was
not significantly increased in studies of lorcaserin, a 5-HT2C receptor
agonist, patients should still be monitored for the development of this
condition. For that reason, individuals with a history of heart failure
should use this agent with caution.
COMBI DRUGS
The combination of phentermine and topiramate has been approved for
long-term use in the treatment of obesity. In initial studies of the anticonvulsant
topiramate, it was observed that patients lost weight while
taking the medication. This prompted further investigation into the use of
topiramate for weight loss in obese individuals. Because of the sedating
effects of topiramate, the stimulant phentermine was added to counteract
the sedation and promote additional weight loss. The phentermine/topiramate
combination is dosed in steps, escalating the dose every 2 weeks, depending on the response. If a patient does not achieve a 5%
weight loss after 12 weeks on the highest dose of this medication, then
it should be discontinued. It is also important to note that this medication
should not be stopped abruptly as seizures may be precipitated.
Topiramate has been associated with birth defects including cleft palate,
and, thus, the combination of phentermine/topiramate is contraindicated
in pregnancy. Other serious adverse effects with the topiramate component
include paresthesias, suicidal ideation, and cognitive dysfunction.
As discussed previously, potential adverse effects such as increased
heart rate may be observed with the phentermine component. Several
drug interactions may occur with this combination. Concomitant use of
MAOIs should be avoided due to the possibility of serotonin syndrome
with the phentermine component. The use of non–potassium-sparing
diuretics with this combination may increase the risk of hypokalemia
(low potassium). Topiramate is also a weak carbonic anhydrase inhibitor,
and use of other carbonic anhydrase inhibitors with this combination
increases the risk of kidney stones. Topiramate may reduce the efficacy
of oral contraceptives, and this is a concern, given the risk of birth defects
with this agent.
