Download Sheet 4 (slide9)

Practice 1:
Slide (9): Adverse drug reactions:
Adverse event : Any untoward medical occurrence that may
present during treatment with a pharmaceutical product but
which does not necessarily have a causal relationship with this
treatment. (there is no cause effect relationship between the drug
and the untoward medical condition).
Ex. patient developed a dry cough after initiating treatment of
Atenolol. We don’t know if the dry cough is caused by the drug or
not. So, we can’t call this an adverse drug reaction nor a side
effect. We call it an adverse event.
Ex. patient developed a heart attack after initiating treatment of
Atrovastatin. We don’t know if the heart attack is caused by the
drug or not. It’s just a bad event started after the initiation of the
drug. This is called an adverse event. (not necessarily that the
drug is the cause but it may be the cause of this event).
- Side effect: Any unintended effect of a pharmaceutical product
occurring at doses normally used in humans, which is related to
the pharmacological properties of the drug. (extension of the
pharmacological effects of the medication that may be beneficial
and not necessarily to be harmful ).
-Adverse reaction: a response to a drug which is noxious and
unintended, and which occurs at doses normally used in humans
for the prophylaxis, diagnosis or therapy of a disease, or for the
modification of physiological functions. (necessarily to be
harmful/noxious).
-both side effects and adverse reactions occur at usual doses of
the drug.
-any undesired conditions that are caused at a high dose of the
drug is called drug toxicity, poisoning or overdose.
* side effects of a drug don’t usually lead to modifications of the
therapy (they may lead to little modifications of the therapy)
unlike adverse drug reactions that are harmful and lead to
modifications of the therapy.
EX. Patient is taking an antihistamine (first generation) and is
suffering from drowsiness and a dry cough. Is this considered a
side effect or a drug reaction?
- this is a tolerable side effect that doesn’t lead to any changes of
the therapy.
Ex. Patient developed an acute kidney injury after initiating
treatment of Lisinopril. This is called an adverse drug reaction and
discontinuation of Lisinopril and addition of a new intervention is
mandatory.
The frequency of a side effect is usually predictable. Ex:
metformin 10% can cause GI upset.
Side effects are dose dependent. (when the dose increases, the
intensity of the side effect increases).
** There are some conditions that are not considered side effects,
adverse drug reactions or adverse drug events. EX. overdose of a
medication, poisoning (intoxication), withdrawal symptoms and
abuse (dependence) symptoms.
- Adverse drug reactions and side effects are consequences due to
medications. Adverse drug events are not necessarily due to
medications. If an adverse event is proved to be due to
medications we can call it an adverse drug reaction or a side
effect depending on the magnitude of changes in the therapy.
-consequences of adverse drug reactions:
1- Discontinuation of medications.
2- May prolong health care facility stay.
3- May require supportive treatment (additional cost).
4- May require Diagnostic procedures (if not sure if the adverse
reaction is due to the medications or not).
5- May affect the prognosis of the disease.
Ex. doxorubicin and daunorubicin are anti-neoplastic agents used
mainly in the treatment of lymphoma and leukemia. Patients who
use these medications usually develop heart failure.
Ex. patient is taking aspirin and developed a hemorrhagic stroke
(disability or mortality consequences).
Types of Adverse effects:
1- Type A adverse effects (Drug actions):
*extension of the drug’s pharmacological effects* and is
predictable with low mortality rate and high incidence and is dose
dependent. Is called drug actions because it depends on the drug
not the patient.
Ex. Patient with HTN is taking Carvedilol, the expected effect of
carvedilol is to decrease BP. Hypotension is an extension of the
intended pharmacological effect of Carvedilol.
Ex. Hypoglycemia is an extension of the pharmacological effect of
Sulfonylureas.
* Type A is a predictable adverse reaction. (it can be predicted by
the mechanism of action of the drug and the risk factors).
* Type A is dose dependent (8 mg of glimepiride will cause more
hypoglycemic effect than 1 mg).
* low mortality rate and high morbidity rate with high incidence.
Other examples: Sedation caused by hypnotic agents,
bradycardia caused by beta blockers and constipation caused by
opioids.
*Treatment: dose adjustment. Sometimes we may discontinue
the medication temporarily until the adverse effects are gone,
then we initiate the drug again at a very low dose and we titrate it
gradually.
* there are some risk factors that may increase the incidence of
type A adverse effects.
Ex. Risk factors that increase the probability of hypotension due to
the use of Carvedilol are: Age (Elderly patients), concomitant use
of other antihypertensive agents, taking Carvedilol at empty
stomach and in a hypovolemic state (excessive bleeding, vomiting
or diarrhea).
* what distinguishes type A adverse effects from type B is that the
prediction depends on the presence of risk factors.
Ex. Skipping meals, Acute or chronic renal impairment and age
(elderly patients) are factors that increase the probability of
hypoglycemia with Glimepiride.
2- Type B adverse effects (Patient reactions):
- the drug is well tolerated by the majority of people, but small
number of people elicit an allergic reaction due to this
medication. It Is dose independent and is not predictable (not on
the dose, mechanism of action or even risk factors).
Ex. Penicillins, thiazide diuretics, fluoroquinolones.
* Type B adverse effects is Acute (occurs after the first dose).
* unexpected and usually severe.
* low incidence and morbidity rate with high mortality rate.
* Allergic reaction: is a hypersensitivity reaction that is caused
when the body recognizes the drug as an antigen. It can be an
immunological or non-immunological reaction.
*Examples on Type B adverse reactions: Rashes, anaphylaxis,
multi-organ failure, agranulocytosis (failure of all bone marrow
elements: WBC’s, RBC’s and platelets are damaged “Aplastic
anemia”) and polycystic hepatitis.
* Treatment: Discontinuation of the medications.
Types of adverse drug reaction depending on time/occurrence:
1- Rapid reactions: occurs only when a drug is administered
rapidly when the drug must be administered gradually.
Ex. Red man syndrome is a rapid reaction that is caused by the
rapid administration of Vancomycin (Vancomycin should be given
in an IV infusion over 0.5 to 2 hours).
Ex: Hypotension is a rapid reaction that is caused by the rapid IV
iron administration.
2- First dose reactions: occurs after the first dose of a course of
treatment and not necessarily thereafter.
Ex. Alpha blockers, hydralazine, ISDN, ACEIs, type 1
hypersensitivity reactions.
These drugs with first dose reactions should be administered in
hospitals or physician clinics.
3- Early reactions: occur early in treatment and then abate with
continuing treatment. These are adverse reactions to which
patients develop tolerance.
Ex. Metformin (nausea and diarrhea), ISDN (Headache and
flushing), ACEIs and ARBs (hyperkalemia), statins (muscle pain)
4- late reactions: occurs rarely or not at all at the beginning of
treatment, but the risk increases with repeated exposure. it
depends on the accumulation of medications (cumulative effect).
Ex. Glucocorticoids (osteoporosis, needs several months),
Metformin (B12 deficiency), Antipsychotics (Dopamine receptor
antagonists) such as Haloperidol (extrapyramidal symptoms:
tardive dyskinesia “involuntarily facial muscle movements” caused
by the imbalance of dopamine in the CNS), withdrawal reactions
(are late reactions but not adverse drug reactions).
5- delayed reactions: are observed after a certain time after
exposure, even if the drug is withdrawn before the reaction
appears. They are not very common.
Ex. Thalidomide was prescribed during pregnancy to ease morning
sickness before it was withdrawn because it caused defects and
deformities of the delivered babies.
Ex. Diethylstilbestrol (causes vaginal adenocarcinoma in women
who where exposed to it in utero).
Ex. Females who took antiepileptic agents during pregnancy, the
cognitive development of their children will be lower than normal.
*Severity of reactions:
-Minor: no antidote, therapy or prolongation of hospitalization is
required (no modifications) like GI upset caused by Metformin.
-Moderate: requires changes in the drug therapy, specific
treatment or an increase in hospitalization by at least one day
(needs modifications like decreasing the dose of the drug or
prophylaxis administration).
-Severe: potentially life threatening, causing permanent damage,
or requiring intensive medical care (needs ICU admission) like
hemorrhagic stroke.
-Lethal: directly or indirectly contributes to the death of the
patient.
** What are the ways that help in deciding whether the adverse
events are drug induced or not?
- we can explain the side effects depending on the underlying
diseases (Ex. Patient with HF and volume overload has been using
enalapril for 10 years. The patient has developed a dry cough
recently. The Dry cough is not drug induced and not caused by
enalapril. It is disease induced (caused due to volume overload).
- Discontinuation of the medication. If the adverse reactions
disappear then they are drug induced.
Naranjo Score: refer to slides 15,16,17 (should be memorized!)
Score : Definite: more than 9
Possible: 1-4
Probable: 5-8
Doubtful: less than zero.