‫‪PHARMACOLOGY‬‬
‫د‪ .‬حسين محمد جمعه‬
‫اختصاصي االمراض الباطنة‬
‫البورد العربي‬
‫كلية طب الموصل‬
‫‪2011‬‬
'off-label' use
use of licensed medicines in an unlicensed way.
In the product literature the
frequency of side-effects is generally described as
follows:
1. Very common greater than 1 in 10
2. Common1 in 100 to 1 in 10
3. Uncommon [‘less commonly’ in BNF]1 in 1000 to 1
in 100
4. Rare1 in 10 000 to 1 in 1000
5. Very rare less than 1 in 10 000
Bioavailability
refers to absorption of the drug. Increased gastric emptying
and induction of liver enzymes increases first pass metabolism
and reduced bioavailability.
Potency
refers to the amount of drug usually needed to produce an
effect, such as relief of pain or reduction of blood pressure. For
instance, if 5 milligrams of drug A relieves pain as effectively as
10 milligrams of drug B, drug A is twice as potent as drug B.
Efficacy
refers to the potential maximum therapeutic response that a
drug can produce.
Frusemide eliminates more salt than hydrochlorothiazide,
hence it has higher efficacy than hydrochlorothiazide.
The difference in speed of acetylation is due to the amount (or
activity) of the enzyme N-acetyltransferase available. Fast
acetylation is a trait which is autosomal dominant inherited.
LIVER ENZYME
INDUCERS
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol
Sulphonylureas
LIVER ENZYME INHIBITORS
Omeprazole
Amiodarone
Allopurinol
Ketoconazole
Disulfram
Erythromycin
Valproate
Isoniazid
Ciprofloxacin
Cimetidine
Ethanol
Sulphonamides Inhibitors of cytochrome CYP3A,
including:
Diltiazem
Verapamil
Ketoconazole and other azole antifungals
Macrolide antibiotics
Ritonavir (Norvir)
Grapefruit products or grapefruit juice
Drug induced lupus:
procainamide
isoniazid
chlorpromazine
penicillamine
sulfasalazine
hydralazine
methyldopa
quinidine
Drugs which can cause gynaecomastia :
digoxin ,oestrogens, spironolactone
cimetidine ,verapamil ,nifedipine , ketoconazole
metronidazole.
Drugs causing galactorrhoea are:
Oral contraceptive pills
Phenothiazines
Metoclopramide
Bromocriptine
Drugs which can cause SIADH :
cyclophosphamide
Chlorpromamide
carbamazepine
Clofibrate
thiazide diuretics
vincristine vinblastine
phenothiazines
tricyclic antidepressants SSRIs
Drugs producing
hypercalcemia
lithium, alkaline antacids
DES,
Thiazides
estrogens
progesterone
Amiodarone
blocks conversion of T4 to T3 and affects
pituitary thyroid axis.
The following changes in thyroid function tests
occur
within 3 months of starting
and are not indicative of thyroid disease:
1. increase in TSH up to 20mU/L
2. increase in T4 to upper normal
3. decreased T3 levels.
Anticholinergic syndrome
occurs following overdose with drugs that have
anticholinergic activity.
tricyclic antidepressants, antihistamines and atropine.
Features :
include flushed skin, urinary retention, tachycardia,
mydriasis (dilated pupils) and agitation.
Physostigmine
a reversible inhibitor of acteylcholinesterase, is
effective in treating
anticholinergic symptoms but there is a significant risk
of cardiac toxicity (bradycardia,AV conduction
defects and asystole).
Concomitant intake with grapefruit juice
increases the concentrations of many drugs in
humans. The effect seems to be mediated mainly
by suppression of the cytochrome P450
enzyme CYP3A4 in the small intestine wall. This
results in a diminished first pass metabolism with
higher bioavailability and increased maximal
plasma concentrations of substrates of this
enzyme. The effect was most pronounced in
drugs with high first pass degradation.
Grapefruit juice blocks special enzymes in the
wall of the small intestine that actually destroys
many medications and prevents their absorption
into the body.
Thus, smaller amounts of the drugs get into
the body than are ingested.
When the action of this enzyme is blocked,
more of the drugs get into the body and the
blood levels of these medications increase.
This can lead to toxic side effects from the
medications.
Amazingly, this remarkable food-drug interaction
was discovered completely by accident over a
decade ago! Researchers were investigating whether
alcohol could interact with felodipine (Plendil) and
used a solution of alcohol with grapefruit juice to
mask the taste of alcohol for the study. Researchers
discovered that blood levels of felodipine were
increased several fold more than in previous studies.
This increased blood level caused an increase in the
effect and side effects of felodipine. Further research
revealed that the grapefruit juice itself was actually
increasing the amount of the study drug in the body.
Research about the interaction of grapefruit juice with
drugs suggests that compounds in grapefruit juice,
called furanocoumarins (for example, bergamottin),
may be responsible for the effects of grapefruit juice.
Researchers believe that furanocoumarins block the
enzymes in the intestines that normally break down
many drugs.
One glass of grapefruit juice could elicit the
maximum blocking effect, and the effect may persist
for longer than 24 hours. Since the effects can last for
such a prolonged period of time, grapefruit juice does
not have to be taken at the same time as the
medication in order for the interaction to occur.
Therefore, unlike similar interactions, where the
interaction can be avoided by separating the
administration of the two interacting agents by a
couple of hours, administration of grapefruit juice with
susceptible drugs should be separated by 24 or more
hours to avoid the interaction. Since this is not
practical for individuals who are taking a medication
daily, they should not consume grapefruit juice when
taking medications that are affected by grapefruit
juice.
The grapefruit juice-drug interaction can lead to
unpredictable and hazardous levels of certain
important drugs
These are medications with which grapefruit juice
should NOT be consumed unless advised by a doctor:
statins
Antihistamines: fexofenadine , terfenadine .
calcium channel blockers nimodipine,felodipine Nitrendipine, Plendil,
nisoldipine ,nicardipine, verapamil
Psychiatric medications: buspirone, triazolam,
carbamazepine, diazepam,midazolam ,sertaline .
Intestinal medications: cisapride .
Immune suppressants: cyclosporine ,tacrolimus.
Pain medications: Methadone
Impotence drug: sildenafil
HIV medication: Invirase, Fortovase
Antiarrhythmics:amiodarone,disopyramide .
The major effect of grapefruit juice appears to
reduce “first-pass” metabolism by reducing
CYP3A4 activity. Because grapefruit juice does not
generally affect the systemic clearance of affected
drugs, it appears that grapefruit juice selectively
reduces intestinal CYP3A4 activity ((prevents their
absorption )) while having little effect on liver
CYP3A4.
Thus Grapefruit juice has no effect on drug
disposition after intravenous administration and
does not alter liver CYP3A4 activity.
Obesity
A dramatic demonstration of the importance of
estrogens in the regulation of fat deposition
comes from transgenic mice that were
genetically engineered to lack a functional
aromatase gene. These mice have very low
levels of estrogen and are obese.
Obesity was also observed in estrogen deficient
female mice lacking the follicle-stimulating
hormone receptor.
The effect of low estrogen on increased
obesity has been linked to estrogen receptor
alpha.
Estrogen receptor
There are two different forms of the estrogen receptor,
usually referred to as α and β,
Both ERs are widely expressed in different tissue types,
however there are some notable differences in their
expression patterns:The ERα is found in endometrium,
breast cancer cells, ovarian stroma cells and in the
hypothalamus.
The expression of the ERβ protein has been documented
in kidney, brain, bone, heart, lungs, intestinal mucosa,
prostate, and endothelial cells.
The ERs are regarded to be cytoplasmic receptors in
their unliganded state, but visualization research has
shown that a fraction of the ERs resides in the nucleus
Selective Estrogen Receptor Modulators
)SERMs) acts on the estrogen receptor .
A characteristic that distinguishes these
substances from pure receptor agonists and
antagonists is that their action is different in
various tissues, thereby granting the
possibility to selectively inhibit or stimulate
estrogen-like action in various tissues .
SERMs are used dependent on their pattern of
action in various tissues:
clomifene is used in anovulation femarelle is
used for managing menopause symptoms and
maintaining bone health ormeloxifene is used
for contraception raloxifene is used for
osteoporosis and reducing risk of invasive
breast cancer tamoxifen and toremifene are
used for breast cancer
The actions of SERMs on various tissues:
Bone turnover and postmenopausal osteoporosis respond
favorably to most SERMs .
Breast - all SERMs decrease breast cancer risk, and
tamoxifen is mainly used for its ability to inhibit growth in
estrogen receptor-positive breast cancer .
Cholesterol and triglycerides - levels respond favorably
to SERMs .
Deep venous thrombosis - the risk may be elevated in at
least some SERMs .
Hot flashes are increased by some SERMs .
Pituitary gland - clomifene blocks estrogen action, leading
to an increase of follicle-stimulating hormone .
Uterus - tamoxifen may increase endometrial carcinoma risk, but
raloxifene and femarelle do not. Data on toremifene and clomifene
is insufficient .
Cancer
Estrogen receptors are over-expressed in around 70%
of breast cancer cases, referred to as "ER positive".
Two hypotheses have been proposed to explain why
this causes tumorigenesis ,and the available evidence
suggests that both mechanisms contribute:
Firstly, binding of estrogen to the ER stimulates
proliferation of mammary cells ,with the resulting
increase in cell division and DNA replication leading to
mutations .
Secondly, estrogen metabolism produces genotoxic
waste .The result of both processes is disruption of cell
cycle ,apoptosis and DNA repair and therefore tumour
formation.
ERα is certainly associated with more
differentiated tumours, while evidence that
ERβ is involved is controversial.
Different versions of the ESR1 gene have
been identified (with single-nucleotide
polymorphisms )and are associated with
different risks of developing breast cancer.
Endocrine therapy for breast cancer involves
selective estrogen receptor modulators( SERMS)
which behave as ER antagonists in breast tissue or
aromatase inhibitors .ER status is used to determine
sensitivity of breast cancer lesions to tamoxifen and
aromatase inhibitors.Another SERM ,raloxifene ,has
been used as a preventative chemotherapy for
women judged to have a high risk of developing
breast cancer. Another chemotherapeutic antiestrogen ,ICI 182,780 (Faslodex) which acts as a
complete antagonist also promotes degradation of
the estrogen receptor.
Estrogen and the ERs have also been
implicated in breast cancer ,ovarian
cancer ,colon cancer ,prostate cancer
and endometrial cancer .
Advanced colon cancer is associated with
a loss of ERβ, the predominant ER in
colon tissue, and colon cancer is treated
with ERβ specific agonists.
Some SERMs may be good replacements for hormone
replacement therapy(HRT), which had been commonly used to
treat menopause symptoms until the publication of wide scale
studies showing that HRT slightly increases the risk of breast
cancer and thrombosis.Some of the above agents still have
significant side-effects which contraindicate widespread use.
SERMs are also commonly used during PCT or Post Cycle Therapy
after the use of anabolic steroids, or during a steroid cycle in case
of the sudden onset of estrogenic symptoms.
Bodybuilders who take hormonal supplements can experience
gynecomastia and similar symptoms because the body
metabolizes some steroids into estrogen. This increase in
estrogen can occur during or after a steroid cycle, so responsible
body builders will usually cycle a SERM after a steroid cycle to
ensure that their body is not flooded with excess estrogen. They
also often keep a SERM on hand in case of emergency.
Immunoglobulin A (IgA):
is the second most common immunoglobulin in blood. It is the
main immunoglobulin found in secretions, such as tears, saliva,
colostrum, mucous membranes of the intestine, respiratory
and reproductive tracts. IgA provides local defense against
microorganisms as they try to infect mucous membranes.
Immunoglobulin G (IgG):
This is the most abundant immunoglobulin and is
approximately equally distributed in blood and in tissue
liquids. Approximately 75% of serum immunoglobulins in
humans is IgG.
Immunoglobulin M ( IgM):
is the third most common immunoglobulin in serum. IgM is the
first class of immunoglobulin that is made by immune cells
when stimulated by antigen. It is also the first class of
antibody that is made by the fetus.
drugs that can induce parkinsonism :
1. Old antipsychotics (for example
haloperidol)
2. New antipsychotics (for example
olanzapine)
3. Anti-nausea agents (for example
prochlorperazine)
4. Antihistamines (for example cinnarizine).
Digoxin toxicity is increased in the presence
of
hypokalaemia
hypercalcaemia
hypomagnesaemia.
Carbimazole acts by blocking the uptake
of iodine into the thyroid gland. Therefore it
will stop the uptake of radioactive iodine
and prevent it working. So you should stop
the carbimazole one or two weeks before
and after taking the radioactive iodine.