PHARMACOLOGY

هعمج دمحم نيسح .

د ةنطابلا ضارملاا يصاصتخا يبرعلا دروبلا لصوملا بط ةيلك 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 Ritonavir and other azole antifungals Macrolide antibiotics (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

used

a solution of (Plendil) and

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. daily,

Since this is not

practical for individuals who are taking a medication

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 aromatase transgenic mice that were genetically engineered to lack a functional 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 ER

α

is found in endometrium , breast cancer cells, ovarian stroma cells and in the hypothalamus .

The expression of the ER

β

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 used for managing menopause is symptoms and maintaining bone health ormeloxifene for contraception raloxifene is used is used for osteoporosis and reducing risk of invasive breast cancer tamoxifen used for breast cancer and toremifene are

The actions of SERMs on various tissues :

Bone turnover and postmenopausal favorably to most SERMs .

Breast osteoporosis respond 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 to an increase of clomifene blocks estrogen action, leading follicle-stimulating hormone .

Uterus tamoxifen may increase is insufficient .

endometrial carcinoma risk, but raloxifene and femarelle do not. Data on toremifene and clomifene

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 waste .

The result of both processes is disruption of cycle , apoptosis formation. and DNA repair genotoxic cell and therefore tumour

ER

differentiated tumours, while evidence that ER

α

β

is certainly associated with more

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 which behave as ER antagonists in breast tissue or aromatase inhibitors .

( SERMS) 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 anti estrogen , ICI 182,780 the estrogen receptor .

(Faslodex) which acts as a complete antagonist also promotes degradation of

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 ER colon tissue, and colon cancer is treated with ER

β β

.

, the predominant ER in 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.