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Cells then enter a new reproductive cycle This speed of recovery of normal tissues is exploited in devis- more or less synchronously purchase alavert 10 mg mastercard allergy treatment 360, and when most are judged ing intermittent courses of chemotherapy alavert 10 mg allergy forecast cambridge ma. Before establishing a • more in the resting state (decrease in growth fraction) buy trandate 100 mg lowest price, combination regimen, Phase 1 trials (see p. Selectivity of drugs for cancer cells is generally low com- • Enhanced cell killing in preclinical models when drugs pared with the selectivity shown by antimicrobial agents are combined. Thus a treatment that reduces a cell netics are of great importance, as drug treatment alters the population from 1 000 000 to 10 000 (a two-log cell kill) behaviour of both malignant and normal cells. Furthermore, cell chemosensitivity within a cancer is not homogeneous owing to random mutations (clonal selection) as the tu- Drug resistance mour grows, the cells remaining after initial doses being Resistance to a cytotoxic chemotherapy agent may be pre- more likely to resist further treatment. Therefore, combin- sent at the outset (primary resistance), or may develop with ing several drugs may be more effective than a single agent repeated drug exposure (acquired resistance). Combination chemotherapy is a influenced by: strategy commonly used to address the problems of tumour resistance. Pgp is an important protective mechanism possessed 516 Neoplastic disease and immunosuppression Chapter | 31 | by many normal cells against environmental toxins and has amounts of these drugs is harmful (mutagenesis, carcino- broad specificity for hydrophobic compounds. Pregnant cells such as the haemopoietic stem cell, cells on excretory staff should not handle these drugs. Certain chemotherapy regimens re- and intestinal cells, and the cells of the blood–brain barrier quire the simultaneous administration of intrathecal meth- all have high expression of Pgp. In those tumours for which cures can be achieved by che- Interactions of anticancer agents motherapy (childhood acute lymphoblastic leukaemia,, Hodgkin’s lymphoma, choriocarcinoma) it is essential that with other drugs optimal doses of initial chemotherapy be administered and The diverse modes of action of cytotoxic drugs offer ample dose intensity maintained in order to avoid the emergence scope for serious unwanted drug–drug interactions, and by of chemoresistance. Drugs that inhibit enzymes and thus delay normal meta- Improving efficacy of chemotherapy bolic breakdown may cause harmful reactions to standard doses of cytotoxics, e. Caelyx is a formulation comprising high ing a dangerous degree of immunosuppression represents concentrations of doxorubicin encased in liposomes. The time of day at which therapy is Hormonal influence on cancer administered can theoretically influence the outcome The possibility of interfering with cancer other than by sur- (chronomodulation). In ovarian cancer, for 33 years with advanced breast cancer: example, patients benefit from debulking surgery (cytoreduction) prior to cytotoxic drug therapy. Its nature was fully cytotoxic agents explained to them both, and also that it was a purely experimental one... When administration of vincristine, two inexperienced doctors were charged they stopped handling the drugs, the contamination with manslaughter (Dyer C 2001 Doctors suspended after injecting ceased. Where this of lambs on a local farm, had noted a similarity between the can be anticipated, prior orchidectomy or anti-androgen proliferation of epithelial cells of the milk ducts in lactation treatment, e. Benign prostatic hypertrophy is also androgen depen- In 19416 it was shown that prostatic cancer with metas- dent, and drug therapy includes use of finasteride, an inhib- tases was made worse by androgen and made better by oes- itor of the enzyme (5a-reductase) that activates testosterone. Adrenocortical steroids are used for their action on spe- cific cancers and also to treat some of the complications of Hormonal agents cancer, e. In leukaemias, corticosteroid may reduce the incidence of The growth of some cancers is hormone dependent and is complications, e. The same effect is achievable, at less cost to the doses are high, and the mineralocorticoid actions are not patient, by administering hormones, or hormone antago- needed and cause fluid retention.

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A patient may be as extensively ‘b-blocked’ by proprano- Restoration of the response after irreversible binding re- lol as by pindolol purchase 10 mg alavert overnight delivery allergy testing metals, i discount alavert 10 mg overnight delivery allergy shots immunotherapy. The agonist action of benzodiazepines on the benzodiazepine receptor Physiological (functional) antagonism in the central nervous system produces sedation best buy depakote, anxiolysis, muscle relaxation and controls convulsions; substances An action on the same receptor is not the only mechanism called b-carbolines, which also bind to this receptor, by which one drug may oppose the effect of another. Ex- cause stimulation, anxiety, increased muscle tone and treme bradycardia following overdose of a b-adrenoceptor convulsions; they are inverse agonists. If the forces that bind Adrenaline/epinephrine and theophylline counteract drug to receptor are weak (hydrogen bonds, van der Waals bronchoconstriction produced by histamine released from bonds, electrostatic bonds), the binding will be easily and mast cells in anaphylactic shock by relaxing bronchial rapidly reversible; if the forces involved are strong (covalent smooth muscle (b2-adrenoceptor effect). A sufficient in- crease of the concentration of agonist above that of the an- tagonist restores the response. For example, abolish exercise-induced tachycardia, showing that the de- enalapril is effective in hypertension because it is structur- gree of blockade is enhanced, as more drug becomes avail- ally similar to the part of angiotensin I that is attacked by able to compete with the endogenous transmitter. Carbidopa competes with levodopa for dopa decarbox- When receptor-mediated responses are studied either in ylase, and the benefit of this combination in Parkinson’s isolated tissues or in intact humans, a graph of the loga- disease is reduced metabolism of levodopa to dopamine rithm of the dose given (horizontal axis) plotted against in the blood (but not in the brain because carbidopa does the response obtained (vertical axis) commonly gives an not cross the blood–brain barrier). S-shaped (sigmoid) curve, the central part of which is a Ethanol prevents metabolism of methanol to its toxic me- straight line. If the measurements are repeated in the pres- tabolite, formic acid, by competing for occupancy of the en- ence of an antagonist, and the curve obtained is parallel to zyme alcohol dehydrogenase; this is the rationale for using the original but displaced to the right, then antagonism is ethanol in methanol poisoning. Drugs that bind irreversibly to receptors include phenoxy- Irreversible inhibition occurs with organophosphorus in- benzamine (to the a-adrenoceptor). Some toxins act in this way; for synthesising new protein; this is why low doses of aspirin example, a-bungarotoxin, a constituent of some snake are sufficient for antiplatelet action. The approach is the basis of Dose–response relationships modern drug design and it has led to the production of Conventionally, the horizontal axis shows the dose and adrenoceptor antagonists, histamine receptor antagonists the response appears on the vertical axis. A steeply rising and pro- cer drugs that act against rapidly dividing cells lack selectivity longedcurveindicatesthatasmallchangeindoseproducesa because they also damage other tissues with a high cell largechangeindrugeffectoverawidedoserange,e. Selective targeting of drugs to less accessible sites Dose–response curves for wanted and unwanted effects of disease offers considerable scope for therapy as technol- can illustrate and quantify selective and non-selective drug ogy develops, e. Drug molecules are three-dimensional Drug A Drug B and many drugs contain one or more asymmetrical or chiral1 centres in their structures, i. For drugs as single enantiomers rather than as racemic mixtures drug A, the dose that brings about the maximum wanted effect is less than the lowest dose that produces the unwanted effect. The difference in weight of drug adminis- Tolerance tered is of no clinical significance unless it is great. Pharmacological efficacy refers to the strength of re- Continuous or repeated administration of a drug is often sponse induced by occupancy of a receptor by an agonist accompanied by a gradual diminution of the effect it pro- (intrinsic activity); it is a specialised pharmacological con- duces. But clinicians are concerned with therapeutic efficacy, to increase the dose of a drug to get an effect previously as follows. By contrast, the term tachyphylaxis describes the phenomenon Therapeutic efficacy or effectiveness, is the capacity of a of progressive lessening of effect (refractoriness) in re- drug to produce an effect and refers to the maximum such sponse to frequently administered doses (see Receptors, effect. Differences in therapeutic efficacy are of great sary to maintain pain relief in terminal care; the effect is due clinical importance, usually more than potency. Tolerance is ac- more than 5% of the sodium load filtered by the glomeruli; quired rapidly with nitrates used to prevent angina, possi- there is no point in increasing the dose beyond that which bly mediated by the generation of oxygen free radicals from achieves this, as this is its maximum diuretic effect.

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Drug effects on other maternal tissues (heart alavert 10 mg with mastercard allergy shots information, lungs purchase genuine alavert online allergy forecast honolulu, kidneys buy discount citalopram on line, central nervous system, etc) are not changed significantly by pregnancy, although the physiologic context (cardiac output, renal blood flow, etc) may be altered, requiring the use of drugs that are not needed by the same woman when she is not pregnant. For example, cardiac glycosides and diuretics may be needed for heart failure precipitated by the increased cardiac workload of pregnancy, or insulin may be required for control of blood glucose in pregnancy-induced diabetes. Therapeutic Drug Actions in the Fetus Fetal therapeutics is an emerging area in perinatal pharmacology. At present, corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected. Phenobarbital, when given to pregnant women near term, can induce fetal hepatic enzymes responsible for the glucuronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Before phototherapy became the preferred mode of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was used for this indication. Administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants. Although their efficacy has not yet been established by controlled studies, digoxin, flecainide, procainamide, verapamil, and other antiarrhythmic agents have been shown to be effective in case series. Predictable Toxic Drug Actions in the Fetus Chronic use of opioids by the mother may produce dependence in the fetus and newborn. A less well understood fetal drug toxicity is caused by the use of angiotensin-converting enzyme inhibitors during pregnancy. These drugs can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to diethylstilbestrol, who may be at increased risk for adenocarcinoma of the vagina after puberty. Teratogenic Drug Actions A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure. Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. The thalidomide phocomelia risk occurs during the fourth through the seventh weeks of gestation because it is during this time that the arms and legs develop (Figure 59–1). Teratogenic mechanisms—The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. Finally, drugs may have important direct actions on the processes of differentiation in developing tissues. For example, vitamin A (retinol) has been shown to have important differentiation-directing actions in normal tissues. Several vitamin A analogs (isotretinoin, etretinate) are powerful teratogens, suggesting that they alter the normal processes of differentiation. For example, folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects (eg, spina bifida).

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