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parameters of pk of drugs in clinical situation

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Slide 1: 

Drug Therapy in Pregnancy A.Pharmacokinetics Changes: Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their pharmacologic and teratogenic effects. Critical factors affecting placental drug transfer and drug effects on the fetus include the following: (1) The physicochemical properties of the drug (2) The rate at which the drug crosses the placenta and the amount of drug reaching the fetus (3) the duration of exposure to the drug

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(4) Distribution characteristics in different fetal tissues (5) The stage of placental and fetal development at the time of exposure to the drug And (6) the effects of drugs used in combination.

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Lipid Solubility: Drug passage across the placenta is dependent on lipid solubility and the degree of drug ionization. Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation. For example, thiopental, a drug commonly used for cesarean sections, crosses the placenta almost immediately and can produce sedation or apnea in the newborn infant. Highly ionized drugs such as succinylcholine and tubocurarine, also used for cesarean sections, cross the placenta slowly and achieve very low concentrations in the fetus.

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Molecular weight: The molecular weight of the drug also influences the rate of transfer and the amount of drug transferred across the placenta. Drugs with molecular weights of 250–500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization; those with molecular weights of 500–1000 cross the placenta with more difficulty; and those with molecular weights greater than 1000 cross very poorly

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. An important clinical application of this property is the choice of heparin as an anticoagulant in pregnant women. Because it is a very large (and polar) molecule, heparin is unable to cross the placenta. Unlike warfarin, which is teratogenic and should be avoided during the first trimester and even beyond (as the brain continues to develop), heparin may be safely given to pregnant women who need anticoagulation.

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Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal antibodies cross the placenta and may cause fetal morbidity, as in Rh incompatibility.

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Placental Transporters During the last decade, many drug transporters have been identified in the placenta, with increasing recognition of their effects on drug transfer to the fetus. For example, the P-glycoprotein transporter encoded by the MDR1 gene pumps back into the maternal circulation a variety of drugs, including cancer drugs (eg, vinblastine, doxorubicin) and other agents. Similarly, viral protease inhibitors, which are substrates to P-glycoprotein, achieve only low fetal concentrations—an effect that may increase the risk of vertical HIV infection from the mother to the fetus

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The hypoglycemic drug glyburide cannot be measured in umbilical blood despite therapeutic maternal concentrations. Recent work has documented that this agent is effluxed from the fetal circulation by the BCRP transporter as well as by the MRP3 transporter located in the placental brush border membrane

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Protein Binding: Protein binding is also important since some drugs show greater protein binding in maternal plasma than in fetal plasma because of a lower binding affinity of fetal proteins. This has been shown for sulfonamides, barbiturates, phenytoin, and local anesthetic agents

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Placental and Fetal Drug Metabolism: Two mechanisms help protect the fetus from drugs in the maternal circulation 1-The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, N-dealkylation , demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way.

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Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol). 2-Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. About 40–60% of umbilical venous blood flow enters the fetal liver; the remainder bypasses the liver and enters the general fetal circulation

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. A drug that enters the liver may be partially metabolized there before it enters the fetal circulation. In addition, a large proportion of drug present in the umbilical artery (returning to the placenta) may be shunted through the placenta back to the umbilical vein and into the liver again. It should be noted that metabolites of some drugs may be more active than the parent compound and may affect the fetus adversely.

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B-Pharmacodynamic Changes: Maternal Drug Actions: The effects of drugs on the reproductive tissues (breast, uterus, etc) of the pregnant woman are sometimes altered by the endocrine environment appropriate for the stage of pregnancy. Drug effects on other maternal tissues (heart, lungs, kidneys, 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

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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

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Therapeutic Drug Actions in the Fetus: Fetal therapeutics is an emerging area in perinatal pharmacology. This involves drug administration to the pregnant woman with the fetus as the target of the drug. For example, 1-corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected.

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2-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.

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3-Administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants. 4- During the last decade it has been shown that maternal use of zidovudine decreases by two thirds transmission of HIV from the mother to the fetus, and use of combinations of three antiretroviral agents can eliminate fetal infection almost entirely.

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Predictable Toxic Drug Actions in the Fetus: 1-Chronic use of opioids by the mother may produce dependence in the fetus and newborn. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. 2- 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.

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3-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.

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Defining a Teratogen To be considered teratogenic, a candidate substance or process should (1) Result in a characteristic set of malformations, indicating selectivity for certain target organs; (2) Exert its effects at a particular stage of fetal development, i.e., during the limited time period of organogenesis of the target organs. And (3) show a dose-dependent incidence.

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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.

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Teratogenic Mechanisms: The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, 1-drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues

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2-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. 3-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.

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4-Finally, deficiency of a critical substance appears to play a role in some types of abnormalities. For example, folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects (eg, spina bifida)

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5-Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol syndrome. In this syndrome, the central nervous system, growth, and facial development may be affected.

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Drug Use during Lactation Most drugs administered to lactating women are detectable in breast milk. Fortunately, the concentration of drugs achieved in breast milk is usually low. Therefore, the total amount the infant would receive in a day is substantially less than what would be considered a "therapeutic dose."

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If the nursing mother must take medications and the drug is a relatively safe one, she should optimally take it 30–60 minutes after nursing and 3–4 hours before the next feeding. This allows time for many drugs to be cleared from the mother's blood, and the concentrations in breast milk will be relatively low. Drugs for which no data are available on safety during lactation should be avoided or breast-feeding discontinued while they are being given.

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Examples: 1- Most antibiotics taken by nursing mothers can be detected in breast milk. Tetracycline concentrations in breast milk are approximately 70% of maternal serum concentrations and present a risk of permanent tooth staining in the infant. Isoniazid rapidly reaches equilibrium between breast milk and maternal blood. The concentrations achieved in breast milk are high enough so that signs of pyridoxine deficiency may occur in the infant if the mother is not given pyridoxine supplements.

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2-Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants. Barbiturates taken in hypnotic doses by the mother can produce lethargy, sedation, and poor suck reflexes in the infant. Chloral hydrate can produce sedation if the infant is fed at peak milk concentrations. Diazepam can have a sedative effect on the nursing infant, but, most importantly, its long half-life can result in significant drug accumulation.

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3-Opioids such as heroin, methadone, and morphine enter breast milk in quantities potentially sufficient to prolong the state of neonatal narcotic dependence if the drug was taken chronically by the mother during pregnancy

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4-Lithium enters breast milk in concentrations equal to those in maternal serum. Clearance of this drug is almost completely dependent upon renal elimination, and women who are receiving lithium may expose the infant to relatively large amounts of the drug.

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5-Radioactive substances such as iodinated 125I albumin and radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer as much as tenfold. Breast-feeding is contraindicated after large doses and should be withheld for days to weeks after small doses. Similarly, breast-feeding should be avoided in mothers receiving cancer chemotherapy or being treated with cytotoxic or immune-modulating agents for collagen diseases such as lupus erythematosus or after organ transplantation.

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B) DRUG Therapy in Infants & Children Half of all children visiting GPs' surgeries will be issued with a prescription, usuallv for short-term medication, especially antibiotics. Using drugs properly in children requires an understanding of the alterations in pharmacokinetics and pharmacoelynamics that occur, especial!} in neonates (age up to 1 month) and infants (age up to 4 years).

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a) pharmacokinetic changes: Gastrointestinal Function: 1-Significant biochemical and physiologic changes occur in the neonatal gastrointestinal tract shortly after birth. In full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours. In preterm infants, the secretion of gastric acid occurs more slowly, with the highest concentrations appearing on the fourth day of life. Therefore, drugs that are partially or totally inactivated by the low pH of gastric contents should not be administered orally.

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2-Gastric emptying time is prolonged (up to 6 or 8 hours) in the first day or so after delivery. Therefore, drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated. In the case of drugs absorbed in the small intestine, therapeutic effect may be delayed. Peristalsis in the neonate is irregular and may be slow. The amount of drug absorbed in the small intestine may therefore be unpredictable; more than the usual amount of drug may be absorbed if peristalsis is slowed, and this could result in potential toxicity from an otherwise standard dose.

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3- An increase in peristalsis, as in diarrheal conditions, tends to decrease the extent of absorption, because contact time with the large absorptive surface of the intestine is decreased. 4-Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of alpha-amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs.

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Drug Distribution: 1-The neonate has a higher percentage of its body weight in the form of water (70–75%) than does the adult (50–60%). Differences can also be observed between the full-term neonate (70% of body weight as water) and the small preterm neonate (85% of body weight as water). Similarly, extracellular water is 40% of body weight in the neonate, compared with 20% in the adult

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Since many drugs are distributed throughout the extracellular water space, the size (volume) of the extracellular water compartment may be important in determining the concentration of drug at receptor sites. This is especially important for water-soluble drugs (such as aminoglycosides) and less crucial for lipid-soluble agents.

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2-Preterm infants have much less fat than full-term infants. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full-term neonates. Therefore, organs that generally accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in less mature infants.

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3-Another major factor determining drug distribution is drug binding to plasma proteins. Albumin is the plasma protein with the greatest binding capacity. In general, protein binding of drugs is reduced in the neonate. This has been seen with local anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital. Therefore, the concentration of free (unbound) drug in plasma is increased initially

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Because the free drug exerts the pharmacologic effect, this can result in greater drug effect or toxicity despite a normal or even low plasma concentration of total drug (bound plus unbound).

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Drug Metabolism: 1-The metabolism of most drugs occurs in the liver . The drug-metabolizing activities of the cytochrome P450-dependent mixed-function oxidases and the conjugating enzymes are substantially lower (50–70% of adult values) in early neonatal life than later. Glucuronide formation reaches adult values (per kilogram body weight) between the third and fourth years of life. Because of the neonate's decreased ability to metabolize drugs, many drugs have slow clearance rates and prolonged elimination half-lives

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If drug doses and dosing schedules are not altered appropriately, this immaturity predisposes the neonate to adverse effects from drugs that are metabolized by the liver 2-Another consideration for the neonate is whether or not the mother was receiving drugs (eg, phenobarbital) that can induce early maturation of fetal hepatic enzymes. In this case, the ability of the neonate to metabolize certain drugs will be greater than expected, and one may see less therapeutic effect and lower plasma drug concentrations when the usual neonatal dose is given.

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Drug Excretion: Neonates have diminished glomerular fil­tration rate and tubular excretion compared with adults, this decreases the clearance of such drugs as penicillin. Older children have renal function similar to that of adult

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B- Pharmacodynamics: Some drugs will demonstrate a reduced effect in neonates compared with adults or older children (e.g. digoxin), while some have an increased effect (e.g. CNS depressants). This is sometimes the result of altered pharmacokinetics (for instance, the volume of distribution of lipid-soluble CNS depressants); in other cases, there are alterations in tissue sensitivity.

Pediatric Drug Dosage : 

Pediatric Drug Dosage

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DRUG Therapy in elderly Drugs are widely used in the elderly: the elderly (over 65 years) account for about 15% of the general population but about 40-45% of prescriptions. The elderly are prone to many chronic degenerative diseases, which may influence drug effects and which promotes prescribing. They may have several medical problems that may lead to multi drug therapy (polypharmacy).

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Often there are difficulties of diagnosis in the elderly and doctors may be excessively enthusiastic in their desire to treat symptoms. Some complaints may be inappropriately treated with drugs, e.g. dizziness caused by age-related loss of postural stability might be treated with prochlorpemzine, which may lead to Parkinsonism and further treatment. Many problems of the elderly are psychosocial and cannot be expected to respond to drugs. Often, drugs are started in the elderly & not discontinued although the original indication for drug has long since resolved.

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A) Pharmacokinetic Changes:  Absorption: There is little evidence for any major alteration in drug absorption with age. However, conditions associated with age may alter the rate at which some drugs are absorbed. Such conditions include altered nutritional habits, greater consumption of nonprescription drugs (eg, antacids, laxatives), and changes in gastric emptying, which is often slower in older persons, especially in older diabetics.

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Distribution: Compared with young adults, the elderly have reduced lean body mass, reduced body water, and increased fat as a percentage of body mass. There is usually a decrease in serum albumin, which binds many drugs, especially weak acids. There may be a concurrent increase in alpha1 -acid glycoprotein, a protein that binds many basic drugs. Thus, the ratio of bound to free drug may be significantly altered. As a result these changes may alter the appropriate loading dose of a drug.

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Metabolism:   The capacity of the liver to metabolize drugs does not appear to decline consistently with age for all drugs. Animal studies and some clinical studies have suggested that certain drugs are metabolized more slowly; some of these drugs are listed in Table 61–2. The greatest changes are in phase I reactions, ie, those carried out by microsomal P450 systems; there are much smaller changes in the ability of the liver to carry out conjugation (phase II) reactions.

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Some of these changes may be caused by decreased liver blood flow There is a decline with age of the liver's ability to recover from injury, e.g., that caused by alcohol or viral hepatitis. Therefore, a history of recent liver disease in an older person should lead to caution in dosing with drugs that are cleared primarily by the liver, even after apparently complete recovery from the hepatic injury.

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Finally, malnutrition and diseases that affect hepatic function—e.g., heart failure—are more common in the elderly. Heart failure may dramatically alter the ability of the liver to metabolize drugs and may also reduce hepatic blood flow. Similarly, severe nutritional deficiencies, which occur more often in old age, may impair hepatic function.

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Elimination: The decline in creatinine clearance occurs in about two thirds of the population. It is important to note that this decline is not reflected in an equivalent rise in serum creatinine because the production of creatinine is also reduced as muscle mass declines with age. The result of this change is marked prolongation of the half-life of many drugs and the possibility of accumulation to toxic levels if dosage is not reduced in size or frequency. Dosing recommendations for the elderly often include an allowance for reduced renal clearance.

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If only the young adult dosage is known for a drug that requires renal clearance, a rough correction can be made by using the Cockcroft-Gault formula, which is applicable to patients from age 40 through age 80:

For women, the result should be multiplied by 0.85 : 

For women, the result should be multiplied by 0.85

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The lungs are important for the excretion of volatile drugs. As a result of reduced respiratory capacity and the increased incidence of active pulmonary disease in the elderly, the use of inhalation anesthesia is less common and parenteral agents more common in this age group.

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B) Pharmacodynamic Changes: It was long believed that geriatric patients were much more "sensitive" to the action of many drugs, showing a change in the pharmacodynamic interaction of the drugs with their receptors. It is now recognized that many (perhaps most) of these apparent changes result from altered pharmacokinetics or diminished homeostatic responses.

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Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies show a decrease in responsiveness to beta- adrenoceptor agonists.

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diminished homeostatic reserve: as a result many drugs that affect homeostasis in vital organs have adisproportionate effect in elderly patients, e.g.antihypertensives may lead to postural hypotensionbecause of reduction of the normal reflex responses The disease state may influence the response to drugs;for instance, patients with rheumatoid arthritis maybe more prone to suffer gastrointestinal bleeding afterNSAIDs.

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Major Drug Groups Central Nervous System Drugs: Sedative-Hypnotics: The half-lives of many benzodiazepines and barbiturates increase by 50–150% between age 30 and age 70. Much of this change occurs during the decade from 60 to 70. For many of the benzodiazepines, both the parent molecule and its metabolites (produced in the liver) are pharmacologically active. The age-related decline in renal function and liver disease, if present, both contribute to the reduction in elimination of these compounds. In addition, an increased volume of distribution has been reported for some of these drugs

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Lorazepam and oxazepam may be less affected by these changes than the other benzodiazepines. In addition to these pharmacokinetic factors, it is generally believed that the elderly vary more in their sensitivity to the sedative-hypnotic drugs on a pharmacodynamic basis as well. Among the toxicities of these drugs, ataxia and other signs of motor impairment should be particularly watched for in order to avoid accidents.

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Analgesics(opioid analgesics): The elderly are often markedly more sensitive to the respiratory effects of these agents because of age-related changes in respiratory function. Therefore, this group of drugs should be used with caution until the sensitivity of the particular patient has been evaluated, and the patient should then be dosed appropriately for full effect.

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Antipsychotic & Antidepressant Drugs When a sedative antipsychotic is desired, a phenothiazine such as thioridazine is appropriate. If sedation is to be avoided, haloperidol is more appropriate. The latter drug has increased extrapyramidal toxicity, however, and should be avoided in patients with preexisting extrapyramidal disease. The phenothiazines, especially older drugs such as chlorpromazine, often induce orthostatic hypotension because of their alpha- adrenoceptor-blocking effects. They are even more prone to do so in the elderly.

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Recommendations for prescribing in the elderly Assess the clinical Situation carefully, consideringother drugs, previous history and the need toprescribe at all. Keep the drug regimen as simple as possible andtreat only major problems.

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Start with the lowest effective dose (often 50% of theusual adult dose) and build up the dose gradually asnecessary. Consider carefully the choice of drug inthe elderly and work from a limited range of drugswith which the prescriber is very familiar. Explain carefully to the patient the proposed therapy, its purposes, administration and its adverseeffects. Verbal explanation may need to besupplemented with written material. Issue a clearprescription for the pharmacist.

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Avoid inappropriate treatment: consider the patient as a whole and not as a collection of symptoms or diseases. Review medication and compliance frequently andbe alert for adverse drug reactions, which maymimic other disease or present in a non-specificmanner in the elderly

REFERENCES : 

REFERENCES BASIC & CLINICAL PHARMACOLOGY- KATZUNG APPLIED BIOPHARMACEUTIOS & P.KINETICS-LEON SHARGEL THE PHARMACOLOGICAL BASIS OF THERAPEUTICS- GOODMAN & GILMAN Clinical pharmacy and therapeutics by Roger Walker

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