In a beat of the heart

Monday, February 25, 2008

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Discovery and development of drugs

· Preclinical drug development.

· Techniques of discovery.

· Preclinical studies in animals.

Preclinical drug development

1. The study of new medicines (drugs) is an exercise in prediction from laboratory studies in vitro and in vivo (animals) which forecast what the agent will do to man.

2. Medical therapeutics rests on:

a. Sensitivity: the desired effect alone is obtained with a minimum of other side effects.

b. Dose: the dose that is safe and without toxic effects on humans.

3. For decades the rational discovery of new medicines has depended on modifications of the molecular structures of the increasing numbers of known natural chemical mediators.

4. The evolution of molecular medicine in recent years – the study of signal transduction, have opened a new approach to the development of therapeutic agents that can target discrete steps in the body’s pathways of chemical reactions.

5. New drug development proceeds:

a. Idea or hypothesis.

b. Design and synthesis of substances.

c. Studies on tissues and whole animals (preclinical studies).

d. Studies in man (clinical studies).

e. Grant of an official licence to make therapeutic claims and to sell.

f. Post-licensing (marketing) studies of safety and comparisons with other medicines.

Techniques of discovery

1. Molecular modelling:

a. Aided by three-dimensional computer graphics.

b. Allows the design of structures based on new and known molecules to enhance their desired, and to eliminate their undesired, properties to create selective compounds.

2. Combinatorial chemistry:

a. Involves the random mixing and matching of large numbers of chemical building blocks to produce ‘libraries’ of all possible combinations.

b. Generate new compounds that are initially evaluated using automated robotic high-throughout screening devices that can handle thousands of compounds a day.

c. These screens utilize radio-labelled ligand displacement on single human receptor subtypes or enzymes on nucleated cells.

3. Biotechnology:

a. Involves the use of recombinant DNA technology / genetic engineering to clone and express human genes.

b. The polymerase chain reaction (PCR) is an alternative to bacterial cloning.

4. Genetic medicines: synthetic oligonucleotides are being develop to target defined sites on DNA sequences or genes or mRNA so that the production of disease-related proteins is blocked.

5. Gene therapy: nucleic acid, in the form of DNA, is administered to modify the genetic repertoire for therapeutic purposes.

6. Immunopharmacology.

7. PET (positron emission tomography): allows non-invasive pharmacokinetic and pharmacodynamic measurements in previously inaccessible sites, e.g. brain.

Preclinical studies in animals

1. Pharmacodynamics: to explore actions relevant to the propose therapeutic use, and other effects at that dose.

2. Pharmacokinetics: to discover how the drug is distributed in and disposed of by the body.

3. Toxicology: to see whether and how the drug causes injury in:

a. single dose studies.

b. repeated-dose studies.

4. Special toxicology involves areas in which a particular drug accident might occur on a substantial scale:

a. Mutagenicity: a bacterial mutagenicity test which demonstrates the induction of point mutations.

b. Carcinogenicity tests: not often required prior to the early studies in man unless there is serious reasons to be suspicious of the drug.

Pharmacodynamics

· Concept of receptor as mediators of drug actions.

· Structure-activity relationship.

· Mechanisms of action.

· Drug-receptor interactions.

· Stereoselectivity.

· Graded and Quantal dose response.

· Clinical potency and efficacy.

· Therapeutic index.

· Bioassay and standardization

Drug receptor theory

1. Drug receptor: any component of a biological system that interacts with a drug and thereby leads to the drug effect.

2. Drugs act by binding to receptors to alter its function selectively.

3. Drug-receptor interaction follows the law of mass action:

K1

D + R ⇌ DR

K2

4. Affinity:

a. A measure of the probability that a drug molecule will interact with its receptor to form a DR complex.

b. At the same concentration, the drug with a higher affinity will form more DR complex than the drug with a lower affinity.

5. Drug response:

a. The response is elicited due to receptor occupation by the drug.

b. The magnitude of the response is proportional to receptor occupancy, i.e. [DR].

6. Intrinsic activity: a measure of the biological effectiveness of the DR complex the drug forms with its receptor.

7. Receptor and disease:

a. Autoimmune disease: in myasthenia gravis, the body produces antibodies that attack the nicotinic receptors at the neuromuscular junction.

b. Receptor mutation can result in permanently altered level of effector activity: a mutation of the thyrotrophin receptor cause the effector system to be permanently switched on, leading to over-secretion of thyroid hormones.

8. Receptor Polymorphism:

a. Increasingly recognized to be important in pharmacology and therapeutics.

b. Current attention is on the polymorphism of the drug metabolizing enzymes (cytochrome enzymes) leading to variations in the pharmacokinetics of a drug in different populations or individuals.

Structure-Activity relationship

1. Receptor groups/sites: the chemical groups of the receptor that participate in the drug-receptor combination and the adjacent portions of the receptor that favor or hinder access of the drug to the active groups.

2. Drugs and receptors interact via covalent or non-covalent bonds.

3. Covalent bonding:

a. Involves mutual sharing of electron pair with consequent high bond energy.

b. Usually irreversible; e.g. MAO inhibitors and organophosphates.

c. Often, the receptors are enzymes and catalyze the formation of the covalently bonded drug-receptor complex.

4. Non-covalent bonding:

a. Responsible for most drug-receptor interactions.

b. Include: ionic bonds, hydrogen bonding, van der Waals forces and hydrophobic interactions.

c. Usually reversible.

5. Drug-receptor interactions involving these binding forces require the interacting moieties of the drug molecule to come into very close proximity with the appropriate interacting moieties of the receptor.

6. The structural arrangement of the binding site of a given receptor thus imposes a strict structural requirement on the drugs that are able to interact or bind to this site.

Mechanisms of Drug Action

Site of drug action Examples
Cell Membrane
Specific receptors · Morphine and Naloxone on opioid receptors.
· Histamine and ranitidine on H2 receptors.

· Epinephrine and propranolol on b-receptors.

Interference with ion flux across membranes. · Verapamil inhibiting Ca2+ across ‘L-type’ voltage-gated calcium channels.
· Benzodiazepines binding on specific site on GABA/CI- complex, increasing its frequency of opening and CI- influx.

· Sulphonylureas binding to ATP-dependent K+ channel decreasing K+ efflux.

Inhibition of membrane bound enzymes · Membrane-bound Na+-K+ ATPase by cardiac glycosides.
· TCAs block pump by which amines are taken up into nerve cells.

· Loop diuretics inhibit Na+-CI- cotransporter on apical membrane of renal tubular cells.

Physicochemical interactions · General and local anaesthetics act on lipid and protein components of nerve cell membranes.
Metabolic processes within the cell
Enzyme inhibition · Monoamine oxidase by phenelzine.
· Xanthine oxidase by allopurinol.

· Cholinesterase by pyridostigmine.

Inhibition of transport processes · Blockade of anion transport in renal tubule cell by probenecid to delay excretion of penicillin & enhance elimination of urate.
Incorporation into larger molecules. · 5-fluorouracil is incorporated into mRNA in place of uracil.
· Cytabarine is incorporated into mRNA in place of cytidine.

Structural analogues · Spironolactone is an analogue of aldosterone.
· Sulphonamides are analogues of P-aminobenzoic acid (PABA).

· Tamoxifen is an analogue of estrogen.

Mimicking natural hormones · Prednisolone as a glucocorticoid.
· Diethylstilbesterol as estrogen.

· L-Dopa is converted to dopamine in CNS.

Enhancing natural processes · Heparin activating antithrombin III.
· Biguanides enhancing glucose uptake in peripheral tissues.

Altering metabolic processes · Inhibition of folic acid synthesis by trimethoprim.
· Inhibition of synthesis of transcription factor that mediates cytokine signaling by corticosteroids.

· Inhibition of transfer of mycolic acid to mycobacterial cell wall by ethambutol.

Outside cells
Direct chemical interaction · Antacids binding theophylline, tetracyclines, propranolol and phenytoin.
· Cholestyramine binds digoxin, warfarin, thiazides and statins.

Osmosis · Magnesium sulphate increasing osmolality of intestinal lumen.
· Mannitol increasing the osmolality of renal tubules.

Drug-Receptor Interactions

1. Agonists:

a. Interact with receptor and elicits a direct response.

b. Activate receptors as they resemble the natural transmitter or hormone.

c. Value in clinical practice rests on their greater capacity to resist degradation and to act for longer than the natural substances.

2. Antagonists:

a. Interact with receptor without eliciting a direct response.

b. Occupy it without activating a response, thereby preventing the natural agonist from exerting its effect.

c. Pure antagonists have no activating effect whatever on the receptor.

3. Partial agonists:

a. Some drugs, in addition to blocking access of the natural agonist to the receptor are capable of a low degree of activation.

b. Produces a lower maximal response, at full receptor occupancy, than does a full agonist.

c. Example: pindolol has intrinsic sympathomimetic activity.

4. Inverse agonists:

a. Produce effects that are specifically opposite to those of the agonist.

b. Example: b-carbolines binding to benzodiazepine receptors in CNS to produce stimulation, anxiety, increased muscle tone and convulsions.

5. Competitive antagonism:

a. An antagonist that binds reversibly to a receptor can be displaced from the receptor by mass action of the agonist.

b. Example: patients on b-blockers can raise their sympathetic drive to release enough norepinephrine to diminish the degree of receptor blockade.

6. Non-competitive antagonism:

a. Prevents the agonist from producing its maximal effect at a given receptor site.

b. Results from irreversible binding of drug to receptor.

c. Not surmountable.

d. Restoration of the response after irreversible binding requires elimination of the drug from the body and synthesis of new receptor.

e. Affinity of agonist for receptor is not diminished.

f. Effect persist long after drug administration has ceased.

g. Example: MAO inhibitors have short half-life, but their anti-depressant effects persist for weeks.

7. Physiological Antagonism:

a. Two drugs causing opposing effects that arise through different mechanisms.

b. Example: the antagonist effects of acetylcholine and norepinephrine on the heart are mediated by both drugs acting as agonists on their respective cardiac receptors.

Stereoselectivity

1. Many drugs, especially those of natural origin, exhibit chirality, i.e. a single drug existing as two enantiomers, the (-) S and (+) R isomers.

2. Molecules that contain one or more chiral centers can exist in isomeric forms.

3. Stereoisomers have identical chemical groups but they are not identical because the groups have different spatial arrangement.

4. The pharmacological significance of stereoisomerism lies:

a. Drug potency: S (-) warfarin is 4 times more potent than R (+) warfarin.

b. Metabolism: R (+) propranolol is more extensively metabolized than S (-) propranolol.

5. As stereoisomers exist commonly as racemic mixtures for therapy, the relative proportions of the two stereoisomers will affect drug potency in various drug brands and formulations.

Graded and Quantal dose response

Graded dose response Quantal dose response
· A response that varies in magnitude in a dose-dependent manner. · All-or-none response: dose of drug required a specified magnitude of effect in a large number of individuals.
· Used for measurable variables: blood pressure, heart rate, diuresis. · Used for nominal variables: convulsions, pain relief, deaths.
· EC50: concentration of drug that produces 50% of maximal effect. · ED50: dose at which 50% of individuals exhibit specified quantal effect.
· Curve: drug effect against log of concentration or dose. · Curve: number of individuals who exhibit effect against log of concentration or dose.
· Tells us about the potency and maximum efficacy of a drug. · Use to generate information on the margin of safety to be expected from a particular drug used to produce a specific effect.

Clinical Potency and Efficacy

Potency Efficacy
· Dose required to produce a given degree of response; the lower the dose.
· The lower the dose required; the higher the potency.

· Measured by EC50.
· Capacity of a drug to produce an effect and refers to the maximum such effect.
· Depends on affinity of the drug for binding and the intrinsic activity of the drug-receptor complex.
· However, a large part depends on pharmacokinetic process that determine drug concentration at receptor site.
· Depends more on its intrinsic ability to trigger off a secondary response mediated by the drug-receptor complex rather than on pharmacokinetic processes.
· This ability lies in the inherent properties of the drug, the drug-receptor binding and the intrinsic activity of the complex formed.

· Used to compare between two drugs that produce similar effects.
· Relative potency: the ratio of doses of two drugs needed to produce the same magnitude of the specified effect.
· Tells us nothing about the dose.
· Simply an indication of a drug’s maximal effect.

· A drug with high efficacy produces a greater maximal effect than a drug with a lower efficacy.

· A potent drug may not have a high therapeutic efficacy. · A drug with high efficacy may not be potent if it requires a large dose to elicit the desired response.

Therapeutic Index

1. The dose of a drug required to produce a desired effect to that which produces an undesired effect.

2. An indication of a drug’s potential to cause toxic effects.

3. Therapeutic index (TI) can be calculated from the following equation:

TI = TD50 / EC50

TD50: the dose that produces toxic effects in 50% of patients treated with the drug.

EC50: the dose that produces a stated therapeutic effect in 50% of patients treated with the drug.

4. Drugs with low therapeutic index must be used with extra caution and requires constant monitoring to detect any possible adverse effects, e.g. digoxin, methotrexate.

5. However, this does not mean that drugs with a high therapeutic index are completely safe and without side effects, e.g. diazepam causes drowsiness and hangover at therapeutic doses.

6. The therapeutic index of a drug can be different if it is being used for different therapeutic effects, e.g. aspirin as an antiplatelet drug has a much higher therapeutic index than aspirin as an anti-rheumatic drug.

Bioassay and Standardization

1. Biological assay (bioassay) is the process by which the activity of a substance is measured on living material.

2. It is used only when chemical or physical methods are not practiceable as in the case of a mixture of active substances, or an incompletely purified preparation, or where no chemical method has been developed.

3. Biological Standardization:

a. A specialized form of bioassay.

b. It involves matching of material of unknown potency with an International or National Standard with the objective of providing a preparation for use in therapeutics and research.

c. The results are expressed as units of a substance, e.g. insulin, vaccines.

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Chronic Pharmacology

· Introduction.

· Interference with self-regulating systems.

· Tolerance.

· Dependence.

· Withdrawal.

· Hazards of chronic drug use.

Introduction

1. The proportion of the population taking drugs continuously for large portions of their lives increases as tolerable suppressive and prophylactic remedies for chronic or recurrent conditions are developed.

2. In some cases long-term treatment introduces significant hazard into patients’ lives and the cure can be worse than the disease if it is not skillfully managed.

3. In general, the dangers of a drug are not markedly increased if therapy lasts years rather than months; exceptions include renal damage due to analgesic mixtures and carcinogenicity.

Interference with Self-regulating Systems

1. Homeostasis: when self-regulating physiological systems are subject to interference, their control mechanisms response to minimize the effects of the interference and to restore the previous steady state of rhythm.

2. If the body successfully restores the previous steady state of rhythm then the subject has become tolerance to the drug.

3. Feedback Systems:

a. The endocrine system serves fluctuating body needs.

b. An administered hormone or hormone analogue activates the receptors of the feedback system so that high doses cause suppression of natural production of the hormone.

c. On withdrawal of the administered hormone restoration of the normal mechanism takes time, e.g. hypothalamic/pituitary/adrenal cortex system can take months to recover sensitivity.

d. Regulation of receptors:

a. The number of receptors on cells, the number occupied and the capacity of the receptor to response can change in response to the concentration of the specific binding molecule or ligand.

b. The effect always tend to restore cell function to its normal or usual state.

Tolerance

1. Tolerance is said to have developed when it becomes necessary to increase the dose of a drug to obtain an effect previously obtained with a smaller dose.

2. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subjected to tachyphylaxis.

3. Down-regulation of receptors: tolerant or refractory state seen in severe asthmatics who no longer respond to b2-agonists due to decrease in receptor density following prolonged use.

4. Physiological compensatory mechanisms: compensatory increases in fluid retention by the kidney can contribute to the tolerance to the anti-hypertensive effects of a vasodilator drug.

5. Enzyme induction: tolerance develops with long-term phenytoin use due to its induction of its own metabolism.

6. In the clinical setting, the dosage of a drug would have to be increased gradually over time to counter tolerance and to produce a therapeutic response.

7. An alternative is to use various combinations of drugs to reduce tolerance to a particular drug and to maximize therapeutic effect.

Dependence

1. Drug dependence: a state arising from repeated, periodic or continuous administration of a drug that results in harm to the individual.

2. The subject feels a desire, need or compulsion to continue using the drug and feels ill if abruptly deprived of it (abstinence or withdrawal syndrome).

3. Drug dependence is characterized by:

a. Psychological dependence: the first to appear; there is emotional distress if the drug is withdrawn.

b. Physical dependence: accompanies psychological dependence in some cases; there is a physical illness if the drug is withdrawn.

c. Tolerance.

4. Psychological dependence:

a. This may occur with any drug that alters consciousness however bizarre, e.g. muscarine and to some that, in ordinary doses, do not, e.g. non-narcotic analgesics, purgatives, diuretics.

b. Psychological dependence can occur merely on a tablet or injection, regardless of its content, as well as to drug substances.

c. Mild dependence does not require that a drug should have important psychic effects; the subjects’ beliefs as to what it does are as important.

5. Physical dependence:

a. Physical dependence and tolerance imply that adaptive changes have taken place in body tissues so that the drug is abruptly withdrawn these adaptive changes are left unopposed, resulting generally in a rebound overactivity.

b. Physical dependence develops to a substantial degrees with cerebral depressants, but is minor or absent with excitant drugs.

c. There is commonly cross-tolerance between drugs of similar, and sometimes even of dissimilar chemical groups, e.g. alcohol and benzodiazepines.

Withdrawal

1. A patient may suffer from withdrawal effects or symptoms after the discontinuation of a drug.

2. Withdrawal symptoms are physical symptoms that manifest in direct association with the withdrawal of the drug.

3. Up-regulation:

a. Prolonged contact with an antagonist leads to formation of new receptors.

b. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiological concentrations of agonist.

c. Example: worsening of angina pectoris in patients following abrupt withdrawal of a beta-blocker as normal concentrations of circulating catecholamines now have access to an increased number of receptors.

4. Down-regulation:

a. After discontinuation of an agonist drug, the number of receptors may decrease to too low a number for the endogenous agonist to produce effective stimulation.

b. Example: withdrawal of adrenaline used to treat chronic obstructive pulmonary disease may result in bradycardia and hypotension.

5. Clinical important consequences have occurred in abrupt withdrawal of the following:

a. Anti-hypertensives.

b. Beta blockers.

c. All depressants: opioids, sedatives, alcohol, hypnotics.

d. Anti-epileptics.

e. TCAs.

f. Anti-parkinsonian agents.

g. Corticosteroids.

Hazards of Chronic drug use

Metabolic changes Specific cell injury
· Thiazides: diabetes.
· Corticosteroids: osteoporosis.

· Phenytoin: osteomalacia.
· Phenothiazines: tardive dyskinesia.
· Chloroquine: retinal damage.

· Methysergide: retroperitoneal fibrosis.

· NSAIDs: nephropathy.

Paediatric Pharmacology

· Drug therapy in pregnancy.

· Teratogenic drug actions.

· Drugs with adverse effects on the fetus.

· Drug therapy in infants and children.

· Drug use during lactation.

· Drugs used during lactation and possible effects on the fetus.

Drug therapy in Pregnancy

1. Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their effects.

2. Factors affecting placental drug transfer and drug effects on fetus:

a. physicochemical properties of the drug.

b. rate at which the drug crosses the placenta and the amount of drug reaching the fetus.

c. duration of exposure to the drug.

d. distribution characteristics in different fetal tissues.

e. stage of placental and fetal development at the time of exposure to the drug.

f. the effects of drugs used in combination.

3. Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation.

4. Drugs with molecular weights of 250-500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization: the choice of heparin as an anticoagulant in pregnant women.

5. Protein binding:

a. if a compound is very lipid-soluble, it will not be affected greatly by protein binding: transfer of these more lipid-soluble drugs and overall rates of equilibration are more dependent on placental blood flow.

b. if a drug is poorly lipid-soluble and is ionized, its transfer is slow and will probably be impeded by its binding to maternal plasma proteins.

c. differential protein binding is also important, since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lowered binding affinity of fetal proteins.

d. this has been shown for sulfonamides, barbiturates, phenytoin, and local anesthetic agents.

6. Two mechanisms help to protect the fetus from drugs in the maternal circulation:

a. the placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it.

b. drugs that have crossed the placenta enter the fetal circulation via the umbilical vein, about 40-60% of which enters fetal liver where it may be partly metabolized.

7. Toxic drug actions in the fetus:

a. chronic use of opioids by the mother may produce dependence in the fetus and newborn: may be manifested after delivery as a neonatal withdrawal syndrome.

b. use of ACE inhibitors during pregnancy can result in irreversible renal damage in the fetus.

Teratogenic drug actions

1. A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure.

2. Mechanisms:

a. direct effect on maternal tissues with secondary or indirect effects on fetal tissues.

b. interfere with the passage of oxygen or nutrients through the placenta.

c. direction actions on differentiation in developing tissues: retinol in normal tissues.

d. deficiency of a critical substance may play a role in some types of abnormalities: folic acid supplements during pregnancy reduce incidence of spina bifida.

3. Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development.

4. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol syndrome.

5. Criteria for a teratogen:

a. result in a characteristic set of malformations, indicating a selectivity for certain target organs.

b. exert its effects at a particular stage of fetal development.

c. show a dose-dependent incidence.

4. Drugs with adverse effects on the fetus

Drug Trimester Effect
ACE inhibitors All, esp. 2nd & 3rd Renal damage.
Aminoglycosides All 8th nerve toxicity.
Amphetamines All · Cystic cerebral cortical lesions.
· Abnormal developmental patterns.

· Decreased school performance.

Androgens 2nd & 3rd · Masculinization of female fetus.
TCAs 1st & 3rd · Congenital abnormalities: imipramine, amitriptyline, and nortriptyline.
· Neonatal withdrawal symptoms: clomipramine, desipramine, and imipramine.

Chloramphenicol Third Increased risk of gray baby syndrome.
Chlorpropamide All Prolonged symptomatic neonatal hypoglycaemia.
Clomipramine Third · Neonatal lethargy.
· Hypotonia.

· Cyanosis.

· Hypothermia.

Cortisone First Increased risk of cleft palate.
Cyclophosphamide First Various congenital malformations.
Cytarabine First, second Various congenital malformations.
Diazepam All Chronic use leads to neonatal dependence.
Ethanol All High risk of fetal alcohol syndrome.
Iodide All · Congenital goitre.
· Hypothyroidism.

Lithium First Cardiovascular defects.
Methadone All Chronic use leads to neonatal dependence.
Metronidazole First May be mutagenic.
Penicillamine First Cutis laxa, other congenital malformations.
Phenytoin All Cleft lip and palate.
Progestins All · Ambiguous genitalia.
· Cardiovascular defects.

Tamoxifen All Increased risk of spontaneous abortion or fetal damage.
Tetracycline All Discoloration and defects of teeth and altered bone growth.
Valproic acid All Various congenital anomalies, especially spina bifida.
Warfarin First, third · Hypoplastic nasal bridge.
· Chondrodysplasia.

· Risk of bleeding.

Drug therapy in infants and children

1. Blood flow at site of administration:

a. sick premature infants requiring intramuscular injections may have very little muscle mass.

b. this is further complicated by diminished peripheral perfusion to these areas, in such cases, absorption becomes irregular and difficult to predict.

c. example of drugs especially hazardous in such situations are cardiac glycosides, aminoglycosides and anticonvulsants.

2. Gastrointestinal function:

a. in full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours: drugs that are partially or totally inactivated by the low pH of gastric contents should not be administered orally.

b. gastric emptying time is prolonged in the first day or so of life: drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated.

c. neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs.

3. Drug distribution:

a. most neonates will experience diuresis in the first 24 – 48 hours of life.

b. since many drugs are distributed throughout the extracellular water space, the size of the extracellular water compartment may be important in determining the concentration of drug at the receptors site: important for water-soluble drugs.

c. premature infants have less fat than full-term infants: organs that accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in more immature infants.

d. protein binding of drugs is reduced in the neonate: local anesthetics, diazepam, phenytoin, ampicillin and phenobarbitone.

e. drugs given to a neonate with jaundice can displace bilirubin from albumin causing kernicterus.

4. Drug metabolism and excretion:

a. because of the neonate’s decreased ability to metabolize drugs, many drugs have slow clearance rates and prolonged elimination half-lives which predisposes the neonate to adverse effects from drugs that are metabolized by the liver.

b. the glomerular filtration rate is much lower in newborns than in older infants, children or adults.

c. drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life.

5. Paediatric dosage forms and compliance:

a. many drugs prepared for children are in the form of elixirs or suspensions.

b. elixirs are alcoholic solutions in which the drug molecules are dissolved and evenly distributed; no shaking is required.

c. suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking.

d. compliance may be more difficult to achieve in children.

Drug use during Lactation

1. Most drugs administered to lactating women are detectable in breast milk though the concentration is usually low.

2. If the nursing mother must take medications and the drug is relatively safe, she should optimally take 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.

3. Most antibiotics taken by nursing mothers can be detected in breast milk.

4. Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants.

5. Opioids such as heroin, methadone and morphine enter breast milk in quantities sufficient to prolong the state of neonatal narcotic dependence.

6. Lithium enters breast milk in concentrations given to those in maternal serum.

7. Drugs such as propylthiouracil and tolbutamide enter breast milk in quantities sufficient to affect endocrine function in the infant.

8. Radioactive substances such as radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer.

Drugs used during lactation and possible effects on fetus

Drug Comment
Chloramphenicol Contraindicated in breast feeding.
Diazepam Will cause sedation in breast-fed infants; accumulation can occur in newborns.
Ethanol Large amounts consumed by mother can produce alcohol effects in infant.
Lithium Avoid breast feeding.
Morphine Prolong neonatal narcotic dependence.
Phenobarbitone Hypnotic doses can cause sedation in the infant.
Phenytoin Amounts entering breast milk may be sufficient to cause adverse effects in infants.
Prednisone Doses 2 or more times physiologic amounts should be avoided.
Tetracycline Should be avoided during lactation.

Geriatric Pharmacology

· Increased risk of adverse effects in elderly.

· Age-related changes in pharmacokinetics.

· Age-related changes in pharmacodynamic response.

· NSAIDs.

· Psychotropic drugs.

· Benzodiazepines.

· Heterocyclic antidepressants.

· Principles of prescribing.

Prescribing for the Elderly

1. As Singapore ages, the number of elderly patients will increase and physicians will have to develop expertise in the management of such patients.

2. The incidence of adverse drug reactions rises with age in the adult, especially after 65 years because of:

a. The increasing number of drugs that they need to take because they tend to have multiple diseases.

b. Poor compliance with dosing regimens.

c. Decrease in physiological renal and hepatic functions.

Age-related changes in pharmacokinetics

1. Absorption of drugs may be slower may be slower because gastrointestinal blood flow and motility are reduced.

2. Distribution:

a. There is a significant decrease in lean body mass so that standard adult doses provide a greater amount of drug per kg.

b. Total body water is less but body fat is increased.

c. Plasma albumin concentrations may be reduced by chronic disease, leading to greater amount of free unbound drug.

3. Metabolism:

a. Metabolism is reduced because liver mass and liver blood flow are decreased.

b. Metabolic inactivation of drugs is slower.

c. Drugs that are normally extensively eliminated in first-pass through the liver appear in higher concentration in the systemic circulation and persist in it for longer, e.g. TCAs.

d. Capacity for hepatic enzyme induction is lessened.

4. Elimination:

a. Renal blood flow, glomerular filtration and tubular secretion decrease with age above 55 years.

b. Risk of adverse effects arises with drugs that are eliminated mainly by the kidney and that have a small therapeutic ratio, e.g. aminoglycosides, chlorpropamide, digoxin, lithium.

Pharmacodynamic response

1. Drugs that act on the CNS produce an exaggerated response and are more likely to depress respiration because vital capacity is reduced in elderly, e.g. sedatives and hypnotics.

2. Response to beta-agonists and antagonists is blunted in old age due to reduction in the number of receptors.

3. Baroceptor sensitivity is reduced leading to the potential for orthostatic hypotension in drugs that reduce blood pressure.

Non-steriodal anti-inflammatory drugs (NSAIDs)

1. NSAIDs are the main drugs used for the treatment of various forms of arthritis and are commonly used by the elderly.

2. Central nervous system:

a. Confusion.

b. Depression.

c. Dizziness.

d. Headache.

e. Insomnia.

f. Decreased hearing and tinnitus.

3. Cardiovascular system:

a. Cause salt and water retention.

b. Increase blood pressure.

c. Antagonize effects of anti-hypertensive drugs like beta-blockers, vasodilators and diuretics.

4. Gastrointestinal tract:

a. Ulceration, bleeding and perforation of upper gastrointestinal tract with chronic NSAID use.

b. Age is one of the risk factors of upper GI toxicity.

5. Kidneys:

a. Functional renal insufficiency, nephrotic syndrome, interstitial nephritis and papillary necrosis have been associated with NSAID use.

b. Functional renal insufficiency is common as NSAIDs inhibit prostaglandin synthesis and prostaglandins are involved in the hemodynamics of the kidneys.

c. Their vasodilatory action is important in maintaining renal blood flow when there is renal vasoconstriction such as in renal insufficiency due to age, atherosclerosis, etc.

6. NSAIDs and drug interactions:

a. Increased risk of bleeding with anticoagulants.

b. Hyperkalaemia with ACE inhibitors.

c. NSAID induced convulsions with quinolones.

d. Enhanced effects of phenytoin and antidiabetic drugs.

Psychotropic drugs

1. In the elderly patients psychotropic drugs are used to treat behavioral disorders associated with dementia or psychiatric illnesses like depression or psychosis.

2. In addition, some of these drugs like benzodiazepines are commonly prescribed for the elderly for complaints like insomnia, anxiety, agitation, etc.

3. Structural or functional changes with aging may result in the elderly being more sensitive to the drug and requiring a lower dose than the younger patient.

4. Therefore, the dosage for the elderly should be appropriately adjusted.

Benzodiazepines

1. Sedation:

a. The common adverse reactions of the benzodiazepines are sedation, drowsiness, ataxia and impaired coordination.

b. Sedation at night is useful for the elderly with insomnia but if the effect is carried over to the next day it can cause confusion and disorientation.

c. Drowsiness coupled with incoordination in an elderly increases the risk of falls.

d. Several studies have shown that the use of benzodiazepines was significantly associated with increased risks of falls and fractures in the elderly.

2. Psychomotor impairment:

a. Psychomotor impairment results in poor judgment, slow reaction time, decreased speed and accuracy of motor function.

b. With increasing age, many older persons may not have good psychomotor function and further impairment induced by drugs will cause distress to the individual and is dangerous for those who still drive a car or operate machinery.

3. Cognitive impairment:

a. Some of the symptoms of cognitive impairment associated with benzodiazepine usage include increased forgetfulness, poor attention and anterograde amnesia.

b. Reduction in memory and attention can be seen even in short-term benzodiazepine usage.

c. In the elderly who is already suffering from these symptoms chronic benzodiazepine usage may worsen the symptoms resulting in inability to cope with the tasks of daily living.

d. But the drug should not withdrawn from chronic users abruptly because of the risk of withdrawn symptoms.

4. Paradoxical effects:

a. Benzodiazepines may cause increased irritability, depression, aggression or socially unacceptable behavior in some individuals.

b. In elderly patients these symptoms should not be attributed to aging or to the worsening of behavioral problems as drugs such as benzodiazepines may induce them.

5. Tolerance and dependence:

a. The risk of tolerance and dependence on the benzodiazepines in the elderly is the same as for the younger patients.

b. The factors that are associated with the risk of dependence are the dose and duration of treatment.

Heterocyclic antidepressants

1. Sedation:

a. The sedative effect of the heterocyclic antidepressans varies with the individual and is usually more pronounced in the initial phase of treatment.

b. Sedation at night may be useful if the patient is also suffering from insomnia.

c. However, sedation during daytime is not desirable as it decreases their activity and also predisposes them to falls and fractures.

2. Cardiovascular effects:

a. Cardiotoxicity manifesting as hypotension, arrhythmias and conduction abnormalities are well recognized in tricyclic overdose.

b. In the patient with no cardiac abnormalities the most common cardiovascular adverse effects of the TCAs are tachycardia and orthostatic hypotension.

c. To the elderly patient orthostatic hypotension is particularly hazardous as it can result in a stroke or myocardial infarction and falls.

d. A simple precaution like warning the patient to change posture from supine to upright gradually may help to reduce the risk of sudden hypotension.

3. Anticholinergic adverse reactions:

a. The common adverse anticholinergic reactions associated with heterocyclic antidepressant usage include dry mouth, blurring of vision, constipation and urinary retention.

b. In the elderly patients with dentures dry mouth may cause pain and difficulties in using the dentures.

c. The mydriatic effect of the antidepressants may aggravate narrow angle glaucoma in the elderly patient.

d. Many elderly males have prostatic hypertrophy and depending on its severity, the heterocyclic antidepressants may precipitate acute urinary retention.

e. Constipation is a common complaint among elderly patients and treatment with heterocyclic antidepressants may worsen the situation.

4. CNS adverse reactions:

a. Common ones are headache, tremor, ataxia, confusion and delirium.

b. These drugs may also lower seizure threshold and precipitate convulsions.

5. Selective serotonin re-uptake inhibitors (SSRIs):

a. Common adverse effects are constipation, diarrhea, nausea and weight loss.

b. They may also cause neurological reactions like agitation, insomnia, tremors, dizziness, seizures and extrapyramidal symptoms.

c. These drugs should be used with greater caution in the elderly patient with Parkinson’s disease.

d. The use of SSRIs has also been associated with hyponatraemia and elderly patients may be at greater risk.

e. In addition, SSRIs are hepatic enzyme inhibitors, they may potentiate the effects of codeine, beta-blockers, calcium antagonists and benzodiazepines.

Principles of Prescribing

1. The benefits of therapy should outweigh the risks of adverse reactions.

2. Dosage:

a. Should be individualized for each patient.

b. To start at the lower end of the dosage range and work upwards titrating with the response of the patient.

3. Drug-drug interactions: as the elderly patient tend to be on polypharmacy, another addition to the patient’s list of medications should not be made without checking for drug-drug interactions.

Poisoning, overdose, antidotes

Causes of toxicity

1 Drug toxicity.

2 Accidental ingestion and suicide attempts:

a drugs: sedative hypnotics, antidepressants, paracetamol, salicylates.

b non-drugs: detergents / solvents, herbicides, insecticides.

3. Industrial toxicity.

4. Environmental & ecotoxicology:

a. air/water/soil pollution.

b. food addictives/preservatives.

c. ozone depletion, nuclear wastes, etc.

Assessment of patient

1. Fast or irregular pulse:

a. salbutamol.

b. antimuscarinics.

c. TCAs.

d. quinine.

e. phenothiazines.

2. Slow respirations: opiate toxicity.

3. Hypothermia:

a. phenothiazines.

b. barbiturates.

c. TCAs.

4. Hyperthermia:

a. amphetamines.

b. MAOIs.

c. cocaine.

d. antimuscarinics.

5. Coma:

a. benzodiazepines.

b. alcohol.

c. opiates.

d. TCAs.

e. barbiturates.

6. Seizures:

a. recreational drug use.

b. hypoglycaemic agents.

c. TCAs.

d. phenothiazines.

e. theophyllines.

7. Constricted pupils:

a. opiates.

b. organophosphates.

8. Dilated pupils:

a. amphetamines.

b. cocaine.

c. quinine.

d. sympathomimetics.

Prevention of absorption

1. When a poison has been inhaled or absorbed through the skin, the patient should be taken from the toxic environment, contaminated clothing removed and the skin cleansed.

2. Oral adsorbents:

a. activated charcoal reduces drug absorption, is easiest to administer and has fewest side effects; it should be given as soon as possible after the poison is ingested.

b. substances not adsorbed by charcoal: iron, lithium, cyanide, strong acids and alkalis, and organic solvents and corrosive agents.

c. activated charcoal also accelerates elimination of poison that has been adsorbed.

d. Fuller’s earth and bentonite: bind and inactivate the herbicides, paraquat and diquat.

e. cholestyramine and colestipol adsorb warfarin.

3. Gastric lavage:

a. best confined to the hospitalized adult who is believed to have taken a significant amount of a toxic substance within 4-6h.

b. worth undertaking in any unconscious patient, provided the airways are protected by a cuffed endotracheal tube.

4. Emesis:

a. in fully conscious patients only, may be used for children and also for adults who refuse activated charcoal or gastric lavage.

b. emesis is induced by ipecacuanha.

c. it can cause prolonged vomiting, diarrhoea and drowsiness that may be confused with effects of the ingested poison.

5. Both emesis and lavage are contraindicated for corrosive poisons, because there is a risk of perforation of the gut, and for petroleum distillates due to the danger of causing inhalational chemical pneumonia.

6. Cathartics:

a. whole-bowel irrigation used for removal of sustained-release formulations: theophylline, iron, aspirin.

b. activated charcoal in repeated dose is preferred.

Specific antidotes

1. Categories:

a. receptors, which may be activated, blocked or bypassed.

b. enzymes, which may be inhibited or reactivated.

c. displacement from tissue binding sites.

d. exchanging with the poison.

e. replenishment of an essential substance.

f. binding to the poison.

2. Dimercaprol:

a. provides –SH groups which combine with the metal ions to form harmless ring compounds which are excreted, mainly in the urine.

b. repeated administration is necessary to ensure that an excess is available until all the metal has been eliminated.

c. used for poisoning by antimony, arsenic, bismuth, gold and mercury.

d. adverse effects: nausea and vomiting, lachrymation and salivation, paraesthesiae, muscular aches and pains, urticarial rashes, tachycardia and a raised blood pressure.

e. gross overdose: overbreathing, muscular tremors, convulsions and coma.

3. Sodium calciumedetate:

a. effective in lead poisoning because of its capacity to exchange calcium for lead.

b. adverse effects: hypotension, lachrymation, nasal stuffiness, sneezing, muscle pains and chills.

4. Dicobalt edetate:

a. forms stable, nontoxic complexes with cyanide.

b. toxic, causing hypertension, tachycardia and hcest pain.

Acceleration of elimination of poison

1. Techniques for eliminating poisons depends directly or indirectly, on removing drug from the circulation and successful use requires that:

a. the poison should be present in high concentration in the plasma relative to that in the rest of the body.

b. the poison should dissociate readily from any plasma protein binding sites.

c. the effects of the poison should relate to its plasma concentration.

2. Repeated doses of activated charcoal:

a. activated charcoal by mouth adsorbs drug that diffuses from the blood into the gut lumen and drugs that are secreted into the bile.

b. repeated-dose activated charcoal is increasingly preferred to alkalinization of urine for phenobarbitone and salicylate poisoning.

3. Alteration of urine pH and diuresis: by manipulation of the pH of the glomerular filtrate, a drug can be made to ionize, become less lipid-soluble, remains in the renal tubular fluid, and so be eliminated in the urine.

4. Alkalinzation:

a. used for salicylate (> 500 mg/l + metabolic acidosis or in any case > 750 mg/l), phenobarbitone or phenoxy herbicides.

b. the objective is to maintain a urine pH of 7.5-8.5 by an i.v. infusion of sodium bicarbonate.

5. Acidification:

a. used for severe, acute amphetamine, dexfenfluramine or phencyclidine poisoning.

b. the objective is to maintain a urine pH of 5.5-6.5 by giving i.v. infusion of arginine hydrochloride (10g) or lysine hydrochloride (10g) over 30 min, followed by ammonium chloride (4g) 2-hourly by mouth.

6. Peritoneal dialysis:

a. involves instilling appropriate fluid into the peritoneal cavity.

b. poison in the blood diffuses into the dialysis fluid down the concentration gradient.

c. the fluid is then drained and replaced.

d. the technique requires little equipment but is one-half to one-third as effective as haemodialysis.

e. used for lithium and methanol poisoning.

7. Haemodialysis and haemoperfusion:

a. a temporary extracorporeal circulation is established, usually from an artery to a vein in the arm.

b. in haemodialysis, a semipermeable membrane separates blood from dialysis fluid and the poison passes passively from the blood, where it is present in high concentration.

c. the principal of haemoperfusion is that blood flows over activated charcoal or an appropriate ion-exchange resin which adsorbs the poison.

d. their use should be confined to cases of severe, prolonged or progressive clinical intoxication, when high plasma concentration indicates a dangerous degree of poisoning.

e. haemodialysis is effective for: salicylate, isopropanol, lithium and methanol.

f. haemoperfusion is effective for: phenobarbitone and other barbiturates, theophylline.

Common poisonings

1. Antimuscarinic syndromes:

a. consist of tachycardia, dilated pupils, dry, flushed skin, urinary retention, decreased bowel sounds, confusion, cardiac dysrhythmias and seizures.

b. commonly caused by antipsychotics, TCAs, antihistamines, antispasmodics.

2. Cholinergic syndromes:

a. comprises salivation, lachrymation, abdominal cramps, urinary faecal incontinence, vomiting, sweating, miosis, muscle fasciculation and weakness, bradycardia, pulmonary edema, confusion, CNS depression and fits.

b. common causes are organophosphates and carbamate insecticides.

3. Sympathomimetic syndromes:

a. these include: tachycardia, hypertension, hyperthermia, sweating, mydriasis, hyperreflexia, agitation, delusions, paranoia, seizures and cardiac dysrhythmias.

b. common causes are amphetamine, cocaine, ephedrine, and theophylline.

4. Sedatives, opioids and ethanol cause respiratory depression, miosis, hyporeflexia, coma, hypotension and hypothermia.

5. Cyanide:

a. causes tissue anoxia by chelating the ferric part of the intracellular respiratory enzyme, cytochrome oxidase.

b. poisoning may occur as a result of self-administration of hydrocyanic acid, by accidental exposure in industry through inhaling smoke from burning polyurethane foams in furniture or from excessive use of sodium nitroprusside.

c. acute poisoning: dizziness, palpitations, a feeling of chest constriction and anxiety.

d. inhaled hydrogen cyanide may lead to death within minutes but when it is ingested as a salt several hours may elapse before the patient is seriously ill.

e. chronic exposure damages the nervous system causing peripheral neuropathy, optic atrophy and nerve deafness.

f. dicobalt edetate is the treatment of choice when the diagnosis is certain; dose is 300 – 600 mg given i.v. over one minute.

6. Carbon monoxide:

a. formed when substances containing carbon and hydrogen are incompletely combusted; poisoning results from inhalation.

b. oxygen transport to cells is impaired and myocardial and neurological injury result; delayed neurological sequelae include parkinsonism and cerebellar signs.

c. treated with hyperbaric oxygen.

7. Methanol:

a. widely available as a solvent and in paints and antifreezes.

b. as little as 10ml may cause permanent blindness and 30ml may kill.

c. acidosis is due to formic acid, which itself enhances pH-dependent hepatic lactate production, so that lactic acidosis is added.

d. clinical features: severe malaise, vomiting, abdominal pain and tachypnoea, loss of visual acuity and scotomata.

e. therapy is aimed at correcting the acidosis, inhibiting methanol metabolism with use of ethanol and eliminating methanol and its metabolites by dialysis.

8. Ethylene glycol:

a. a constituent of antifreeze for car radiators.

b. metabolism to glycolate and oxalate causes acidosis and renal damage.

c. first 12 hours after ingestion: increasing acidosis, pulmonary edema and cardiac failure.

d. 2 –3 days: renal pain and tubulr necrosis.

e. acidosis is corrected with i.v. sodium bicarbonate, ethanol is given to inhibit metabolism of ethylene glycol and haemodialysis is used to eliminate the poison.

9. Hydrocarbons:

a. chiefly cause CNS depression and pulmonary damage from inhalation.

b. vital to avoid aspiration into the lungs during attempts to remove the poison or in spontaneous vomiting.

c. gastric aspiration should be performed only if a cuffed endotracheal tube is in place.

10. Dinitro-compounds:

a. used selectively as weed killers and insecticides.

b. they are absorbed through the skin and the hands, face or hair are usually stained yellow.

c. symptoms: copious sweating and thirst proceed to dehydration and vomiting, weakness, restlessness, tachycardia and deep, rapid breathing, convulsions and coma.

d. treatment is urgent and consists of cooling the patient and attention to fluid and electrolyte balance.

e. phenoxy herbicides cause nausea, vomiting, pyrexia, hyper-ventilation, hypoxia and coma; their elimination is enhanced by urine alkalinization.

11. Paraquat:

a. a widely used herbicide which is extremely toxic if it is ingested.

b. ulceration and sloughing of the oral and esophageal mucosa are followed 5 – 10 days later by renal tubular necrosis.

c. subsequently there is pulmonary edema followed by pulmonary fibrosis.

d. treatment is urgent and includes gastric lavage, activated charcoal or aluminium silicate by mouth as adsorbents, and osmotic purgation.

Paracetamol poisoning

1. Severe hepatic and renal damage can result from taking 150 mg/kg (about 10g or 20 tablets) in one dose.

2. Patients specially at risk are:

a. those whose enzymes are induced as a result of taking drugs or alcohol for their livers and kidneys form more NABQI.

b. those who are malnourished to the extent that their livers and kidneys are depleted of glutathione.

3. The INR and plasma creatinine are used to monitor hepatic and renal impairment respectively.

4. Clinical signs:

a. do not become apparent for 24-48h and liver failure, when it occurs, does so between 2 and 7 days after the overdose.

b. there may be vomiting and right upper quadrant pain.

c. later there is jaundice and encephalopathy from liver damage and renal failure.

5. Do an emergency blood level when 4h have elapsed since ingestion.

6. Empty the stomach if > 7.5g has been taken.

7. Give N-acetylcysteine by IVI, 150 mg/kg in 200 ml of 5% dextrose over 15 min.

8. If the INR exceeds 2 there is risk of infection and gastric bleeding, and an antimicrobial plus either sucralfate or histamine antagonist should be given prophylactically.

Salicylate overdose

1. Moderate overdose (500 – 750 mg/l):

a. nausea and vomiting.

b. epigastric discomfort.

c. tinnitus and deafness.

d. headache, sweating and pyrexia.

e. hyperpnoea.

f. hypokalaemia.

g. restlessness.

2. Severe overdose (> 750 mg/l):

a. pulmonary edema.

b. convulsions.

c. coma with severe dehydration and ketosis.

3. Mixed acid-base disturbance:

a. respiratory alkalosis due to direct stimulation of the respiratory center.

b. metabolic acidosis due to accumulation of lactic and pyruvic acids.

4. Gastric lavage:

a. worth undertaking at least up to 12 hr after overdose for tablets may lie as an insoluble mass in the stomach.

b. activated charcoal is worth giving as it adsorbs salicylate.

5. Correction of dehydration (< 4.3 mg/l): dextrose 5% given i.v. with added potassium.

6. Acid-base disturbances (> 4.3 mg/l): sodium bicarbonate is used to correct metabolic acidosis (blood pH < 7.2) and to alkalinize the urine to remove salicylate.

7. Removal of salicylate from the body: activated charcoal given in repeated doses or haemodialysis when plasma salicylate exceeds 750 mg/l and there is renal failure, or in any event exceeds 900 mg/l.

no choice.. using pda...

Sunday, February 24, 2008

what occupational history wold u take for a pt with asthma? dermatitis?
give reasosn for your answer.

during pre employment exam, what advice wld u give a pt with insulin dependent diabetes mellitus applying for a job requiring frequent travel regionally and extended stays overseas?
a hep b carrier applying for a job as a bartender?
an asthmatic applyuing for a job as a baker.

write notes on preemployment examination
health effects of noise,.\

how would u manage a a clerk who works in an office environment with low back pain?
excluding therapeutic detials.

an 18 y o female trainee chef in a catering school presents with a hand rash, which started a few week s after she startyed the course. she has apast history of bronchila asthma but no previous skin disease.
what additional inf would suggest her skin condition is work related?
how would u manage this pt if her condition if work relatied?

a worker consults u wioth a rash of the hands and forearms
what are the possible occupational causes of the rash?
what ar ethe preventive measures that can be taken if the rash is due to his occupationj?

a 19 y o trainee in the hotel and catering school presents with wheezing during his hotel posting which is part of his training in the 3 year cours.e the wheezing started a few weeks after her began work in the housekeepign department of the hotel. he has a past hhistory of broncial asth,a but no history of skin disease.
what addition info in the history will suggest that his condition is related to his work?
describ ethe investivation needed to confirm the diagnosis.
how would u manage this patient if his condition is work related?
exclude therapeutic detials

a 40 y o male preduiction worker in a furniture making factory presnt swith numbness ofht eright hand for the last 3 months. he is a known diabetic for the last 10 years well vontrolled with oral hypogylcaemic agents.

what additional info in the hitory would u ask for?
describe th einvestigation needed to confirm the diagnosis
how would u manage this case if his condtition if work related?

mr gan, a 52 yo lorry drive who has been in good health previously noticed that his hands tremble at rest in recent monthsw.
this has become worse and he has difficulty holding a cup. he also has difficulties getting up from a sitting position and walkling at his usual pace.
his doc told him he has parkinson's disease. and that the problem will get progressively worse, though medications can control some of the symptoms.

mr gan is very upset, as he is awidower and has to support two school going children aged 9 and 13 as well as his 73 y o mother who lives with him
he has no siblings. discuss the immediate care needs of mr gan and his family

phc
discuss the reasons for home visits in a community based care provided by the family physician.

mdm tan a 72 y o chin has been discharged from hosp after a stroke which left her aphasic. but able to walk with a quad stick. she is living with her unmarried daughter who works as a tchr in asecondary sch. her son is married na dlives with his family.
discuss the med and nursing care that she will need.
what community health services ar eavailable for her?
what are the health care needs of elderly people? 60 to 75 yo who are other wise well? what is the role of th eprimary care doctior in meeting the needs you haev described? give examoples to illustrate your ans.

discuess the health needs of older singaporeans. descruibe the barriers that mayu exist in their seeking of health care,.

mrs chong a 45 y o overweight pt with hhypertension comes to the clinic for her regular followup visit, she asks her doc for advice on the type of oil she shld use in her cooking as she has difficulty decding betwen the two brands. veg old nad soyabean oil.

discuss the health consequences of obesity and the measures thaqt can be taken to control obesity in the population.

mrs tan a 50 y o pt with htn comes to the clinic for her regular fu. her bp is 150/90 and her ldl c level is 3.6 mmol/l. 2.6 - 3.3 mmol/l desirable. she has not been complaint with her diet.
what further info would u obtain from her b4 advising her on her diet?

discuss the primary prevention of intellectual disabilities in children 12 yrs and below. what are the health and social needs of children with such disabilities>

discuss the health consequences of obesity and the measures that can be taken to control obesity in the population.

discuss the role of earlty intervention programmes for children with physical disabilities.
or intellectual disabilities.

why is the health of school children impt? discuss their health needs.

discuss the rol eof the the doctor in the prevention of disabilitioes among pre school children.

in a survey of 30 clerical staff in a company, a qeustionaire was administered to assess the work stress scores and the depression scores. the work stres scale ranges from 0 to 20 with 20 indicating high stress. the depression scaleranges from 0 to 9 with 9 indicating severe depression. a strong positive relationship between the two scores was seen. the authors concluded thaty work stress among clerical staff in the company leads to depression.
what is the study design? draw a diagram to show the relationship btwn work stress and depression scores.
comment on the conclusion of th eauthors.

in a rct of antiviral therapy in reducing the risk of hcc in hep b virus carries, 651 asian pt with hbv related cirrhosis were randomized to receive lamivudine or placebo. development of hcc on followup was taken as an end point of study. after a median followup of 32 monhs, hcc was diagnosed in 3.9% of the lamivudine treated patients and in 7.4% of the controls. (p=0.047)
comment on the use of a placebo in this trial, making specific reference to the study hypothesis in your asnwer.
from the results given, is there any evidence that the anti viral drug lamivudine reduses subsequent development of hcc in HBV carriers?
what further information would you like to help you judge if such therapy should be instituted for similar patients outside the trial,. explain your answer.

om
discuss the occupational factors that yuou would consider in the mangement of a pt presenting with type 2 dm.
desribe the management of a needle stick injuries in a health care worker.

as a gp , how would you manage a 35 y o female worker who is exposedto inorganic lead and suffering from bleeding hemorrhiods? exclude therapeutic detials.

u r a doctor in the poly, your pt adrian is a 32 y o foreign construction worker who complainsof having high fever associated with generalized body aches for the past 4 days.
give 3 of the most likely differential diagnosee and the history yu wld take to differentiate betwn them
what phyiscal signs wld u look for to help u in your diagnossi?>
what are the indications for a referral to the hospt?

a secretary in an office uses a computer for most of tghe working day. what are some of the ehalty effcts associated with this type of work?
how can these effects be prevented?

write notes on occupational health problems of nurses, motor vehicle mechanics.

a healthy 26 y o technical officer who has been offered a postition in a uni sci lab comes to u for her preemployment examination. she plans to have her first child in the near future.
what questions would u ask her in the history taking?
wha8t advice would u give her?
]
\

describe the risk factors and primary preventive strategies for a type 2 dm. how would you advise a45 year old patient on self care.
what are the components of a national dm control programme? illustrate your answer with examples.

describe the surveillance of communicable diseases in singapore indicating its uses.

describe the primary secondary and tertiary prevention of cvs disease.

describe therisk fastors for stroke and outline the primary prevention strategies for its control .

mr salim a 70 y o man has copd diagnosesd 5 years ago. he has ghad 5 hosp admissions in the last one year becasyue of his medical condition.
\dicuss the care of mr salim wityh regard to
prevention of frequent admissions becase of copd.
family and community support needed to help him cope with his medical prob.

a med student was pricked by a needkle just ater performing a venepuncture.
what are the possible health consequences of thi even.
what immediate and longer term measures and investigations shld be taken with regard to this incident.?
how can such incidents be prevented?

Mrs chan a 50 yo secretaryhas just been dischrgaed from hosp foloowing anacute asthma attack. Wrtie verbatim the advice you would give her on the ations to tak iin preventing further asthma attacks.

HPB
desctribe the compoentn fo a healthty lifestyle program. why is it impt to promiote healthy lifestyles in the workplace?

pt:yes i want to stop smioking but i do not noe how to stop.
at what stage of behavior change is the patent?
how would you help him quit smoking?

what are the health consequcnes of a sedantary lifesyyle in working adults?whjat can be done to promite physical activities in this group?

23 y o female works as clerk and has a child who is 3 months old. she comes for family planning advice and wishes to be on the pill.
what relevant history would you take from her?
what relevant physical findigns would you like to check?
besides the pill, what are the alternatives for family planning?

In a beat of the heart

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Monday, February 25, 2008

no choice.. using pda...

Sunday, February 24, 2008

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