Download Free Medical Factors Modifying Drug Actions and Effects PowerPoint Presentation

Factors Modifying Drug Actions and Effects PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Pharmacology, which is titled "Factors Modifying Drug Actions & Effects", to know about the factors modifying drug actions and effects.

Tags : Pharmacology, Factors Modifying Drug Actions, Effects

Published on : Jul 20, 2021 | Views : 2446 | Downloads : 3

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

FACTORS MODIFYING DRUG ACTIONS & EFFECTS Assoc. Prof. Galya Stavreva, MD, PhD Experimental & Clinical Pharmacology MU − Pleven (2015)
Slide 2-

Lecture Outline Factors Modifying Action of Drugs Drugs’ factors Hosts’ factors Physiological Factors Pathological Factors (Diseases) Genetic Factors Environmental Factors Drug interactions A multitude of host, drug & environmental factors influence drug response. Understanding of these factors can guide choice of appropriate drug & dose for individual patient.
Slide 3-

1. Drugs’ factors Physical properties (physical state, crystal structure, size of particulate solid drugs) determine their absorption and bioavailability, as well - the power of the drug effect. Physico-chemical properties: lipophilicity, pK-value, the Michaelis affinity constant (Km) - the affinity of an enzyme to its substrate. When the value of Km is the high affinity of the enzyme is low, and vice versa. Сhemical structure Drug dosage forms Dose: dosis pro dosi; dosis pro die; dosis pro cura (cursu) Repeated and prolonged drug administration: cumulation, tolerance.
Slide 4-

2. Physiological Factors Age Sex Pregnancy Body weight Lactation Food
Slide 5-

Drugs and Age of Patients Most drugs are developed and tested in young to middle-aged adults Drug consumption is different Dosage regimen cannot be based on body weight or surface area extrapolated from adult dosage Therapeutic disasters: Gray Baby Syndrom: chloramphenicol Thalidomide: Teratogenic effect Isotretinion (Accutane®): Teratogenic effect
Slide 6-

Thalidomide prescribed as a sedative or hypnotic. Afterwards, it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became an over the counter drug in Germany on October 1, 1957. Shortly after the drug was sold in Germany, between 5,000 and 7,000 infants were born with phocomelia (malformation of the limbs). Only 40% of these children survived. Throughout the world, about 10,000 cases were reported of infants with phocomelia; only 50% of the 10,000 survived. http://en.wikipedia.org/wiki/Thalidomide
Slide 7-

AGE PERIODS Premature infants:< 36 weeks gestation Full-term infants: 36-40 weeks gestation Neonates: 1st 4 weeks post-natal Infants: 5-32 weeks post-natal Children : 1-12 years Adolescents: 12-16years Geriatrics: > 65 years
Slide 8-

Changes in body proportions & composition with growth and aging From Puig M: Body composition and growth. In Nutrition in Pediatrics, ed. 2, edited by WA Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996
Slide 9-

High body water: >70% of BW gastric acid secretion liver microsomal enzymes; limited metabolic clearance: glucuronidation pathway is not developed the first year plasma protein binding - increase in unbound drug in serum Lower body fat: highly lipid-soluble drugs distribution is diminished (diazepam) GFR & tubular secretion Immaturity of BBB in neonates. 2.1 Drugs in Neonates
Slide 10-

PEDIATRIC PHARMACOLOGY CHILDREN ARE NOT SMALL ADULTS! Compliance problem • Poor communication • Inconvenient dosage forms • Unpalatability • Unreliable measurement • Spillage, etc Medication dosage: BW versus BSA
Slide 11-

There are a few formulae for calculation of dose of the children under 12 years. Clark's Rule = (Weight of the child in kg /150) X Adult dose Dilling's Formula= (Age/20) X Adult dose Young's Rule= (Age X Adult dose)/Age+12 The dose required for the age between 12 to 16 years will be from ½ to 2/3 of the adult dose. Dose of sodium bicarbonate for a child of 6 years Adult dose of sodium bicarbonate is 1g (1-4 g). Young’s Rule the required dose will be = 6 x 1/ (6+12) = 6/20 =0,3g
Slide 12-

Body Surface Area for Drug Dosage Calculations based on the child’s weight are inaccurate Physiological differences (body water, fat): larger doses of some drugs on a mg/m2 basis BSA is calculated from height and weight (nomogram) The surface area rule is the most accurate Approximate child’s dose = Body surface area X adult dose / 1.7
Slide 13-

Calculation of Drug Dosages, 7th Edition Ogden, Sheila JNomogram image, p. 364, Copyright Elsevier for C4203 Approximate child’s dose = Body surface area of the child X adult dose / 1.7
Slide 14-

PEDIATRIC PHARMACOLOGY GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity. Chloramphenicol – Gray-baby syndrome – (inadequate glucouronidation of chloramphenicol with drug accumulation). Sulfonamides – Hyperbilirubinemia & Kernicterus The children can tolerate iron, belladonna preparations relatively better than adult but they can not tolerate opium and morphine preparations except in very small doses.
Slide 15-

PEDIATRIC PHARMACOLOGY Tetracyclines - permanent teeth staining Corticosteroids - growth & development retardation Antihistaminics - hyperactivity. Administration of drugs during the first year of life can be a challenge due to rapid changes in body size, body composition, and organ function.
Slide 16-

Intramuscular Injections Vastus lateralis is the preferred site for children under the age of 3. Ventrogluteal site is the preferred site for children over the age of 3. The child should be walking. 2007 Thomson Delmar Learning, a division of Thomson Learning Inc. Anterior view of the location of the vastus lateralis muscle in a young child. Remember: Children are vulnerable. Be kind and patient. Enjoy the children; you will receive more than you give.
Slide 17-

2.2. GERIATRIC PHARMACOLOGY Elderly constitute 12% of the population but consume 31% of prescribed drugs in US Elderly more sensitive to drugs and exhibit more variability in response Altered pharmacokinetics Multiple and severe illnesses Multiple drug therapy and usage Poor compliance “Individualization of treatment is essential: each patient must be monitored for desired responses and adverse responses, and the regime must be adjusted accordingly”
Slide 18-

Changes in Geriatric Patients body fat (25-30%) - reduces plasma levels of lipid soluble drugs total body water by 25% - increases concentration of water soluble drugs and intensity of response; greater risk for dehydration concentration of serum albumin- malnourishment decreases albumin and results in increased drug levels Metabolism: hepatic functions in elderly and drug levels increase (diazepam, theophylline)
Slide 19-

Changes in Geriatric Patients Stomach pH ; blood flow ; decrease in gut motility (slow onset) In the elderly, muscle decreases by 25%. Excretion: decline (40-50%) of renal function in elderly may lead to higher serum drug levels and longer drug half-life. Reduced renal clearance of active metabolites may enhance therapeutic effect or risk of toxicity (e.g., digoxin, lithium, aminoglycosides, vancomycin)
Slide 20-

Pharmacodynamic Changes Alterations in receptor levels may change: Beta-blockers less effective in the elderly patients. Age-related changes resulting in sensitivity to certain classes of drugs place the elderly at risk for adverse drug reactions CNS depressants (e.g., benzodiazepines) resulting in delirium, confusion, agitation and sedation Anticoagulants and hemorrhage e.g., in combination with NSAIDs, salicylates. Alpha-blockers resulting in orthostatic hypotension Anticholinergic medications resulting in dry mouth, constipation, urinary retention, blurred vision, confusion
Slide 21-

Effects of Aging on Volume of Distribution (Vd)
Slide 22-

Polypharmacy Defined Treatment with multiple medications (> 5 meds per regimen) for a variety of conditions and symptoms that include excessive or unnecessary medications that place the patient at risk for an adverse drug reaction. Balance between avoiding excessive or unnecessary use of medications and providing beneficial therapies.
Slide 23-

Increased incidence of chronic conditions as the Diabetes Hypertension Heart Failure Ischemic Heart Disease Asthma/COPD Arthritis Alzheimer’s Disease Urinary problems
Slide 24-

Adverse Drug Reactions in Geriatrics Seven times more likely in elderly • 16% of hospital admissions • 50% of all medication-related deaths Drug accumulation secondary to reduced renal function Polypharmacy : dangerous practice (drug-drug interactions) Greater severity of illness Cont.
Slide 25-

Presence of multiple pathologies Increased individual variation Inadequate supervision of long-term therapy Poor patient compliance Reasons for non-compliance include complex drug regimens, intentional non-adherence, and dementia and cognitive impairment.
Slide 26-

Start with a low dose and titrate slowly Simplify regimen (once or twice daily dosing) Consolidate medications Use of blister packs, pill boxes, calendars, watches, other reminders Reduce costs (e.g., generics, pill splitting)
Slide 27-

2.3. SEX Females body size ; D Testosterone the rate of biotransformation of drugs metabolism of some drugs in female (Diazepam) Females are more susceptible to autonomic drugs (estrogen inhibits choline estrase) Gynaecomastia is ADR occuring only in men (metoclopramide, chlorpromazine, digitalis) Antihypertensive drs (clonidine, beta-blockers, diuretics) interfere with sexual function in males.
Slide 28-

2.4. Drug Therapy During Pregnancy Drug treatment in pregnancy is complicated mainly by two aspects: general concerns do exist regarding potentially harmful effects of drugs on the embryo. The fear of a second disaster as with thalidomide still present; physiological changes occuring during pregnancy may have an influence on pharmacokinetics and pharmacodynamics and subsequently efficacy of drugs.
Slide 29-

1/3 to 1/2 of pregnant women take at least one prescription drug and most take more Some used to treat pregnancy side effects –Nausea –Pre-eclampsia –Constipation Some medications used to treat chronic disorders –Hypertension –Diabetes –Epilepsy –Cancer –Infectious Diseases Drugs of abuse
Slide 30-

Pregnancy GI transit time is prolonged by about 30-50%. This could alter the rate and amount of absorption and the plasma concentration of drugs, which are either given as slow release forms or those, which are metabolised in the gut wall. Vd almost doubles during the later course of pregnancy; slight increment in renal clearance. treatment failures with ampicillin in pregnancy can be due to lower plasma concentrations.
Slide 31-

Pregnancy Plasma concentration/time profile of ampicillin, once after i. v. administration of 500 mg after delivery (= week 0, no pregnancy) and at week 40 of gestation; note, that a dose of 935 mg has been given at week 40 to achieve a comparable Cmax and AUC. P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.
Slide 32-

Pregnancy Progesterone influences biotransformation of drugs, metabolised by CYP3A4 (methyprednisolone). The microsomal oxidation of carbamazepine to it's active metabolite doubles during pregnancy. Cardiac output  GFR and renal elimination of drugs. Lipophilic drugs cross placental barrier & slowly excreted.
Slide 33-

The concept of teratology One of the most important factors determining the sensitivity of the embryo is the gestational age: During the first 2 weeks (blastogenesis) the law of all-or-none applies. During day 15 to 60 malformations maybe induced, depending on the exact date of exposure (organo-genesis, embriogenesis). Birth defects are known to occur in 3-5% of all newborns. Teratogenesis (teras, meaning 'monster' or 'marvel‘) Sensitivity to drugs decreases during the foetal period (after 9 week), later exposure to xenobiotics may induce functional defects or growth retardation.
Slide 34-

Effects of Teratogens at Specific Stages of FetalDevelopment
Slide 35-

ppt slide no 35 content not found
Slide 36-

Thalidomide (1957–1961)
Slide 37-

In 1962, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. USA: 17 babies
Slide 38-

Thalidomide is racemic: it contains both left- and right-handed isomers. The (R) enantiomer is effective against morning sickness. The (S) is teratogenic and causes birth defects. The enantiomers can interconvert in vivo. The (S) enantiomer intercalates (inserts) into the DNA in G–C (guanine – cytosine) rich regions. (S)-thalidomide (R)-thalidomide
Slide 39-

Drugs with documented teratogenic or embryotoxic effect P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.
Slide 40-

FDA pregnancy category A - Controlled studies in women fail to demon-strate a risk to the fetus in the first trimester, and the possibility of fetal harm appears remote (only 8 drugs: folic acid, vit A, vit C, vit D in physiol. D) B - Animal studies do not indicate a risk to the fetus and there are no controlled human studies, or animal studies do show an adverse effect on the fetus but well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus (250 medicines; penicillins, erythromycin, metthyldopa, lansoprazole). Cont.
Slide 41-

C - Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women. However, potential benefits may overweight the potential risk (700 drs; atenolol, aminophylline). D - Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may make use of the drug acceptable despite its risks (phenytoine, metotrexate, doxiciclin, enalapril, cyclophosphamide). Cont.
Slide 42-

X - Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit (statins, dinoprost). Whereas categories A to C define the degree of risk, categories D and X offer a risk-benefit evaluation.
Slide 43-

Some recommended drugs for selected indications during pregnancy P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.
Slide 44-

2.5. Drug Therapy during Breast Feeding Drugs get through breast milk and can effect infant Little research done on this aspect because of dangers involved in these studies - Adverse effects are described (penicillin, tetracycline) Concentration of drugs differ in milk. Lipid soluble drugs are in higher concentration; Milk is weakly acidic: weak bases are concentrated. Generally most drugs are in too low a concentration to be harmful to infant. Some drs can lead to toxicity in the child if enter the milk in pharmacological quantities - laxatives. Cont.
Slide 45-

Some drugs are contraindicated because of known risk: nicotine, amphetamines, lithium, marijuana, anticancer drugs. Some drugs to be avoided: amiodarone, TTC, quinolones, aspirin, benzodiazepines. The infant should be monitored if betalytics (bradycardia), corticoids (infants´adrenal functions) or lithium (intoxication) are prescribed to mother. Others: metronidazole gives milk an unpleasant taste; bromocriptine and diuretics suppress lactation.
Slide 46-

Lactation Risk Categories – LRC)
Slide 47-

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Slide 48-

L1 – safest: Paracetamol, Ibuprofen, Epinephrine. LACTATION RISK CATEGORIES (LRC) (Hale, 2004; 2008): L2 – safer: Diclofenac, Fentanyl, Cetirizine, Omeprazole, cephalosporins. L3 – moderately safe: Acarbose, Acetylsalicylic acid, Indometacin, Codeine, Morphine, Midazolam, Triazolam, Acebutоlol, Dimetinden. L4 – hazardous: Colchicine, Lithium, Ergobrevine, Ergotamine. L5 – contraindicated: ACE inhibitors (enalapril etc.)
Slide 49-

ppt slide no 49 content not found
Slide 50-

2.6. Species and race Rabbits are resistant to atr; rats & mice – to digitalis. Afro-americans require higher and mongols – lower D of atr & ephedrine to dilate their pupil. Beta-blockers and ACE inhibitors are less effective as antihypertensive in afro americans. Around 80% of Asian people have a variant of the gene coding for the enzyme alcohol dehydrogenase. Alcohol flush reaction (also known as Asian flush syndrome, Asian flush) is a condition in which an individual's face or body experiences flushes or blotches as a result of an accumulation of acetaldehyde.
Slide 51-

3. Pathological FactorsDiseases cause individual variation in drug response Renal and liver insufficiency are the main modulators of drug effect. Renal failure decreases drug elimination. Liver failure decreases drug metabolism
Slide 52-

3.1. Renal Disease Renal excretion is reduced in relation to GFR - raised plasma levels tubular function Plasma albumin Drugs (and their metabolites) excreted predominantly by the kidney accumulate in renal failure:digoxin-lithium- gentamycin- penicillin. Risk of toxicity after usual doses: aminoglycosides, digoxin, lithium, enalapril, atenolol, methotrexate CLcr essential in deciding on an appropriate dose regimen
Slide 53-

Prescribing for patients with renal disease Check the renal status CLCR Consider how the drug is eliminated if non-renal elimination accounts for less than 50% of total elimination, than dose reduction will probably be necessary monitor therapeutic and unwanted effects when appropriate also TDM use potentially nephrotoxic drugs - with special care aminoglycosides, NSAIDs, ACEI
Slide 54-

Nephrotoxicity Reduction of GF: NSAID – decreased PGI2 – vasoconstriction of afferent arteriole ACEI – decresed AGII – dillatation of efferent arteries renal vasoconstriction – cyclosporin, amphotericin Chronic interstitial nephritis, papillary necrosis (phenacetin, NSAID) Tubular damage (MTX) Praecipitation (sulphonamides)
Slide 55-

There is no reliable biomarker describing hepatic impairment. In chronic liver disease : serum albumin is the most useful index of drug metabolizing capacity or prothrombin time also shows a moderate correlation with drug clearance of drugs. such indices of hepatic function serve mainly to distinguish the severly affected from the milder cases (in contrast to serum cr or Clcr in renal impairment). 3.2. Liver disease
Slide 56-

Influence of liver disease Altered pharmacokinetics a) increased bioavailability - reduced first-pass metabolism - decreased first-pass activation of pro-drugs b) decreased protein binding c) decreased elimination Altered drug effect Worsening of metabolic state
Slide 57-

Liver Disease Prolong duration of action = ↑ (t1/2). Plasma protein binding for warfarin, tolbutamide; adverse effects. Hepatic blood flow clearance of morphine, propanolol. Impaired liver microsomal enzymes - diazepam- rifampicin- theophylline
Slide 58-

Prescribing for patients with liver disease: if possible, use drugs that are eliminated by routes other than the liver response and untoward effects should be monitored (and therapy adjusted accordingly) predictable hepatotoxins (cytostatic drugs) should only be used for the strongest of indications avoid drugs that interfere with hemostasis (anticoagulants, aspirin)
Slide 59-

Drug-induced hepatotoxicity Jiwon Kim. An Overview of Drug-Induced Liver Disease US Pharm. 2005;11:HS-10-HS-21. http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm
Slide 60-

4. Genetic Factors Pharmacogenetics is the study of the relationship b/w genetic factors and drug response. All key determinants of drug response (transporters, metabolizing enzymes, ion channels, receptors with their couplers and effectors are controlled genetically. Pharmacogenomics is the use of genetic information to guide the choice of drug & dose on an individual basis. It intends to identify individuals who are either more likely or less likely to respond to a drug, as well as those who require altered dose of certain drug.
Slide 61-

Genetic Factors GENETIC POLYMORPHISM The existence in a population of two or more phenotype with respect to the effect of a drug. Idiosyncrasy abnormal drug reaction due to genetic disorder. Acetylation. Oxidation. Succinylcholine apnea. Glucose 6-phosphate dehydrogenase deficiency.
Slide 62-

Genetic Factors Polymorphism of N-acetyl transferase 2 gene results in rapid & slow acetilator status (acetyl transferase - non-microsomal). • Isoniazid, sulphonamides, procainamide, etc. Slow acetylator phenotype - isoniazid peripheral neuropathy; procainamide-induced lupus. Rapid acetylator phenotype - hepatitis.
Slide 63-

Pseudocholinesterase deficiency Succinyl choline (Sk. muscle relaxant) Succinylcholine apnea due to paralysis of respiratory muscles. Malignant hyperthermia By succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum. abnormal Ca release, muscle spasm, temp. Genetic Factors
Slide 64-

Genetic Factors Deficiency of Glucose–6 phosphatedehydrogenase (G-6-PD)G-6-PD deficiency in RBCs is responsible for hemolytic anemia upon exposure to some oxidizing drugs. Antimalarial drug: primaquine, quinine. Long acting sulphonamides, nalidixic acid. Fava beans ( favism).
Slide 65-

5. Chronopharmacology The study of rhythmic, predictable-in-time differences in the effects and/or pharmacokinetics of drugs. It investigates the effects/side effects of drugs upon temporal changes in biological functions or symptoms of a disease as well as drug effects as a function of biologic timing. Circadian Rhythm. A biological rhythm is an adaptive phenomenon to predictable changes in environmental factors linked to the rotation of the earth around its axis in 24 hours as well around the sun in 365 days.
Slide 66-

Circadian rhythms are endogenously driven by biological clocks found in single cells, flowers, animals and men and in which "clock genes" are expressed. Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei.
Slide 67-

Types of rhythm Ultradian < 20 h Circadian ~ 24 h Infradian > 28 h Circaseptan ~ 7 days Circamensual ~ 30 days Circannual ~ 1 year
Slide 68-

ppt slide no 68 content not found
Slide 69-

CVS BP rises about 20% immediately after awaking. 2 hrs after arising are the peak hrs for MI, hemorragic stroke, thrombotic events. Reasons: physical activity catecholamine level platelet aggregation vascular tone intrisic thrombolytic activity
Slide 70-

5. Environmental Factors Microsomal Enzyme Inducers Tobacco Smoke. Smokers metabolize drugs more rapidly than non smoker. Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP 1A. Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than who are non exposed. Polychlorinated biphenyls used in industry, cruciferous vegetables also induce CYP 1A
Slide 71-

Food-Drug Interaction Drug-food interactions may decrease absorption: Calcium containing foods and tetracyclin High fiber foods reduce absorption Drug-food interactions may increase absorption: High calorie food more than doubles the absorption of squinavir Drug may cause upset stomach if taken without food –Choose alternative drug? –Increase dose if taken with food? –Take shortly before or after meal?
Slide 72-

Food-Drug Interaction Grapefruit juice may inhibit metabolism of certain drugs, raise the blood levels (co- administration of grapefruit juice produce a 40% increase in blood levels of felodipine- drug for hypertension), and lead to toxicity level. Grapefruit juice may inhibits cytochrome CYP3A isoenzyme and decrease metabolism of certain drugs: One glass (200 ml) is sufficient.
Slide 73-

REFERENCE FACTORS MODIFYING DRUG DOSE-RESPONSE RELATIONSHIP M. Imad Damaj, http://www2.courses.vcu.edu/ptxed/m2/powerpoint/download/Damaj%20DR%20Modification.PDF Body composition and growth. In Nutrition in Pediatrics, ed. 2, edited by WA Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996 Jiwon Kim. An Overview of Drug-Induced Liver Disease US Pharm. 2005;11:HS-10-HS-21. http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm http://www.medpharm-sofia.eu/ P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63. B. G. Katzung, Basic and Clinical Pharmacology, 12th ed., Appleton&Lange, 2012. H. P. Rang, M. M. Dale, J. M. Ritter, Pharmacology, 7th ed., Churchill Livingstone, 2012. Lippincott's Illustrated Reviews Pharmacology, 4th Edition\Chapter 14 Bailey DG. Grapefruit-medication interactions. CMAJ. 2013 Apr 2;185(6):507-8 Journal of Chronotherapy and Drug Delivery (ISSN: 2249-6785)