Special aspects of drugs action 2 0 1 2 - 1 1 - 1 1
2 ADVERSE EFFECTS SIDE EFFECTS = OR
ADVERSE AND TOXIC REACTIONS ADVERSE EFFECTS all unfavorable actions of drug observed after therapeutic doses type and risk depends on margin of safety some adverse effects, under very specific conditions, may be sometimes considered as desired (in different than original indication)
TOXIC EFFECTS all actions of drug observed after overdosing 2 0 1 2 - 1 1 - 1 1
3 1 1 / 1 1 / 2 0 1 2
4 ADVERSE EFFECTS OF DRUGS PREDICTABLE directly connected to the drugs mechanism of action GI injury after NSAIDs hyperkalemia after ACEI UNPREDICTABLE independent from the drugs mechanism of action hypersensitivity reactions after penicillins 1 1 / 1 1 / 2 0 1 2
5 ADVERSE EFFECTS OF DRUGS on-target result from drug binding to its intended receptor often class effect off-target results from drug binding to a target or receptor for which it is not intended mediated by the immune system idiosyncratic reactions 6 D D Intended tissue Unintended tissue Intended receptor Intended receptor Unintended receptor Unintended receptor DX DX metabolism metabolism On-target adverse effects dose too high chronic activation or inhibition effects On-target adverse effects correct receptor, but incorrect tissue dose too high chronic activation or inhibition effects Off-target adverse effects incorrect receptor is activated or inhibited Off-target adverse effects incorrect receptor is activated or inhibited Toxic cellular adverse effects Principles of pharmacology, LWW, 3rd Ed, 2012 ADVERSE EFFECTS ALLERGIC REACTIONS IMPACT ON FETUS CARCINOGENIC ACTION most of drugs become antigens after binding with some macromolecules more often in patient with some allergic history reactions are different from therapeutic effects of drug characteristic for the patient not for a drug similar reactions, but not Ig-mediated may be due to direct histamine release 1-8% (3%) congenital defects first trimester fetal death, spontaneous abortion, severe congenital malformations teratogenic action second and third trimesters fetal death, abortion, biochemical disturbances embriotoxic action preterm period changes in fetal function e.g. respiratory depression after opioids the same drug may cause different defects in various animals and various drugs may cause the same defects many differnt compounds may be potentially carcinogenic great interspecies differences 1 1 / 1 1 / 2 0 1 2
8 TYPE I T Y P E S
O F
A L L E R G I C
R E A C T I O N S
TYPE II TYPE III TYPE IV immediate IgE-mediated symptoms within minutes degranulation of mast cells and basophils e.g. anaphylaxis, asthma, hay fever, urticaria formation of Ag-Ab complexes activation of complement cascade, membrane attack complex and cell lysis e.g. blood transfusion reactions or drug- induced levels of Ag-Ab complexes; deposition on basement membranes in tissues and vessels activation of complement (C5a, C3a, C4a) symptoms within 3-4 days e.g. glomerulonephritis, arthritis delayed-type; responses after 2-3 days cell-mediated local inflammatory response with tissue damage and influx of Ag- nonspecific inflammatory cells (macrophages) e.g. contact dermatitis IDIOSYNCRATIC REACTIONS state of increased reactivity of organizm to specific chemical (drug) substance appear unpredictably the reaction is quantitatively altered probably due to altered metabolism of compound (genetically or acquired) often the reason is in various enzymopathies idiosyncratic reaction causing symptoms similar to allergy is called pseudoanafilactoidal reaction 1 1 / 1 1 / 2 0 1 2
9 TOXIC REACTIONS OVERDOSE absolute toxic doses of drugs cumulative due to the accumulation of doses greater than eliminated relative toxic effects after therapeutic doses e.g. liver and kidney failure the use of inhibitors of liver metabolism other drug-drug interactions effector tissues alterations (disease) 1 1 / 1 1 / 2 0 1 2
10 2 0 1 2 - 1 1 - 1 1
11 APOPTOSIS (programmed cell death) NECROSIS (uncontrolled cell death) ordered self-destruction without damage to surrounding tissue
coordinated activation of a number of dedicated proteins enzymatic digestion of cellular content, denaturation of proteins, disruption of cell membranes of
12 reduce or eliminate exposure to the drug administer specific treatment based on antagonizing mechanism or altering metabolism provide supportive measures MONITORED THERAPY measurements of plasma/serum drug concentrations in case of low therapeutic index in case of the simultaneous use of many drugs with possible interactions in case of kidney or liver failure
13 FACTORS INFLUENCING DRUGS ACTION 14 AGE SEX BODY WEIGHT GENOTYP PHYSIOLOGICAL STATE PATHOLOGICAL STATE PREVIOUS DRUG EXPOSURE infants children geriatric impact of sex hormones doses for lean body mass obesity pregnancy pregnancy lactation changes in GI motility other diseases e.g. kidney, liver failure various enzymopathies tachyphylaxis & tolerance allergy DIET & ENVIRONMENT grapefruit juice herbal roducts PHARMACOGENETICS succinylcholine metabolism 1:2000-3000 patients (Caucasians) 1000-fold reduced affinity prolonged action of drug due to defects in activity of pseudocholinesterase artificial respiration is needed until the drug is cleared 1 1 / 1 1 / 2 0 1 2
15 PHARMACOGENETICS isoniazid metabolism (also dihydralazine, procainamide) differences in acetylation (AR trait) less enzyme (NAT2) rather than abnormal form slow acetylators ca. 45% of whites and blacks in the USA in Europe mainly northern latitudes fast acetylators 90% of Asians and Inuits in the USA slow acetylators blood level of isoniazid is increased 4-6-fold higher incidents of autoimmune disorders free drug inhibits P450 enzymes 1 1 / 1 1 / 2 0 1 2
16 PHARMACOGENETICS warfarin metabolism (CYP2D9) also phenytoin, losartan and tolbutamide differences in hydroxylation
clopidogrel (CYP2C19) loss of activity re-stenosis and re-thrombosis polymorphisms decreased amount of active drug 1 1 / 1 1 / 2 0 1 2
17 PHARMACOGENETICS hemolysis glucose-6-phosphate dehydrogenase defficiency sulfonamides, some antimalarial agents, nitrofurantoin, chloramfenicol, some antifungal agents hemoglobinopathies
methemoglobinemia reduced nicotine adenine dinucleotide (NADH) diaphorase system defficiency reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system local anesthetics (benzocaine, prilocaine), amyl nitrite and isobutyl nitrite, nitroglycerin, sulfatiazole 1 1 / 1 1 / 2 0 1 2
18 PREGNANCY critical factors affecting placental drug transfer physicochemical properties of drugs rate at which drugs cross the placenta amount duration of exposure distribution in fetal tissues stage of placental and fetal development effects of drugs in combination 1 1 / 1 1 / 2 0 1 2
19 PREGNANCY lipid solubility lipophilic drugs cross the placenta readily, highly ionized slowly e.g. thiopental vs. succinylcholine molecular weight drugs with MW > 1000 cross placenta poorly e.g. heparins vs. warfarin placental transporters PgP pumps out many drugs e.g. some anticancer or anti-HIV agents may be responsible for transplacental passage of large molecules e.g. antibodies 1 1 / 1 1 / 2 0 1 2
20 PREGNANCY protein binding for highly lipid-soluble drugs protein binding does not affects transplacental passage depends more on placental blood flow differences between maternal (higher) and fetal (lower) protein binding placental and fetal drug metabolism some enzymes are located in placenta inactivation of drugs or formation of toxic metabolites drugs go to the fetal circulation via umbilical vein 40-60% of blood from this vein enters the fetal liver drugs in placental artery may be shunted through the placenta to the vein 1 1 / 1 1 / 2 0 1 2
21 PREGNANCY maternal drug action effects of drugs on the reproductive system are altered by hormones therapeutic action in fetus new area in pharmacology e.g. glucocorticoids stimulates fetal lungs development phenobarbital inducing fetal liver enzymes decreases the risk of jaundice anti-HIV agents decrease the risk of vertical HIV transmission some antiarrhythmic predictable toxic action in fetus when toxic action is due to a mechanism of action 1 1 / 1 1 / 2 0 1 2
22 PREGNANCY teratogenic drug action multifactorial single-dose effects of cumulative effect drugs may interfere with oxygen and/or nutrients transport direct action on fetal tissues (differentiation) consequences of deficiency (e.g. folic acid) drugs may also cause intrauterine growth retardation, miscarriage, stillbirth, neurocognitive delay 1 1 / 1 1 / 2 0 1 2
23 PREGNANCY absorption constipation delayed motility of GI tract may cause increase in absorption of some poorly absorbed drugs distribution increased volume of distribution increased plasma and extracellular volume additional compartment (fetus) finally, concentrations of many drugs are decreased decreased protein binding physiological hypoalbuminemia increased free fraction may counter balance decreased concentrations due to increased Vd 1 1 / 1 1 / 2 0 1 2
24 PREGNANCY metabolism increased biotransformation gestagens induce liver enzymes however, phase II reactions may be decreased conjugation with glucoronic acid or sulfuric acid
excretion increased renal excretion in the end of pregnancy very often renal excretion is decreased 1 1 / 1 1 / 2 0 1 2
25 CATEGORIES FOR DRUGS USED IN PREGNANCY 1 1 / 1 1 / 2 0 1 2
26 A animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus B adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities CATEGORIES FOR DRUGS USED IN PREGNANCY 1 1 / 1 1 / 2 0 1 2
27 C studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus; however, the benefits of therapy may outweigh the potential risk D animal studies have shown an adverse effect and there are no adequate and well- controlled studies in pregnant women or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women CATEGORIES FOR DRUGS USED IN PREGNANCY 1 1 / 1 1 / 2 0 1 2
28 X studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities the use of the product is contraindicated in women who are or may become pregnant LACTATION most of drugs enter the breast milk, but in low (subtherapeutical concentrations) the medication should be taken 30-60 after nursing and 3-4 hours before the next nursing examples of drugs achieving high concentration in breast milk: tetracyclines isoniazid hypnotics and sedatives opioids 1 1 / 1 1 / 2 0 1 2
29 PEDIATRIC PHARMACOLOGY two major problem ethical inability to obtain true informed consent children rapid growth and development
five groups of children: preterm infants term infants till the end of first month from 1 month to 2 years of age from 2 years to 12 years of age from 12 years to 18 years of age 1 1 / 1 1 / 2 0 1 2
30 PEDIATRIC PHARMACOLOGY absorption increased membrane permeability in GI tract drugs are more irritant to GI mucosa slow increase in gastric acid in preterm children fluctuations of gastric acid levels initiation of gastric acid secretion is delayed when children ar not oral feeding decreased gastric emptying in the first few hours after delivery and is slow up to the end of 1 year impact of food dramatic increase after 2 years of age (together with splanchnic blood flow) 1 1 / 1 1 / 2 0 1 2
31 PEDIATRIC PHARMACOLOGY absorption variable intestinal motility in infants often slow in the beginning and then increased decreased activity of some enzymes in GI tract lower levels of bile acids and lipase
irregular absorption from muscles in neonates (esp. preterm infants) low blood flow through the muscles
exessive percutaneous absorption in preterm children resulted in higher toxicity 1 1 / 1 1 / 2 0 1 2
32 PEDIATRIC PHARMACOLOGY distribution higher total (70-77%) and extracellular (40%) water amount small preterm neonates even 85% loading doses are sometime necessary different distribution of water-soluble drugs differences starts to be insignificant after 1 year of age
differences in body fat preterm (1%) vs. full-term neonates (15%) different distribution of lipid-soluble drugs 1 1 / 1 1 / 2 0 1 2
33 PEDIATRIC PHARMACOLOGY distribution reduced protein binding decreased albumin level decreased drug-binding affinity
higher pharmacological effects despite lower plasma concentration of total drug competition with bilirubin binding kernicterus (?) in hyperbilirubinemia displacement of drugs from albumins
easier penetration through the blood-brain barrier 1 1 / 1 1 / 2 0 1 2
34 PEDIATRIC PHARMACOLOGY metabolism activities of P450-dependent mixed-function oxidases, demethylation enzymes and the conjugating enzymes (with glucuronates) are lower in neonates (50-70% of the adult value) glucuronate activity reaches normal value about 3-4 years of age sulfate cojugation is greater some enzymes work normally various metabolites in children and adults in older children (12-36 months) half-life of many drugs is shorter than in adults e.g. theophyllin, phenytoin 1 1 / 1 1 / 2 0 1 2
35 PEDIATRIC PHARMACOLOGY excretion GFR in preterms and neonates in much lower than in older children esp. in preterm (before 34 week of gestation) children in some cases (e.g. penicillin) MIC after single dose is within therapeutic range 6-times longer than in adults (administration every 12 hours) less frequent dosing GFR reaches the adult value after 6-12 months and thenafter even exceeds it tubular secretory function mature at slower rate 1 1 / 1 1 / 2 0 1 2
36 PEDIATRIC PHARMACOLOGY some drugs are used in children because of very specific indications e.g.: indomethacin closure of patent Botals duct prostaglandin E 1 maintaining the patency of Botals duct theophylline apnea of prematurity
some drugs may have altered action in children e.g.: phenobarbiltal hyperactivity 1 1 / 1 1 / 2 0 1 2
37 PEDIATRIC PHARMACOLOGY some specific adverse effects of drugs in children: nephrocalcinosis after furosemid renal failure and bowel perforation after indomethacin growth suppression after glucocorticoids hyperactivity after phenobarbital hepatotoxicity after valproic acid Reys syndrome after aspirin gray baby syndrome after chloramphenicol 1 1 / 1 1 / 2 0 1 2
38 PEDIATRIC PHARMACOLOGY problems with appropiate formulation of drugs lack of suitable for children
during IV administration of small dose by electric infusion pump a large part of dose may be lost may adhere to IV tubes, catethers
39 PEDIATRIC PHARMACOLOGY children are not small adults infants are not small children newborns are not small infants preemies are not small newborn 1 1 / 1 1 / 2 0 1 2
40 PEDIATRIC DOSING the most reliable pediatric doses are provided by manufacurer and are given in mg/kg or mg/body surface 1 1 / 1 1 / 2 0 1 2
41 Youngs rule Clarks rule d dose for a child D dose for adult age given in years weight given in kilograms 70 average weight of adult age + 12
D x age d = 70
D x weight d = PEDIATRIC DOSING 4-years old child weighted 16 kg calculate single dose according to the recommended dose of amoxicillin and according to the doses for adults: adults: daily dose 0.75-1.5 g in 3 single doses recommended daily dose for 4-years old child: 20-40 mg/kg in 3 single doses 1 1 / 1 1 / 2 0 1 2
42 single dose for a child: from 16 kg x 20 mg/kg / 3 doses = 320 mg / 3 106 mg to 16 kg x 40 mg/kg / 3 doses = 640 mg / 3 212 mg single dose according to Clarks rule: from 250 mg x 16 kg / 70 kg 57 mg to 500 mg x 16 kg / 70 kg 114 mg single dose according to Youngs rule: from 250 mg x 5 / (5 + 12) 73.5 mg to 500 mg x 5 / (5 +12) 147 mg GERIATRIC PHARMACOLOGY very often persons over 65 are elder
geriatric pharmacology starts over 75 years of age
for some drugs age-related changes in action are great for other minimal
many additional diseases may influence drugs action 1 1 / 1 1 / 2 0 1 2
43 GERIATRIC PHARMACOLOGY absorption altered nutritional habits greater consumption of OTC drugs, herbal preparations delayed gastric emptying esp. in patients with diabetes mellitus decreased gastric acid secretion increased absorption of acid-unstable drugs most of drugs do not have altered GI absorption decreased splanchnic blood flow less complete absorption more slowly absorption
1 1 / 1 1 / 2 0 1 2
44 GERIATRIC PHARMACOLOGY distribution reduced lean body mass (muscles) often increased fat tissue reduced total water amount decreased albumin level (about 20%) reduced hepatic synthesis of albumins decreased protein binding increased plasma drug concentration (but not always increased tissue drug concentration due to decreased tissue blood flow) concurrent increase in alpha-acid glycoprotein 1 1 / 1 1 / 2 0 1 2
45 GERIATRIC PHARMACOLOGY metabolism reduction of hepatic enzyme activity reduction of hepatic mass, volume and blood flow reduced ability of liver to recover after injury impact of malnutrition of heart failure on liver function phase I reactions are decreased phase II reaction are often unchanged 2 0 1 2 - 1 1 - 1 1
46 GERIATRIC PHARMACOLOGY excretion age-related decline in renal function decreased renal blood flow CrCl is decreased in about 2 / 3 of the population sometimes 12- or 24-hour urine collection is necesarry not always reflected as increased serum creatinine level (reduced muscle mass) decline about 10% per decated (after 20 years of age) altered tubular secretion and reabsorption urine is more alkaline
47 GERIATRIC PHARMACOLOGY 3-5 times greater incidence of iatrogenic complications 20-40% adverse drug reaction of hospitalized patients receive unnecessary drugs esp. high risk of delirium after many psychoactive drugs noncompliance 50% of elder patient side effects mental impairment difficult instructions inability to pay for a drugs
1 1 / 1 1 / 2 0 1 2
48 Rang & Dales Pharmacology, Churchill Livingstone, Elsevier, 6th Ed, 2007 Brenner & Stevens: Pharmacology, 3 Ed, 2010 Brody human pharmacology. Molecular to clinical. Mosby, Elsevier, 5th Ed, 2010. Katzung & Trevors Pharmacology, Examination and Board Review, McGraw Hill, Lange, 9th Ed, 2010 Modern Pharmacology with Clinical Applications, LWW, 6th Ed, 2004 Principles of pharmacology. The pathophysiologic basis of drug therapy. WK, LWW, 3rd Ed, 2012 Podstawy farmakologii dla lekarzy, farmaceutw i studentw medycyny, Volumed, 1996 Basic and Clinical Pharmacology, McGraw Hill, Lange, 11th Ed, 2009 Stedmans Medical Dictionary, LWW, 28th Ed, 2006 Lippincotts Illustrated Reviews: Pharmacology, LWW, 3rd Ed, 2000 Goodman & Gilmans The Pharmacological Basis of Therapeutics, McGraw Hill, 11th Ed, 2006 1 1