L6 PK Physical implications - Paediatrics - geriatrics Flashcards
(21 cards)
Paediatric populations - 4
Neonate: Birth – 1 month
Infant: 1 month – 2yrs
Child: 2-12yrs
Adolescent: 12-16yrs
PK implications of Absorption due to Developmental changes - 7
- Gastric acidity
- rates of gastric & intestinal emptying
- SA of the absorption site
- GI enzyme systems
- GI permeability
- biliary function
- I.M., subcutaneous, percutaneous absorption: skin, muscle, fat, water content, degree of vascularization
Newborn-infant - 6
- Differences in therapeutic efficacy & toxicant susceptibility at a given dose
- Immature PK processes – not fully developed
- Significant growth & maturational changes of physiological & biochemical processes with postnatal development
- genetic & environmental factors influence maturation
- tremendous interindividual variability: changes at different rates & patterns
- premature birth: more pronounced anatomical & functional immaturity of the organs involved in PK processes
Age-dependent factors affecting GI absorption (PK outcome relative to adult levels) – 9
- Gastric pH
- Gastric emptying time
- Intestinal SA
- Intestinal transit time
- Pancreatic & biliary function
- Bacterial flora
- Enzyme/transporter activity
- Rate & extent of absorption
- GI first-pass effects
Pharmacokinetic implications: Gastric secretions - 2
- High gastric pH enhances BA of basic compounds (ampicillin, penicillin G), but reduces BA of acidic compounds (phenobarbital)
- Deficiency of bile salts & pancreatic enzymes reduces BA of drugs that require solubilization or intraluminal hydrolysis for adequate absorption (pro-drug esters)
Pharmacokinetic implications: Gastrointestinal motility - 2
- Alters physio-chemical properties
- Possible interaction with anatomical & physiological factors of the GT
Pharmacokinetic implications: GI metabolism & transport - 2
- Bacterial flora alters GI motility & ability to metabolize compounds
- approaches adult populations by 4 years of age
Pharmacokinetic implications: GI first-pass effects - 2
- Improved oral BA (Immature GI metabolic reactions; transporters & other active efflux processes )
- Reduced oral BA (drugs dependent upon carrier-mediated uptake systems
Pharmacokinetic implications: Distribution - 4
1.Enhancements in cardiac output, organ blood flows & tissue perfusion
2. changes in membrane permeabilities & maturation of carrier-mediated transport systems
3. changes in tissue binding affinities
4. Developmental changes in Vd due to high relative proportion of total body water & low proportion of fat (relative to adults ):
- Increase in Vd for water-soluble compounds
- Lower Vd for fat-soluble drugs
Pharmacokinetic implications: Plasma protein binding - 4
- Distribution & elimination of compounds
- Larger unbound fractions
- Lower total plasma protein levels
- Lower binding affinities to albumin & a1 –acid glycoprotein (penicillin, phenobarbital, phenytoin & theophylline)
Pharmacokinetic implications: Metabolism & Elimination – 4
- Same metabolites as adults; rates of metabolite formation can be different
- Underdeveloped & inefficient hepatic &/or renal elimination pathways
- Hepatic blood flow, plasma protein binding & intrinsic clearance (maximal enzymatic or transport capacity of the liver)
- Phase I reactions: cytochrome P450 (CYP) enzymes (rate & pattern of postnatal development; genetic polymorphisms; interindividual differences)
Physiological Implications: Changes in body composition - 2
- reduction in total body water & lean body mass, resulting in a relative increase in body fat
- Vd increase in lipophilic compounds
Physiological Implications: Cardiac structure & function - 7
- Increase pigmentation, collagen & elastic fibres
- Endocardial thickening
- Decreased cardiac output & stroke volume
- Lengthening of recovery time after exercise
- Increase in BP & peripheral vascular resistance
- Greater rise in systolic than diastolic BP
- Increased circulation transit time
Physiological Implications: GI system - 7
Stomach & duodenum
1. decreased secretion of HCl and pepsin (less acidic conditions)
2. atrophy of gastric mucosa
3. gastric emptying similar to that of young subjects
Small intestine
4. reduced absorption of several substances (e.g. sugar, Ca, Fe)
5. digestion & motility remain relatively unchanged
6. atrophy of intestinal macro & micro-villi
7. possible bacterial overgrowth in intestine
Physiological Implications: Liver & pancreas - 6
Pancreas
1. amylase remain constant
2. lipase, trypsin decrease dramatically
3. secretin-stimulated pancreatic juice & bicarbonate concentrations remain unchanged
Liver
4. progressive reduction in liver volume & liver blood flow
5. moderate alteration of hepatic structure & enzymatic functions
6. increase in the size of hepatocytes
Physiological Implications: Renal System - 5
- Decreased renal blood flow, GFR & tubular secretion
- Decreased renal mass (reduction in nephrons)
- Plasma creatinine: no associated increase (age-related loss of muscle mass); not a reliable indicator of GFR
- Acid-base balance maintained
- Reduced response to stress: inability to deal with acid loads
Pharmacokinetic Implications: Changes in Absorption –
- Increased Gastric pH - Change in degree of ionization
- Increased Gastric emptying time - Delayed transfer to small intestine
- Decreased Gastric secretion & motility- Delayed dissolution
- Decreased Peristalsis - Reduced mixing of intestinal contents
- Decreased Mesenteric blood flow rate - Decreased [gradient]
- Decreased Macro & micro- villi of mucosa - Reduced absorbing SA
- Decreased Mucosal connective tissue - Change in epithelial transfer
Pharmacokinetic Implications: Absorption – 6
- conflicting results
- Decreased absorption of vitamin B12, iron & calcium: reduced (active transport mechanisms)
- Levodopa: increased absorption
- Digoxin: decreased BA
- Clomethiazone, cimetidine, propranolol: higher extent of absorption
- Quinidine, chlordiazepoxide: reduced rate of absorption
Pharmacokinetic Implications: First-pass metabolism & bioavailability - 3
- Reduction in first-pass metabolism
- BA of drugs undergoing extensive first-pass metabolism (propranolol & labetalol): increased
- BA of prodrugs that need to be activated in the liver (enalapril & perindopril): decreased
Pharmacokinetic Implications: Distribution - 2
- polar compounds (water soluble): smaller Vd (higher serum levels); little net effect on the elimination half life (gentamicin, digoxin, ethanol, theophylline, & cimetidine).
- nonpolar compounds (lipid soluble): increased Vd; prolongation of half-life ((diazepam, thiopentone, lignocaine, & chlormethiazole).
Pharmacokinetic Implications: Clearance - 4
Hepatic
1. reduction in liver blood flow affects clearance of drugs with a high extraction ratio.
2. enzyme inhibition, pathways of conjugation: no major effects of ageing
Renal
3. Reduction in renal function : water-soluble antibiotics, diuretics, digoxin , water-soluble b- adrenoceptor blockers , lithium, & NSAIDs
4. Drugs with a narrow therapeutic index (aminoglycoside antibiotics, digoxin, & lithium): likely serious adverse effects; accumulation
