Pharmacokinetics-Distribution MBBS PDF

Pharmacokinetics- Distribution MBBS AP DR TEE YEE SIM Distribution Learning Outcome 1. Explain the physiological barriers to drug distribution. ***(C2) 2. Explain the clinical implications of plasma protein binding. ***(C2) 3. Explain the concept of apparent volume of distribution with examples. ***...

Pharmacokinetics- Distribution MBBS AP DR TEE YEE SIM Distribution Learning Outcome 1. Explain the physiological barriers to drug distribution. ***(C2) 2. Explain the clinical implications of plasma protein binding. ***(C2) 3. Explain the concept of apparent volume of distribution with examples. ***(C2) 4. Explain redistribution of drugs. ***(C2) Manipal University College Malaysia 2 Distribution Distribution is defined as the reversible transfer of drugs between body-fluid compartments. After absorption, a drug enters the system circulation and is distributed in the body fluids. Factors affecting drug distribution: Rate of blood flow Presence of special barriers (BBB, placental barriers), transporters Diseases Manipal University College Malaysia Lipid solubility, water Solubility, pH Binding of a drug to plasma proteins or tissue proteins 4 Physiological barriers to drug distribution include: Blood-brain barrier Blood-CSF and CSF-Brain barrier Placental barrier Manipal University College Malaysia 5 A. Blood-brain barrier Protects the brain tissue from toxic substances and neurotransmitters from the blood Lipid soluble, unionized form →rapidly crosses BBB (e.g. thiopental, morphine) Lipid-insoluble and ionized particles →cannot cross BBB (dopamine, acetylcholine) Inflammation (cerebral meningitis), viral infection, heat stress →increased permeability of BBB Manipal University College Malaysia 6 B. Blood-CSF and CSF-Brain Barrier Blood-CSF barrier →non-ionized lipid soluble drugs can pass through it CSF-Brain barrier →no occluding zonulae →extremely permeable to drug from CSF to brain Clinical advantage: Penicillin injected by intrathecal route →crosses CSFbrain barrier →increases concentration of penicillin in brain →can be used for the treatment of brain abscess Manipal University College Malaysia 7 C. Placental barrier Placental barrier is a lipid membrane Transfer across placental barrier is mainly by passive diffusion for lipid soluble unionized drugs Polar, quaternary compounds, high molecular weight substances cannot cross placental barrier It is an incomplete barrier → fetal exposure is likely to occur with most of the drugs → drug administration during pregnancy should be restricted Manipal University College Malaysia 8 Plasma protein binding Acidic drugs bind to plasma albumin (warfarin, penicillin) Basic drugs bind to α1 acid glycoprotein (propranolol, quinidine) Highly plasma protein bound drugs: have low volume of distribution Acts as a temporary reservoir of the drug Makes the drug long acting Difficult to be removed by dialysis ( in poisoning) Renal failure, liver disease→ low albumin level →increase in free form of drug → toxicity MI, inflammatory disease →high level of α1 acid glycoprotein →basic drug (propranolol) binding is increased Manipal University College Malaysia 9 Displacement reactions These reactions might result in drug-drug interactions leading to harmful effects Two or more drugs can bind to the same plasma protein Drugs with high affinity will displace the drugs with low affinity from the binding sites Increase plasma concentration of the displaced drug →can lead to toxicity Clinically significant in case of highly bound drugs and drugs with smaller apparent volume of distribution Clinically important displacement reactions: Salicylates/sulfonamides displace tolbutamide (antidiabetic) →hypoglycaemia Salicylates displace warfarin (anticoagulant) →increased risk of bleeding Sulfonamides/vitamin K displace bilirubin →kernicterus in neonates Manipal University College Malaysia 10 Apparent Volume of Distribution aVD = Dose administered i.v. Plasma concentration defined as the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment. Body fluid compartments 70kg male Manipal University College Malaysia 12 Volume of Distribution If a drug does not cross capillary walls (heparin, insulin), given by IV route → aVd = plasma water volume (3 L) Highly plasma protein bound, less tissue protein bound → low aVd (warfarin) Less plasma protein bound, high tissue protein bound → high aVd aVd more than actual body volume → drug is widely distributed in body including muscle and adipose tissue (digoxin) aVd < 5 L Drug is retained in the vascular compartment (heparin, warfarin, insulin) aVd >16 L ( in a 70kg male) Drug is restricted to the extracellular fluid (ECF) (aspirin, tolbutamide) aVd > 46 L Distributed throughout the total body water (ethanol, phenytoin) or penetration in various tissues (digoxin 500L, paracetamol, chloroquine 13000L) Manipal University College Malaysia 13 Manipal University College Malaysia 14 Redistribution of drugs Thiopentone is highly lipid soluble →get distributed brain (organ with high blood flow and rapidly crosses BBB due high lipid solubility →produces anaesthesia. Hence it is rapid acting →from plasma, it is redistributed to other less perfused organs (muscle, fat) through passive diffusion. The drug remains in the muscle and fat for longer period and slowly released into the plasma. This small concentration in the plasma can produce some adverse effects, like drowsiness. Other drugs undergoing redistribution: ketamine, diazepam Manipal University College Malaysia 15 MODEL QUESTIONS 1. Define the following terms: a. Bioavailability b. First pass metabolism c. Apparent volume of distribution 2. Explain the pharmacological basis for the following: a. Bioavailability of drugs with high first pass metabolism is increased in liver disease b. Highly plasma protein bound drugs have low volume of distribution c. Thiopentone sodium is rapid and ultra-short acting d. Aspirin absorption is decreased in achlorhydria e. Alkalinization of urine is done in acidic drug poisoning f. Milk reduces absorption of tetracyclines Manipal University College Malaysia 16 MODEL QUESTIONS 3. Explain the effects of following factors on drug absorption: a. Lipid solubility b. pH and ionization 4. Explain the effects of following factors on bioavailability of drugs: a. Particle size b. Gastric emptying c. First pass metabolism 5. Explain the clinical implications of plasma protein binding. 6. Explain drug displacement reactions with examples. 7. Explain redistribution with an example. Manipal University College Malaysia 17 Manipal University College Malaysia 18