2. Pharmacokinetics Flashcards
what is pharmacokinetics and what are the 4 main stages?
-what the body does to the drug
-absorption, distribution, metabolism, excretion
What is the absorption stage in pharmacokinetics?
-the movement of a drug from its site of administration to the systemic circulation, often crossing a membrane to be absorbed
-not all drugs need to be in the systemic circulation to be effective e.g iv drugs, inhaled drugs, certain antibiotics
Explain how the location of drug absorption depends on the route of administration and its properties (pH)- give examples
-stomach- can start to absorb acids, particularly weak acids
-gut- has large absorptive surface area of villi and microvilli
-alkali drugs given by mouth are poorly absorbed until they reach the intestine
Explain why the pH of drugs matter in absorption
-in an acidic environment a drug which is weakly acidic will be more lipid soluble and move across the membranes easily
-in an alkali environment a drug which is weakly acidic will be less lipid soluble and not move across membranes easily
What 5 factors affect drug absorption?
- rate of gastric emptying:
-fast= fast delivery to gut where most absorption occurs
-slow=slow delivery to gut - disease- surface area of bowel may be reduced leading to reduced absorption
- transit time through gut- surface area of bowel may be reduced leading to reduced absorption
- blood flow- in hypotension blood flow may be restricted reducing IM absorption
- age:
-older person gastric emptying is slowed
-neonates and infants delayed gastric emptying
Explain how drugs can diffuse through lipid membranes
-lipophilic drugs can easily move through lipid membranes (don’t like water)
-lipophobic drugs cannot move through lipid membranes by diffusion (they like water and prefer aqueous environments)
Explain how drugs can pass plasma membranes through carrier mediated transport
-drugs can cross the membrane using transporters, making them saturated
-despite a high concentration of drug molecules, the number of molecules that can pass through the membrane depends on the number of carrier proteins
What is the distribution phase of pharmacokinetics?
-the movement of a drug throughout the body
-as drugs move through the circulation they may bind to plasma proteins and partition into adipose and other body tissues
Explain why drugs partition into body fat (distribution)
-body fat is a large non-polar body compartment
-it has a low blood supply so drugs are delivered to body fat more slowly
-only important for a few acutely given drugs e.g highly lipid soluble general anaesthetics
-chronically given drugs may however accumulate in body fat
What effect does drugs bound to plasma proteins have?
-the most common is albumin
-only the free unbound drug can exert a pharmacological effect
-concentration of plasma proteins also affect drug activity
What 5 factors affect drug distribution?
- adiposity (amount of fat in the body may hold certain drugs)
- plasma protein concentration, effected by
-chronic alcohol use
-malnutrition
-age
-pregnancy - blood flow (shock may impair drug distribution)
- membrane permeability
-preterm babies have increased permeability including blood brain barrier and certain infections increase permeability e.g meningitis - body water content
-very high in preterm infants
-reduced in older age
What is drug metabolism?
-the enzymatic conversion of one chemical entity to another
-utilises the cytochrome P450 (CYP450) system of enzymes
What is the role of drug metabolism and where does it occur?
-make drugs more water soluble so that they can be excreted via urine
-occurs mostly in the liver, but may occur in the gut, lung and plasma
What are the 2 phases of drug metabolism?
phase 1 Enzymatic:
-reactions are catabolic (breaks down chemicals) and the products can be more chemically reactive (catalysed by CYP450)
phase 2 conjugation:
-reactions involve conjugation the attachment of a chemical group (sulphate, methyl, acetyl)
Explain the importance of CYP450 enzymes in drug metabolism
-drug metabolising enzymes are embedded in the smooth endoplasmic reticulum
-CYP450 is a family of enzymes with the important role of metabolising drugs in the liver
-metabolise steroids, caffeine, paracetamol, phenytoin
-regulated by inducers and inhibitors
How can one drug affect the metabolism of another?
-some drugs act as inducers, they speed up the activity of specific CYP450 enzymes e.g ethanol
-some drugs act as inhibitors they slow down the activity of specific CYP450 enzymes e.g fluconazole
What effect does CYP450 inducers have on drug metabolism, drug activity and therapeutic effect?
-drug metabolism increases
-drug activity decreases
-therapeutic effect decreases
What effect does CYP450 inhibitors have on drug metabolism, drug activity and therapeutic effect?
-drug metabolism decreases
-drug activity increases
-side effects and toxicity increases
What are active drug metabolites?
-in some cases drugs can become more active following metabolism
-drug metabolites can be active and very long lived (benzodiazepines), or they can be toxic (paracetamol)
What is first pass metabolism?
-relevant to drugs administered orally
-occurs in the liver and gut wall
-metabolism is so efficient that concentration of drug reaching systemic circulation is substantially less then that absorbed
-therefore a much larger dose needs to be given orally
-e.g salbutamol undergoes significant first pass metabolism
What are the 3 processes of drug excretion?
-glomerular filtration
-active tubular secretion
-passive diffusion
How is renal clearance involved in drug excretion?
-rate of renal elimination is the main factor which determines their duration of action
-some drugs are excreted unchanged- 100% e.g frusemide, 75% e.g benzylpenicillin
How is biliary excretion a method of drug excretion?
-liver cells can transfer some drugs from plasma to bile using carrier system
-these drugs are then delivered to the small intestine where they are hydrolysed and free drug released or excreted via faeces
-free drug then can be reabsorbed into the blood stream and return to the liver
What is half life and what is its importance in pharmacokinetics? give an example
-half life is the time taken for the peak concentration of drug in the plasma to decrease by 50%
-this is dependent on clearance by metabolism and renal elimination
-important as needs considering for dosing intervals and residual effects
-ibuprofen 2 hours
