Flashcards in Session 2 - Pharmacokinetics and Pharmacodynamics Deck (50)
What is pharmacokinetics?
What the body does to the drug
What is pharmacodynamics
What the drug does to the body
What is pharmacogenetics
The effect of genetic variations on pharmacokinetics/dynamics
What is enteral delivery?
Enteral Delivery includes drug routes via the GI tract, including the oral, sub-lingual and rectal routes.
What is parenteral delivery?
Parental Delivery are the drug routes not via the GI tract, including intravenous, subcutaneous, transdermal, intrathecal and intramuscular.
What two main factors effect peak plasma concentration of a drug?
Rate of uptake of a drug
First pass metabolism
Give three passive factors which effect the systemic entry of a drug?
o Drug Liphophilicity.
o Molecular size
o pH changes
Give three active factors which effect the systemic entry of a drug?
o Presence of active transport systems
o Splanchnic blood flow (reduced in shock and heart failure)
o Drug destruction by gut and/or bacterial enzymes
WHat is oral bioavailability?
Oral Bioavailability is the proportion of a dose given orally (Or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form. Bioavailability can be expressed as amount or rate.
How is oral bioavailability calculated?
AUC oral/AUC IV x 100
What are the three consitutents of first pass metabolism/
What three factors effect drugs in the gut lumen?
Gastric acid, proteolytic enzymes, grapefruit juice
How does the gut wall effect drug absorption?
P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen,
What occurs in the liver in terms of first pass metabolism?
Substances absorbed in the ileum enter the portal circulation and are taken to the liver, where enzyme systems metabolise them
What is drug distribution?
Ability of drug to dissolve in the body
What four factors effect the distribution of drugs?
lo Lipophilicity / Hydrophobicity
The more lipophilic a drug molecule is, the more of it will move out of the blood plasma into tissues with a higher lipid content
o Protein Binding
If drug binding to plasma proteins such as albumin is considerable, entry into other tissues and the amount of drug free to exert pharmacological effect will be reduced
o Tissue Protein Binding (e.g. muscle)
If a drug binds strongly to tissue proteins it will have the effect of moving the drug from the plasma, thus decreasing its plasma concentration. This can affect the amount of free drug available for pharmacological effect.
o The mass or volume of tissue and density of binding sites within that tissue
This can vary significantly between individuals, for example in a patient with a large muscle mass Digoxin binding would be effected as it has a very high affinity to Na/K ATPase.
Do protein bound drugs act pharmacologically?
When is it important if drugs are displaced from their protiein binding sites? 3
1. High protein binding
2. Low volume of distribution
3. Drug has a narrow therapeutic ratio
Give four factors which effect protein binding (physiological and pharmacological)
o Renal failure
o Displacement by other drugs
What are the three compartments of body fluid?
Intracellular space - 55%
Interstitial space - 33%
Intravascular space - 12%
What is the literage of each compartment?
Intracellular - 23l
Interstitial - 14l
Intravascular - 5l
What is passive movement of drugs between compartments determined by?
What is the volume of distribution a measure of?
The Volume of Distribution is a measure of how widely a drug is distributed in body tissues. It is a calculated pharmacokinetic space into which a drug is distributed
Equation for Vd
Volume of Distribution (Vd)= (Total Amount of Drug in Body)/(Plasma Concentration of Drug at Time=Zero)
If Vd is <5l where is drug?
If vd <15 where is drug?
ECF (intravascular + interstitial space)
What has happened if Vd exceed body weight?
Tissue binding has occured
Outline phase one metabolism
Include enzyme system and high-energy cofactor
Most drug molecules are stable and relatively unreactive (a pro-drug) so in Phase I metabolism a reactive group is exposed on the parent molecule or added to the molecule via Oxidation, Reduction and Hydrolysis reactions.
The process requires a complex enzyme system called the Cytochrome P450 (CYP450s) system and a high-energy cofactor (NADPH). These enzymes are both Inducible and Inhibitable, and are located on the external face of the endoplasmic reticulum in hepatocytes.
What effects phase 1 metabolism?
A wide range of factors, including sex, age, genetics, cardiac output, and a disease state affects the metabolism of drugs. CYP450 enzymes can also be inhibited and induced by both prescription and OTC drugs.
Some drugs already have a reactive group on their molecule so they can bypass Phase I. Morphine is a good example of this.
Name 6 enzyme cyp450 inducers
Sulphonylureas & St. John’s Wort
Name 9 cyp450 inhibitors
Cimetidine & Ciprofloxacin
Outline phase 2 metabolism
The reactive intermediate from Phase I is conjugated with a polar molecule to form a water-soluble complex. The process is also known as conjugation.
Glucoronic acid is the most common conjugate, as it’s an available by-product of cell metabolism. Drugs can also be conjugated with sulphate ions and glutathione.
Phase II metabolism requires specific enzymes and a high-energy cofactor, uridine diphosphate glucuronic acid (UDPGA).
What does drugs becoming ionic increase the ability of?
increasing the ability of the kidney to excrete them via passive glomerular filtration and active tubular secretion.
Give two tranpsorters responsible for excretion of metabolised drugs in kidney?
Organic Anion and Cation Transporters
Give three factors effecting renal elimination
Renal Blood Flow, Plasma Protein Binding and Tubular Urinary pH
What is clearance?
The volume of plasma that is completed cleared of drug per unit time`
What is total clearance the sum of?
Total Clearance = Hepatic Clearance + Renal Clearance
What are the two outputs of the kidney?
Renal vein and the ureter
What is the clearance equation?
learance=(Amount in urine × Urine flow rate)/(Arterial Plasma Concentration)
Give three factors effecting total clearance?
Heart – CVS/Circulatory factors affecting blood flow to the main organs of elimination
Renal – Factors affecting Renal elimination
Hepatic – Factors affecting Hepatic elimination
The half-life of a drug is the amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured.
How is half-life calculated?
alf Life= (0.693 × Volume of Distribution)/Clearance
What are first order kinetics?
This means that Metabolism is Proportional to Drug Concentration – 1st Order Kinetics.
What do you get with log graphs in first order kinetics?
First Order Kinetics gives a straight line when a log scale is on the Y-axis versus time.
What occurs in second order kinetics?
The enzymes (e.g. CYP450s) are saturated. The rate of decline of plasma drug level is a constant, regardless of concentration. Because of this Zero Order drugs are more likely to result in toxicity.
What is steady state calculated by?
Steady State Concentration in Plasma (CpSS)= (Dose Rate)/Clearance
What is a loading dose?
Irrespective of whether a drug is given by continuous infusion or by divided doses, when starting from a plasma concentration of zero, the time then taken to reach a steady state concentration in plasma is 4-5 half-lives of the drug.
If clinicians want to achieve a therapeutic concentration as quickly as possible without waiting for these 4-5 half-lives, they can use a loading dose. A loading dose aims to fill the compartments contributing to the drugs volume of distribution by using a larger than normal dose. The size of the loading dose is calculated using the known Vd of the drug and the desired therapeutic concentration.
Give two drugs you would use a loading dose with
Heparin and Digoxin
Give the loading dose calculation?>
Loading Dose (Dose L)= Vd ×CpSS