Week 1: Concepts in Clinical Pharmacology Flashcards
Dosing Instruction Abbreviations: BD
Twice Daily
Dosing Instruction Abbreviations: NOCTE
At night
Dosing Instruction Abbreviations: OD
Once a day
Dosing Instruction Abbreviations: QDS
Four times a day
Dosing Instruction Abbreviations: STAT
Single one off dose
Dosing Instruction Abbreviations: TDS
Three times a day
Pharmacokinetic Abbreviations: Cmax
Maximum concentration
Pharmacokinetic Abbreviations: Cp
plasma concentration
Pharmacokinetic Abbreviations: CpSS
Plasma concentration at steady state
Pharmacokinetic Abbreviations: CYP
Cytochrome P450
Pharmacokinetic Abbreviations: Tmax
Time to maximum concentration
Pharmacokinetic Abbreviations: Vd
Volume of Distribution
Administrative Route Abbreviations: IM
Intramuscular
Administrative Route Abbreviations: IV
Intravenous
Administrative Route Abbreviations: LD
Loading Dose
Administrative Route Abbreviations: PO
Oral
Administrative Route Abbreviations: PR
Per rectum
Administrative Route Abbreviations: SC
Subcutaneous
Administrative Route Abbreviations: SL
Sublingual
As a clinician, you are given the Apparent Volume of Distribution for three drugs. These have been tested in a clinical trial in a male patient, 35 yrs old of normal build. The values are given below. What real fluid compartments do you think these drugs are distribute between?
Drug 1: 0.12 L/kg
Drug 2: 0.26 L/kg
Drug 3: 3.4 L/kg
- 12 L/kg is 8.4 L - mainly plasma (e.g. insulin)
- 26 L/kg is approx 18 L- extracellular (e.g. penicillin)
- 4 L/kg is approx 238 L- mainly intracellular (morphine)
The idea is to show how changes in Vd broadly correlate to fluid compartments and their related set of binding sites.
Two female patients in their early twenties were being assessed for treatment with haloperidol for psychotic illness. Both patients were about 1.7m in height, but one patient weighed 46 kg, the other 92 kg.
Given the normal Vd for haloperidol is about 18L/kg, how would you expect this weight difference to affect its value?
How do you think this information would affect your initial dosing regime with haloperidol in these patients?
You may consider using a lower than normal dose to avoid the possibility of overdose in the underweight patient. In the obese patient you would probably start with normal doses and adjust from there.
The very high Vd for Haloperidol of 18L/Kg indicates that it is widely distributed throughout the rest of body tissues and it is comparatively lipid soluble. The patient with a weight of 92 kg is evidently more obese than the other patient. You would expect the value of Vd to increase due to its increased distribution in body adipose for this patient
For the patient with a weight of 46 kg she is underweight for her height is evidently less obese. You would then expect the value of Vd to decrease due to decreased volume of adipose tissue.
What factors referenced to three major systems would you expect to affect Clearance and why?
HRH
Hepatic – If you have hepatic deficit you would expect lowered clearance due to the reduction in available Phase I and II enzymes for metabolism
Renal –Similarly if renal clearance is affected either by reduced filtration, active OATP and OCTP transport and reduced tubular secretion then clearance will be affected adversely
Heart/Cardiac Output – If cardiac output is reduced then the rate of blood flow to the liver and kidneys also drop again meaning clearance will be reduced.
A 53 yr old man is admitted to hospital with a long history of alcohol abuse. He is severely jaundiced and has suspected renal failure. He is also underweight for his height.
Before you begin any drug therapy, what effect might you expect there to be on clearance of any drugs you might prescribe?
a. Alcohol abuse and jaundice point to liver failure. This would be expected to reduce clearance for many drugs therefore longer half life
b. Renal failure would also be expected to affect clearance half life
c. Reduced weight would also be expected to result in a lower volume of distribution for drugs partitioning in to body tissues
d. Therefore would have to take all this into account before starting therapy as each would affect doses of most drugs administered.
e. Problems with reduced clearance mean that systemic toxicity becomes more of a problem.
Drug Elimination Half Life – t1/2
The terms for the volume of distribution and clearance are used by clinicians to calculate the overall figure summarising first order elimination kinetics the half-life.
This is approximately
t1/2≈ 0.7 x Vd/CL
Assuming linear elimination kinetics approximate the time taken to get to CpSS for drugs with the following half-lives.
i. 2.5 hrs
ii. 6 hrs
iii. 12 hrs
iv. 24 hrs
v. 36 hrs
times each by 4 to 5, the number of half live required to reach CpSS
If the elimination half life was very much shorter than the dosing interval, could you reach a reasonably stable CpSS by the oral route?
Penicillin has a half life of 30 minutes. It is usually given four time per day. Describe the changes in concentrations across 24 hours.
The time take to peak absorption is about 1 hour with penicillin but the idea here is to show that some drugs when given orally, will not reach a steady state due to their short half-life. This is not necessarily a therapeutic problem as they can still be highly efficacious over these relatively brief intervals.
4 main factors affecting pharmacokinetics of a drug
The main factors affecting entry and removal of the drug can be remembered
using the mnemonic acronym ADME.
- Absorption - Drug In
- Distribution
- Metabolism
- Excretion Drug Out - Elimination
What is meant by enteral delivery?
Many drugs are given orally which forms the major group for enteral delivery, that is drugs that are given via the GI tract. This category also includes the sub-lingual and rectal routes.
What is meant by parenteral delivery?
This includes all the other routes that are not the GI. These are especially important in acute medicine and are used to overcome the problems presented by GI absorption
List 3 parenteral delivery routes
Intravenous Subcutaneous Transdermal Intramuscular Intrathecal.
In addition, the routes across specialised epithelia come under this heading.
main passive factors affecting systemic entry of a drug
lipophilicity
molecular size
changes in pH
main active factors affecting systemic entry of a drug
Important active factors include presence of active transport systems; splachnic blood flow (reduced in shock and heart failure) and drug destruction by gut and/or bacterial enzymes.
What is first pass metabolism?
metabolism carried out by the gut and liver
As virtually all molecules absorbed by the gut will travel via the portal circulation to the liver, hepatic first pass metabolism can again significantly reduce the amount of available drug as measured by its extraction ratio.
Can occur in:
o The Gut Lumen
• Gastric acid, proteolytic enzymes, grapefruit juice
• E.g. Benzylpenicillin, insulin, ciclosporin
o The Gut Wall
• P-glycoprotein efflux pumps drugs out of the intestinal enterocytes
back into the lumen e.g. ciclosporin
o The Liver
• E.g. Propranolol is extensively metabolised
What is bioavailability?
Bioavailability refers to the relative amount of drug that reaches the systemic circulation once it has overcome all the barriers to its absorption. This fraction will depend on the route used.
This is calculated as (Amount of Drug Reaching Systemic Circulation) divided by (Total Amount of Drug Administered)
Clinically, this is calculated by looking at the Total Area Under the Curve or AUC that describes the drugs plasma concentration over time for both the numerator (top) and denominator (bottom) parts of the above equation.
True or false?
The oral route and its subsequent enteral passage will normally involve more barriers to systemic uptake than the intramuscular or subcutaneous route.
True. Therefore the oral route has limits to bioavailability - the relative amount of drug that reaches the systemic circulation once it has overcome all the barriers to its absorption.
What is the bioavailability of a drug administered through IV?
= 1 or 100%
Oral availability is usually defined by comparing the fraction (F) of drug that gets into the body after oral (po) versus IV administration. Therefore a drug administered through IV would have the same numerator and denominator.
This is calculated as (Amount of Drug Reaching Systemic Circulation) divided by (Total Amount of Drug Administered)
What letter is used to denote oral bioavailability?
F
F = AUC(oral) / AUC (IV)
Which two factors largely determine oral availability of a drug?
Oral availability defines how much drug gets ‘on board’ after oral ingestion. It is determined by ‘absorption’ and ‘first pass’ metabolism.
e.g. good drug absorption and low first pass metabolism will result in very high oral availability
Absorption refers to the ability of a drug to cross the gut wall into the portal vein.
First-pass metabolism describes presystemic drug elimination and can occur in the gut wall, portal vein or liver. The liver is usually the most important contributor.
How is the term absorption defined in terms of oral availability?
Absorption refers to the ability of a drug to cross the gut wall into the portal vein.
Do high rates of first pass metabolism result in high or low oral availability?
low
First pass metabolism can occur in the gut wall, portal vein (uncommon) and in the liver.
Note that high rates of metabolism at either site result in low oral availability.
What is meant by distribution in pharmokinetics?
Once a drug gets into the bloodstream it is first distributed around the body over large distances by bulk flow in the bloodstream and then over shorter
distances by diffusion. The concentration of a drug can vary greatly throughout the different tissues.
The distribution of a drug throughout all the body
tissues is determined by its physical and chemical (or physicochemical) properties.
Major factors affecting distribution of a drug throughout the body
- Lipophilicity/ Hydrophobicity
- The degree to which it binds to plasma protein
- The degree to which it binds to tissue proteins
- The mass or volume of tissue and density of binding sites within that tissue
How does Lipophilicity/ Hydrophobicity impact distribution of a drug throughout the body ?
-The more lipophilic a drug molecule is,
the greater it will partition out of the blood plasma into tissues with a higher lipid content (for example the brain or adipose tissue)
How does plasma protein binding impact distribution of a drug throughout the body ?
If binding to plasma proteins such as albumin is considerable, this will reduce its entry into other tissues and also the amount of drug freely available to exert a pharmacological effect.
How does tissue protein binding impact distribution of a drug throughout the body ?
The degree to which it binds to tissue proteins – e.g. muscle. This will have the effect of moving the drug from plasma and decreasing its plasma concentration. This can affect the amount of free drug available for pharmacological effect.
How do tissue properties impact distribution of a drug throughout the body ?
The mass or volume of tissue and density of binding sites within that tissue
o This can vary significantly from individual to individual. For a patient who is a body builder, their large muscle mass would, for example, affect digoxin binding as it has a very high affinity to Na/K ATPase.
o Digoxin is also highly lipophilic, so in an obese individual, digoxin would also be heavily bound, thus reducing its plasma concentration
o Conversely, in a supermodel with relatively reduced muscle and minimal adipose tissue, then more digoxin would stay in her plasma.
The major fluid compartments in order of drug movement are modelled as
Plasma
Extracellular Fluid
Intracellular Fluid
Passive movement of drug between these main fluid compartments will be primarily determined by lipophilicity, although some drugs are actively carried or transported across these fluid compartments.
What is the most important factor deterring which major fluid compartment a drug will move into?
lipophilicity