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What are the 4 questions to be asked when prescribing drugs?

Is drug getting into patient? (Pharmaceutical process)

Is drug getting to site of action? (Pharmacokinetic process)

Is drug producing desired effect? (Pharmacodynamic process)

Is this translated to therapeutic effect (Therapeutic effect)

1

Discuss the principles of Drug Formulation

Tablets: Rate of action depends on dissolution. Solubility and acid stability must be considered.

Liquid: e.g. use of soluble aspirin compared to aspirin tablets treating myocardial infarction, headaches

Compliance: developing a tablet with a slow rate of action (slow dissolution) so that it only needs to be taken once a day is useful as it increased patient compliance - simple to remember,

2

What are the different sites of administration?

Sublingual

Oral

Intravenous

Intramuscular

Subcutaneous

Topical (directly to skin)

Rectal

Transdermal patch (absorbed through skin)

Inhalation

3

What are the Advantages of Topical Administration?

Concentrates drug at site of action

Less systemic absorption, less off-target effects (side effects)

E.g. Local steroids for treating skin diseases, inhaled steroid for asthma

4

What is meant Oral Bioavailability of a Drug?

Proportion of drug given orally (or any other route except IV) that reaches circulation unchanged

5

How can Oral Bioavailability of a Drug be expressed?

Amount: depends on first pass metabolism and gut absorption. GI absorption can be altered by food, disease

Rate of availability: depends on pharmaceutical factors and rate of gut absorption.

Amount is measured by Area Under Curve (AUC) of blood drug level vs time plot.

Rate is measured by peak height and rate of rise of drug level in blood.

6

What is the Therapeutic Ratio?

Gives you an idea of how safe the drug is

Defined as LD(50) / ED(50). [LD = Lethal Dose, ED = Effective Dose)

Or

Maximum Tolerated Dose / Minimum Effective Dose

 

Large ratio - large therapeutic index

7

What is meant by First Pass Metabolism?

Drug administered IV enters directly into the systemic circulation and has direct access to the rest of the body.

Drugs administered orally are first exposed to liver (via portal system) and may be extensively metabolised before reaching the rest of the body (systemic circulation).

Such drugs include lignocaine, opiates, propranolol, glycerol trinitrate

8

How can First Pass Metabolism be avoided?

By using different routes of administration:

Parenteral (IV, IM, SC)

Rectal (note drainage to both portal and systemic systems)

Sublingual (under the tongue and not swallowed e.g. Use of GTN in angina)

9

How would you determine the Volume of Distribution?

Theoretical volume into which drug is distributed if this occurred instantaneously.

This is obtained by extrapolation (extending the line) of plasma levels to zero time.

Calculated as amount given/ plasma concentration at time '0'

10

Discuss Drug Binding to Proteins

Free drug determines its action at receptor.

Many drugs also bind to plasma proteins and protein binding interactions could occur.

It is the FREE level of drug that exerts an effect not the total level.

Displacement of drugs from binding sites causes Protein Binding Drug Interactions.

11

Why is the Free Level of Drug important in certain situations?

If the drug is highly bound to albumin (>90%) or drug has a small volume of distribution of drug has a low therapeutic index.

If the drug has a low therapeutic index (= low therapeutic ratio), a small change in concentration of the drug could have adverse side effects.

Examples are warfarin and tolbutamide.

12

What is a Class I drug?

Otherwise known as an Object Drug

Drug is used at dose lower than number of albumin binding sites.

Most drug molecules are bound to albumin and concentration of free drug is low.

13

What is a Class II drug?

Otherwise known as a precipitant drug.

Used at greater doses than number of available binding sites and thus displaces the Class I drug from these binding sites.

Most albumin molecules contain a bound drug; the concentration of free drug is significant.

14

Describe Binding interactions

Transient (temporary)

Although free drug levels rise (I.e. Greater effects at receptors), elimination rate will also rise (since this depends on free drug levels).

Steady state is resorted quickly in a few days.

When a patient is taking one of the object drugs, adding on the precipitant drug will temporarily lead to higher free levels of the object drug and therefore higher risk of toxicity.

This is because displacement of Class I drug occurs when a Class II drug is administered simultaneously.

15

Give some Protein Binding Drug Interaction Examples

Object Drug: Warfarin; Precipitant Drug: Sulphonamides, aspirin, phenytoin

Object Drug: Tolbutamide; Precipitant Drug: Sulphonamides, aspirin

Object Drug: Phenytoin; Precipitant Drug: Valproate

16

What is meant by 1st Order Kinetics?

Rate of elimination is proportional to drug level (the higher the drug dosage, the faster the rate of elimination)

Constant fraction of drug eliminated in unit time - rate of decline of plasma drug level is proportional to drug level.

Half life can be defined.

17

What is meant by Zero Order Kinetics?

Rate of elimination is constant.

This enzyme is saturated.

Rate of decline of plasma drug level is constant.

18

Describe drug metabolism at different doses

At high doses drug metabolism is zero order that is constant and independent of drug dose.

At low doses, drug metabolism is first order that is proportional to drug dose.

During repeated drug administration, a new steady state will be reached within 5 half lives of that drug.

This is irrespective of dose or frequency of administration.

If the half life is long and a rapid effect is desired, a loading dose is therefore needed. The loading dose volume is often determined by the volume of distribution.

19

Emergency Presentation: Atrial fibrillation

Need to control heart rate quickly.

Digoxin (half life - 36h)

If maintenance dose used, will take 5x36h (180h) to reach steady state.

Therefore need to use a loading dose - as the half life is long but a rapid effect is desired.

The loading dose is often determined by the volume of distribution.

20

Does Drug Pharmacokinetics matter?

Yes!

1st order kinetics - predictable therapeutic response from dose increases (most drugs behave like this)

Zero order kinetics - therapeutic response can suddenly escalate as elimination mechanisms saturate.

21

When are drug interactions in metabolism likely to matter clinically?

Drugs with low therapeutic ratio

Drug is being used at minimum effective concentration (e.g. OC pill)

Drug metabolism follows zero order kinetics

22

Describe Drug Metabolism

Metabolism (predominantly liver)

Excretion (predominantly renal)

Liver Metabolism: Phase I (oxidation, reduction, hydrolysis) and Phase II conjugation (glucuronidation, Acetyl, methyl, sulphate).

23

How is Phase I carried out?

By mixed function oxidases in liver.

Consists of NADPH cytochrome P450 reductase, cytochrome P459 in liver microsomes, low substrate specificity, affinity for lipid soluble drugs

Main CYP isoenzymes 1A2, 2C9, 2C19,2D6, 3A4

Enzymes are inducive and inhibitable (competitive, non-competitive)

24

Give some examples of enzymes inducers

Enzyme Inducer: phenobarbitone; Drug affected: warfarin, phenytoin

Enzyme Inducer: Rifampicin; Drug affected: oral contraceptive

Enzyme Inducer: cigarettes; Drug affected: theophylline

Enzyme Inducer: Cimetidine; Drug affected: warfarin, diazepam

25

What are Potentiators of Warfarin action?

Alcohol: inhibits metabolism

Aspirin, sulphonamides, phenytoin: displacement from plasma proteins

Broad spectrum antibiotics: reduced Vit, K synthesis by bacteria in gut

Aspirin: reduced platelet function

26

What are Inhibitors of Warfarin action?

Barbiturates, fiamoicin: induce liver metabolising enzymes

27

In liver disease, be careful with drugs with a low therapeutic ratio. Give some examples

Cellular dysfunction: warfarin, phenytoin, theophylline

Portasystemic shunts: opiates, propranolol

Reduced blood flow: opiates, propranolol lignocaine

Reduced albumin affects drug binding to plasma proteins.

28

Describe kidney (renal) excretion of drugs

Only the free fraction of drug is filtered - enters the glomerular filtrate.

Drugs can be actively secreted by the tubules (e.g. Pencillin is secreted by proximal tubule very quickly).

Passive reabsorption of drug is dependent on pH. pK of drug is pH at which half of it is ionised, half is non-ionised, Only the non-ionised moiety is lipid soluble and crosses membranes easily (gets reabsorbed back into the body).

For weak acids (e.g. Aspirin), making the urine alkaline will make the drug ionised so there will be less tubular absorption because the charged drug stays in the tubule lumen.

For weak bases (e.g. Amphetamine), acid urine increases excretion. Acid urine will ionise a weak base, making the charged drug stay in the tubule lumen.

29

Give a clinical example: Aspirin poisoning

Aspirin is a weak acid so to eliminate aspirin, forced alkaline dieresis is required (as alkaline urine decreases absorption of weak acids) in an aspirin overdose