Intro to drug kinetics and drug toxicity - part 2

Question 1

How are drugs administered?

Answer 1

Intravenous
Intramuscular
Subcutaneous 
Topical
Inhalation - rapid, targeted
Oral - portal circulation - 1st pass metabolism
Sublingual - rapid, no 1st pass

Question 2

Pharmacokynetic - what happens to drugs?

Answer 2

Absorption, metabolism, distributed and excreted

Question 3

Where is a drug absorbed?

Answer 3

Gut to blood to ECF to ICF by passive diffusion

Question 4

What is gastric emptying critical for?

Answer 4

Drug absorption

Question 5

Where are most drugs absorbed? Why?

Answer 5

Intestine as SA is greater her than the stomach

Question 6

What is bioavailability?

Answer 6

Fraction of unchanged drug reaching the system circulation following any route of administration
(proportion of the drug which enters the systems circulation following an route of admin)

Question 7

What does bioavailability depend on?

Answer 7

Absorption
First pass metabolism
Food: can decrease the oral availability of sparingly lipid soluble drugs (i.e. atenolol oral availability decreased by 50% by food)

Question 8

State the bioavailability of different drugs

Answer 8

Lidocaine 15%
Propanolol 20%
Moprhine 30%
Paracetamol 57%
Theophilline 81%
Diazepam 97%

Question 9

Drug distribution - physiochemical properties of the drug?

Answer 9

Molecular size
Oil/water partition coefficient
Degree of ionization that depends on pKa
Protein binding

Question 10

Drug distribution - Physiological factors?

Answer 10

Organ or tissue size
Blood flow rate
Physiological barriers;
- blood capillary membrane
- cell membrane
- specialised barriers

Question 11

What do acid drugs mainly bind to?

Answer 11

Albumin (plasma protein)

Question 12

What do basic drugs mainly bind to?

Answer 12

α1-acid glycoprotein (plasma proteins)

Question 13

Plasma protein - What does displacement of one acid drug by another acid drug result in?

Answer 13

Transient increase of free drug concentration

Question 14

What does an increase in the free drug concentration result in?

Answer 14

Increase in the clearance of the free drug form the circulation

Question 15

Rate of drug distribution - perfusion limited tissue distribution? Permeability rate limitations or membrane barriers?

Answer 15

Perfusion-limited tissue distribution;

• Immediate equilibrium of drug in blood and tissue
• Only limited by blood flow
• Highly perfused; liver, kidneys, lung, brain
• Poorly perfused; skin, fat, bone, muscle

Permeability rate limitations or membrane barriers;

• Blood brain barrier
• Blood testis barrier
• Placenta

Question 16

What does the blood brain barrier do?

Answer 16

Acidic brain cells trap ionised weak base as no pores

Question 17

What does the placenta barrier allow diffusion of and what does it resist?

Answer 17

Sugars, fats and oxygen diffuse from mother’s blood to fetus
Urea and CO2 diffuse from fetus to mother
Maternal antibodies actively transported across placenta
Some resistance to disease (passive immunity)
Most bacteria are blocked
Many viruses can pass including rubella, chickenpox, mono, sometimes HIV
Many drugs are toxins and can pass including alcohol, heroin, mercury

Question 18

What drugs easily pass the placenta barrier?

Answer 18

Lipid soluble and mostly un-ionised drugs pass more easily compared to more polar and ionised ones

Question 19

How are dugs eliminated?

Answer 19

Drug is oxidised or conjugated = metabolite or stable adducts formed = renal elimination or biliary elimination

Question 20

How are drugs metabolised?

Answer 20

De-activation;

• Decrease of pharmacological effect
• Decrease toxicity

Activation;

• Increase pharmacological effect
• Increase toxicity

Conjugate formed and excreted

Question 21

Phase I reactions of metabolism?

Answer 21

Intro/exposure of a polar group by oxidation, reduction or hydrolysis
Metabolites = polar = excreted
C-H group can be turned into a C-OH converting non pharmacological active compound into active
Toxic compound can be created

Question 22

Phase II reactions of metabolism?

Answer 22

Attachment of an endogenous molecule to a drug or Phase I metabolite, glucoronide, sulphate, acetyl

Outcome products = heavier in m.w. = less effective

Question 23

What is a major difference between phase I and phase II reactions?

Answer 23

Phase I predominantly produces more active compounds while Phase II produces less active

Question 24

What are the enzymes of drug metabolism - phase I and II?

Answer 24

Phase I - Oxidation;
- Cytochrome P450;
In liver
Several forms of cytochrome
Varying substrate specificity
Catalytic activities show large inter-individual difference

Phase II; Conjugation;
- Transferases; 
Glucoronyl-
Sulpho-
Acetyl-
Methyl-

Question 25

Cytochrome 3A4

Answer 25

Inhibitors; - Reduce clearance = increase blood levels - E.g erytromycin Inducers; - Increase clearance = decrease blood levels - E.g Phenytoin

Question 26

What is genetic polymorphism?

Answer 26

Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes Most clinically studies - CYP2C9, CY2C19, CYP2D6

Question 27

CYP2D6 polymorphism? What does this result in?

Answer 27

8% caucasians lack CYP2D6 | Poorer metaboliser for CV, psychiatric and opiate drugs

Question 28

How does biliary excretion occur?

Answer 28

Bile is secreted by hepatic cells of the liver Absorption of fats 90% of bile acid is reabsorbed from intestine and transported back to the liver for resecretion More metabolites are excreted in bile than parent drugs due to increased polarity

Question 29

What factors influence the secretion of bile?

Answer 29

Molecular weight (i.e. > 300) Polarity (higher polarity more bile excretion) Nature of biotransformation Gender, diseases, drug interactions

Question 30

How do drugs and bile interact?

Answer 30

Some drugs and metabolites excreted by liver cells into bile, pass into the intestine. Reabsorption from the gut during the process of enterohepatic recycling may prolong the pharmacological effect of a drug

Question 31

Which drugs are renally eliminated?

Answer 31

Water soluble Ionised E.g Digoxin

Question 32

Which drugs are hepatically eliminated?

Answer 32

Lipid soluble Un-ionised E.g propanolol, cyclosporin

Question 33

Nephron's structure and their functions?

Answer 33

Glomerular filtration; (120ml/min) - Only unbound protein filtered - Negligible for high protein bound drugs Distal tubule; passive reabsorption; - Lipid solubility - Water soluble drugs - Urine - Lipid soluble drugs; Blood - Only un-ionised drug - Changes in urine pH important for weak acids/bases ``` Proximal tubule; active secretion; - Free and bound drug secreted - Highly cleared drugs: Renal blood flow - Two pump: Acids (uric) e.g. Penicillin, Thiazide diuretics Base e.g. Pancuronium ``` Glomerular filtration and active secretion = add drug to tubular fluid Passive reabsorption = transfers it back into the blood

Question 34

Renal clearance?

Answer 34

Excretion = Filtration + Secretion - Reabsorption GFR = 120ml/min (if kidney not working as well = lower GFR = less elimination of drug = drugs build up) CLR = Rate of excretion Plasma concentration >GFR – net secretion < GFR – net reabsorption = GFR – secretion = reabsorption or filtration only

Question 35

What determines the renal clearance of a drug?

Answer 35

Net contribution of filtration, secretion and reabsorption

Question 36

What is the therapeutic index? Higher therapeutic index means?

Answer 36

Margin between the therapeutic dose and the toxic dose. | Higher the therapeutic index is safer the drug is.

Question 37

What factors effect metabolism?

Answer 37

``` HIGH blood level Excessive dosing and/or decreased clearance risk of TOXICITY Decreased clearance; - Normal variation - Saturable metabolism - Genetic enzyme deficiency - Renal failure - Liver failure - Age (neonate or elderly) - Enzyme inhibition ``` LOW blood level Dose to low or clearance to high risk of NO EFFECT Increased clearance; - Normal variation - Poor absorption - High first pass metabolism - Non compliance - Enzyme induction ``` Environmental Disease Genetic Age Drug interaction ```