Intro to drug kinetics and drug toxicity - part 2 Flashcards
How are drugs administered?
Intravenous Intramuscular Subcutaneous Topical Inhalation - rapid, targeted Oral - portal circulation - 1st pass metabolism Sublingual - rapid, no 1st pass
Pharmacokynetic - what happens to drugs?
Absorption, metabolism, distributed and excreted
Where is a drug absorbed?
Gut to blood to ECF to ICF by passive diffusion
What is gastric emptying critical for?
Drug absorption
Where are most drugs absorbed? Why?
Intestine as SA is greater her than the stomach
What is bioavailability?
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)
What does bioavailability depend on?
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)
State the bioavailability of different drugs
Lidocaine 15% Propanolol 20% Moprhine 30% Paracetamol 57% Theophilline 81% Diazepam 97%
Drug distribution - physiochemical properties of the drug?
Molecular size
Oil/water partition coefficient
Degree of ionization that depends on pKa
Protein binding
Drug distribution - Physiological factors?
Organ or tissue size Blood flow rate Physiological barriers; - blood capillary membrane - cell membrane - specialised barriers
What do acid drugs mainly bind to?
Albumin (plasma protein)
What do basic drugs mainly bind to?
α1-acid glycoprotein (plasma proteins)
Plasma protein - What does displacement of one acid drug by another acid drug result in?
Transient increase of free drug concentration
What does an increase in the free drug concentration result in?
Increase in the clearance of the free drug form the circulation
Rate of drug distribution - perfusion limited tissue distribution? Permeability rate limitations or membrane barriers?
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
What does the blood brain barrier do?
Acidic brain cells trap ionised weak base as no pores
What does the placenta barrier allow diffusion of and what does it resist?
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
What drugs easily pass the placenta barrier?
Lipid soluble and mostly un-ionised drugs pass more easily compared to more polar and ionised ones
How are dugs eliminated?
Drug is oxidised or conjugated = metabolite or stable adducts formed = renal elimination or biliary elimination
How are drugs metabolised?
De-activation;
- Decrease of pharmacological effect
- Decrease toxicity
Activation;
- Increase pharmacological effect
- Increase toxicity
Conjugate formed and excreted
Phase I reactions of metabolism?
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
Phase II reactions of metabolism?
Attachment of an endogenous molecule to a drug or Phase I metabolite, glucoronide, sulphate, acetyl
Outcome products = heavier in m.w. = less effective
What is a major difference between phase I and phase II reactions?
Phase I predominantly produces more active compounds while Phase II produces less active
What are the enzymes of drug metabolism - phase I and II?
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-
Cytochrome 3A4
Inhibitors;
- Reduce clearance = increase blood levels
- E.g erytromycin
Inducers;
- Increase clearance = decrease blood levels
- E.g Phenytoin
What is genetic polymorphism?
Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes
Most clinically studies - CYP2C9, CY2C19, CYP2D6
CYP2D6 polymorphism? What does this result in?
8% caucasians lack CYP2D6
Poorer metaboliser for CV, psychiatric and opiate drugs
How does biliary excretion occur?
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
What factors influence the secretion of bile?
Molecular weight (i.e. > 300)
Polarity (higher polarity more bile excretion)
Nature of biotransformation
Gender, diseases, drug interactions
How do drugs and bile interact?
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
Which drugs are renally eliminated?
Water soluble
Ionised
E.g Digoxin
Which drugs are hepatically eliminated?
Lipid soluble
Un-ionised
E.g propanolol, cyclosporin
Nephron’s structure and their functions?
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
Renal clearance?
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
What determines the renal clearance of a drug?
Net contribution of filtration, secretion and reabsorption
What is the therapeutic index? Higher therapeutic index means?
Margin between the therapeutic dose and the toxic dose.
Higher the therapeutic index is safer the drug is.
What factors effect metabolism?
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
