Pharmacokinetics Flashcards
What are some e.gs of routes of drug delivery?
Oral rectal - 50% first pass sublingual - rapid, no first pass transdermal - sustained effect intrathecal - CSF topical - local effect inhalation - rapid + targeted
What does pharmacokinetics look at?
Looks at the ADME properties of the drug - absorption, distribution, metabolism, excretion
How does a drug penetrate the various biological membranes to get to its site of action?
passive diffusion
what is relevance of gastric emptying?
Gastric Emptying critical for drug absorption. The SA of the intestine is larger than the stomach. –> Most drugs are absorbed from intestine bc of this
What is bioavailability?
Fraction of unchanged drug reaching the system circulation following any route of administration (intravenous injection = 100% bioavailability in circulation)
What factors 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)
How does the bioavailability differ between drugs?
Lidocaine 15% Propanolol 20% Morphine 30% Paracetamol 57% Theophilline 81% Diazepam 97%
What modulates the distribution of the drug in the body? (2 main components)
Physiochemical properties of the drug, e.g: Molecular size, Oil/water partition coefficient, Degree of ionization that depends on pKa, Protein binding Physiological factors: Organ or tissue size Blood flow rate Physiological barriers (blood capillary membrane, cell membrane, specialised barriers)
What do plasma proteins do? Give 2 examples of plasma proteins:
They’re involved in drug binding in blood e.g. albumin and α1-acid glycoprotein
What is the main difference between albumin and α1-acid glycoprotein?
Acidic drugs will mainly bind to albumin. Basic drugs will mainly bind to α1-acid glycoprotein
What happens when one acid drug is displaced by another acid drug?
Displacement of one acid drug by another acid drug results in transient increase of “free” drug concentration. Increase in the free drug concentration results in increase in the clearance of the free drug form the circulation Drug / drug protein interactions are rarely clinically significant.
What are the 2 main factors that can modulate the RATE of drug distribution?
Perfusion-limited tissue distribution (only limited by blood flow) permeability rate limitations (or membrane barriers)
What are some permeability rate limitations (membrane barriers)? (3)
BBB - blood-brain barrier BTB - blood-testis barrier Placenta
What are some highly and poorly perfused tissue examples?
Highly perfused - liver, kidneys, lung, brain Poorly perfused - skin, fat, bone, muscle
How do brain blood vessels differ to normal blood vessels?
Brain blood vessels don’t have pores - they have tight junctions . They are surrounded by glial brain cells to support the barrier. Things can’t leave by diffusion, it has to leave by carrier-mediated transport. acidic brain cells trap ionised weak bases (such as morphine)
What does the placenta barrier allow? What can pass through and what is blocked?
Sugars, fats and oxygen diffuse from mother’s blood to fetus Urea and CO2 diffuse from the fetus to mother Maternal antibodies actively transported across placenta = this gives 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
Which type of drugs can pass the placenta barrier more easily?
Drugs that are lipid soluble and mostly un-ionised can easily pass the barrier to the foetus compared to the more polar and ionised ones.
What are the two possible outcomes of drug metabolism?
De-activation: decrease of pharmacological effect and decrease of toxicity. Activation: increase of pharmacological effect and increased toxicity (i.e. chemical carcinogenesis)
Explain the phase I and II reactions of drug metabolism?
Drugs can either go to phase I or phase II metabolism.
phase I reactions:
Introduction, or exposure, of a polar group by oxydation, reduction or hydrolysis (catalised by CYP450)
At this point if the metabolites are sufficiently polar can be excreted
A C-H group can be turned into a C-OH converting non pharmacological active compound into active. DANGER: Toxic compound can be created as well
phase II reactions:
Attachment of an endogenous molecule to a drug or Phase I metabolite, glucoronide, sulphate, acetyl
The outcome products are heavier in molecular weight, so tend to be less effective.
MAJOR DIFFERENCE between Phase I and Phase II reaction is that Phase I predominantly produces more active compounds while Phase II produces less active
What enzymes are involved in the phase I and II reactions of drug metabolism?
Phase I – oxidation = Cytochrome P450
This is the major drug-metabolising enzyme system found in the liver. From a super family of several form i.e. multiple forms of cytochrome
Cytochromes possess varying substrate specificity. Catalytic activities show large inter-individual differences
Phase II – conjugation = Transferases: Glucoronyl- Sulpho- Acetyl- Methyl-
What is quetiapine used for? What enzyme does it use?
What do inhibitors and inducers for this enzyme do?
Used for schizophrenics - uses cytochrome 3A4 (CYP3A4)
When administering a drug to patients on quetiapine you need to make sure it doesnt interfere with the CYP3A4.
How can drugs be eliminated once metabolised?
How does biliary excretion / elimination work?
What factors influence secretion in bile?
Molecular weight (i.e. > 300)
Polarity (higher polarity more bile excretion)
Nature of biotransformation
Also gender, diseases, drug interactions
Some drugs and metabolites excreted by the 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 are the 2 major organs for drug elimination from the body?
Kidney and liver.
Drugs high in water or ionised will be excreted unchanged in the kidney, whereas drugs very lipid soluble or largely unionised will be processed by the liver.
How does elimination in the kidneys work regarding the nephrons?
Only unbound proteins filter from the Bowman’s capsule into the proximal tubule.
Several pumps in the nephron facilitate the filtration.
What is renal clearance?
GFR = glomerular filtration rate
The net contribution of filtration, secretion and reabsorption will determine the renal clearance of a drug, an index of the efficiency of the renal excretion processes.
Renal diseases may interfere with drug elimination
What is the therapeutic index?
The margin between the therapeutic dose and the toxic dose. Higher the therapeutic index is safer the drug is.
How does blood level affect 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
What are some general factors affecting drug metabolism?
environmental, disease, genetic, age, drug interaction
What is genetic polymorphism?
The occurrence of a variant form of an enzyme/receptor through the inheritance of drug-metabolising enzymes.
most clinically studied: CYP2C9, CYP2C19, CYP2D6
