Pharmacokinetics Flashcards
Define absorption
Process of transfer from the site of administration into the general or systemic circulation
Name the routes of medicinal administration
- Oral
- IV
- Intra Arterial
- Intramuscular
- Subcutaneous
- Inhalational
- Topical
- Sublingual
- Rectal
- Intrathecal
What must all drugs do when delivered into the body
Cross at least one membrane in its passage from site of administration to the general circulation (including intracellular sites)
Exception of IV or IA
Four different ways substances can move across the plasma membrane
- Passive diffusion
- Diffusion through pores or ion channels
- Carrier mediated processes
- Pinocytosis
What property do drugs need to have in order to move passively across the plasma membrane
Lipid solubility to cross phospholipid bilayer
Rate of diffusion is proportional to concentration gradient, area and permeability of membrane and inversely proportional to thickness
What property do drugs need to have to move down ion channels
Be very small water-soluble molecules
What substance do carrier proteins need to move substances into a cell and why
ATP
Substances moved against their concentration gradient
What are carrier proteins also called
ATP-binding cassette
How many carrier proteins (ABCs) do we have
49
What is so special about P-gp
An ABC that removes a wide range of drugs from cytoplasm to extracellular side
What drug inhibits P-gp
Verapamil to increase conc. of anti-cancer drugs in the cytoplasm,
How do substances move down carrier proteins passively
facilitated diffusion
or co-transport to move it against a conc. gradient
How many SLCs (solute carriers) are there
300
Where is OAT1 found
Kidney
Role of OAT1
Secretes Penicillin and Uric acid
What drug blocks the action of OAT 1
Probenecid so uric acid is excreted
What drugs tend to be taken up by cells via pinocytosis
Amphotericin into the liposome
What is the basic property for most drugs
Ionisation as they can be either weak acids or bases
What property do ionised drugs have
Water-soluble
What property do non-ionised drugs have
Lipid soluble
What is the PKa of a drug
pH at which half of the substance is ionised and half is unionised
Where are weak acids best absorbed
Stomach
Where are weak bases best absorbed
Intestines
pH in urine vs plasma and what is the consequence of an aspirin overdose because of this
Lower in urine than plasma
Aspirin overdose is a weak acid so will be largely un-ionised and reabsorbed into plasma
How do we prevent aspirin overdose
Alkalinise urine with IV bicarbonate to reduce reabsorption of aspirin + elimination
Easiest delivery of drugs
Oral route
Why is the oral route efficient
Large SA and high blood flow of small intestines gives rapid and complete absorption of oral drugs
What is the major determinant of drug absorption
Drug structure
What properties do drugs need to have to maximise absorption
- Drugs need to be lipid-soluble to be absorbed from gut
What is the problem with highly polarised drugs
Only partially absorbed and most passes into faeces (Olsalazine)
Drug must disintegrate and dissolve to be absorbed rapidly
When is Olsalazine given
Colonic IBD
Problem with drugs that are faced with low pH of the stomach
They may be unstable
How do we overcome drugs that may become unstable at low pH levels
They are formulated to dissolve slowly or have a coating resistant to the acidity of the stomach (enteric coating)
How can gastric emptying be delayed
Food, drugs or trauma
How can gastric emptying be faster
Gastric surgery
What four major barriers do drugs have to pass to reach circulation
Intestinal Lumen
Intestinal Wall
Liver
Lungs
What three bonds can be spilt in the stomach
Peptide
Ester
Glycosidic Bonds
Role of colonic bacteria in drug metabolism
Hydrolysis and reduction of drugs
What is a special property of the upper intestinal walls
Rich in cellular enzymes
Name a cellular enzyme in the upper intestinal wall
MAO (Mono Amine Oxidases)
How can drug absorption be limited in the intestines
Luminal membrane of enterocytes contains P-gp which moves drugs back out into the intestinal lumen
How does extensive bowel surgery affect drug absorption
Poor oral absorption as little surface left
What circulation do drugs absorbed from the intestines move down and to where
Splanchnic circulation to the liver
How do we avoid hepatic drug metabolism
Deliver drug to region of gut not drained by splanchnic
How long does IV, Interosseous take until effect
30-60 seconds
How long does inhalation and endotracheal drug delivery take for it to have an effect
2-3 minutes
How long does it take for sublingual drug delivery to take effect
3-5 minutes
How long does it take for intramuscular drug delivery to take effect
10-20 minutes
How long does it take for subcutaneous drug delivery to take effect
15-30 minutes
How long does it take for rectal delivery to take effect
5-30 minutes
How long does it take for drugs to take effect by indigestion
30-90 minutes
Why do we need potent, non-irritant drugs to move across human epidermis
Effective barrier to water-soluble compounds which can limit rate of absorption of lipid soluble drugs
How do we deliver drugs transcutaneously
Using transdermal patches
When is intradermal and subcutaneous drug delivery used
Used for local effect (local anaesthetic) or contraceptives
Why are intradermal and subcutaneous drug deliveries effective
Avoids barrier of stratum corneum
How is intradermal and subcutaneous drug delivery limited
Blood flow
What two factors effect intramuscular drug delivery
Blood flow
Water solubility
How are intramuscular drugs delivered
Depot injection
Incorporate lipophilic formulation which releases drugs over days
Disadvantage of intranasal drugs
Low level of proteases and drug metabolising enzymes
Advantage of intranasal drugs
Good SA
Benefits of inhalation drugs
Large SA
Blood flow
Limitations of inhalation drugs
Risk of toxicity to alveoli
Delivery of non-volatile drugs
What drugs are used inhalation ally
Volatiles
General Anaesthetics
Locally acting drugs
Why are asthma drugs non-effective inhalation-wise
Only 5% delivered to small airways
Non-volatile
Describe the equilibrium shifts with IV drug injections
- High initial plasma conc.
- Rapid perfusion of drug into tissue
- Drug perfusion slows
- Plasma conc. decreases
- Conc. in highly perfused tissues decrease
Where does reversible protein binding occur
To albumin
Why is protein binding needed
Lowers free conc. of drug and releases bound drug when plasma conc. decreases
How is albumin-bound drug released
Redistribution
Elimination
What is the consequence of irreversible binding of drugs to plasma proteins
Basically eliminated as they can’t enter circulation
What property of drugs allow ease of movement from blood to brain
Lipid-soluble
What drugs struggle to moves across BBB
Water-soluble
How do mechanisms prevent too high a conc. of drugs in the brain
Efflux transporters being present
How are drugs removed from the brain other than efflux transporters
Diffusion into plasma via Active Transport in CSF
What drug property is important in pregnancy
Lipid-soluble, SMALL drugs that can readily move across the placenta
LARGE molecules don’t cross the placenta
What is the issue with drugs moving through placenta
Blood flow through it is slow so slow equilibration with foetus
What drug will not pass the placenta
Heparin
Why are drugs not easily metabolised by foetus
Low levels of drug metabolising enzymes so rely on maternal elimination
How do opiates given to the mother during labour effect the newborn
Persist in them as they have to eliminate them (causes sleepy baby)
Define metabolism
Transformation of drug molecule into a different molecule
Define excretion
Molecule is expelled in liquid, solid or gaseous waste
What happens during metabolism of drugs
Drugs converted to water-soluble products and removed in urine
What would be the consequence is lipid-soluble drugs remain lipid soluble
Reabsorbed
What is phase I drug metabolism
Transformation of drug to more polar metabolite by exposing or adding a functional group (-OH, NH2)
Oxidation and reduction reactions by CYP450
Where are CYP450 found
SER
Which CYPs are involved in drug metabolism
CYP1-4
What two environmental factors induce P450 enzymes
Smoking
Alcohol
What drugs/foods inhibit P450
Grapefruit
Cimetidine
differences in CYPs
They metabolise at different rates
Where else can drugs be metabolised
Plasma, lung or gut
What enzyme metabolises Ethanol and in which phase
Alcohol dehydrogenase - phase I
What enzymes inactivates noradrenaline
Monoamine Oxidase
What enzyme inactivated 6-nercaptopurine
Xanthine
What are phase II reactions
Involves formation of a covalent bond between drug or its phase I metabolite and endogenous substrate
Property of products form phase II reactions
Less active
Where do phase II reactions take place
Cytoplasm
Mitochondrial
Microsomal
Difference between products of phase I and phase II reactions
Phase I - Active or inactive
Phase II - Inactive. water soluble
What type of drugs are excreted in fluids
Low molecular weight polar compounds
What drugs are excreted in solids
High MWT compounds excreted in bile
What drugs are excreted in gases
Volatiles
Formula for total excretion
Glomerular filtration + tubular secretion - reabsorption
Describe faecal excretion of drugs
high weight molecules taken up by HEPATOCYTES
Into BILE
Drugs reabsorbed and re-enter hepatic portal vein
