Pharmacokinetics Flashcards
Pharmacokinetics
The journey of a drug through the body (ADME):
Administration Absorption Distribution Metabolism Excretion Removal
Why is pharmacokinetics important?
Determines dose of drug available to tissues
Administration of drugs
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Systemic effect
The entire organism
E.g. cannabis, aspirin, nicotine (patch)
Local effect
Restricted to one area of the organism
E.g. salbutamol, antacid, betnovate
Enteral vs Parenteral
Enteral = gastro-intestinal admin
Parenteral = outside GI tract
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Drug molecules move around the body in two ways:
Bulk flow transfer (i.e. in the bloodstream) Diffusional transfer (i.e. molecule by molecule over short distances)
NOTE: drugs have to transverse both aqueous and lipid environment
Compartments = aqueous (e.g. blood, lymph, ECF, ICF)
Barriers = lipid (i.e. cell membranes - epithelium, endothelium)
How can drugs cross these barriers?
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Also pinocytosis (drug embeds themselves into the membrane) - doesn’t happen very often
Which of these three routes is least relevant for absorption of drugs?
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Diffusion across aqueous pores
The drugs have to be very small
Water soluble = small - diffuse through aqueous pore (but not many are that small)
Lipid soluble = just diffuse
Drug via oral route
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…..
Non-polar substances can freely dissolve in non-polar solvents. I.e. can penetrate lipid membranes freely.
Very important:
Most drugs are either weak acids or weak bases
Therefore drugs can exist in ionised (polar) and non-ionised (non-polar) forms - the ratio depends on the pH
Henderson-Hasselbalch equation
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10^(pKa - pH) = [AH]/[A-] or [BH+]/[B]
Note: if the ratio is 1 = equilibrium
TRUE OR FALSE:
PKa of drug does not change
TRUE
pH of different body compartments do change
….
Acids = if pH is below pKa = more unionised
Bases = if pH is below pKa = more ionised
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What is ion-trapping?
Drugs can be very localised within certain compartments
E.g. aspirin can easily transport from the stomach (lower pH than pKa)m but there are lots of ionised aspirin in the blood due to the pH
Why might treatment with intravenous sodium bicarbonate increase aspirin excretion
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IV sodium bicarbonate will increase urine pH
High pH = more ionised drug
Excretion needs high ionisation (otherwise it’s lipid soluble and diffuses back into the bloodstream)
E.g. people who overdose are given bicarbonate to facilitate excretion of drug
Factors influencing drug distribution
Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental)
Localisation in tissues
Regional blood flow
The more blood goes to a particular tissue, the more drug reaches that tissue
Highly metabolically active tissues = denser capillary networks
NOTE: eating a meal = more blood directed to the gut, exercise = more blood directed to skeletal muscle
Extracellular binding (plasma-protein binding)
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If a drug is bound to plasma protein, it’s not leaving the blood.
E.g. warfarin is heavily plasma-protein bound (well over 90%). Therefore, adjust dose
NOTE: acidic drugs are heavily plasma-protein bound (e.g. aspirin = 50-80% bound)
Multiple drugs = if two of them are bound to plasma proteins, they can displace each other (e.g. 5% of unbound warfarin —> 10% unbound warfarin)
Capillary permeability
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Most capillaries = continuous structure (H2O filled gap junction)
Water soluble drugs = need some mechanism to get across membrane (especially blood brain barrier with tight junctions)
Localisation in tissues
Some drugs can just sit in the tissue (mostly adipose tissue - very little blood supply)
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Really fat-soluble drugs = vast amounts are distributed into adipose tissue
It will slowly leak back into the blood, but it will take a long time
E.g. general anaesthetic = very lipid-soluble (after 24 hours, you suddenly feel very drowsy - drugs are leaking out of adipose tissue)
Two major routes of drug excretion
Kidney - eliminate drug in urine
Liver - secreted into bile and lost in faeces
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Excretion in kidney
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Mostly active secretion (kidney has hundreds of transporters for drugs)
If drug remains lipid-soluble it will diffuse across again into the bloodstream
Excretion in liver
Biliary excretion (large molecular weight molecules can concentrate) Active transport systems for water soluble drugs - into bile (bile acids and glucuronides)
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Enterohepatic cycling - why is it a problem for excretion?
Drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver and excreted again
This leads to drug persistence
Other routes of excretion (usually of little quantitative importance)
Lungs, skin, GI secretions, saliva, sweat, milk, genital secretions
E.g. breathalyser
Consider all of. The pharmacokinetic processes acting simultaneously:
Can predict time course of drug action
Bioavailability
Linked to absorption
Proportion of the administered drug that is available within the body to exert its pharmacological effect
Apparent volume of distribution
Linked to distribution
The volume in which a drug appears to be distributed - an indicator of the pattern of distribution (e.g. in adipose tissue)
Fatsoluble drugs can distribute more so than water-soluble
Biological half-life
Linked to metabolism/excretion
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
Clearance
Linked to excretion
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time.
(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes)
