Pharmacokinetics Flashcards
What are the 4 main parts of pharmacokinetics
Absorption – drug absorption permits entry either directly or indirectly into the plasma
Distribution – the drug may then reversibly leave the blood and distribute into the interstitial and intracellular fluids
Metabolism – the drug may be biotransformed by metabolism in the liver or other tissues
Excretion – the drug and its metabolites are excreted from the body in urine, bile or faeces
Factors affecting the rate of absorption
Route of administration
Dosage
Lipid solubility
Major routes of drug administration
- Topical - applied where needed e.g skin ointments, aerosols
- Parenteral - avoids the gut e.g injections
- Enteral - reaches target after absorption from gut e.g paracetamol
Drugs will tend to exist in the… state when exposed
to an environment with a pH opposite to their own stated
Ionic
• Stomach = pH 2
• Plasma = pH 7.4
• Urine = pH 8
What form will aspirin (pKa 3.5) be in these area
Stomach - neutral form
Plasma - ionised
Urine - ionised
What is ion trapping
When the drug ionises and gets trapped in an area as it can no longer cross the membrane
Distribution of drug throughout body
What effects rate of distribution
Membrane Permeability
• Drugs diffuse faster through the highly
permeable renal capillaries
• BBB
Blood Perfusion
• Drug reaches highly vascularised tissues
more rapidly e.g. lung/liver
What effects extent of distribution
Lipid Solubility
• Most drugs are small molecules that can
passively diffuse across membranes in their
uncharged (neutral) state.
Plasma Protein Binding
• Drugs exist either dissolved in the blood as
bioavailable (free drug) or bound to plasma
proteins (PPB)
• When drugs are PPB they are not bioavailable
• Drugs can interact and one drug may displace
another e.g. aspirin displaces diazepam from
albumin
Tissue Binding
• Drugs can bind to tissues either rich in fat (if
drugs are very lipid soluble) or specific cellular
components e.g. proteins, mineral, pigments
• A couple that are new and require more detail
Drugs that bind to plasma proteins such as albumin exhibit…
Slower acting and prolonged therapeutic effects - as it stays in body for longer period of time
Also slower elimination
Tissue can bind to drugs e.g tetracycline…
Accumulate slowly in bones and teeth as they have high affinity for calcium
Formula to calculate volume of distribution
Vd= dose administered/ initial apparent plasma concentration
What is bioavailability
The proportion of a drug that passes into the systemic circulation after administration.
Factors affecting bioavailability
Absorption
• Solubility of the drug
• Chemical instability in the GI tract
• Drug formulation
Metabolism
• Metabolism in the gut/liver
• ‘first pass metabolism’
High first pass metabolism leads to… bioavailability
Low
How to overcome high first pass metabolism
- Larger dose
- Different method of administration e.g IV
Morphine and propranolol show high rates of first pass metabolism so oral dose is increase compared to IV dose
How does the body metabolise drugs
- Reducing lipid solubility
- Altering biological activity
The end result of metabolism is usually the abolition of biological activity.
Enzymatic modification of a drug
What do the CYP450 enzymes do
Oxidation
Hydroxylation
Dealkylation
Deamination
Hydrolysis
Are located in most cells but are primarily found in the liver and GI tract
Involved in metabolising approximately 75% of all drugs
Aspirin is hydrolysed to…
Salicylic acid which is analgesic, antipyretic
and anti-inflammatory properties
What does conjugation do
further decreases lipid solubility and almost always results in pharmacologically inactive metabolite
Conjugate excreted in urine or bile
Commonest conjugation reaction is glucuronidation
What is enterohepatic circulation
- Drug is metabolised to conjugate in liver
- Conjugate is excreted in the bile from gall bladder into the gut
- Conjugate undergoes bacterial hydrolysis in gut back into drug and free glucuronide
- Drug is reabsorbed into hepatic portal vein and transported to
liver
Renal drug excretion steps
- glomerular filtration
- active tubular secretion
- passive diffusion across tubular epithelium
Drug molecules that are transferred by tubular lumen by two carrier systems…
OATS (organic anion transport system) and OCTS (organic cation transport system)
- Plasma protein binding is not a barrier to carrier mediated
transport as drugs have higher affinity to transporter than plasma protein - Carrier systems can transport drugs against an electrochemical gradient (requires energy)
- Not affected by pH
- Many drugs share same transporter → can lead to competition
- Most effective mechanism for drug elimination
80% of renal blood flow filtered through 1.
20% of renal blood flow filtered through 2.
- Proximal tubule
- Glomerulus
Role of probenecid
Binds to organic anion transporter and outcompetes penicillin, effectively inhibiting tubular secretion and prolonging effects of penicillin
