Pharmacokinetics

• What is pharmacokinetics?

  -The study of what happens to a drug or chemical in your body over time, including how much of it gets to where it needs to go and how long it stays there.
• What is biotranslocation?

  -Study of drug absorption and distribution
• What is biotranformation?

  -Study of the means by which drugs are stored and eliminated from the body.
• What must you consider in pharmacokinetics?

  -How much of the administered drug reaches the target organ?

  -Where in the body does the drug go?

  -How long does the drug stay in the body for?
• What are the properties of a "perfect drug"?

  --Stable form amenable to introduction into the body

  -Pass into the body

  -Able to reach biological target

  -Remains in the body long enough to have a therapeutic effect

  -No toxic/produce harm whilst in the body

  -Exits the body when job is done.
• What determines absorption?

  -Chemical properties of drug determine absorption.

  -Lipophilicity and hydrophilicity are the most important physical properties of a drug.
• What is LogP?

  -LogP refers to the log partition and tells us how hydro/lipo philic a drug is.
• Class 1 drug (amphiphilic)

  Propranolol
• Class 2 lipophilic drug

  Naproxen
• Class 3 hydrophilic drug

  Ranitidine
• Class 4 drug

  Furosemide
• Does drug size matter?

  -Yes, hydrophilic drugs able to pass through membranes
• What is ionisation?

  -Protonation/deprotonation resulting in charged molecules.

  -About 85% of marked drugs contain functional groups that are ionised to some extent between pH 1.5-8.

  -Ionised form of drug can't get through membrane, non-ionised form can.
• What is pKa?

  -pH value at which equal amounts of ionised and non-ionised forms exist
• What does a pKa= 4 mean?

  -Ionised and non-ionised forms of drug exist at pH4
• What are the 3 types of drug administartion?

  -Enteral: Oral, sublingual, rectal, inhalation.

  -Topical: Application to other epithelial surfaces i.e., skin, vagina, nasal mucosa.

  -Parenteral: Subcutaneous, intramuscular, intravenous, intrathecal. Example includes epidural which is injected into the spine.
• What is bioavailability?

  -The fraction of administered dose that reaches the systemic circulation.

  -If bioavailability is 0.75 this means 75% of the drug is in the circulation

  -Does not represent the amount of drug reaching molecular target
• What affects oral bioavailability?

  -75% usually absorbed 1-3hrs after administration

  -GI motility

  -Splanchnic blood flow (blood flow to intestines).

  -Formulation of medicine

  -Physiochemical properties of drug(s). Drug may get into circulation but not to desired receptor.

  -Incomplete absorption

  -Loss in faeces

  -1st pass metabolism
• What is the volume of distribution (Vd)?

  -The volume of fluid required to contain the total amount of drug in the body (D) at the same concentration as that present in the plasma.

  -Unit is in litres

  -Vd cannot be smaller than volume of intravascular plasma which is around 3L
• Warfarin Vd

  -0.1-0.2

  -3mg is the dose

  -Warfarin has high degree of binding to plasma proteins
• What affects tissue distribution?

  -Physiochemical features of drug

  -Pharmacological properties of drug (binding of molecules to plasma or tissue proteins allows specific uptake into tissue.)

  -Blood flow to organ/ tissues

  -Barriers of organ/tissue
• Why are the physiochemical features of a drug important?

  -Because if drug is too big e.g., heparin it will not cross membranes well

  -pKa of drug matters. pH difference between plasma and tissue can lead to accumulation
• What physiochemical properties of drugs are important?

  -Hydrophobic substances tend to become enriched in fat tissue (obesity can influence distribution of some drugs).

  -Drugs with high affinity for Ca2+ can become enriched in bone and teeth. e.g., tetracyclines which then causes discolouration.
• Why are pharmacological properties of drugs important?

  -At therapeutic concentrations, many drugs are bound to various plasma proteins.

  -Only the unbound fraction is therapeutically active.

  =Drugs generally bind to particular sites on plasma proteins like albumin, lipoproteins, glycoproteins and β globulins.

  -Binding is saturable like binding of a ligand to a receptor. That might allow specific uptake into tissue.
• Why is blood flow to organs/tissue important in distribution?

  -The rate at which a drug is distributed to various organs depends on the proportion of cardiac output the organ receives.

  -Drugs are rapidly distributed to highly perfused tissues like the brain, heart, liver, and kidney get approx.1200ml/min

  -To skin, bone and fat drugs are perfused at approx.250ml/min.
• Why are barriers of organ/tissue important in tissue distribution?

  -Brain endothelium is highly impermeable making it hard to get drugs into the brain.

  -Placenta protects unborn child. The placenta has a wide range of protective mechanisms in place to prevent uptake of harmful compounds (e.g., transporters for chemotherapeutics, antibiotics etc).

  -Lipid soluble drugs can pass readily from mother to foetus. Perfusion is a limiting factor, so drugs equilibrate at a slower rate in the foetal compartment.
• Where does drug metabolism occur on a tissue level?

  -Kidneys

  -Liver

  -Lungs

  -Liver main organ of excretion & protects body from toxic compounds
• Where does drug metabolism occur on a cellular level?

  -Mitochondria

  -Smooth ER
• What are the aims of metabolism?

  1. Try and inactivate a toxic compound/make drug potentially less toxic

  2. Increase excretion of drug by kidney.

  -Body does not know difference between a drug or a toxic compound, so it metabolises all of them to try and protect the body.

  -Metabolism begins before the drugs reach the general circulation.
• What is phase 1 metabolism?


  -Reactions that change the drug molecule through oxidation, reduction or hydrolysis

  -Aim to make drug more reactive e.g., adding hydroxyl group to make drug water soluble increases secretion by kidney

  -Tends to decrease biological activity and can change nature of drug
• Phase 1 Metabolism example:

  -Aspirin/salicylic acid

  -Acetyl group is hydrolysed off creating hydroxyl group

  -Add glucuronic acid with carboxyl group
• What is Phase II metabolism?

  -Involves formation of covalent bond

  -Results in H2O soluble conjugate

  -Helps excretion

  -Products of Phase II metabolism are predominately inactive
• Phase II metabolism drug example:

  -Codeine

  -10% of codeine is converted into Morphine by the cytochrome CYP2D6

  -O-methyl groups removed and reduced to hydroxyl group and converted into glucuronide. -Increases the analgesic effects. -Morphine better analgesic than codeine.
• CYP2D6 Deficiency:


  -Affects 6-10 % of Caucasians, 3-6% of Mexican Americans, 2- 5% of African Americans and ~1% of Asians Americans.

  -These people are "poor metabolisers"

  -Inherited non-functional gene from both parents with no CYP2D6 activity
• What are intermediate metabolisers?


  -People who have one non-functional gene from parent

  -Some CYP2D6 activity but lower than normal
• What are extensive metabolisers?


  -People with normal CYP2D6 activity

  -At least one functional gene
• What are ultrarapid metabolisers?


  -People who have higher than normal CYP2D6 activity

  -Metabolise drugs faster than they should

  -Plasma concentration lower than it should be

  -Depends on ethnicity

  -30% Ethiopians, 4% Caucasian north American, 10% Greek & Portuguese, 1% Scandinavian
• What is 1st pass metabolism?


  -Metabolism that begins before drugs reach general circulation

  -Occurs in liver, lungs, intestinal wall and lumen
• What factors affect metabolism?

  -Genes e.g., CYP2D6

  -Smoking can sometimes increase drug metabolising enzymes including some for anti-depressants

  -Diet
• What affects do grapefruits have on metabolism?

  -Grapefruits contain furanocoumarins which inhibit cytochrome CYP3A4 & CYP1A2

  -Reduces first pass effect

  -If drug it metabolised by this cytochrome it will be metabolised much slower and the levels will build up in the body.

  -These compounds in grapefruit juice can affect: immunosuppressants e.g., ciclosporin, statins e.g., simvastatin and calcium channel blockers e.g., nifedipine.

  -For drugs metabolised by P450 isoforms can lead to increased plasma levels dangerous for drugs with narrow TI