1212 Week 15

1212 Week 15

1. Lecture 1

   • Blood Barriers
     • lipophilic drugs can cross all barriers so distribution is only affected by perfusion rate
     • hydrophobic/large drugs are rate limited by barriers and so have limited distribution
     • IV thiopental has fast onset and distribution in the brain but duration of action is short because it is redistributed to slower perfusing organs causing levels in the brain to fall
     • blood brain barrier
       • capillaries in the brain are surrounded by neurons and astrocytes
       • lipid drugs are free to diffuse
       • polar drugs have to exit via carrier-mediated transport
       • L-DOPA can cross the BBB but dopamine can't so has to be converted by DOPA decarboxylase in the brain
       • Dopamine is also converted in the periphery so carbidopa is used to selectively block DOPA decarboxylase in the periphery
       • Dopamine is used to treat parkinsons
     • the placenta
       • regulates the exchange of substances betweem mother and foetal blood
       • metabolic barrier that includes p-glycoproteins
   • Distribution
     • the reversible movement of drugs from the systemic circulation otthe cells and interstitium
     • capillaries allow paracellular diffusion so drugs can enter the ECM
     • hydrophilic and large drugs can't cross the membrane so can only access exposed targets - extracellular and membrane proteins
     • lipophilic drugs can enter the cells and interact with intracellular targets
     • the permeability of blood-tissue boundaries varies between tissues
     • drugs are diluted evenly within minutes but distribution isn't equal
     • perfusion rates control the rate of diffusion of drugs into tissues
     • drugs in the blood bind to proteins to maintain a gradient between the blood and tissues to ensure a continual diffusion of drug into the tissues
     • drugs bind to proteins in the tissues leading to accumulation - is the conc is higher than in the blood it is called sequestion
     • distribution between fluid compartments depends on permeability across barriers, binding within comparments, fat:water partitions and pH partitions

2. Lecture 2

   • Metabolism
     • examples
       • Tamoxifen - breast cancer, has to be converted to endoxifen so it can bind to oestrogen receptors and affect cell proliferation
       • Paracetamol
         • can be converted to NAPQI which kills liver cells
         • NAPQI can form a complex with GSH which isn't toxic
         • If you overdose you run out of GSH cystine has to be administered to stimulate GSH production
     • chemical modification of chemical compounds making them more excretable, less active and less toxic
     • age, diseases and genetics all affect metabolism so dosages have to be revised for each patient
   • Phase 1 and 2
     • phase 1 examples
       • Oxidation - Phenacetin - carcinogenic, prodrug to paracetamol so paracetemol can be taken instead
       • Reduction - Chloramphenicol - its nitro group is reduced to an amine group and is used as broad spectrum antibiotic eye drops
       • Hydrolysis - Apirin and Procaine - both are hyrdolysed to their active forms, procaine was used a anaesthetic in dentistry
     • phase 2 example - Aspirin - after undergoing phase 1 it is then glucuronidated
     • phase 1 - modification of drugs by oxidation, reduction or hydrolysis
     • phase 2 - modification of drugs by the addition of a new chemical group, conjugation
     • phase 1 reactions are catalysed by cytochrome P450s and result in the addition of hydroxyl group making them more polar
     • phase 2 reactions are glucuronidation, sulphination and N-acetylation
     • glucuronidation makes the drug hydrophilic so it can be secreted by the kidneys
     • if a drug already has a hydroxyl group it may undergo phase 2 directly
     • drug downfall is normally caused by it metabolites not the drug itself
   • Enzyme Induction
     • exposing the body to a drug induces enzymes involved in metabolism
     • examples
       • rifampicin - induces CYPs and speeds up the metabolism of any drugs it affects
       • phenytoin and carbamazepine - promote the induction of their own enzymes
       • cimetidine - inhibits enzymes and is used to treat ulcers, it also inhibits warfarin metabolism so there is increased haemorrhaging
     • toxicity - anticonvulsants increase the metabolism of vitamin D3 causing bone demineralisation

3. Lecture 3

   • Excretion
     • renal is the most important pathway for drug and metabolite excretion
     • occurs through bile, faeces, lungs, saliva, sweat, tears and milk
     • 25% of CO is recieved by the kidneys of which 10% is filtered at the glomeruli (120ml/min)
   • OATS and OCTS
     • OATs - organic anion transporters
     • OCTs - organic cation transporters
     • bith exist in the apical and basement membranes
     • bensylpenicillin, methoraxate and ibuprofen are recognised by OATs and OCTs
     • drugs absrobed by OATs and OCTs can have their half lives increased by drugs that block OATs and OCTs
     • example of increased half life - benzylpenicillin 40mins normally but can be increased by probenecid
   • Renal Excretion
     • renal excretion = (filtration+secretion) - reabsorption
     • glomeruli blood vessels and membranes are porous so all small drugs and metabolites are filtered freely
     • protein bound drugs aren't filtered
     • secretion is the diffusion and active transport form the capillaries to the lumen of the tubules
     • epithelial cells contain protein families that carry out active carrier-mediated transport
     • reaborption reduces urine production to 1-2ml/min which concentrates solutes in the tubule but lipophilic drugs can be reabsorbed
     • pH can be used to treat overdoses - alkaline urine accelerates weakly acidic drug excretion and acidic urine accelerates weakly alkaline drug excretion
   • Bilary Excretion
     • some drugs are actively transported by the liver into bile and excreted in faeces
     • sinusoids are connected to hepatocytes with OATs and OCTs that allow polar drugs and metabolites into the cells
     • drugs can then enter the bile canaliculi and be excreted into the gut via the bile
     • enterohepatic cycling slows elimination and prolongs the duration of drug action