Pharmacokinetics

Pharmacokinetics

1. Aim of Treatment

   • obtain a drug concentration at the target side.  effective for an appropriate amount of time.  minimising side effects. 
   • Branches
     • ADME - can vary with a single change  Absorption  Distribution  Metabolism  Excretion 

2. Absorption

   • in order to be absorbed the drug must enter the blood stream.  How quickly the drug is absorbed depends on the route of administration.  
   • Fatty food decreases stomach emptying  takes longer to feel effects of ethanol after fatty food meal CO2 increases stomach emptying 
   • Topical
     • Skin, cornea or mucous membranes 
     • often used for local effect because most drugs are poorly absorbed through unbroken skin. 
     • provides: slow but steady rate of delivery, patch, hyoscine for motion sickness, nicotine patch.
   • Sublingual
     • sprays pastes dissolvable tablets 
     • Direct response useful when drugs unstable at gastric pH or when rapidly metabolised by liver
   • Rectal
     • useful if patient is: vomiting, post-OP or an epileptic child
     • Anytime other routes of administration are difficult to achieve 
   • Oral
     • most absorption occurs in the intestines  
     • H2O soluble poorly absorbed  lipid soluble highly absorbed 
   • IV
     • Fast, most certain  100% absorption  Bolus (all at once) or infusion (overtime)
   • Subcutaneous & intramuscular
     • faster effect than oral but depends on:  - diffusion through tissue  - greater the blood flow the greater the absorption 
   • Inhalation
     • significant absorption via the lung  volatile anaesthetics  bronchodilators 

3. Distribution

   • barriers to drug movement.  Cell membrane  Epithelial barrier 
   • Prevention
     • Partitioning in body fat - large non-polar compartment  - little distribution to the fat  - no pharmacologic action 
     • binding to plasma proteins prevents the drug from being distributed
     • dependant on:  - free drug concentration  - protein concentration in plasma  - most cases binding is not saturated  - drugs can compete for protein binding 

4. Metabolism

   • many of the drugs are lipid soluble and need to change to water soluble in order to leave the body
   • occur via enzymatic reactions majority take place in the liver 
   • Phase One
     • In many cases drugs lose their activity when they convert into a metabolite.  some drugs can be converted to an active metabolite - called prodrug 
     • some metabolites of drugs are toxic - bioactivation 
   • Cytochrome P450 (CYP450)
     • reactions that are catalysed by this superfamily of enzymes 
     • Located in the smooth ER of;  - Liver (greatest source)  - kidney  - lung  - skin 
   • Enzymes as Drug Targets
     • drugs binds to active site on the enzyme.  drug acts as a substrate.  OR drug acts as an inhibitor. 

5. Enzyme Inhibition

   • Competitive Inhibition
     • combines with free enzyme - prevents substrate binding  Two things want the same spot. 
     • Theoretically, increasing the substrate conc will restore the reaction rate back to normal. 
   • Non-competitive
     • has no effect on substrate binding.  substrate and inhibitor binds independently and at different sites.  result is an inactive enzyme. 
   • Suicide Inhibition
     • inhibitor destroys or inactivate the enzyme.  To get an effect the enzyme must be resynthesised.  Only type of inhibition where the enzyme conc decreases. s

6. CYP450

   • divided into families and subfamilies.  activity can be altered - Phenobarbitone = induces more activity from the enzyme. 
   • CYP2E1
     • 2 = Family  E = Subfamily  1 = Specific enzyme 
     • Role in Drug Metabolism
       • Substrates:  Paracetamol  Halothane  Chloroform 
       • Induced by:  - Ethanol  - Acetone 
       • Inhibited by:  - Disulfiram  - Garlic (dialysis sulfide)  - CCl4 (suicide inhibitor) 
   • Other Important CYP450 enzymes
     • CYP2A4 - responsible for metabolism of ~70% of clinically used drugs Stubstrates - cocaine, cyclosporine, diazepam & estrogen  Induced - dexmethasone & SJW Inhibited - ketoconazole and grapefruit 
     • Drug Interaction with SJW  Induction of CYP3A4 can decrease the effectiveness of other drugs metabolised by this enzyme.  pregnancy has occurred because SJW caused oral contraception to be metabolised more quickly. 

7. Bioavailability

   • (F) - Fraction of dose that is absorbed unaltered.  Units - % or decimal equivalent.  F=A/D  A - amount of drug absorbed  D - dose 

8. Excretion

   • Majority of drugs are excreted by the kidneys 
   • 3 important components:  1. Glomerular filtration  2. Tubular secretion  3. Tubular reabsorption 
   • Golmerular Filtration
     • Renal blood flow is 1.5 l/min 10% of that appears as filtrate  Only free drugs may be flitered  - PROTEINS ARE TOO LARGE  - ALBUMIN MW 68,000, only MW < 20,000 will be filtered
   • Tubular Secretion
     • Cells in proximal convoluted tubular secrete ~90% of drugs.  - Strong acids & bases - Most effective mechanism of drug elimination.  
     • transporters can strip drug bound proteins which are then removed by carrier mediated transport. 
   • Tubular Reabsorption
     • reabsorption of nutrients occurs in the renal tubule  - Glucose  - Amino acids  - Vitaims  - Unionised drugs may also be reabsorbed = can be modified by pH (ion trapping) 
   • Other Organs
     • Gall Bladder -  Liver secretes ~1 L of bile per day  - After metabolism, drugs can be secreted into bile for excretion  - If the liver is disease or impaired, secretion of the bile can be impaired which can cause drugs to accumulated.  Gall bladder also regulates bile acids and bilirubin.  when the gall bladder is damaged these accumulate and jaundice occurs. 
     • Lungs  - primarily secrete gases and other volatile substances.  - As a general rule any drug for chemical that can be absorbed by inhalation can be excreted via exhalation.  - NO2 doesn't dissolve in the blood and therefore is rapidly excreted through the lungs  - Ethanol is soluble in the blood and therefore leaves via the lungs slowly. 
     • Sweat & Siliva  - sometimes side effects such as skin irritation can occur due to a drug being excreted though sweat.  - Drugs excreted into the saliva are generally swallowed. 

9. Half Life

   • t1/2 = time required for the drug concentration to fall to 1/2 its original value.  will vary between drugs units are usually hours 
   • Some drugs will always remain in the body, during long term administration.  accumulation occurs until the amount lost equals dose given - steady state (Css) 
   • Things to remember
     • the larger the Vd the longer the half life, takes longer to remove the drug. - tissues 

10. Clearance

    • Cl = volume of plasma completely cleared of drug per unit of time  Units - I/h 
    • E = Cl*c  E - elimination  Cl - clearance  c - drug concentration 

11. First Order Elimination Rate

    • most drugs exhibit first order elimination kinetics  - rate elimination is dependant on the dose  - The higher the does the more drug that is eliminated 
    • A few exceptions - some drugs exhibit zero order kinetics  Ethanol - takes time to sober up. 

12. Dose response curves

    • Effective Dose  - Estimates the frequency that each dose elicits the desired response in a population  ED50 - effective dose for 50% of the population 
    • Lethal Dose  TD50 - dose which kills 50% of the population 

13. Therapeutic Index

    • Vd Rules
      • Small - confined to plasma  large - distributed throughout the body