introductory pharmacology - drug disposition (PH2) Flashcards
1
Q
pharmacokinetics
A
what the body does to the drug
2
Q
drug disposition
A
- the fate of drugs in the body (pharmacokinetics = what the body does to the drug)
- made up of:
- > absorption
- > distribution
- > metabolism
- > excretion
3
Q
absorption
A
- the process by which a drug enters the body from its site of administration (eg. tablet/capsule are swallowed/administered orally)
- note that the lumen of the GI. tract is outside the body, therefore whilst the drug/medicine is in the lumen of the GI tract it is still technically outside, only once the drug leaves the lumen of the GI tract and enters the cells of the GI tract is it absorbed/described as being inside the body
4
Q
distribution
A
- the process by which a drug leaves the site of administration, enters the blood and subsequently the tissues perfused by the blood (aka once the drug is absorbed it is distributed to different tissues that the blood perfuses)
- once within a tissue, further blood-independent distribution, dictated by a concentration gradient, may occur by diffusion (or carrier mediated transport)
- > many lipophilic (tending to combine with or dissolve in lipids or fats) drugs move from ECF into ICF (?)
5
Q
metabolism
A
- the process by which tissue enzymes (principally in the liver - hepatic metabolism) catalyse the chemical conversion of a frequently lipid soluble to an often less active and more polar form which is more readily excreted from the body
- metabolism + excretion = elimination
6
Q
excretion
A
- the processes that remove the drug, or its metabolites from the body (principally the kidneys - renal excretion) but other routes may be important for specific agents
- some drugs can be excreted/appear in breath/sweat and lactating females, however the most common form of excretion is the kidneys
- metabolism + excretion = elimination
7
Q
elimination
A
metabolism + excretion (2 linked processes)
8
Q
overview of drug disposition
A
- absorbtion -> distribution -> metabolism -> excretion
- drugs are ingested (via oral administration etc) -> they then go to the stomach where absorption is very limited (ethanol is readily absorbed in the stomach however) or to the small intestine where most absorption occurs
- any drug that is absorbed does not directly enter directly into the systemic circulation -> they go via the portal circulation from the stomach/ intestines to the liver for metabolism (hepatic metabolism)
- metabolism renders the drug into a form that is more readily excreted, hepatic metabolism makes the drug more polar as the kidneys only excrete polar drugs
- some drug metabolites return to the small intestine from the liver in a seperate route from the blood, typically pumped via the bile through bile ducts and into small intestine where it may be reabsorbed (this introduces a further cycle between the liver and intestines through a separate route)
- drugs that are not absorbed in the intestines are excreted in the faeces
- there is a 2 way distribution between the liver and vascular compartment, therefore once in vascular compartment can return to liver where it can undergo metabolism
- once in vascular compartment there is a 2 way distribution between vascular compartment and the kidneys and vascular compartment and the interstitial water
- > from the kidneys the drug is then excreted
- > from the interstitial water there is a further 2 way distribution/process between interstitial water and intracellular water (once the drug is in the interstitial water, as long as it is lipophilic or supported by transporters it can leave the lipid layer and enter the intracellular water)
9
Q
physicochemical factors controlling drug absorption
A
- 1.solubility (the drug within a medication must dissolve/dissolution/be released from the tablet/capsule in order to be absorbed)
2. chemical stability (some drugs are destroyed by acid in the stomach, or enzymes such as pepsin in the gastrointestinal/ GI tract, if the drug isn’t stable it can be destroyed)
3. lipid to water partition coefficient (absorption of a drug commonly occurs by simple diffusion across membranes, although some agents are transported, for a given drug concentration gradient across the membrane, the rate of diffusion increases with the lipid solubility of the drug -> the rate of transport depends upon how readily the drug moves into the membrane) - > for a drug to move into the cell by passive diffusion there must be a concentration gradient and the drug must have a degree of lipid solubility to cross the membrane
- > lipid solubility determines how efficiently and how rapidly a drug is absorbed across the membrane
- > the lumen of the GI tract = an (aq) environment, and the membrane = lipid environment therefore drugs only cross membrane if they have high solubility
- > deltaCm = conc. gradient across the membrane, which drives rate at which drug moves across the membrane
10
Q
degree of ionization and pH
A
- many drugs exist as weak acids, or weak bases, existing in both ionized and unionized forms
- unionized acid = AH, ionized acid = A- (+ H+)
- unionized base = B (+ H+), ionized base = BH+
- acid = agent which donates proton
- pH is a measure of H+ conc -> as pH increases, proton conc/ [H+] decreases
- > acid becomes more ionized (loses a proton) as pH increases (acid donates protons, reaction is driven to the right)
- > as pH decreases, tendency for base to pick up H+ increases/base accepts proton and becomes more ionized (reaction is driven to the left)
- > only unionized forms readily diffuse across the lipid bilayer unaided (Fick’s law of diffusion)
11
Q
degree of ionization calculation
A
- degree of ionization depends upon pKa of the drug and local pH of the medium in which it dissolves
- pKa = pH at which 50% of the drug is ionized and 50% is unionized
- if the pKa and pH are different, use the Henderson-hasselbalch equation
- proportions of ionized and unionized drugs can be calculated by the Henderson-hasselbalch equation (do worked examples)
- > relevant as local anaesthetics occur in charged and uncharged forms, however only uncharged forms can get into the nerves
- > take home message of Henderson-hasselbalch equation = as pH increases for acid, percentage of drugs ionized increases (acidic drugs become increasingly ionized)
12
Q
Henderson-hasselbalch equation (for an acid)
A
pKa - pH = log (AH/A-)
->eg. aspirin (weak acid) pKa=3.5, at any pH above 3.5, most of aspirin will be ionised
13
Q
Henderson-hasselbalch equation (for a base)
A
pKa - pH = log (BH+/B)
->eg. morphine (weak base) pKa=8
14
Q
degree of ionization and absorption
A
- absorption of weak acids is facilitated by the pH of the stomach lumen (bases are not readily absorbed until they reach the small intestine)
- the overwhelming majority of absorption (even weak acids) occurs in the small intestine (as it has a large surface area for absorption in comparison to the stomach)
- > base absorption will occur in small intestine, acid absorption can occur in stocmach, however most absorption occurs in small intestine
- weak acids and weak bases are well absorbed, strong acids (pKa 10) are poorly absorbed
- > absorption of strong acids and strong bases by diffusion is very poor in stomach or small intestine
- > acidic drugs become less ionized in an acidic acid; basic drugs become less ionized in a basic environment
15
Q
phenytoin
A
- acid
- pKa = 8.3
- majority are ionized at any pH > 8.3
