Pharmacology 2

Question 1

what are the 4 processes influencing drug disposition?

Answer 1

absorption
distribution
metabolism
excretion

Question 2

how do most drugs leave the body?

Answer 2

in urine
either as unchanged compounds or more commonly chemically transformed compounds rendered more polar by metabolism
(excretion in bile is occasionally significant)

Question 3

drugs are xenobiotics, what does this mean?

Answer 3

compounds which don’t exist naturally or exist in much lower concentrations

Question 4

what does drug metabolism act to do?

Answer 4

convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney from the renal tubules allowing them to be excreted
also converts drugs to metabolites which are usually pharmacologically less active than the parent compound

Question 5

less often, metabolism converts drugs to metabolites which do what?

Answer 5

metabolites which may be converted from inactive prodrugs to active compounds or gain activity
metabolites which have unchanged activity
metabolites which possess a different type or spectrum of action

Question 6

what is the main organ of drug metabolism?

Answer 6

liver

but the GI tract, lungs and plasma also have activity

Question 7

drug metabolism often proceeds in 2 sequential phases, what happens in phase 1?

Answer 7

catabolic phase
involves oxidation, reduction and hydrolysis
makes drug more polar, adds a chemically reactive group which permits conjugation

Question 8

what happens in phase 2?

Answer 8

anabolic phase
involves conjugation
adds an endogenous compound increasing polarity allowing it to be excreted through the kidneys

Question 9

what is cytochrome P450?

Answer 9

part of monooxygenase family
haem protein located in endoplasmic reticulum of liver hepatocytes (and elsewhere) mediating oxidation reactions in phase 1 of drug metabolism of many lipid soluble drugs

Question 10

other types of cytochrome P?

Answer 10

74 types classified as CYP on basis of amino acid sequence similarities
types of CYP defined by gene family, gene subfamily and individual gene

Question 11

describe the cytochrome P450 cycle

Answer 11

drug enters cycle as drug substrate (RH)
molecular oxygen provides two atoms of oxygen
one atom of oxygen is added to the drug to yield the hydroxyl product ROH
ROH leaves the cycle and the second oxygen combines with protons to form H20

Question 12

what reactions occur in phase 2?

Answer 12

conjugation of chemically reactive groups (e.g hydroxyl, thiol or amino) with glucuronyl, sulphate, methyl or acetyl groups
glucuronidation is common reaction involving transfer of glucuronic acid to electron -rich atoms of the substrate

Question 13

why is paracetamol toxic in high doses?

Answer 13

relates to altered metabolism of paracetamol when in high doses
in normal levels its metabolised to glucoronate and a sulphate but in overdose these processes are saturated and P450 mixed function oxidases produce a toxic metabolite (N acetyl-p-benzoquinone-imine)

Question 14

how can N acetyl-p-benzoquinone-imine (NAPBQI) inactivated?

Answer 14

conjugation with glutathione but if toxic dose depletes the glutathione stores then the NAPBQI interacts with cellular proteins causing hepatocellular necrosis and more rarely renal tubular necrosis

Question 15

how is paracetamol poisoning treated?

Answer 15

can possibly give activated charcoal orally if within 1hr of ingestion
if within 4 hrs then determine plasma concentration to determine likelihood of liver damage
if plasma concentration is above normal treatment line then administer antidote N acetylcysteine (NAC) by IV Infusion

Question 16

how does NAC work in paracetamol poisoning?

Answer 16

increases synthesis of glutathione permitting increased conjugation and elimination of NAPBQI

Question 17

3 basic processes involved in renal excretion of drugs?

Answer 17

glomerular filtration
active tubular secretion
passive reabsorption by diffusion across the tubular epithelium

Question 18

glomerular filtration occurs freely for which drugs?

Answer 18

those with molecular weight <20,000 provided they aren’t bound to large plasma proteins (only unbound drug molecules can enter filtrate by glomerular filtration)

Question 19

how is clearance by glomerular filtration calculated?

Answer 19

GFR X fraction of drug unbound in plasma (Fup)

GFR usually 120

Question 20

how much of renal plasma flow is filtered through glomerulus?

Answer 20

20%

other 80% delivered to peritubular capillaries of proximal tubule

Question 21

how are drugs actively secreted into the lumen of the nephron at the proximal tubule?

Answer 21

via 2 independent transporter systems

• organic anion transporter (OAT) - handles acidic drugs and the marker for renal plasma flow (PAH)
• organic cation transporter (OCT) - handles basic drugs

Question 22

most effective mechanism for drug elimination?

Answer 22

tubular secretion

Question 23

how does the OAT work?

Answer 23

at the basolateral membrane organic anions (OA) enter the cell by either diffusion or in exchange for alpha-ketoglutarate via OATs
a-KG is transported into cell against concentration gradient via Na+ dicarboxylase transporter
at the apical membrane, OA enters the lumen via either multidrug resistance protein 2 (MRP2) or OAT4 (in exchange for a-KG)

Question 24

how do OCTs work?

Answer 24

at the basolateral membrane, organic cations (OCs) enter the cell either by diffusion or OCT (both against concentration gradient and driven by negative potential of cell interior)
at the apical membrane, OC enters the lmen via either multidrug resistance protein 1 (MRP1) or OC/H+ antiporters (OCTN)

Question 25

how much water filtered at glomerulus is reabsorbed

Answer 25

99%

Question 26

how are drugs reabsorbed across distal tubule?

Answer 26

concentration of urine favours passive reabsorption via diffusion

Question 27

what factors influence reabsorption?

Answer 27

lipid solubility (drugs with high lipid solubility will be extensively reabsorbed and excreted slowly)
polarity (highly polar drugs will be excreted without reabsorption)
urinary flow rate (diuresis decreases reabsorption)
urinary pH (degree of ionisation of weak acids and bases can strongly influence their reabsorption)

Question 28

how does urinary pH influence reabsorption

Answer 28

alkaline = increases excretion of acids
acidic = increases excretion of bases
(e.g urinary alkalinisation can be used to accelerate the excretion of aspirin which is acidic in cases of overdose)

Question 29

how can tubular secretion of drugs concentrate drugs in the tubular fluid against an electrochemical gradient?

Answer 29

through carrier proteins

saturable process so each carrier protein has a transport maximum (Tm) for a particular drug

Question 30

how can drugs that are highly protein bound be secreted at the renal tubules?

Answer 30

free drug concentration is reduced by first round of secretion which establishes new equilibrium between bound and free drug
free drug concentration is further reduced by another round of secretion which causes additional drug to dissociate from protein

Question 31

5 examples of things which are secreted via OATs?

Answer 31

penicillins
probenecid 
acetazolamide/furosemide/thiazides
uric acids
glucuronic acid, glycine and sulphate conjugates of phase 2 metabolism

Question 32

3 examples of drugs secreted via OCTs?

Answer 32

morphine
neostigmine
amiloride, triamterene

Question 33

possible problem with different drugs sharing the same transporter system?

Answer 33

the drugs may compete with each other for secretion leading to interactions

e. g - probenecid can retard excretion of penicillin
e. g - frusemide and thiazides may retard excretion of uric acid causing gout