Pharmacology Part 5 Flashcards
How do most drugs leave the body?
In the urine as unchanged compounds or chemically transformed compounds rendered more polar by metabolism
What other ways can drugs be excreted?
Bile
Sweat
Milk
What is a xenobiotic?
a drug
What does drug metabolism act to do?
Convert parent drugs into more polar metabolites that are not reabsorbed by the kindney
Convert into metabolites that are pharmacologically less active
What may occasionally happen to metabolites in drug metabolism?
Be converted from inactive prodrugs to active compounds or gain activity
have unchanged activity
possess a different type, or spectrum of action (aspirin and its metabolite salicylic acid
What is the main organ of drug metabolism
Liver
GI tract, lungs and plasma also have activity
What are the two sequential phases of drug metabolism
Phase I
-makes drug more polar, adds chemically reactive group permitting conjugation
Phase II
Adds an endogenous compound increasing polarity
What are the processes involved in phase I
Oxidation
Reduction
Hydrolysis
What are the processes involved in phase II
Conjugation with glucuronyl, sulphate, methy, acetyl, glycol or gluthione
Describe the phases of aspirin metabolism
Phase I (Catabolic) Drug to derivative (aspirin to salicylic acid)
Phase II
(anabolic) Derivative to conjugate (salicylic acid to glucuronide)
What mediates oxidation reactions (Phase I) of drug metabolism of lipid soluble drugs?
Haem proteins located in the endoplasmic reticulum of liver hepatocytes (and elsewhere)
What is the CYP family classified by?
on the basis of amino acid sequence similarities
What do CYP family have in common in terms of function?
distinct, but frequently overlapping substrate specificities
What are the main gene families in the human liver?
CYP1, CYP2 and CYP3
Describe the monooxygenase P450 cycle?
Drug enters the cycle as substrate
Molecular oxygen provides two atoms
One atom of oxygen is added to the drug to yield the hydroxyl product- which leaves the cycle- the second combines with protons to form H2O
What do phase II reactions produce and where do they occur?
Inactive products
In the liver
What is glucoronidation?
common reaction involving the transfer of glucuronic acid to electron-rich atoms of the substrate (N, O, or S, forming amide, ester, or thiol bonds))
Which endogenous substances undergo glucoronidation?
bilirubin, adrenal corticosteroids
What is significant about clearance of phase I and phase II products
Almost always cleared from blood quicker than parent compound
What are the three processes involved in renal excretion?
- glomerular filtration
- active tubular secretion
- passive reabsorption by diffusion across the tubular epithelium
For what drugs does glomerular filtration occur freely?
MW less than 20000, provided they are not bound to large plasma proteins
What is unimportant in glomerular filtration
Drug charge
What happens if drug binds appreciably to plasma protein?
GFR will be less than total plasma concentration
What % of renal plasma flow is directed through the glomerulus vs the peritubular capillaries of the proximal tubule?
20%
What two transporter systems are found in the proximal tubules?
Organic anion transporter
Organic cation transporter
What is the role of OAT and OCT
Actively secrete drugs into the lumen of the nephron
What does the AOT handle?
Acidic drugs, endogenous acids and the marker for renal plasma flow (PAH)
What does the OCT handle?
Basic drugs
What is the most effective mechanism of drug elimination by the kidney?
Tubular secretion
What is special about tubular secretion of drugs?
Can concentrate drugs in tubular fluid agains electrochemical gradient
What kind of process in tubular secretion?
Saturable- each carrier has a transport maximum for a particular drugs
What occurs in tubular secretion that cannot in GF?
Can secrete drugs that are high protein bound
What might some drugs sharing a transporter system cause?
compete with each other for secretion leading to interactions, e.g:
- Probenecid has been used to retard the excretion of penicillins
- Frusemide and thiazides may retard the excretion of uric acid and precipitate gout
What percentage of water filtered at the glomerulus is reabsorbed?
99%
What does concentration of urine favour?
Passive reabsorption of drugs across the distal tubule by diffusion
What factors affect reabsorption rate?
> 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 – the degree of ionisation of weak acids and bases can strongly influence their reabsorption
What does alkaline pH do to excretion?
Increases excretion of acids
What does acidic pH do to excretion ?
Increases excretion of bases
What is the clinical relevance on urinary alkalisation?
can be used to accelerate the excretion of aspirin (weak acid) in cases of overdosage
