Flashcards in Pharmacology 4 - Elementary drug metabolism Deck (43):
What most drugs leave the body in?Where else are drugs excreted via? (3)
Urine (excretion via the bile is occasionally significant + minor contributions via exertion via the sweat or milk)
What kind of molecule must drugs be to be excreted by the body? Why?
PolarSo that they can be regularly reabsorbed by the kidney facilitating excretion
What is a xenobiotic?
A foreign chemical substance that is found within an organism that is not naturally produced by or expected to be present within that organism
What does metabolism usually do in terms of rendering the activity of the drug?What are 3 other things that metabolism less rarely does to drug activity?
Usually make the drug less pharmacologically activeConverts them from inactive to active compounds or gain activityHave unchanged activityPossess a different type, or spectrum of action
What is an example of a drug that gains activity during metabolism?
Codeine to morphine
What is an example of a drug that has unchanged activity after metabolism?
Diazepam to nordiazepam
What is an example of a drug that possess a different type, or spectrum, of action after metabolism?
Aspirin (anti-inflammatory and andti-platelet) to salicylic acid (anti-inflammatory with no anti-playlet activity)
What is the main organ of drug metabolism?What other places have metabolism activity? (3)
How many steps does drug metabolism usually have?
2 sequential steps
What is the purpose of phase 1 drug metabolism?
To make the drug more polar and also to add a chemical "handle" permitting conjugation during phase 2
What are the 3 things involved in phase 1 drug metabolism?
What is the purpose of phase 2 drug metabolism?
To add an endogenous compound increasing polarity for excretion
What is the 1 thing involved in phase 2 drug metabolism?
Conjugation(some drugs skip straight to phase 2 whilst some drugs are excreted unchanged)
What are examples of the chemicals that are drugs are conjugated with during phase 2 drug metabolism?
What are the 2 phases of drug metabolism of aspirin (acetylsalicylic acid)?
Aspirin is converted to salicylic acid (OH added) before being converted to the conjugate (glucuronide) during phase 2
What are the cytochrome P450 (CYP) family of monooxygenases?
Haem porteins located in the endoplasmic reticulum of liver hepatocytes (and elsewhere) mediating oxidation reaction (phase 1) of many lipid soluble drugs
How many gene families is the Cytochrome P450 family of monooxygenases made up of?
74 gene families - it is a superfamily
what are the main 3 gene families in the liver?
What are 3 examples of common cytochrome P450s?
CYP3A4 - accounts for 50% of metabolism of all presciription drugsCYP2D6CYP2C
What are the basics of what happens in the monooxygenase P450 cycle?
Drug enter the cycle as a drug substrate, RHMolecular oxygen (O2) provides 2 atoms of oxygenOne atom of oxygen is added to the drug to yield the hydroxyl product (ROH) which leaves the cycle The second oxygen combines with protons to form H2Othis is mediated by monooxygenases
In phase 2 reactions, what type of groups on the drugs are the endogenous molecules commonly added to?
Chemical reactive groups e.g. hydroxyl (OH), thiol (SH) or amino (NH2)
What is a common reaction in phase 2 that tends to detoxify most drugs?
What does glucuronidation commonly involve?
The transfer of glucuronic acid to electron-rich atoms on the drug (such as N, O or S ) forming amide, ester or thiol bonds
what enzyme mediates glucuronidation?
what are 2 endogenous substances that are subject to glucuronidaiton?
Give an example of a drug that is excreted by the kidneys very fast and drugs that are excreted by the kidneys very slowly?
Penicillin = extremely fastDiazepam = extremely slow
What are the 3 basic processes by which the kidney filters?
Glomerular filtrationActive tubular secretionPassive reabsorption by diffusion across the tubular epithelium
What drugs are freely filtered during glomerular filtration?
Drugs with a MW less than 20000 (most) provided they are not bound to large plasma proteins (which are not filtered)*drug charge is unimportant
How do many drugs exist in the blood?
In an equilibrium between unbound and protein-bund forms e.g. albumin (only unbound drugs can enter the filtrate via glomerular filtration)
What is the equation for clearance by filtration?
CL(fil) = GFR x fraction of drug unbound in plasma (fup)
What is GFR?
The glomerularfiltration rate (normally 120ml min-1)
What are the names of the 2 independent transporter systems that are present in the epithelial cells of the proximal tubule that actively secrete drugs into the lumen of the nephron?
Organ anion transport (OAT)Organic cation transporter (OCT)
What does the organic anion transporter handle? (3)
Acidic drugs (e.g. penicillins)Endogenous acids (e.g. uric acid)The marker for renal plasma flow (i.e. para-aminohippuric acid)
What does the organic cation transporter handle?
Basic drugs e.g. morphine
What of the 3 mechanisms for drug elimination by the kidney is the most effective?
Excretion by tubular secretion e.g. benxylpenicillin and PAH
How is the rate at which a drug is secreted from the body related to the concentration of the drug?
They are linearly related (as plasma concentration of drug increases, the rate of excretion also increases)
Are the transporters across the epithelial cells of the proximal tubule able to become saturated?
Yes - each carrier has a transport maximum (Tm) for a particular drug
How can drugs that are highly protein-bound be secreted?
By tubular secretion
How can frusemide and thiazides lead to gout?
They are both excreted by the same tubular transporter system as uric acid meaning they can compete with the transport system leading to a build up of uric acid
Why are drugs passively reabssrobed across the distal tubule by diffusion?
Concentration of the urine favours this
What are the factors that influence drug reabsorption? (4)
Lipid solubility (drugs with high lipid solubility will be extensively reabsorbed and excreted slowly)Polarity (highly polar drugs will be excreted without reabsorption)Urine flow rate (diuresis decreases reabsorption)Urinary pH
How does alkaline and acidic pH affect the excretion of acidic and alkaline drugs?
Alkaline pH = increases excretion of acidsAcidic pH = increases excretion of bases