Lecture 9: Pharmacokinetics III Drug elimination Flashcards
Drug elimination
-Irreversible loss of drugs from the body
- It occurs by 2 processes:
-> Metabolism: enzymatic conversion of one chemical entity to another within the body.
-> Excretion:
elimination from the body of drug, or drug metabolites.
There are drugs that leave in the same state/way but most of the drugs to be excreted have to be metabolized
Main routes of drug elimination
- The kidneys: most drugs leave the body in the urine, either uncharged or as polar metabolites.
- The hepatobiliary system: some drugs are secreted into bile via the liver, but most of these are then reabsorbed from the intestine (there are exceptions)
- The lungs: important for volatile/gaseous anaesthetics.
- Excreted with milk or sweat (minor amounts): could have effects on the baby if breastfeeding.
Main types of drug metabolism (biotransformation)
Drug metabolism: evolved as a defence system against plant toxins.
-Lipophilic substances not eliminated efficiently by the kidney -> need to be metabolized to more polar products and then excreted in urine.
2 kinds of reactions phase I and phase II
Phase I reactions:
-General characteristic
-P450 monooxygenases
-other reactions
-Reactions are catabolic (oxidation, reduction or hydrolysis)
-Products often more reactive + toxic or carcinogenic than the parent drug.
-Reactions often introduce a reactive group, this group then serves as the point of attack for the conjugating system of Phase II to attach a substituent such as glucuronide.
-Both phases decrease lipid solubility, ^ renal elimination.
-Some drugs administered in inactive (prodrug) for; altered metabolically by Phase one reactions to active the drug.
-Take place mainly in liver.
- to reach metabolizing enzymes, drug must cross the plasma membrane.
-> Polar molecules do this less readily than non-polar molecules except where there are specific transporters.
Reactions involve oxidation, reduction and hydrolysis. They:
- usually form more chemically reactive products, which can be pharmacologically active, toxic or carcinogenic.
- often involve a monooxygenase system in which cytochrome P450 plays a key role.
Induction of P450 enzymes can greatly accelerate hepatic drug metabolism. It can increase the toxicity of drugs with toxic metabolites. It can lower effective plasma concentration of drugs.
Other Phase I reactions:
- Alcohol dehydration: in addition to CYP2E1, metabolises ethanol.
- Xanthine oxidase
- Monoamine oxidase: inactives biologically active amines.
- Reductive reactions: less common than oxidations.
- Hydrolytic reactions: (aspirin) do not involve microsomal enzymes but occur in plasma and tissues.
Phase II reactions:
-General characteristics
-Reactions are synthetic (‘anabolic’) and involve conjugation (attachment of chemical moieties to a drug or to a metabolite resulting from phase I metabolism)
-Both phases decrease lipid solubility, ^ renal elimination.
Take place mainly in liver.
- to reach metabolizing enzymes, drug must cross the plasma membrane.
Reactions involve conjugation (glucuronidation) of a reactive group (often inserted during phase I reaction) and usually leads to inactive and polar products that are readily excreted.
bioactive metabolites
- Metabolites may have pharmacological actions similar to those of the parent compound (benzodiazepines) and they may be toxic (acetaminophen, methanol)
prodrugs
inactive precursors that are metabolized to active metabolite. Converts to active form in body.
- Some drugs become active after they have been metabolised (clopidogrel) these are prodrugs. (drug has to go through BBB to become active) and designed to overcome problems of drug delivery.
microsomal enzyme induction
A # of drugs, such as ethanol increase the activity of microsomal oxidase and conjugating systems when administered repeatedly.
-Many carcinogenic chemicals also have this effect called induction which is result of:
- increased synthesis and/or
-reduced breakdown of microsomal enzymes.
Define Stereospecificity of drugs; first-pass (pre-systemic) metabolism; and enterohepatic recirculation of drugs
FIRST-PASS (PRE-SYSTEMIC):
- extracted efficiently by the liver or gut wall; amount reaching systemic circulation less than amount absorbed.
- reduces bioavailability
- Presystemic metabolism important for aspirin, levodopa, propranolol, morphine.
- When administered by mouth
- much larger dose needed per os (than IV)
ENTEROHEPATIC RECIRCULATION OF DRUGS:
- Liver cells transfer various drugs from plasma to bile by means of transport that involve P-glycoprotein.
- Hydrophilic drug conjugates (Particularly glucuronides) are concentrated in bile and delivered to intestine, the glucuronide is hydrolysed, releasing active drug once more; free drug can then be reabsorbed and the cycle repeated.
-Morphine
Renal clearance
- Most drugs, unless highly bound to plasma protein, cross the glomerular filter freely.
- weak acids and weak bases are actively secreted/ rapidly excreted.
- Lipid-soluble drugs passively reabsorbed by diffusion across the tubule.
Characterize & compare three fundamental processes that account for renal drug excretion
- Glomerular filtration: glomerular capillaries allow drug molecules of molecular weight below about 20,000 Da to diffuse into the glomerular filtrate. (cannot be excreted by urine)
- Active tubular secretion:
Up to 20% of renal plasma flow is filtered through the glomerulus leaving atleast 80% if delivered drug to pass on to the peritubular capillaries of proximal tubule.
Molecules transferred by 2 independent and non-selective carrier systems.
-1- transport acidic drugs (endogenous uric acid)
-2- transport organic bases. - Passive reabsorption: diffusion from the concentrated tubular fluid back across tubular epithelium.
99% of water reabsorbed
Lipid-soluble drugs are excreted poorly. - excreted in urine.
