Drug elimination Flashcards

Question

Other phase 1 enzymes

Answer 1

Aspirin esterase Alcohol dehydrogenase Butrylcholinesterase CYP450s

Answer 2

``` Aka Plasma Cholinesterase Hydrolyses Suxamethonium Structurally similar to Ach Overactivates cholinergic receptors on muscles to cause paralysis Neuromuscular blockers ```

Answer 3

Aka Acetylsalicylate deacetylase | In plasma, hydrolyses aspirin to salicylate

Answer 4

In liver cell (hepatocyte) cytoplasm Oxidases ethanol to acetaldehyde Requires NAD+

Answer 5

Anabolic - make up If drug has reactive group either in the parent molecule or product of phase 1 Usually occurs in liver but also lung/kidney Product usually inactive PRODRUGS

Answer 6

Attachment of a substituent group

Answer 7

Catabolic - break down Functionalisation Introduction of reactive group. Products more reactive and sometimes more toxic

Answer 8

Inactive drug -> Active drug Diacetyl-morphine -> Morphine Valacidovir -> Aciclovir L-Dopa -> Dopamine

Answer 9

Mass transport in gut = faeces Water soluble, filtered out by kidney = urine Volatile gases = exhaled air Secreted into glands = sweat and breast milk

Answer 10

Physiochemical properties of drugs and metabolites

Answer 11

Sum of all organ CL processes. | Volume of plasma or blood cleared of the drug per unit of time to achieve overall elimination of drug from the body.

Answer 12

Plasma drug concentration

Answer 13

Initial drug concentration

Answer 14

Total clearance (CLtot) / Volume of distribution (Vd)

Answer 15

Volume of blood required to contain drug at plasma concentration

Answer 16

t1/2 = Ln2 / Kel (On Log Scale) Time taken for plasma drug concentration to reduce by half In regards to steady state, 4-5 half-lives are needed to reach the point at which drug accumulation and elimination are balanced.

Answer 17

Kidneys Hepato-biliary system Lungs

Answer 18

Most common conjugation reaction Important for both endogenous compounds (EG Bilirubin) and exogenous compounds Mediated by UDP-glucuronyl transferases Due to their polar nature, glucuronides are usually inactive and rapidly excreted

Answer 19

Mainly by conjugation with sulphate and glucuronic acid. Only a minor proportion metabolised by CYP450 to a toxic metabolite (NAPQI). Toxic metabolite normally detoxified by glutathione

Answer 20

Pathways of conjugation are saturated and co-factors are depleted and as such more paracetamol is metabolised via CYP450. Toxic metabolites reacts with liver proteins instead of glutathione (depleted). Tissue damage occurs leading to hepatic necrosis.

Answer 21

Each member of a population will be described as either a fast or a slow metaboliser. Can have implications for therapeutic efficacy and/or toxicity of certain drugs

Answer 22

Normal enzyme activity Lower plasma conc of the parent drug Higher conc of the metabolite Generally normal therapeutic response

Answer 23

Low enxyme activity Higher plasma conc of the parent drug Lower conc of the metabolite May lead to exaggerated therapeutic response at normal doses

Answer 24

Individuals at extreme ages are affected. ``` Neonates (premature) - Low CYP and conjugating activity Glucuronyl transferase N-acetyltransferase Lack of use of morphine in labour ``` Elderly - CYP activity declines slowly with age More variability in half-life of many drugs Issues for drug development Increased half-life of diazepam (memory impairment)

Answer 25

Genetic constitution Age Disease

Answer 26

Exposure to chemicals represents an important factor in the perturbation of drug metabolising enzymes. These compounds either induce or inhibit drug metabolising agents. Induction and inhibition represents two important mechanisms by which drug interactions occur.

Answer 27

Drugs Smoking/alcohol Environment exposure (including diet)

Answer 28

An increased synthesis of enzymes (Phase 1 and 2). Results in increased metabolism of inducing agent (autoinduction). Different inducers induce different enzymes/isozymes. Smoking and ethanol (chronic exposure) both act as inducer. Drugs which act as inducers of drug metabolising enzymes often induce their own metabolism.

Answer 29

Inhibition of the CYP system is caused by many drugs. Reduced rate of metabolism and increased pharmacological effect. For a drug to produce its pharmacological effect, it should achieve adequate concentrations at the site of action. Basis of several drug-drug interactions. Ethanol acts acutely to inhibit drug metabolism.

Answer 30

20% of renal blood flow filtered through glomerulus. Drugs if MW <20,000 diffuse into glomerular filtrate. Plasma albumin (MW 68,000) almost completely held back. Lipid solubility and pH don't affect GH. Highly ppb drugs found at lower concentration in filtrate than in plasma. ppb is a barrier to glomular filtration

Answer 31

80% of renal blood flow passes the peritubular capillaries of the proximal tubule. Drug molecules transferred to tubular lumen by two carrier systems which can transport against an electrochemical gradient. Most effective method for drug elimination. ppb is not a barrier to carrier mediated transport. Many drugs share the same transporter which can lead to competition. Low specificty

Answer 32

Volume of urine = ~1% of the filtrate. Drug concentration increases as water is reabsorbed. Highly lipid soluble drugs have high tubular permeability and are slowly excreted. Highly water soluble drugs have low tubular permeability and concentrate in urine.

Answer 33

Decreased drug effectiveness on chronic exposure. Need to increase drug dose. In multiple drug therapy there may be problems when inducer is withdrawn from regimen. Basis of many drug-drug interactions. EG Rifampicilin and oral contraceptives

Answer 34

Acidic drugs accumulate in basic fluid compartments and visa versa. EG Aspirin is a weak acid (pKa = ~3.5) so can move through lipid membrane.

Answer 35

Volatile gases are eliminated by exhalation. Water soluble compounds are often eliminated to some degree unchanged in the urine. Also may be excreted in the bile. Lipid-soluble compounds typically undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile.

Answer 36

``` Elimination mechanisms (such as enzymes) are typically not saturated at therapeutic doses of drugs, although there are a few exceptions (ie phenytoin). Increasing dose will disproportionately increase concentration (linear to non-linear kinetics). Often described with michaelis-menten kinetics. ```

Answer 37

Many drugs are weak acids (proton donator) or bases (proton acceptor). Degree of ionisation changes with respect to pH of solution - dependent on pKa of drug. An orally administered basic compound with pKa 8.0 will be predominantly in ionised form in the stomach.

Drug elimination Flashcards

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