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Medsci 204 > ADME > Flashcards

ADME Flashcards

1
Q

What does ADME stand for?

A

Absorption
Distribution
Metabolism
Excretion

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2
Q

What happens to a drug concentration between the site of administration and the site of action and why?

A

The concentration decreases due to binding to plasma proteins, storage in tissues, metabolism, biliary secretion and renal excretion.

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3
Q

What physiochemicaly properties of drugs influence their ‘ADME’?

A

Solubility in lipids and H20 (non-polar or ionised), which is important for absorption, distribution and excretion.
Chemical structure influences susceptibility to metabolism.

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4
Q

What are the three major organs (and 1 minor organ) involved in ADME, and what process are they involved in?

A
  1. GI tract (absorption)
  2. Liver (metabolism)
  3. Kidney (excretion)
  4. Lungs (absorption and excretion of volatile anaesthetic gases)
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5
Q

What characteristics of the biological membrane influence drug solubility, and how?

A

The membrane is permeable to lipid soluble drugs. Small, uncharged and lipid soluble molecules will distribute faster and more widely than bulky, ionised, less lipid soluble drugs.

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6
Q

List the four main mechanisms of transport across biological membranes:

A
  1. Transcellular diffusion
  2. Facilitated diffusion
  3. Active transport
  4. Endocytosis
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7
Q

Describe passive diffusion:

A

Most important mechanism and applies to non-polar, lipid-soluble drugs. Concentration gradient is the driving force, so no energy is required.

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8
Q

Describe facilitated diffusion:

A

For a few drugs movement occurs faster than predicted and appears to depend on an oscillating carrier protein. This depends on the concentration gradient so no energy is required.

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9
Q

What are the usual substrates for facilitated diffusion (and example)?

A

Sugar and amino acids, not so important for drugs e.g. tetracycline diffusion into bacteria.

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10
Q

Describe active transport:

A

This proceeds against a concentration gradient and requires energy. This can become saturated and is specific to organs or the liver, kidney, BBB and gut epithelium.

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11
Q

What does active transport allow the cell to do?

A

Accumulate compounds essential for growth (such as amino acids, vitamins, sugar, methoxtrexate and glucuronides).
Remove waster products.
Protects against toxins.

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12
Q

Describe endocytosis and the three steps involved:

A

Internalisation of large molecule by cell mainly for drugs with a molecular weight greater than 1000 e.g. cytokines, hormones, growth facyors, immunoglobulins, nanoparticles.

  1. Substrate binds to receptor.
  2. Invagination of receptor-substrate complex.
  3. Budding off and delivery of vesicle into cell.
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13
Q

Describe filtration and the two places it occurs:

A 
This occurs for drugs which cannot cross biological membranes.
Blood capillaries- contain fenestrations that allows rapid interchange between blood and intestinal fluid.
Glomerular capillaries (kidney)- extremely porous allowing passage of all plasma constituents except macromolecules with molecular weights greater than 30,000.
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14
Q

Define drug absorption:

A

This is the passage of the drug from the site of administration into the general circulation.

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15
Q

What is the difference in absorption between IV and oral drug administration?

A

IV- 100% absorbed immediately.

Oral- Several barriers, absorption not 100% (delayed and incomplete).

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16
Q

Define the rate of absorption:

A

How rapidly the drug gets from the site of administration to the general circulation.

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17
Q

Define the extent of absorption:

A

How much of the administered dose enters the general circulation (% bioavailability=F).

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18
Q

How can rate and extent be shown graphically?

A

Drugs must have a high enough rate and extent to reach a minimum therapeutic level and have an effect. Graphing plasma concentration (mg/L) against time (hours).

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19
Q

What are the two routes by which drugs can be administered?

A

Enteral (GI tract)

Parenteral (all others)

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20
Q

Name the enteral ways by which drugs may be administered:

A

Oral (po), sublingual and rectal.

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21
Q

Name the parenteral ways by which drugs may be administered:

A

IV, subcutaneous, intradermal, intramuscular and lungs.

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22
Q

What are the differences in IV and oral administration methods in relation to rate and extent of absorption?

A

IV- rate is immediate and extent is 100%

Oral- rate is gradual and extent is incomplete

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23
Q

What are the advantages of IV administration

A

Very rapid, precise contraol (100% bioavailable), avoids problems of absorption, or drug breakdown before entering the blood. This is good for drugs which are too irritating to be taken by mouth or by tissue injection (e.g. anti-cancer drugs).

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24
Q

What are the disadvantages of IV administration?

A

Skill is required for administration, careful preparation of injected material in a sterile sense and hazardous as there is no recall of incorrect administration, dosage.

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25
Q

What are the advantages of oral (po) administration?

A

This is the more common route as it is the safest, most convenient and economic method.

26
Q

What are the disadvantages of oral (po) administration?

A

Slow (1/2 to 3 hours) for effect, unpredictable with regard to rate, extent and reproducibility.

27
Q

What four steps does a drug tablet pass through once entering the stomach, and what happens to the remainder?

A
  1. Disintegration (drug particles exposed to gut fluids)
  2. Dissolution (drug dissolved in gut fluids)
  3. Absorption (drug dissolved in portal blood)
  4. Metabolism (variable fraction destroyed by liver enzymes)

The remainder is available for distribution to tissues (bioavailability).

28
Q

Describe some features influencing the oral bioavailability of drugs:

A

Decomposition in acidic gastric juices, decomposition by hydrolytic gut enzymes, degradation by gut microorganisms, food in the gut, metabolism by gut wall enzymes, metabolism by liver before reaching systemic circulation.

29
Q

What are the three main patient factors influencing absorption?

A

Stomach emptying rate.
Intestinal motility.
Interactions with food.

30
Q

How does stomach emptying rate determine the rate of absorption?

A

Rate increases with hunger, mild exercise, metaclopramide (vomiting).
Rate decreases with hot meals, vigorous exercise, pain, migrane, labour and drugs (narcotics, anticholinergics, tricyclic antidepressants).

31
Q

How does intestinal motility influence absorption?

A

Increased motility due to gastroenteritis and diarrhoea lead to decreased transit time which is important for drugs with low H2O solubiltiy such as digoxin and OCs which reduce bioavailability.

Decreased motility by various drugs such as narcotics, anticholinergics, tricyclics.

32
Q

How does food in the gut influence absorption?

A

Food in the gut can interact with the drugs such as chelation of tetracycline with metal ions such as Ca2+, Al3+ or Fe2+. This is how milk can reduce bioavailability.

33
Q

How is capillary permeability different in the brain?

A

The brain capillaries have no pores and have a layer of glial cells to form the blood-brain-barrier so only lipid soluble drugs diffuse across brain capillaries unless they undergo active transport.

34
Q

Describe how body fluid is compartmentalised:

A

There is 3L in plasma, 11L in extracellular fluid and 28L in intracellular fluid. H2O soluble drugs are restricted to the extracellular fluid and plasma (14L). Lipid soluble can move into the intra-cellular fluid also.

35
Q

How is drug distribution related to blood flow?

A

The tissue that receives more blood receives more drugs. The heart, lungs, brain, liver and kidney receive drug very rapidly, while there is a slower rate to less well perfused organs, such as muscle, skin and fat.

36
Q

Name the major sites of drug metabolism:

A

Liver (major), GI tract (gut bacteria and proteases), intestinal wall (CYPs), plasma (esterases e.g. acetylsalicylate) and specialised tissues (monoamine oxidases in nerve endings).

37
Q

What effects do metabolising enzymes have on drugs:

A

This makes the drug more H2O soluble, so it is less likely to diffuse into cells to reach receptors. This favours increased excretion in urine or bile. This usually abolishes activity and terminates drug action.

38
Q

What are three exceptions to drug metabolism abolishing drug activity and give examples?

A

Prodrugs can promote activity e.g acetylsalicylate, zidovudine.
No change in activity e.g. diazepam to noradiazepam.
Produce toxic metabolites e.g paracetamol.

39
Q

What are phase 1 and phase 2 drug metabolism reactions?

A

Phase 1- addition or uncovering of a reactive group.

Phase 2- conjugation of endogenous molecule with drug.

40
Q

Describe phase 1 metabolism reactions:

A

Oxidation, reduction and hydrolysis to make the molecule more susceptible to phase 2 reactions.

41
Q

Describe phase 2 metabolism reactions:

A

Glucuronide, sulphate, amino acids (GSH) and acetylation/methylation make the molecule more polar and ideals the substrate for active transport and secretion.

42
Q

What is the most important reaction in phase 1, and the most important class of enzymes involved in this?

A

Oxidation.
Cytochrome P450 dependent mixed function oxidase system located on the smooth endoplasmic reticulum. CYP1, CYP2 and CYP3 encode enzymes involved in drug metabolism.
It requires O2, NADPH and cytochrome P450 reductase.

43
Q

Chemically display the oxidation reaction:

A

Drug + O2 + H+ + NADPH —> Oxidised drug + H2O + NADP+

44
Q

Describe the metabolism of phenytoin:

A

The highly lipophilic drug undergoes phase 1 via hydroxylation by CYP to form a slightly water soluble drug which is inactive.

Phase 2 occurs with conjugation by UDP glucuronosyl transferase to produce a very water soluble drug, with a much larger molecular weight due to UDP attachment.

45
Q

Do all drugs undergo pahse 1 and phase 2 reactions in metabolism?

A

Some drugs may avoid phase 1 if they already have the OH group present.

46
Q

List some personal factors influencing drug metabolism:

A 
Organ function (liver, kidney, heart, gut)
Age, sex and pregnancy
Diet, cigarettes, alcohol
Diseases and other drugs
Patient- genetic constitution
47
Q

Describe the effect of age on drug metabolism, and what is an exception of this?

A

There is a slight decrease in metabolism with age, but not a huge range.
Propranolol is cleared faster in men (greater metabolism).

48
Q

How does theophylline dosing and half-life in different populations vary?

A

In premature neonates half life is 30-60 hours, so the maintenance dose (mg/kg/day) must be low (2).

In children half life is 2-4 hours so dose must be high due to rapid metabolism (17).

In adults, half life is 6-10 so dose must be lower (9) to maintain.
In smoking adults half life is 4-6 so dose must be higher (14) to maintain.

49
Q

How is metabolism induced in the body?

A

Enzyme synthesis is initiated within 24 hours of exposure, which increases over 3-5 days.
Effect decreases over 1-3 weeks after inducing agent is discontinued.

50
Q

What other factors may induce drug metabolism?

A

Environmental factors- Smoking, BBQ meat, cruciferous veges, high protein diet, ethanol, exposure to insecticides and PCBs.

Other drugs- Barbituates, phenyoin, rifampicin, St John’s wort.

51
Q

How is metabolism inhibited in the body?

A

Rapid onset within 1 day with an exaggerated response with increased risk of toxicity.

52
Q

What are some factors which inhibit drug metabolism?

A

Reversible inhibitors (mainly competitive) such as cimetidine, ketoconazole, quinolone antibiotics, HIV protease inhibitors, grapefruit juice.

Heavy metals (complex with CYP) include lead, cadium and mercury.

53
Q

What is the outcome of a standard dose of most drugs in a patient population?

A

20% will have no response (very efficient metabolites).
50-60% will get some therapeutic benefit.
20% will get adverse effects (low capacity to metabolise leading to toxic build up).

54
Q

Define drug excretion:

A

This process whereby compounds are removed from the body to the external environment.

55
Q

Name the three sites of drug excretion:

A

Kidney- most important.

Biliary excretion- important for some drugs, usually molecular weight greater than 400 and ionised e.g. glucuronides (MW + 177).

Lungs- e.g. anaesthetic gases.

56
Q

What role does the kidney play in drug excretion?

A

It has a significant role in regulating volume and composition of body fluids, conserves essential substances and removes waste products.

It has specialised transport systems e.g. electrolytes, glucose and amino acids.

Removes H2O soluble drugs and metabolites (depends on physico-chemical properties).

57
Q

What are the three main mechanisms by which drugs are excreted from the kidney?

A
  1. Glomerular filtration of unbound drug, rate (GFR) about 130mL/min in healthy adult, 10% of renal blood flow (20% plasma).
  2. Active secretion of both free and protein-bound drug by transporters:
    anions- urate, penicillin, glucuronide and sulphate conjugates
    cations- choline, histamine, basic drugs e.g. amines
  3. Filtrate 100-fold concentrated in tubules for a favourable concentration gradient for reabsorption by passive diffusion.
58
Q

Describe the renal excretion of benzylpenicillin (BP):

A
  1. 35% BP free and available for filtration; 20% of plasma filtered leads to 7% BP filtered.
  2. Active secretion by acid pump of free and bound BP.
  3. No passive reabsorption, as BP is ionised in urine.
  4. Little or no drug in blood stream.
    Clearance of BP about 600mL/min, similar to renal plasma flow.
59
Q

What features influence renal drug excretion in an individual?

A

Gender (female 80% renal function of males), age (decreases 10% every decade), pregnancy (renal function increases 50%) and disease (renal disease and heart failure reduce blood flow to kidneys).

60
Q

Why is creatine clearance used as an index of kidney function?

A

Because it is an endogenous compound produced in catabolism of muscle which is not actively secreted/absorbed, only glomerularly filtered.

61
Q

What factors can influence the renal excretion of drugs?

A

Competitive inhibition of tubular secretion e.g. renal clearance of penicillin decreases 90% by probenecid.

Sodium bicarbonate alkalinises urine, so increased pH and ionisation of weak acids (e.g. salicylate and methotrexate), reabsorption leads to increased excretion.
Ammonium chlordide acidifies urine to enhance excretion of basic drugs (e.g. amphetamines).

Increased urinary flow dilutes drug concentration in tubule which decreases the concentration gradient for passive readsorption of drug, leading to enhanced excretion. Dehydration has the opposite effect.

62
Q

How can pH influence urinary excretion of methamphetamine:

A

Treatment with ammonium chloride makes urine acidic to increase excretion.
Taking baking soda makes urine more alkaline to decrease excretion and prolong drug effect.

Medsci 204 (8 decks)

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