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Pharmacology > PK: Movement Across Cell Barriers & Ion Trapping > Flashcards

PK: Movement Across Cell Barriers & Ion Trapping Flashcards

1
Q

4 principles of pharmacokinetics

A

ADME

  1. Absorption
  2. Distribution
  3. Metabolism
  4. Excretion
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2
Q

What does endocytosis apply to

A

Large molecules

Drugs get engulfed

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3
Q

Formula for bioavailability

A
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4
Q

What does distribution depend on (5)

A
  1. Lipophilicity - a lipophilic drug will be distributed easier
  2. Blood flow e.g. brain vs skin
  3. Capillary permeability
  4. Plasma and tissue binding (albumin slows the process)
  5. Volume of distribution
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5
Q

Formula for Volume of Distribution

A
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6
Q

Principle of first order kinetics

A

Rate of elimination is proportional to the [drug] conc in the body

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7
Q

Zero order kinetics principle

Give an example

A

Amount of drug eliminated is independent of drug conc in the body

ie rate of elimination is constant

e.g. aspirin

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8
Q

Define steady state

A

Rate of administration = rate of elimination

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9
Q

What is the most important route of elimination

What challenge faces this route of elimination and how is it overcome

A

Kidney

Cannot get rid of lipid soluble drugs as they are passively reabsorbed

  • Liver turns lipophilic drugs into water-soluble substances that are easily removed by kidneys
  • 2 metabolic rxns do this In liver
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10
Q

Name the 6 INDUCERS of phase I of excretion in the liver

A

PCRABS

  • Phenytoin
  • Carbamazepine
  • Rifampin
  • Alcohol - chronic
  • Barbituates
  • St John’s Wort
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11
Q

Name the 7 inhibitors of phase I of elimination in the liver

A

GPACMAN

  • Grapefruit
  • Protease inhibitors
  • Azole anti-fungals
  • Cimetidine
  • Macrolides (except azithomycin)
  • Amiodarone
  • Non-DHP CCBs (dialtiazem and verapamil)
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12
Q

Overview of the 2 compartment model

A
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13
Q

What is one of the first barriers an oral medication must overcome

A

Epithelial lining of the GIT

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14
Q

What is the major barrier to drug transport

A

The hydrophobic core of a biological membrane

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15
Q

What are the compartments a drug can move through

A
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16
Q

What effect does the acidic environment of the stomach have on the ionised state of a drug

A
  • Acidic drugs remain unionised in the stomach due to the acidic environment of the stomach
  • Basic drugs cannot be absorbed so they pass into pyloric sphincter into SI and are absorbed there
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17
Q

Define first pass metabolism

A

Drugs travel to the liver via the portal system, where they are immediately metabolised

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18
Q

Define enterohepatic cycling

A

Some drugs are secreted back into the SI via bile

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19
Q

Why might not all the drug dose be absorbed

A

Molecules may bind to intestinal content, so they cannot pass through mucosal cells

While other may be broken down by bacterium in ileum and colon

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20
Q

oral dose vs IV dose

A
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21
Q

How does an oral drug get to site of action

A
  • Must cross the epithelial cell barrier that lines the GIT, and is then ABSORBED into blood
  • Then carried by blood to tissues (BULK FLOW) - crosses endothelial cell barrier from blood to tissue (DISTRIBUTION)
22
Q

Influence of chemical nature of drug on bulk flow

A

Irrelevant

23
Q

Influence of chemical nature of drug on diffusion

A

Diffusion depends on the drug

24
Q

Where is the epithelial barrier present

What does it consist of

A

At GI mucosa and renal tubule

Consists of cells tightly connected to each other

25
Q

What do CNS and placenta contain

A

An impermeable layer of periendothelial cells (pericytes)

26
Q

Name the 4 main ways a drug crosses the membrane

A
  1. By diffusing directly through lipid (main way)
  2. By combination with a transmembrane carrier protein that binds a molecule on 1 side of the membrane then changes conformation and releases it on the other
  3. By diffusing through aqueous pores formed by special proteins (aquaporins) that traverse the lipid
  4. By pinocytosis (trapping within the cell of a small vesicle containing EC constituents e.g. insulin at BBB)
27
Q

Define Fick’s Law

A

Rate of diffusion depends on the conc gradient of the drug across the membrane and on the thickness, area and permeability of the membrane

28
Q

What is diffusion directly through the lipid membrane dependent on

A

Conc of drug

Oil/water partition coefficient

Conc of protons

SA of absorbing membrane

** not saturable and low structural specificity

29
Q

Facilitated diffusion

A

Passive in the direction of its electrochemical gradient

30
Q

Where is the active transport mechanism (with the carrier protein) important

A
  • BBB
  • GIT: 5-fluorouracil
  • Renal tubule: penicillin
  • Biliary tract
  • Placenta
31
Q

What AA enters the brain by means of facilitated diffusion

A

L-dopa

32
Q

Unsaturable vs saturable process

A
33
Q

What is diffusion proportional to

A

The square root of MW

34
Q

What is the MW of most drugs

A

200-2000 Da

35
Q

How is lipid solubility measured

A

By the oil:water partition coefficient

i.e. how avidly a drug dissolves in lipid compared to how avidly it dissolves in water

Drugs with a high oil:water partition coefficient will be lipophilic and be able to readily traverse membranes

36
Q

Define ion trapping

What sort of substances does it occur with

A

Occurs when a drug, in its ionised state, gets trapped on 1 side of a membrane that divides 2 compartments with different pH values

Occurs with weak acids and weak bases (exist in both ionised and unionised form)

In either case the ionised form has very low lipid solubility and is virtually unable to permeate membranes except where a specific transport mechanism exists - % depends on pH of solution

37
Q

What would happen to weak acids in an acidic solution

A

They will not lose their proton in an acidic solution and therefore not become charged/ionised

38
Q

What will happen to weak bases in a basic solution

A

Will not gain a proton in a basic solution and therefore will not become charged/ionised

39
Q

HH equation for a weak base

A
40
Q

HH equation for a weak acid

A

pKa = -log(H+ dissociation constant)

41
Q

What does it mean when pH = pKa

A

The conc of ionised is the same as the conc of unionised

42
Q

Example of application of HH equation

A
43
Q

What effect does ion trapping have on pH partition

A

Ionisation affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments

Ratio is governed by pH and pKa (HH)

44
Q

What effect does ion trapping have on the drug at equilibrium

A

The total (ionised and unionised) concentration of the drug will be different in the 2 compartments, with an acidic drug being concentrated in the compartment with high pH (ion trapping) and vice versa

45
Q

pKa values of different drugs

A
46
Q

What happens when we alkalinise the urine

A

We can increase ionisation of acidic substances in the renal tubule and thereby prevent their tubular reabsorption

IV Na+ bicarbonate infusion will increase plasma pH, increase urine pH and therefore increase salicylate excretion

47
Q

What sort of molecules can diffuse passively across the cell membrane

A

Small non-polar molecules

48
Q

How do some drugs (e.g. levodopa and valproate) traverse the BBB

A

Via transporters, which either facilitate entry into the brain or diminish it by pumping the compound from the endothelial cell interior back into the bloodstream

49
Q

How does active extrusion of drugs from the brain occur

A

Via P-glycoprotein, an ATP-driven drug efflux transporter, and related transporter proteins

50
Q

What happens to CNS-acting drugs in the brain

A

Actively extruded from the brain

e.g. certain opioid, anti-depressant, anti-psychotic and anti-epileptic drugs

51
Q

Overview of transport of molecules

A
52
Q

What drugs can cross the placental barrier

A

Drugs with a MW of < 600

  • teratogens

Pharmacology (23 decks)

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