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Cell physiology and pharmacology > Lecture 16- Pharmacokinetics I > Flashcards

Lecture 16- Pharmacokinetics I Flashcards

1
Q

pharmacokinetics can be summarised by (4)

A
  1. Absorption
  2. distribution
  3. metabolism
  4. elimination
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2
Q

drug in

A

Absorption

Distribution

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3
Q

Drug out

A

metabolism

elimination

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4
Q

how can drugs be administered (2)

A

1) enterally
2) parenteral

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5
Q

enteral routes

A

deliveraly into intervenal environemnt of the body - GI tract

  • sublingual
  • oral
  • rectal
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6
Q

parenteral

A

delivery via any other route that are not GI

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7
Q

Drug administration mnemonic

A

Oi! It is Sir!

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8
Q

Oi! It is Sir!

A

oral

intravenous

intramuscular

transdermal

intranasal

subcutaneous

sublingual

inhalation

rectal

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9
Q

majority of drugs given via

A

oral route

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10
Q

oeal route

A
  • Drugs mixes with chyme and enters the intestine
  • Intestine 6-7m in length and 2.5cm in diameter
  • Total SA for absorption= 30-35m2
  • GI peristalsis ensures mixing of the drugà meaning drug is presented to GI epithelia
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11
Q

typical trait time (time it takes to pass from stomach to the end of the s.intestine) for oral route

A

3-5 hours

  • long time to be asborbed in the small intestine
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12
Q

oral availability

A

The fraction of drug that reaches thesystemic circulation after oral ingestion.

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13
Q

drug absorption can occur via 4 routes

A
  1. Passive diffusion
  2. Facilitated diffusion
  3. Primary/secondary active transport
  4. Pinocytosis
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14
Q

passive diffusion is a common mechanism for

A

lipophilic drugs and weak acid/bases

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15
Q

example of lipophilic drug

A

steroids diffuse directly down conc fradient into GI capillaires

  • no polar
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16
Q

some drugs are weak acids and bases

A

can be protonated or unprotonated

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17
Q

when weak acid is protonated

A

uncharged

think COO-

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18
Q

when bases are deprotonated

A

uncharged

think NH3+

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19
Q

drugs pass more readily through membrane when

A

uncharged

  • protonated acids can pass
  • deprotonated bases can pass
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20
Q

if a drug has a pkA of 5 and the ph of the samll intestine is 6

A

most of the drug will be deprotonated

—> in weak acids onyl protonated speicies wil pass the membrane

  • only 10% lipopholic and can cross the GI epithelial
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21
Q

faciliated diffusion is carried out by

A

solute carrier transporters (SLC)

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22
Q

SLC transport

A

Molecules (or solutes) with net ionic + or – charge (charged molecules) within GI pH range can be carried across epithelia

–>Passive process based on electrochemical gradient for molecule

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23
Q

SLCs are either

A

Organic Anion Transporters (OATs) or Organic Cation Transporters (OCTs)

  • highly expressed GI, hepatic and renal epithelia
24
Q

secondary active transport (SLC transport)

A

SLC can also enable drug transport in GI by secondary active transport

  • Doesn’t utilise ATP
  • Transport driven by existing (ATP created) electrochemical gradient across GI epithelial membrane e.g. Renal OATs and OCTs
25
Q

factors affecting drug absorption

A

Physiochemical factors

GI physiology

First pass metabolism by GI and liver

26
Q

Physiochemical factors

A
  • GI length and surface area
  • Drug lipophilicy/ pKa (how protonated the drug is at GI pH)
  • Density of SLC expression in GI
27
Q

GI physiology

A
28
Q

first pass metabolism

A

Reduces availability of drug reaching systemic circulation- therefore affects therapeutic potential

29
Q

where can first pass metabolism occur

A

in the Gut lumen, walls or liver

30
Q

first pass metabolism reduces

A

oral availability

First pass metabolism can occur in the gut wall, portal vein (uncommon) and in the liver.

31
Q

which enzymes facilitate first pass metbaolism in the luver

A

Phase 1 and 2 enzymes

32
Q

phase 1 enzymes

A

Cytochrome P450s

33
Q

phase II

A

conjugating enzymes

34
Q

bioavailiability

A

Fraction of a defined dose which reaches its way into a specific body compartment

35
Q

which is the most common reference compartment used for bioabailability

A

circulation (CV)

  • for CV compartment bioavailability reference IV bolus is used
36
Q

IV bolus

A

no physical/ metabolic barriers to overcome

37
Q

bioavailability equation

A
38
Q

stages of drug distribution

A

1) Bulk flow- large distance via arteries to capillaries

2) Diffusion- capillaries to interstitial fluid to cell membrane to targets

3) Barriers to diffusion- interactions/ local permeability/ non-target binding

39
Q

major factors affecting drug distribution

A

1) Drug molecule lipophilicity/ hydrophilicity

2) Degree of drug binding to plasma and tissue protein

40
Q

1) Drug molecule lipophilicity/ hydrophilicity

A
  • If drug is largely lipophilic can feely move across membrane barriers
  • If drug is largely hydrophillic (mostly protonated at Gi pH) journey across membrane barriers dependent on factors described for absorption
    • Capillary permeability
    • Drug pKa and local pH
    • Presence of OATs/ OCTs
41
Q

2) Degree of drug binding to plasma and tissue protein

A
42
Q

drug diffusion across capillaries

A
  • Differing levels of capillary permeability
  • Variation in entry by charged drugs into tissue interstitial fluid/target site
  • Capillary membranes also express endogenous transporter and OAT/OCTs
43
Q

types of capillaries

A

continous

fenestrated

sinsusoid

44
Q

continous capillaries

A

very tight gap junctions (BBB)

45
Q

fenestrated capillaries

A

less tight intercellular celft

fenestrations

46
Q

sinusoid capillaries

A

leaky large synuses

big fenestrations

47
Q

Degree of drug binding to plasma and or tissue proteins Albumin as an example

A
  • Only free drug molecules can bind to target site
  • Binding to plasma/ tissue proteins (albumin) decreases free drug available for binding
48
Q

which ar ethe 3 main body comparments

A
  • Plasma
  • Interstitial
  • Intracellular
49
Q

Increasing penetration by drug into interstitial and intracellular fluid compartments leads to:

A
  • Decreasing plasma drug concentration
  • Increasing Volume of distribution
50
Q
A
51
Q

apaprent volume of distribition

A

Models grouping of main fluid compartments as through all in one compartment.

  • Summarises movement out of plasma à interstitial à intracellular compartment
  • Vd value dependent on push/pull factors described
52
Q

smaller Vd (vol of dist) values

A

less penetration of interstitial, intracellular fluid compartments

53
Q

Larger Vd values

A

greater penetration of interstitial/ intracellular fluid compartmentd

54
Q

volum of dist (Vd) equation

A
55
Q

Vd units

A
  • Vd units:
    • Litres (assume standard 70kg body wt)
    • Litres/kg (more referenced to individual patient body wt)
56
Q

what can affect apparent volume of distribution

A
  • Changes in regional blood flow
  • Hypoalbunimea (affecting protein binding)
  • Marker increase or decrease in body weight
  • Drug interactions
  • Renal failure
  • Drugs narrow therapeutic ration
  • Pregnancy
  • Paediatrics
  • Geriatric
  • Cancer patients
  • Anaesthetics

Cell physiology and pharmacology (20 decks)

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