Lecture 16- Pharmacokinetics I

Question 1

pharmacokinetics can be summarised by (4)

Answer 1

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

Question 2

drug in

Answer 2

Absorption

Distribution

Question 3

Drug out

Answer 3

metabolism

elimination

Question 4

how can drugs be administered (2)

Answer 4

1) enterally
2) parenteral

Question 5

enteral routes

Answer 5

deliveraly into intervenal environemnt of the body - GI tract

• sublingual
• oral
• rectal

Question 6

parenteral

Answer 6

delivery via any other route that are not GI

Question 7

Drug administration mnemonic

Answer 7

Oi! It is Sir!

Question 8

Oi! It is Sir!

Answer 8

oral

intravenous

intramuscular

transdermal

intranasal

subcutaneous

sublingual

inhalation

rectal

Question 9

majority of drugs given via

Answer 9

oral route

Question 10

oeal route

Answer 10

• 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

Question 11

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

Answer 11

3-5 hours

• long time to be asborbed in the small intestine

Question 12

oral availability

Answer 12

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

Question 13

drug absorption can occur via 4 routes

Answer 13

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

Question 14

passive diffusion is a common mechanism for

Answer 14

lipophilic drugs and weak acid/bases

Question 15

example of lipophilic drug

Answer 15

steroids diffuse directly down conc fradient into GI capillaires

• no polar

Question 16

some drugs are weak acids and bases

Answer 16

can be protonated or unprotonated

Question 17

when weak acid is protonated

Answer 17

uncharged

think COO-

Question 18

when bases are deprotonated

Answer 18

uncharged

think NH3+

Question 19

drugs pass more readily through membrane when

Answer 19

uncharged

• protonated acids can pass
• deprotonated bases can pass

Question 20

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

Answer 20

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

Question 21

faciliated diffusion is carried out by

Answer 21

solute carrier transporters (SLC)

Question 22

SLC transport

Answer 22

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

Question 23

SLCs are either

Answer 23

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

• highly expressed GI, hepatic and renal epithelia

Question 24

secondary active transport (SLC transport)

Answer 24

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

Question 25

factors affecting drug absorption

Answer 25

Physiochemical factors GI physiology First pass metabolism by GI and liver

Question 26

Physiochemical factors

Answer 26

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

Question 27

GI physiology

Question 28

first pass metabolism

Answer 28

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

Question 29

where can first pass metabolism occur

Answer 29

in the Gut lumen, walls or liver

Question 30

first pass metabolism reduces

Answer 30

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

Question 31

which enzymes facilitate first pass metbaolism in the luver

Answer 31

Phase 1 and 2 enzymes

Question 32

phase 1 enzymes

Answer 32

Cytochrome P450s

Question 33

phase II

Answer 33

conjugating enzymes

Question 34

bioavailiability

Answer 34

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

Question 35

which is the most common reference compartment used for bioabailability

Answer 35

circulation (CV) - for CV compartment bioavailability reference IV bolus is used

Question 36

IV bolus

Answer 36

no physical/ metabolic barriers to overcome

Question 37

bioavailability equation

Answer 37

Question 38

stages of drug distribution

Answer 38

**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

Question 39

major factors affecting drug distribution

Answer 39

**1) Drug molecule lipophilicity/ hydrophilicity** **2) Degree of drug binding to plasma and tissue protein**

Question 40

1) Drug molecule lipophilicity/ hydrophilicity

Answer 40

* 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

Question 41

2) Degree of drug binding to plasma and tissue protein

Question 42

drug diffusion across capillaries

Answer 42

* 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

Question 43

types of capillaries

Answer 43

continous fenestrated sinsusoid

Question 44

continous capillaries

Answer 44

very tight gap junctions (BBB)

Question 45

fenestrated capillaries

Answer 45

less tight intercellular celft fenestrations

Question 46

sinusoid capillaries

Answer 46

leaky large synuses big fenestrations

Question 47

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

Answer 47

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

Question 48

which ar ethe 3 main body comparments

Answer 48

* **Plasma** * **Interstitial** * **Intracellular**

Question 49

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

Answer 49

* Decreasing plasma drug concentration * Increasing Volume of distribution

Question 51

apaprent volume of distribition

Answer 51

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

Question 52

smaller Vd (vol of dist) values

Answer 52

less penetration of interstitial, intracellular fluid compartments

Question 53

**Larger Vd values**

Answer 53

greater penetration of interstitial/ intracellular fluid compartmentd

Question 54

volum of dist (Vd) equation

Answer 54

Question 55

Vd units

Answer 55

![]() * Vd units: * Litres (assume standard 70kg body wt) * Litres/kg (more referenced to individual patient body wt)

Question 56

what can affect apparent volume of distribution

Answer 56

* 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