D8 - drug absorbtion Flashcards

1
Q

Pharmacokinetics

A
  • Branch of pharmacology that concerns itself with what the body does to the drug
    • Why does it matter
      ○ A drug needs to have properties that allow It to reach the tissue where the receptors are that it has to bind
      ○ Knowing how much/how often to give a drug
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2
Q

Pharmaceutical phase

A
  • Ingestion

- Disintegration and dissolution

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3
Q

Absorption routes

A
  • How it gets from site of administration into the systematic circulation
    1. Enteral route (oral)
      a. Easiest and most common - used 80% of the time
      b. Also includes
      i. Buccal - putting a pill against the cheek
      ii. sublingual routes - putting the pill under the tongue
      c. Safest due to protection of GI tract and liver - barriers protecting the body
      d. Drugs encounter barriers - GI wall, blood vessel walls,
    2. Parenteral route (non-oral)
      a. Any non-oral route
      b. Bypass protective effect of the liver/GIT
      c. Less safe - bypasses protective functions of gut wall and liver
      d. Requires clinical environment - usually cannot be done at home
      e. 4 routes (syringes at different angular injection and depth of delivery of the needle)
      i. Intramuscular
      ii. Subcutaneous
      iii. Intravenous
      iv. Intradermal
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4
Q
  1. Enteral route (oral)
A

a. Easiest and most common - used 80% of the time
b. Also includes
i. Buccal - putting a pill against the cheek
ii. sublingual routes - putting the pill under the tongue
c. Safest due to protection of GI tract and liver - barriers protecting the body
d. Drugs encounter barriers - GI wall, blood vessel walls,

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5
Q
  1. Parenteral route (non-oral)
A

a. Any non-oral route
b. Bypass protective effect of the liver/GIT
c. Less safe - bypasses protective functions of gut wall and liver
d. Requires clinical environment - usually cannot be done at home
e. 4 routes (syringes at different angular injection and depth of delivery of the needle)
i. Intramuscular
ii. Subcutaneous
iii. Intravenous
iv. Intradermal

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6
Q

e. 4 routes (syringes at different angular injection and depth of delivery of the needle)

A

i. Intramuscular
ii. Subcutaneous
iii. Intravenous
iv. Intradermal

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7
Q

Oral drug absorption

A

○ Occur along the length of GI
§ Mostly in practise occurs in the upper small intestine - duodenum
§ Because it has a long length and massive surface area
§ Well vascularised and high perfusion - drug uptake is effective
§ Folds and villi increase surface area 600 fold
○ Drugs encounter different environments as they transit the GI tract
§ PH, enzyme expression, fluidity of contents (eg. Acidic stomach)
§ Implications for ionisable drugs - amines, carboxylic acids

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8
Q

How are drugs absorbed

A
  • Traditional view
    ○ Most small amphipathic drugs (drugs that are slightly water soluble and slightly lipid soluble) diffuse via transcellular route - diffuse across the membrane of epithelial cells lining the GI tract
    § Not to big, lipid and water solubility, ionisation status
    ○ Very small hydrophilic drugs enter via paracellular route
    § Via gaps in tight junctions at the interface of cells
    § Eg. Alcohol
    • Newer view
      ○ Membrane drug transporters - control drug influx(out of the lumen into the enterocyte)/efflux (removing drugs and returning them to the lumen) on basolateral membrane (drugs on basolateral membrane - moving drugs into the blood stream) and across cell membranes
      § SLC (solute carriers ) - assist passive drug transport
      □ Facilitate transport in any direction - passive drug transport (facilitated transport)
      § ABC Class transporters - ATP - dependant transport (active transport)
      ○ Transported expression varies in different anatomical settings
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9
Q

influx SLC

A
  • Most are bidirectional solute carrier class - SLC

* Able to move cationic (amines) ions and anionic ions (acids)

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10
Q

Efflux ABC

A

• ABC type
• Unidirectional - only pump drugs out of cells
• Important in tumour cells - often confer resistance on tumours by pumping drugs out of tumours
• P-glycoprotein
○ Major role in GI drug absorptions
○ Also called ABCB1
○ Gut wall

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11
Q

P- glycoprotein

A

○ P-gp is clinically significant
§ ATP-dependant pump that decreases oral absorption of many lipophilic drugs
§ Pumping action driven by ATP hydrolysis
§ Drug pumped out across the membrane - efflux pathway
○ Member of ATP binding cassette ABC type
§ Encoded by ABCB1 gene
○ Strongly expressed in GI epithelium
§ Acts as efflux transporter to return absorbed drug to gut lumen
§ Hundreds of drugs are substrates for this - ideally these would be reduced
○ Expressed at liver canaliculi, BBB, proximal tubules, proximal tubes. placenta, testes
○ Drugs that are substrates for this proteins have limited absorption because they get pumped out of cells

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12
Q

Factors controlling drug absorption

A
  • Transcellular transport in GI-tract is influences by the physiochemical properties of drugs
    • Lipinski’s Rule of Five
      ○ Molecular mass less than 500g/mol
      ○ Calculated log octanol/water partition coefficient (LogP) of 5 or less (a measure of drug lipophilicity)
      ○ Less than 5 hydrogen bond donors (ie. Sum of OH and NF)
      ○ < 10 H-bond acceptors (sum of O and N atoms)
    • For good drug absorption, drugs should meet these 4 criteria
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13
Q

Lipinski’s Rule of Five

A

○ Molecular mass less than 500g/mol
○ Calculated log octanol/water partition coefficient (LogP) of 5 or less (a measure of drug lipophilicity)
○ Less than 5 hydrogen bond donors (ie. Sum of OH and NF)
○ < 10 H-bond acceptors (sum of O and N atoms)

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14
Q

Lipophilicity

A

a. LogP
§ Assesses partitioning behaviour of drug in simple biphasic system: water and octanol (model 8-carbon solvent)
§ LogP value needs to be less than 5
§ Must not be too lipo/hydrophilic - must have a good balance
§ Molecule should be spread somewhat evenly in the two layers

	b. Polar surface area (PSA)
		i. Surfaces of drug molecule can contain polarised atoms (usually O or N)
		ii. Computational PSA prediction calculates sum of tabulated surface contributors of polar fragments - how much surface area is occupied by polarised atoms - if a molecule is too polar it wont be able to penetrate 
			1) PSA estimates can predict human intestinal absorption of drugs 
			2) PSA also predicts toxicity, protein binding, receptor promiscuity
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15
Q

LogP

A

§ Assesses partitioning behaviour of drug in simple biphasic system: water and octanol (model 8-carbon solvent)
§ LogP value needs to be less than 5
§ Must not be too lipo/hydrophilic - must have a good balance
§ Molecule should be spread somewhat evenly in the two layers

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16
Q

b. Polar surface area (PSA)

A

i. Surfaces of drug molecule can contain polarised atoms (usually O or N)
ii. Computational PSA prediction calculates sum of tabulated surface contributors of polar fragments - how much surface area is occupied by polarised atoms - if a molecule is too polar it wont be able to penetrate
1) PSA estimates can predict human intestinal absorption of drugs
2) PSA also predicts toxicity, protein binding, receptor promiscuity

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17
Q

Egan’s egg

A

§ Statistically, orally administered drugs fall within an egg shaped distribution of LogP and PSA values

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18
Q

Drug ionisation and drug absorption

A

○ Drug often contain ‘functional groups’ that can adopt positive or negative charge
§ Allows drugs to be classified as either acids or bases
○ Acids
§ Carboxyl group which is ionised at near neutral
§ Ionised in duodenum
○ Basic
§ Often has nitrogen atoms which carries a positive charge in acid
§ Non-ionised in neutral
§ Ionised in stomach

	○ Only non-ionised can diffuse across lipid membranes 
		§ Bases mainly absorbed in duodenum
		§ Acids absorbed in stomach (but still mostly duodenum because of surface area)
		§ Overall, mostly duodenum because of massive surface area
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19
Q

Drug concentrations in blood

A

□ Administered to healthy volunteer patients
□ Given dose, blood samples taken and prepared for instrumental analysis
□ Measure drug levels via high performance liquid chromatography-mass spectrometry

20
Q

Plasma concentration - time profile

A

□ Initially rises and then gets metabolised and starts falling
□ Cmax - maximum concentration
□ Tmax - time at which the maximum plasma concentration is at its maximum
® Need to know whether the dose achieves minimum level required to achieve a therapeutic response
□ MEC: minimum effective concentration - bottom barrier of the therapeutic window
□ MTC: minimum toxic concentration
□ AUC: area under curve, total blood exposure
□ Therapeutic window: drugs produce beneficial effects when blood concentration is within this range

21
Q

Cmax

A

Cmax - maximum concentration

22
Q

Tmax

A

Tmax - time at which the maximum plasma concentration is at its maximum

23
Q

MEC

A

MEC: minimum effective concentration - bottom barrier of the therapeutic window

24
Q

MTC

A

MTC: minimum toxic concentration

25
Q

AUC

A

AUC: area under curve, total blood exposure

26
Q

Therapeutic window:

A

Therapeutic window: drugs produce beneficial effects when blood concentration is within this range

27
Q

Kinetics

A

○ First order - constant proportion (% of drug in body) removed per unit time
§ Amount of drug removed per time period depends on the amount present
§ Fall exponentially with time
§ Linearized by log transformation
§ Constant proportion is removed over time
○ Most drugs follow first order kinetics

	Zero order kinetics 
		§ Fixed amount of drug is removed per unit time 
			□ Levels or drug in plasma fall in linear manner with time (linear-linear graph)
		§ Usually because capacity of the body to metabolise drug is saturated at the dose at which the drug is used 
		§ Uncommon in therapeutic drug doses used in clinical medicine 
			□ Toxicology 
			□ Alcohol,  phenytoin (anticonvulsant)
28
Q

First order

A

○ First order - constant proportion (% of drug in body) removed per unit time
§ Amount of drug removed per time period depends on the amount present
§ Fall exponentially with time
§ Linearized by log transformation
§ Constant proportion is removed over time
Most drugs follow first order kinetics

29
Q

Zero order kinetics

A

Zero order kinetics
§ Fixed amount of drug is removed per unit time
□ Levels or drug in plasma fall in linear manner with time (linear-linear graph)
§ Usually because capacity of the body to metabolise drug is saturated at the dose at which the drug is used
§ Uncommon in therapeutic drug doses used in clinical medicine
□ Toxicology
□ Alcohol,
phenytoin (anticonvulsant)

30
Q

Steady state

A

Steady state
§ Most drugs require several regularly spaced doses to achieve stable “steady state” concentrations within the therapeutic window
□ Only a few drugs achieve a sufficient patient response with a single dose
® Most need repeated doses at regular intervals
□ Takes 4 to 5 elimination T1/2 (half lives) to reach steady state level in blood
® Steady state - peaks and troughs are the same from one dose to the next
® T1/2 - elimination half life - time taken for plasma concentration to fall by 50%
First 2 doses provide little benefit as the blood concentration does not reach therapeutic window

31
Q

4 ADME

A

4 ADME processes influence different regions of time-plasma concentration profiles
§ Absorption
§ Distribution
§ Metabolism
§ Elimination
The reason the plasma concentration curve varies is because drugs have different ADME processes

	Plasma concentration curve varies because they have different ADME properties  Also different between individual patients
32
Q

Route of administration influences shape of time-plasma concentration curves

A
○ Intravenous 
			§ Rapid initial increase - good for emergency need 
			§ Immediately reaches therapeutic window 
			§ Quickly falls back out of the therapeutic window 
		○ Intramuscular 
			§ Relatively quick response 
			§ More sustained 
		○ Subcutaneous 
			§ Relatively quick response 
			§ More sustained 
		○ Oral 
			§ Long term benefit 
Slow onset
33
Q

Intravenous

A

§ Rapid initial increase - good for emergency need
§ Immediately reaches therapeutic window
Quickly falls back out of the therapeutic window

34
Q

Intramuscular

A

§ Relatively quick response

More sustained

35
Q

Subcutaneous

A

§ Relatively quick response

More sustained

36
Q

Oral

A

○ Oral
§ Long term benefit
Slow onset

37
Q

Different drug formulation strategies can produce distinct blood profiles for orally administered drugs

A
○ Capsule 
			§ Releases payload quickly
		○ Coated tablet 
			§ Enteric coating will survive acidic environment in stomach 
			§ Used for drugs that are unstable in acid environment or that might cause damage to the stomach
			§ Slower release 
		○ Capsule with coated drug pallets 
			§ When taken, some of the payload is released early which the rest is released later 
			§ Sustained response 
		○ Matric tablet 
			§ Distinct matrices 
Sustained response
38
Q

Capsule

A

Releases payload quickly

39
Q

Coated tablet

A

§ Enteric coating will survive acidic environment in stomach
§ Used for drugs that are unstable in acid environment or that might cause damage to the stomach
Slower release

40
Q

Capsule with coated drug pallets

A

§ When taken, some of the payload is released early which the rest is released later
Sustained response

41
Q

Matrix tablet

A

§ Distinct matrices

Sustained response

42
Q

Drug Bioavailability

A
  • How effectively a drug is absorbed
    ○ Usually refers to administration via the GI tract
    • Reported as F - fraction of the administered dose that is absorbed
      ○ Ie. 1 = fully absorbed dose
      ○ Less that one - fraction that is absorbed
    • Assesses extent to which the drug is absorbed - not the rate at which it is absorbed
    F for fraction - for bioavailability
    ○ Proportion of drug reaching systemic circulation after ingestion
    § Some unabsorbed fraction
    Some metabolised in gut wall or liver
43
Q

Factor F for fraction - for bioavailability

A

○ Proportion of drug reaching systemic circulation after ingestion
§ Some unabsorbed fraction
Some metabolised in gut wall or liver

44
Q

Determining bioavailability (F)

A
Determining bioavailability (F)
		○ Estimate ratio of the area under curve - AUC for time-plasma concentration profiles of the same drug given via oral versus i.v. routes 
			§ i.v. administration bypasses metabolism in GIT and liver, so AUC reflects maximal bioavailability 

F= AUC oral/AUC i.v.

45
Q

Improving bioavailability via pro-drugs

A
  • Converting hydrophilic non permeable drugs in lipophilic drugs that can cross membrane barriers
    • Masking: sticking a chemical group to make it less polar
    • Hydrophilic groups can be masked by adding metabolism sensitive lipophilic substituents to form a pro-drug
      ○ Metabolism will cleave off the added group to release the active ingredient
      Can create significant gains in LogP