Kinetics: Lecture 11: Physiological Factors Related To Drug Absorption

Front 1

List 4 parenteral routes of administration.

Back 1

1. Intravenous Bolus (IB)

2. Intravenous Infusion (IV inf)

3. Intramuscular injection (IM)

4. Subcutaneous injection (SC)

Front 2

Name 3 enteral routes of administration.

Back 2

1. Buccal or sublingual (SL)

2. Oral (PO)

3. Rectal (PR)

Front 3

List 2 routes other than enteral and parenteral.

Back 3

1. transdermal

2. inhalation and intranasal

Front 4

What is the bioavailability of IV bolus?

Back 4

Complete, 100%, systemic drug absorption. Rate of bioavailability considered instantaneous.

Front 5

What are the advantages of IV bolus?

Back 5

Drug has immediate effect.

Front 6

List 2 disadvantages of IV bolus?

Back 6

1. increased chance for adverse rxn

2. possible anaphylaxis

Front 7

What is the bioavailability of IV inf?

Back 7

1. complete 100% systemic absorption

2. rate of drug absorption controlled by infusion rate.

Front 8

What is the bioavailability of buccal or sublingual routes?

Back 8

Rapid absorption from lipid soluble drugs.

Front 9

What is an advantage of buccal or sublingual routes?

Back 9

No "first pass" effects.

Front 10

What is the bioavailability of the oral route?

Back 10

Absorption may vary. Generally slower than IV or IM.

Front 11

What are 2 advantages of the oral route?

Back 11

1. Safest and easiest route.

2. May use immediate-release and modified-release drug products.

Front 12

What is the bioavailability of the rectal route?

Back 12

Absorption may vary from suppository. More reliable absorption from enema (solution).

Front 13

The rectal route's advantages?

Back 13

1. Useful when patient can not swallow medication.

2. Used for local and systemic effects.

Front 14

The bioavailability of the transdermal route?

Back 14

1. Slow absorption, rate may vary.

2. Increased absorption with occlusive dressing.

Front 15

List the advantages of the transdermal route.

Back 15

1. Transdermal delivery system (patch) is easy to use.

2. Used for lipid-soluble drugs with low dose and low MW.

Front 16

What is the bioavailability of the inhalation and intranasal route?

Back 16

1. Rapid absorption.

2. Total dose is variable.

Front 17

What is an advantage of the inhalation and intranasal route?

Back 17

May be used for local or systemic effects.

Front 18

Two illustrations of passive diffusion?

Back 18

1. Fick's Law

2. Henderson-Hasselbach

Front 19

3 examples of carrier-mediated transport?

Back 19

1. Intestinal examples

2. Facilitated diffusion

3. Active transport

Front 20

Describe facilitated diffusion of drug movement?

Back 20

Carrier mediated, moves along concentraton gradient, requires no energy expenditure.

Front 21

Describe the active transport of drug movement?

Back 21

Carrier-mediated and requires energy.

Front 22

List the 5 general mechanisms of drug movement?

Back 22

1. Passive diffusion

2. Carrier-mediated transport

3. Vesicular transport

4. Pore transport

5. Ion pair formation

Front 23

Two examples of vesicular transport.

Back 23

1. Exocytosis

2. Endocytosis

Front 24

Give an example of ion-pair formation.

Back 24

propranolol + oleic acid results in a neutral and so more lipophilic entity

Front 25

Lipid diffusion will be displayed by an ? molecule.

Back 25

Lipid diffusion will be displayed by an un-ionized molecule.

Front 26

Low molecular wt molecules may display what?

Back 26

Aqueous diffusion

Front 27

List 3 specialized mechanisms of intestinal absorption.

Back 27

1. Co-absorption with lipids

2. Active transport

3. Pinocytosis

Front 28

Describe co-absorption with lipids?

Back 28

This is a specialized mechanism of intestinal absorption that involves some highly lipid soluble drugs that are absorbed from the gut along with long chain fatty acid and their monoglycerides, fat-soluble vitamins and cholesterol. (ex. griseofulvin)

Front 29

Describe active transport?

Back 29

This a specialized mechanism of intestinal absorption that involves some drugs that are similar to nutrients that are naturally actively transported (ex. levodopa and methyldopa are taken up by an amino acid transport system, some anticancer drugs compete with pyrimidines for active transport system)

Front 30

Describe pinocytosis?

Back 30

It is a specialized mechanism of intestinal absorption that involves some large MW drugs (ex. the complex of intrinsic factor and vitamin B12) are taken up by pinocytosis.

Front 31

List 12 general factors affecting gut absorption.

Back 31

1. pH

2. Area of absorbing surface

3. Dissolved drug concentration

4. GI secretions

5. Bacterial metabolism of drugs.

6. Metabolism during absorption.

7. Clearance after absorption.

8. GI motility

9. Disorders

10. Drug interactions

11. Enteric shunts

12. Food and nutrients

Front 32

Generally how does the pH of gastric contents affect its absorption?

Back 32

The pH of gastric contents affects the degree of ionization of a drug and therefore its absorption.

Front 33

Concerning pH, drugs that are ? than 0.01% ionized are absorbed ? and erratically.

Back 33

Only slowly and erratically absorbed.

Front 34

In the STOMACH, what are the pka values of the bases and acids that are hardly absorbed?

Back 34

In the stomach, bases with pka values of more than 5 and and acids with a pka values of less than 2 are hardly absorbed.
A mucus layer shields the absorption surface from the bulk of the gastric contents.

Front 35

In the INTESTINES, what are the pka values of the bases and acids that are hardly absorbed?

Back 35

In the intestines, bases with pka values of more than 8 and acids with pka values of less than 3 are hardly absorbed (except when they have a high Po/w). Basic drugs are too highly ionized to be absorbed in the stomach but are then absorbed in the intestines.

Front 36

Why does most absorption take place in the small intestine (as opposed to the stomach)?

Back 36

Because the area of the absorbing surface is larger (about 200m^2 including the microvilli).

Front 37

A good proportion of a drugs absorption may be absorbed in the intestine because of the surface area size in spite of what?

Back 37

This might happen even if the pka of a drug favors gastric absorption.

Front 38

For solid oral dosage forms, what must occur before absorption?

Back 38

Disintegration and dissolution.

Front 39

First order absorption process depends on the ? of ? drug.

Back 39

First order absorption process depends on the concentration of dissolved drug.

Front 40

The highest concentration of a drug is on a ? stomach.

Back 40

The highest concentration is on an empty stomach. Lower conc.s are achieved with meals.

Front 41

What 2 GI secretions may affect gut absorption?

Back 41

1. Gastric acid

2. Enzymes

Front 42

Describe how Gastric acid affects gut absorption?

Back 42

Gastric acid hydrolyzes a number of esters. This results in inactivation for certain drugs or the activation of certain other drugs. (ex. chlorazepate-diazepam)

Front 43

Describe how enzymes affect gut absorption?

Back 43

Proteolytic enzymes break up polypeptide drugs (ex. insulin, oxytocin)

Front 44

Describe how the bacterial metabolism of drugs affect gut absorption?

Back 44

Commensal bacteria resident in the gut produce enzymes that could act on drugs or drug metabolites. For instance, they act on glucoronide conjugates, the liberated drug moiety may then proceed along the enterohepatic shunt.

Front 45

Describe some instances of metabolism during absorption that affects gut absorption?

Back 45

1. SO4 conjugating enzymes present in the intestinal mucosa can cause the inactivation of certain drugs (ex. chlorpromazine) during absorption.

2. AA decarboxylase and monoamine oxidase in the gut mucosa can inactivate part of an orally administered dose of levodopa (used to tx parkinsonism). The rest of the dose can be decarboxylated in the periphery with only 1% entering the brain intact to be converted to dopamine. This is prevented by concomitant administration of the dopa decarboxylase inhibitor carbidopa. (Carbidopa does not enter the brain).

3. Hydrolytic enzymes in the gut mucosa can inactivate glyceryl trinitrate (so given s/l). Hydrolysis of drugs such as ASA and dexamethasone phosphate does not result in loss of pharmacologic activity.

Front 46

For clearance after absorption (a factor affecting gut absorption) what is the limiting factor for the absorption of lipid soluble drugs?

Back 46

Blood supply via the sub-mucosal capillaries is the limiting factor for the absorption of lipid soluble drugs.

Front 47

The faster the removal of a drug from its site of absorption, the greater the what? What does this facilitate?

Back 47

The faster the removal of a drug from its site of absorption, the greater the concentration gradient. This facilitates absorption either by lipid or aqueous diffusion.

Front 48

Binding to blood proteins ? the elimination of a drug and ? the concentration of free drug, ? the concentration gradient across the absorption surface. What does this facilitate.

Back 48

Binding to blood proteins reduces the elimination of a drug and reduces the concentration of free drug, increasing the concentration gradient across the absorption surface. This facilitates absorption.

Front 49

Concerning GI motility, what do non-propulsive movements do?

Back 49

They contribute to solid dosage form disintegration and dissolution.

Front 50

Concerning GI motility, what determines the contact time between dissolved drug and absorbing surface?

Back 50

Propulsive movements and Transit time.

Front 51

Explain how propulsive mvmts and transit time may determine the contact time b/n drug and absorbing surface?

Back 51

1. For drugs that are poorly absorbed from the intestine, drugs that increase contact time (opiate and cholinergics) increase absorption.

2. For drugs that are not absorbed in the stomach, slowing the rate of gastric emptying (eg. by a fatty meal) slows the rate of absorption; stimulating gastric emptying (eg. metoclopramide) increases the rate of absorption.

Front 52

Some disorders affect gut absorption. Explain how Crohn's disease may do this?

Back 52

In some patients, Crohn's disease (inflammation of the small intestine and colon) causes a decrease in absorption of certain drugs (eg. trimetoprim) and an increase in the absorption of others (eg. clindamycin).

Front 53

Some disorders affect gut absorption. Explain how Celiac disease may do this?

Back 53

In some pts., celiac disease (inflammation of mainly the proximal small intestine) causes a decrease in absorption of certain drugs (digoxin) and an increase in others (eg. clindamycin)

Front 54

Some disorders affect gut absorption. Explain how achlyrodia may do this?

Back 54

In aclhyrodia pts (low level of acids in stomach). Weakly basic drugs cannot form soluble salts and so precipitate out. (recall for solid dosage forms solution must proceed absorption)

Front 55

Some disorders affect gut absorption. Explain how HIV-AIDS may do this?

Back 55

HIV-AIDS pts show increased gastric transit time, achlorhydia, and diarrhea.

Front 56

Some disorders affect gut absorption. Explain how CHF may do this?

Back 56

In CHF pts the reduced bl flow to the gut and reduced intestinal motility result in decreased and/or erratic drug absorption.

Front 57

Most drug interactions result in what?

Back 57

Decreased absorption.

Front 58

What can tetracyclines form? (drug-drug intrxn)

Back 58

Insoluble chelates can form it tetracyclines (or ciprofloxacin) are administered along with iron preparations or antacids or foods containing polyvalent cations.

Front 59

How can anticholinergics affect gut absorption? (drug-drug)

Back 59

Anticholinergics (or drugs with anticholinergic effects) slow gastric emptying and so delay absorption.

Front 60

How may proton-pump inhibitors affect gut absorption? (drug-drug)

Back 60

It may render the stomach achlorhydric.

Front 61

How may non-absorbable ion-exchange resins affect gut absorbtion? (drug-drug)

Back 61

Non-absorbable ion-exchange resins such as cholestyramine can adsorb other drugs and so reduce their absorption.

Front 62

Give an example when a drug-drug intrxn actually enhances absorption?

Back 62

Allopurinol increases iron absorption by inhibiting a limiting transport system.

Front 63

List some enteric shunts that may affect gut absorption?

Back 63

1. First-pass effect

2. Enterohepatic shunts

3. Other enteric shunts
- saliva (eg, clonidine)
- gastric juice (quinine)
- Bronchial secretions (bialamicol)

Front 64

Food can interact ? or ? with a drug.

Back 64

Food can interact physically or chemically with a drug (esp. if the drug is taken shortly after a meal).

Front 65

What can fatty foods do the drug absorption?

Back 65

reduces absorption of certain drugs (viagra) and increases absorption of others (griseofulvin)

Front 66

What can food do to bile flow?

Back 66

It can increase bile flow (and result in double peaks).

Front 67

What can food cause in gastric emptying?

Back 67

It can cause a delay in gastric emptying (and result in double peaks).

Front 68

What can food do to the gut pH?

Back 68

It can change it.

Front 69

What can food do in the lumen?

Back 69

It can change the metabolism of a drug in the lumen.

Front 70

Food can also reduce a drug's ? to the gut mucosa.

Back 70

Irritation.

Front 71

How might vit.B-12 affect gut absorption?

Back 71

VitB-12-intrinsic factor complex is carried to the ileum, it binds to a receptor. There is then a seperation and VitaminB12 gets absorbed.

Front 72

How might grapefruit juice affect gut absorption?

Back 72

It inhibits the pre-systemic absorption (gut and/or liver) or certain drugs and so increase their bioavailability.

Front 73

For sublingual and buccal absorption into circulation is what?

Back 73

It is direct, this circumvents the possibility of first pass effects.

Front 74

What molecules are rapidly absorbed by the sublingual route?

Back 74

Lipid soluble molecules. This is useful for emergency drugs like glyceryl trinitrate and isoprenaline.

Front 75

How can the absorption of ionizable drugs, generally speaking, be increased?

Back 75

By suppressing their ionization (like by using a buffer)

Front 76

Suppositories are solid but soften and melt at ? temperature.

Back 76

Melt at body temperature.

Front 77

Drugs absorbed thru the rectal mucosa get into the ? ? and so avoid the ? ? effects.

Back 77

Drugs absorbed thru the rectal mucosa get into the vena cava and so avoid first pass effects.

Front 78

Why are enemas subject to first pass effects?

Back 78

Enemas get into the colon and may reach the ileum and so may be subject to first pass effects.

Front 79

Vaginal preps are generally intended for what? However, what occurs?

Back 79

Generally intended for local effects, but absorption thru the vaginal mucosa occurs.

Front 80

Drugs designed for conjunctival instillation generally act how?

Back 80

Locally.

Front 81

Does absorption occur in conjunctival instillation?

Back 81

To some extent.

Front 82

Nasal drug delivery could be used for what kind of effects?

Back 82

Local or systemic.

Front 83

Nasal mucosa has a rich supply of blood vessels. So what can it deliver?

Back 83

It can deliver a rapid therapeutic effect.

Front 84

The lung has a large what?

Back 84

A large absorption surface.

Front 85

What do the airways filter?

Back 85

Inhaled matter to remove foreign material.

Front 86

What controls the extent to which inhaled material can penetrate the airways?

Back 86

Droplet size (aerosolization helps) and velocity of application. Devices such as spacers can improve depth of inhalation.

Front 87

What kind of effects are possible thru the skin?

Back 87

Both local and systemic.

Front 88

What kind of drugs penetrate the dermis?

Back 88

Lipid-soluble drugs.

Front 89

What kind of drugs cannot penetrate the dermis?

Back 89

Hydrophilic/ionizable drugs are impeded (unless drived thru by some other means such as electrophoresis).

Front 90

Why are subq injections more painful?

Back 90

Because of rich sensory innervation of skin.

Front 91

Subcutaneous is aka what?

Back 91

Hypodermic

Front 92

Would a larger volume be given subq or intramuscular (IM)?

Back 92

Larger volumes may be give IM.

Front 93

Following parenteral injections (subq, IM) how is the drug disseminated?

Back 93

Drug is disseminated after passage thru capillary (MW < 3000 or intermediate) or lymphatic (MW > 20000) endothelium.

Front 94

What is the MW of parenteral drugs disseminated thru the capillary endothelium?

Back 94

MW < 3000 or intermediate

Front 95

What is the MW of parenteral drugs that are disseminated through the lymphatic endothelium?

Back 95

MW > 20000 or intermediate

Front 96

Drugs that may otherwise be irritating to tissues may be administered how?

Back 96

Parenterally (IM, subq)

Front 97

Besides subq and parenteral IM injections name some other parenteral injections?

Back 97

1. Intradermal

2. Intraperitoneal

3. Intrathecal

4. Intra-arterial

5. Intracardiac

Front 98

What are intradermal injections used for?

Back 98

For test sera.

Front 99

What are intraperitoneal injections used for?

Back 99

They are rarely used in man. There is a large absorption area so diffusion into blood is rapid.

Front 100

Where and why are intrathecal drug administration used?

Back 100

Given in subarachnoid space for local action on meninges or spinal nerve roots.

Front 101

What are intra-arterial injections used for?

Back 101

They are used in animal experiments to localize administration to a specific organ.

Front 102

What are intracardiac injections used for?

Back 102

During cardiac surgery when the heart is exposed.

Front 103

What is the "depot effect"?

Back 103

When drug effect is prolonged.

Front 104

List 5 possible causes of the depot effect?

Back 104

1. By use of vasoconstrictor (like epinephrine)

2. Use of a less soluble salt (like procaine, penicillin, protamine ZN insulin)

3. Use of oil solutions

4. Use of pellets (like steroid hormones)

5. Absorption of a drug onto colloidal surface particles.