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1 Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology LSU Health Sciences Center New Orleans, LA

Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology

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Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology LSU Health Sciences Center New Orleans, LA. Pharmacodynamics Drug actions and their mechanisms. DRUGS. RECEPTORS. RECEPTORS. RECEPTORS. PHARMACOLOGICAL RESPONSES. Pharmacokinetics - PowerPoint PPT Presentation

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Page 1: Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology

1

Principle of Pharmacology

Pharmacokinetics

Dr. Guangyu WuDepartment of PharmacologyLSU Health Sciences Center

New Orleans, LA

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DRUGS

PHARMACOLOGICAL RESPONSES

RECEPTORS RECEPTORS RECEPTORS

PharmacodynamicsDrug actions and their mechanisms

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Absorption - Transfer of drug from site of administration to systemic circulation

Distribution - Transfer of drug from systemic circulation to tissues

Elimination - Removal of drug from the bodyExcretionMetabolism

Pharmacokinetics

The study of drug movement into, within and out of the body, which includes absorption, distribution and elimination.

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Drug (A) Administration

AbsorptionFree drug [A]

Systemic circulation A + P APPlasma protein-bound drug (AP)Protein-drug complex

Excretion

Site of action

AR A + R

Other storage tissues

AT A + T

Unchanged A

Drug metabolite (A’)

A’

Distribution

Distribution

Pharmacologicaleffects

Metabolism

plasma

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0

10

20

30

40

50

60

70

80

90

0 10 20 30 40 50 60 70 80 90 100

Time (h)

[Dru

g]

Drug 1

Drug 2

Physical PropertiesStructureLipid solubility Ionization state

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• Mechanisms of drug transport

• Drug administration

• Drug absorption

• Drug distribution

• Drug elimination – excretion

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PHARMACOLOGICAL EFFECTS

DRUG DRUG DRUG DRUG

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1. Passive diffusiona. Passive diffusion of non-electrolytesb. Passive diffusion of electrolytes

2. Filtration 3. Carrier-mediated transport

a. Active transport b. Facilitated diffusion

4. Receptor-mediated endocytosis 5. Ion-pair transport

Mechanisms of Drug Transport

Endogenous compounds and drugs

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1. Passive diffusion – Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side.

Primary means by which drugs cross membranes

Mechanisms of Drug Transport

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1. Passive diffusion

Membrane

A AA

A

AA

A

AA

A

Mechanisms of Drug Transport

Driving force: the concentration gradient across the membrane

A

Membrane

A AA

A

AA

A

A

A

AA

A A

Compartment 1

Compartment 2 Compartment 2

Compartment 1

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Mechanisms of Drug Transport

1. Passive diffusion

1) Passive diffusion of non-electrolytes

2) Passive diffusion of electrolytes

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1. Passive diffusion

1) Passive diffusion of non-electrolytes

Lipid-water partition coefficient (Kp) - the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid (representing membrane) and an aqueous buffer (representing the plasma).

Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous phase.

If the drug is more soluble in the lipid, Kp is higher. If the drug is more soluble in the aqueous phase, Kp will be lower.

The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases.

One can control the Kp by modifying the side groups on the compound. The more C and H on the compound, the more lipid soluble, and thus the higher the Kp. The more O, S and the more water-soluble the compound, and the lower the Kp.

Mechanisms of Drug Transport

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1. Passive diffusion

1) Passive diffusion of non-electrolytes

Mechanisms of Drug Transport

The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes

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1. Passive diffusion

2) Passive diffusion of electrolytes

Electrolytes: tend to ionize in physiological solutions.

Two main categories – weak acids and weak bases. Weak acids: HA H+ + A- R-COOH, R-OH and R-SHWeak bases: BH+ B + H+ R-NH2

Most drugs are either weak acids or weak bases.

Mechanisms of Drug Transport

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1. Passive diffusion

2) Passive diffusion of electrolytes

pKa: the pH at which half of the molecules are in the ionized form and one half are in the unionized form.

pKa is a characteristic of a drug.

Henderson-Hasselbalch equations: For acids: pH = pKa + log [A-]/[HA]For bases: pH = pKa + log [B]/[BH+]

pH and drug concentration are log based scale - Every point

difference in pH is 10-fold difference in drug concentration

Mechanisms of Drug Transport

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1. Passive diffusion

2) Passive diffusion of electrolytes

Mechanisms of Drug Transport

3 4 5 6 7 8 9 10 11pH

pH < pKa

Predominate forms: HA and BH+

pH > pKa

Predominate forms: A- and B

HA H+ + A-

BH+ H+ + B

pH = pKa

HA = A-

BH+ = B

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1. Passive diffusion

2) Passive diffusion of electrolytes

Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes by passive diffusion.

By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred

Mechanisms of Drug Transport

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Body compartment 1

Body compartment 2

HApH = 3

1 0.01

H+ + A-

HA H+ + A-

1 100pH = 7

1.01 molecules

101 molecules

Membrane

Acidic drug - pKa = 5

Drug accumulation

Mechanisms of Drug Transport

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Body compartment 1

Body compartment 2

HApH = 3

1 0.01

H+ + A-

HA H+ + A-

1 100pH = 7

1.01 molecules

101 molecules

Membrane

Acidic drug - pKa = 5

Mechanisms of Drug Transport

Lipid solubility:Higher Kp – faster Lower Kp - slower

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Body compartment 1

Body compartment 2

HB+pH = 3

100 1

H+ + B

0.01 1pH = 7

101 molecules

1.01 molecules

Membrane

Basic drug - pKa = 5

Drug accumulation

Mechanisms of Drug Transport

HB+ H+ + B

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2. Filtration- Passage of molecules through pores or porous structures.

The rate of filtration

a. Driving force: The pressure gradient in both sides.

a. The size of the compound relative to the size of the pore.

i. Smaller compound – transfer rapidlyii. Larger compound – retainediii. Intermediate compound – barrier

Mechanisms of Drug Transport

Lipid soluble – passive diffusion Water soluble – filtration

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2. Filtration

The rate of filtration:

In biological systems: Filtration is the transfer of drug across membrane through the pores or through the spaces between cells

a. Capillary endothelial membranes

b. Renal glomerulus

Mechanisms of Drug Transport

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Interstitial fluid

Capillary endothelium cells

Blood

Mechanisms of Drug Transport

2. Filtration

Interstitial fluid

• Most substances (lipid-soluble or not) – cross the capillary wall – very fast• Lipid soluble and unionized – filtration and passive diffusion – at the same time

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3. Carrier-mediated transport

Mechanisms of Drug Transport

1) Active transport

2) Facilitated diffusion

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3. Carrier-mediated transport

Drug

CarrierReceptor

Mechanisms of Drug Transport

Membrane

a. Carrier or receptor-mediated• Reversible binding• Resemble with endogenous substances that are normal substances for

that particular transport system (sugars, amino acids)b. Selectivity - not for all the drugsc. Energy-dependent - ATP hydrolysisd. One-way process – against drug concentration gradient - drug accumulatione. It can be saturated – Drug/receptor ration – enzyme-catalyzed reactions f. Can be inhibited – ATP inhibitors, structural analogous compounds

1) Active transport

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3. Carrier-mediated transport

Mechanisms of Drug Transport

a. Carrier or receptor-mediatedb. Selectivityc. It can be saturatedd. Does not require ATP – concentration gradient e. Bi-directional – no drug accumulation

2) Facilitated diffusion

Drug

CarrierReceptor

Membrane

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4. Receptor-mediated endocytosis

- more specific uptake process

Drugs (peptide hormones, growth factors, antibodies, et al) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalized, forming endosomes.

Receptor-ligand complex may take four different pathways:

a. Receptor recycles, ligand degraded b. Receptor and ligand recyclec. Receptor and ligand degradedd. Receptor and ligand transported

Mechanisms of Drug Transport

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pH 7.4

Endosome, pH = 5

Transferrin Fe3+

Transferrin receptor

EndocytosisRecycling

High affinity – FeLow affinity - receptor

High affinity - receptor

Low affinity – FeHigh affinity - receptor

Plasma,

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5. Ion-pair transport

+

_

+_

+_

+

_

Mechanisms of Drug Transport

Highly ionized

Carrier

Passive diffusion

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Routes of Drug Administration

- The properties of the drug (such as water soluble or lipid soluble) and the therapeutic objectives (effective rapidly or slowly; long-term, restricted to a local site).

- Major routes:

1. Enteral administration:1) Oral 2) Sublingual3) Rectal

2. Parenteral administration: 1) Intravenous (IV)2) Intramuscular (IM)3) Subcutaneous (SC)

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Routes of Drug Administration

1. Enteral administration:

Advantages: the most common route

a. Safeb. Convenientc. Economical

Disadvantages a. Limited absorption - Some drugs can be destroyed by digestive

enzyme and low gastric pH in GI tractb. Irregularities in absorption in the presence of food or other drugs c. Emesis as result of gastric irritation Requires patient cooperation d. May be metabolized by first-pass effect

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Liver

Rest of body

Oral

IV

First Pass EffectDrugs administrated orally are first exposed to the liver and may be extensively metabolized before reaching the rest of body.

Example: Nitroglycerin – 90% cleared

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Routes of Drug Administration

1. Enteral administration:

1) Oral: most common route

most variable

most complicate pathway to the tissues

first-pass metabolism/effect

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Routes of Drug Administration

1. Enteral administration:

2) Sublingual:

Placement under the tongue and diffuse into the capillary network

Bypass first pass effect

For potent drugNitroglycerin – nonionic, lipid soluble, potent

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Routes of Drug Administration

1. Enteral administration:

3) Rectal: used when it is unable to use oral ingestion such as unconscious patients or children. About 50% of the drug absorbed from the rectum will bypass the liver – less first-pass effect

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Routes of Drug Administration

2. Parenteral administration: Drugs - poorly absorbed or not stable in the GI tract

Advantages: Better regulated and more predictable absorptionCan more accurately select effective doseAvoids first pass effect

Disadvantages: Risk of infection – asepsis must be maintained

Pain associated with injectionDifficulties in self medication

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Routes of Drug Administration

2. Parenteral:

1) Intravenous administration (IV): The most common parenteral route

Advantages: Can attain desired drug concentration immediately Dosage can be readily adjustedBypass first pass effectCan give certain irritating (GI tract) solutions (blood vessel –insensitive;

drug dilution by blood)

Disadvantages:Cannot be reversed – overdose May introduce bacteria through contamination – hemolysis

Unfavorable reaction – the rate of infusion Must maintain patent vein – repeated IVDrugs in oily vehicles, extremely lipid soluble drugs that precipitate in

blood, or drugs that may cause hemolysis, cannot be given.

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Routes of Drug Administration

2. Parenteral:

2) Intramuscular administration: Injected into the muscle - aqueous solution or nonaqueous suspension (in oil vehicles)

Absorption by filtration or bulk flowBypass first-pass effect of the liverConstant and slow absorption Absorption dependent on blood flowAbsorption rate can be intentionally altered by mixing with oil - slow down, or by jagging, local heating or exercise – facilitate

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Routes of Drug Administration

2. Parenteral:

3) Subcutaneous administration - drugs are injected underneath the skin. It can be used only for drugs that are not irritating to tissues. Otherwise, severe pain, necrosis may occur.

Absorption by filtration or bulk flow.Bypass first-pass effect of the liver. Slow and constant absorption – generally slower than IM.Absorption rate can be intentionally altered.

Aqueous solution – fast absorptionSuspension in oil – slow absorptionImplanted solid drug under the skin – slow absorption

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Absorption of DrugsTransfer of drug from the site of

administration to the systemic circulation

1. Sites of absorption through the GI tract2. Factors that modify absorption in the GI tract3. Bioavailability4. Other sites of drug administration/absorption

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Absorption of Drugs

1. Sites of absorption through the GI tract

1) Mouth2) Stomach3) Small intestine 4) Large intestine

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Absorption of Drugs

1. Sites of absorption through the GI tract

1) Mouth:

a. Small amount of surface area but good blood flow – best for potent drugs.

b. Transfer by passive diffusion – good for lipid soluble drugs.

c. pH = 6. Weak base drugs have better absorption.

Nicotine pKa 8.5 Mouth

GI tract pH 6 1-5Ionization more lessAbsorption 4 times faster

d. Can bypass first pass effect.

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1. Sites of absorption through the GI tract

2) Stomach: a. Moderate surface area – more than mouth, less than small intestine.

b. Good blood supply.

c. Drugs absorbed in the stomach will experience first pass effect.

d. Transfer by passive diffusion.

e. Low pH (1-2) – ionization - Drugs that are weak acids will be absorbed better than weak base drugs.

f. Ion trapping: Accumulation of weak base drugs in the stomach.

Absorption of Drugs

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1. Sites of absorption through the GI tract

3) Small intestinea. The primary site for most drugs.

b. Large surface area - Folds, villi and microvilli and high blood perfusion rate.

c. pH = 5-8.

d. Passive diffusion.

e. Absorption can also take place by active transport, facilitated diffusion, endocytosis and filtration.

Absorption of Drugs

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1. Sites of absorption through the GI tract

4) Large intestine

a. Not important for drug absorption, if the drug is absorbed effectively in small intestine.

b. Can be a site of absorption for incompletely absorbed drugs.

c. Less absorption then small intestine – less area and solid nature of contents.

d. Rectum can be used for drug administration.

For drugs that cause irritation to the stomach

After GI surgery

Children

Partially avoids liver first pass effect: The half of blood flow goes into liver, the half of blood flow enters the systemic circulation directly.

Absorption of Drugs

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2. Factors that modify absorption in the GI tract1) Drug solubilization

2) Formulation factors

3) Concentration of drug at the absorption site

4) Blood flow at the absorption site

5) Surface area of absorption

6) Route of administration

7) Gastric emptying

8) Food

9) Intestinal motility

10) Metabolism of drug by GI tract

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane.

Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot gain access to the surface of cells.

- largely hydrophobic yet have some solubility in aqueous solutions

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

1) Drug solubilization – breaking drugs into smaller, more absorbable particles

Solid Granules fine particles:

Solution

disintergration deaggregation

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

2) Formulation factors – materials added to the drug during processing can affect the solubilization of the drug.

a. Fillers – add bulk to the tablet

b. Disintegrators – cause tablet to break down into granules

c. Binders – hold tablet together

d. Lubricants – prevent tablet from sticking to machinery

Formulation factors - not clinically important if the drug is absorbed effectively and may have important influence on drug absorption for these drugs which are not effectively absorbed in the GI tract - influence drug’s bioavailability.

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

3) Concentration of drug at the absorption site

Passive diffusion

Driving force – the concentration gradient.

The higher the concentration of the drug, the faster the rate of absorption.

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

4) Blood flow at the absorption site

- maintain concentration gradient – driving force

Blood

Membrane

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

5) Surface area of absorption

small intestine

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

6) Route of administration

GI tract – first pass effect

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

7) Gastric emptying

small intestine – primary site of drug absorption

Anything that delays/accelerates gastric emptying will decrease/increase drug absorption.

For all drugs - acidic, basic or neutral substances.

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

8) Food

High fat food – delay gastric emptying – slow absorption

Absorption of Drugs

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2. Factors that modify absorption in the GI tract9) Intestinal motility

– depends on whether the drug is completely absorbed under normal condition.

a. Completely absorbed early upon entry into the small intestine, increasing intestinal motility will not significantly affect absorption.

b. Not completely absorbed before entry into the small intestine, increasing/decreasing intestinal motility will slow down/facilitate drug absorption.

Absorption of Drugs

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2. Factors that modify absorption in the GI tract

10) Metabolism of drug by GI tract

a. Drug metabolizing enzymes in the GI tract

b. Proteases in the GI tract

c. Microbes in the GI tract - metabolize certain drugs

- Drug metabolites are not usually absorbed.

Absorption of Drugs

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3. Bioavailability

Fraction of administrated drug that reaches the systemic circulation

Absorption of Drugs

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3. Bioavailability

Determination of Bioavailability

Absorption of Drugs

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4. Other sites of drug administration/absorption.

1). Lung – gases, liquid droplets or solid particles

Advantages: The drug can have local effects - Epinephrine for asthma.

The drug can have systemic effects - general anesthetics Large surface area, limited thickness of pulmonary membrane and

high blood flow allow for almost instant absorption by diffusion

Avoid first pass effect

Disadvantages:Administration is cumbersome - must use specific machines or

equipmentPatients must be able to inhale with certain timing and depth in order

to get full effects of drugImpaction may occur, if drug particles size is too large to pass through

the bronchi and reach the alveoli.

Absorption of Drugs

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4. Other sites of drug administration/absorption

2) Skin – Most drugs that are incorporated into creams or ointments are applied to the skin for local effect.

Drug absorption through the skin - Passive diffusion – lipid

solubility

Absorption of Drugs

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Drug Distribution

Transfer of drug from systemic circulation to tissues

Interstitial fluid

Blood – plasma

Intracellular

Capillary endothelium cells

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Drug Distribution

1. Factors that affect drug distribution1) Regional blood flow2) Capillary permeability3) Rate of transfer from interstitial fluid into tissues4) Binding to plasma proteins

2. Barriers to drug distribution

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Drug Distribution

1. Factors affecting distribution:

1) Regional blood flow – unequal distribution of cardiac output

Perfusion rate: blood flow to tissue mass ratio

Higher: heart, kidney, liver, lung and brainModerate: muscle and skinLow: adipose tissue

The perfusion rate affects the rate at which a drug reaches the equilibrium in the extracellular fluid of a particular tissue.

The greater the blood flow, the more rapid the drug distribution from plasma into interstitial fluid. Therefore, a drug will appear in the interstitial fluid of liver, kidney and brain more rapidly than it will in muscle and skin.

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Tissue Perfusion rate (ml/min/100g

tissue)Lung 400Kidney 350Muscle 5Skin 5Adipose tissue 3

Blood perfusion rates in adult humans

Drug Distribution

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1. Factors affecting distribution

2) Capillary permeability Drug transfer through capillary – filtration

a. Capillary structure: Capillary size and fenestrae size

Liver: larger fenestrae - greater filtration potentialBrain: smaller fenestrae – lower capillary permeability

Liver – slit junctionBrain – tight junction -blood-brain barrier

Drug Distribution

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MEMBRANE MEMBRANE

Slit junctionDrugs

Liver Brain

Endothelial cells

Tight junction

Lipid soluble drugs

Large fenestrae

Small fenestrae

Blood-brain barrier

Passive diffusion Carrier-mediated transport

Drug Distribution

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1. Factors affecting distribution

2) Capillary permeability Drug transfer through capillary – filtration

a. Capillary structure:

b. Chemical nature of the drug:

Drug size Drug structure: Hydrophobic drugs: passive

diffusion – blood flow Hydrophilic drugs – fenestrae - filtration

Drug Distribution

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3) Rate of transfer from interstitial fluid into tissues

Passive diffusion, active transport and endocytosis.

Passive diffusion - the most common and quickest means

Drug Distribution

Interstitial fluid

Blood – plasma

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4) Binding to plasma proteins - reversible

Drug Distribution

Interstitial fluid

Capillary endothelium cells

Blood

Cells and tissues

A + P = AP

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4) Binding to plasma proteinsa. Consequence of drug binding to plasma proteins:

Cannot go to its receptor at the site of actionCannot be distributed to body tissues Cannot be metabolized by enzymes Cannot be excreted from the body

b. Bound drugs are pharmacologically inactive.c. Drug binding to plasma protein will delay the onset of drug action. d. Drug binding to plasma proteins will decrease the intensity of drug

action.

e. Drug binding to plasma proteins may prolong drug action. Reservoir of non-metabolized drug in the bodySurmin – trypanosomiasis – A single IV injection may be effective for three months.Warfarin – 97% bound to plasma proteins and 3% free.

Drug Distribution

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4) Binding to plasma proteins

f. Types of plasma proteins:

Albumin:

• The primary serum protein responsible for drug binding• 68 kD with pI = 5 • The strongest affinity for weak acid and hydrophobic drugs. • 1 or 2 selective high affinity binding sites for week acid drugs.

Drug Distribution

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4) Binding to plasma proteins

f. Types of plasma proteins:

Lipoproteins:

• Lipid-soluble drugs• The binding capacity is dependent on their lipid content.• Binding ability of lipoproteins is VLDL > LDL > HDL.• Patient – more free drug available for absorption in

patients with high HDL than patients with high LDL.

Drug Distribution

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4) Binding to plasma proteins

f. Types of plasma proteins:

alpha1-acid glycoprotein:

• Alpha1- globulin• 44KD• One high affinity binding site and binds only basic

drugs• Plasma concentration - inducible by acute injury,

trauma, and stress.• The half time: 5.5 days.• Patient with trauma taking a basic drug – side effect

Drug Distribution

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More plasma proteinsLess free drug available

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Drug Distribution

2. Barriers to drug distribution:

1) Blood-brain barrier

MEMBRANE

CNS

Tight junction

passive diffusion Carrier-mediated transport

Tight junction Small fenestrae

Endothelial cells

Interstitial fluid

Polar or ionized

Lipid soluble drug

X

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Drug Distribution

2. Barriers to drug distribution:

2) Placental transfer

Placenta - Not a barrier – most drugs• Fenestrae – MW cut off 600• MW < 600 – free transfer• MW > 600 – restricted• Lipid soluble drugs - passive diffusion. • May have profound affects on fetal development.

3) Blood testicular barrierRegulates the passage of steriodsPrevents chemotherapeutic agents from reaching the

testis

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Excretion of Drugs

Drugs are removed from the body or drugs are transferred from the internal to the external environment

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Excretion of Drugs

1. Sites for drug excretion:

1) Kidney - Urine2) Liver – Bile 3) Skin 4) Lung5) Milk

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Excretion of Drugs Glomerular filtration

Active secretion

PassiveReabsorption(unionized, lipid soluble)

2. Renal excretion

1) Glomerular filtration

• Drugs from glomerulus into the renal tubules• Pressure – blood flow - 20% of blood volume is filtered

at the glomerulus• Drug transport is dependent on

a. Size - MW cut off = 5000 > 75,000 – restricted

b. Charge - charged substances are filtered slower c. Shape – globular proteins are filtered slower

• Lipid soluble drugs – also by passive diffusion

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Excretion of Drugs Glomerular filtration

Active secretion

PassiveReabsorption(unionized, lipid soluble)

2. Renal excretion

1) Glomerular filtration

2) Active secretion

• Active transport systems:Organic acids/AnionsOrganic bases/Cations

• Relatively non-specificAnion/acid system – penicillins, phenobarbital, uric

acid, et al.Cation/base system – morphine, catecholamines, histamine, et al.

• In some cases can remove protein-bound drugs from the blood

• Possess all the characteristics of active transport (e.g. saturation, energy requirement, competition, unidirectional – accumulation and excretion

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Excretion of Drugs Glomerular filtration

Active secretion

PassiveReabsorption(unionized, lipid soluble)

2. Renal excretion1) Glomerular filtration 2) Active secretion

3) Passive reabsorption

• Formation of concentration gradient of drug in tubular filtrate

• Transfer of unionized, lipid soluble drugs back to the blood by pass diffusion – passive reabsorption

• Excretion of ionized, lipid-insoluble drugs• More ionization – more secretion• pH of urine = 4.5 – 8 • Acidification of urine causes reabsorption of

weak acids - Ammonium chloride or ascorbic acid– decrease pH – enhance excretion - forced acid diuresis

• Forced alkaline diuresis - - Bicarbonate – increase pH – ionization of weak acids – faster excretion

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3. Secretion from the liver:

• Liver - Metabolizing enzymes• Drugs are filtered from liver capillaries into interstitial fluid – liver has larger fenestrae

which will allow the filtration of most drugs• Drugs in interstitial fluid are transported into hepatocytes by

a. Passive diffusion b. Carrier-mediated transport

• Drugs are actively transported from the hepatocytes into the bile capillaries by 4 active transport systems

a. Acidsb. Basesc. Neutral compoundsd. Bile acids

• Lipid insoluble or ionized drugs – excretion • Enterohepatic cycling: Liver Bile intestine

a. Lipid soluble – reabsorption from intestine to bile – transport back to the liverb. Prolong drug actionc. Conserve endogenous substances – VD3, B12, folic acid, estrogens.

Excretion of Drugs

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4. Pulmonary excretion

Gasses and volatile liquids

Simple diffusion from the blood into the airway

Excretion of Drugs

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5. Sweat and saliva

Drugs or drug metabolites

Passive diffusion

Drug taste after i.v. administration

Side reaction of the skin

Excretion of Drugs

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6. Milk

Passive diffusion

Milk pH 6.5 – ion trapping of weak bases

Plasma protein binding decreases drug concentration in milk

Not very important for mother, but may be important for infant

Excretion of Drugs