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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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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
5
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
53
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
54
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
84
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
85
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
86
4. Pulmonary excretion
Gasses and volatile liquids
Simple diffusion from the blood into the airway
Excretion of Drugs
87
5. Sweat and saliva
Drugs or drug metabolites
Passive diffusion
Drug taste after i.v. administration
Side reaction of the skin
Excretion of Drugs
88
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