Download Drug

Principle of Pharmacology
Pharmacokinetics
Dr. Guangyu Wu
Department of Pharmacology
LSU Health Sciences Center
New Orleans, LA
1
Pharmacodynamics
Drug actions and their mechanisms
DRUGS
RECEPTORS
RECEPTORS
RECEPTORS
PHARMACOLOGICAL RESPONSES
2
Pharmacokinetics
The study of drug movement into, within and out of the body,
which includes absorption, distribution and elimination.
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 body
Excretion
Metabolism
3
Other storage tissues
Site of action
Pharmacological
effects
AR
plasma
Drug (A)
Administration
Absorption
AT
A+R
A+T
Distribution
Unchanged
A
Free drug [A]
Excretion
Distribution
Metabolism
Systemic circulation
A+P
AP
Plasma protein-bound drug (AP)
Protein-drug complex
A’
Drug metabolite (A’)
4
90
[Drug]
80
Drug 1
70
60
Physical Properties
50
40
Drug 2
30
Structure
Lipid solubility
Ionization state
20
10
0
0
10 20 30
40 50 60
70 80 90 100
Time (h)
5
•
•
•
•
•
Mechanisms of drug transport
Drug administration
Drug absorption
Drug distribution
Drug elimination – excretion
6
DRUG
DRUG
DRUG
DRUG
PHARMACOLOGICAL EFFECTS
7
Mechanisms of Drug Transport
1. Passive diffusion
a. Passive diffusion of non-electrolytes
b. Passive diffusion of electrolytes
2. Filtration
3. Carrier-mediated transport
a. Active transport
b. Facilitated diffusion
4. Receptor-mediated endocytosis
5. Ion-pair transport
Endogenous compounds and drugs
8
Mechanisms of Drug Transport
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
9
Mechanisms of Drug Transport
1. Passive diffusion
Compartment 1
A
A
A
A
A
A
A
A
A
Compartment 1
A
A
A
Compartment 2
A
A
Membrane
A
A
A
Membrane
A
A
Compartment 2
A
A
A
A
A
Driving force: the concentration gradient across the membrane
10
Mechanisms of Drug Transport
1. Passive diffusion
1) Passive diffusion of non-electrolytes
2) Passive diffusion of electrolytes
11
Mechanisms of Drug Transport
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.
12
Mechanisms of Drug Transport
1. Passive diffusion
1) Passive diffusion of non-electrolytes
The higher the Kp, the more lipid soluble, the faster
the rate of transfer across biological membranes
13
Mechanisms of Drug Transport
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-SH
Weak bases: BH+ B + H+ R-NH2
Most drugs are either weak acids or weak bases.
14
Mechanisms of Drug Transport
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
15
Mechanisms of Drug Transport
1. Passive diffusion
2) Passive diffusion of electrolytes
HA
H+ + A -
BH+
H+ + B
pH < pKa
pH = pKa
pH > pKa
Predominate forms: HA and BH+
HA = ABH+ = B
Predominate forms: A- and B
pH
3
4
5
6
7
8
9
10
11
16
Mechanisms of Drug Transport
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
17
Mechanisms of Drug Transport
Acidic drug - pKa = 5
pH = 3
Body compartment 1
1
0.01
HA
H+ + A -
HA
H+ + A -
1.01 molecules
Membrane
Body compartment 2
pH = 7
1
100
101 molecules
Drug accumulation
18
Mechanisms of Drug Transport
Acidic drug - pKa = 5
pH = 3
Body compartment 1
1
0.01
HA
H+ + A -
HA
H+ + A -
1.01 molecules
Membrane
Body compartment 2
pH = 7
1
100
101 molecules
Lipid solubility:
Higher Kp – faster
Lower Kp - slower
19
Mechanisms of Drug Transport
Drug accumulation
Basic drug - pKa = 5
pH = 3
Body compartment 1
100
1
HB+
H+ + B
HB+
H+ + B
0.01
1
101 molecules
Membrane
Body compartment 2
pH = 7
1.01 molecules
20
Mechanisms of Drug Transport
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 rapidly
ii. Larger compound – retained
iii. Intermediate compound – barrier
Lipid soluble – passive diffusion
Water soluble – filtration
21
Mechanisms of Drug Transport
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
22
Mechanisms of Drug Transport
2. Filtration
Interstitial fluid
Capillary endothelium cells
Blood
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
23
24
Mechanisms of Drug Transport
3. Carrier-mediated transport
1) Active transport
2) Facilitated diffusion
25
Mechanisms of Drug Transport
3. Carrier-mediated transport
1) Active transport
a.
b.
c.
d.
e.
f.
Carrier or receptor-mediated
•
Reversible binding
•
Resemble with endogenous substances that are normal substances for
that particular transport system (sugars, amino acids)
Selectivity - not for all the drugs
Energy-dependent - ATP hydrolysis
One-way process – against drug concentration gradient - drug accumulation
It can be saturated – Drug/receptor ration – enzyme-catalyzed reactions
Can be inhibited – ATP inhibitors, structural analogous compounds
Drug
Carrier
Receptor
Membrane
26
Mechanisms of Drug Transport
3. Carrier-mediated transport
2) Facilitated diffusion
a.
b.
c.
d.
e.
Carrier or receptor-mediated
Selectivity
It can be saturated
Does not require ATP – concentration gradient
Bi-directional – no drug accumulation
Drug
Carrier
Receptor
Membrane
27
Mechanisms of Drug Transport
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.
b.
c.
d.
Receptor recycles, ligand degraded
Receptor and ligand recycle
Receptor and ligand degraded
Receptor and ligand transported
28
29
Plasma, pH 7.4
High affinity – Fe
Low affinity - receptor
Transferrin
High affinity - receptor
Fe3+
Transferrin receptor
Endocytosis
Recycling
Low affinity – Fe
High affinity - receptor
Endosome, pH = 5
30
Mechanisms of Drug Transport
5. Ion-pair transport
Highly ionized
Passive diffusion
+
+
+
_
_
+
_
_
Carrier
31
Routes of Drug Administration
-
The properties of the drug (such as water soluble or lipid soluble)
and the therapeutic objectives (effective rapidly or slowly; longterm, restricted to a local site).
-
Major routes:
1. Enteral administration:
1) Oral
2) Sublingual
3) Rectal
2. Parenteral administration:
1) Intravenous (IV)
2) Intramuscular (IM)
3) Subcutaneous (SC)
32
Routes of Drug Administration
1. Enteral administration:
Advantages: the most common route
a. Safe
b. Convenient
c. Economical
Disadvantages
a. Limited absorption - Some drugs can be destroyed by digestive
enzyme and low gastric pH in GI tract
b. 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
33
First Pass Effect
Drugs administrated orally are first exposed to the liver and may
be extensively metabolized before reaching the rest of body.
IV
Liver
Rest of body
Oral
Example: Nitroglycerin – 90% cleared
34
Routes of Drug Administration
1. Enteral administration:
1) Oral:
most common route
most variable
most complicate pathway to the tissues
first-pass metabolism/effect
35
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 drug
Nitroglycerin – nonionic, lipid soluble, potent
36
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 firstpass effect
37
Routes of Drug Administration
2. Parenteral administration:
Drugs - poorly absorbed or not stable in the GI tract
Advantages:
Better regulated and more predictable absorption
Can more accurately select effective dose
Avoids first pass effect
Disadvantages:
Risk of infection – asepsis must be maintained
Pain associated with injection
Difficulties in self medication
38
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 adjusted
Bypass first pass effect
Can 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 IV
Drugs in oily vehicles, extremely lipid soluble drugs that precipitate in blood,
39
or drugs that may cause hemolysis, cannot be given.
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 flow
Bypass first-pass effect of the liver
Constant and slow absorption
Absorption dependent on blood flow
Absorption rate can be intentionally altered by mixing with oil slow down, or by jagging, local heating or exercise – facilitate
40
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 absorption
Suspension in oil – slow absorption
Implanted solid drug under the skin – slow absorption
41
Absorption of Drugs
Transfer of drug from the site of
administration to the systemic circulation
1.
2.
3.
4.
Sites of absorption through the GI tract
Factors that modify absorption in the GI tract
Bioavailability
Other sites of drug administration/absorption
42
Absorption of Drugs
1. Sites of absorption through the GI tract
1)
2)
3)
4)
Mouth
Stomach
Small intestine
Large intestine
43
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
pH
Ionization
Absorption
Mouth
6
more
4 times faster
GI tract
1-5
less
d. Can bypass first pass effect.
44
Absorption of Drugs
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.
45
Absorption of Drugs
1. Sites of absorption through the GI tract
3) Small intestine
a.
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.
46
Absorption of Drugs
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. 47
Absorption of Drugs
2. Factors that modify absorption in the GI tract
1) 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
48
Absorption of Drugs
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
49
Absorption of Drugs
2. Factors that modify absorption in the GI tract
1) Drug solubilization – breaking drugs into smaller, more
absorbable particles
Solid
disintergration
deaggregation
Granules
fine particles:
Solution
50
Absorption of Drugs
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.
51
Absorption of Drugs
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.
52
Absorption of Drugs
2. Factors that modify absorption in the GI tract
4) Blood flow at the absorption site
- maintain concentration gradient – driving force
Membrane
Blood
53
Absorption of Drugs
2. Factors that modify absorption in the GI tract
5) Surface area of absorption
small intestine
54
Absorption of Drugs
2. Factors that modify absorption in the GI tract
6) Route of administration
GI tract – first pass effect
55
Absorption of Drugs
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.
56
Absorption of Drugs
2. Factors that modify absorption in the GI tract
8) Food
High fat food – delay gastric emptying – slow absorption
57
Absorption of Drugs
2. Factors that modify absorption in the GI tract
9) 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.
58
Absorption of Drugs
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.
59
Absorption of Drugs
3. Bioavailability
Fraction of administrated drug that reaches the
systemic circulation
60
Absorption of Drugs
3. Bioavailability
Determination of Bioavailability
61
Absorption of Drugs
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 equipment
Patients must be able to inhale with certain timing and depth in order to
get full effects of drug
Impaction may occur, if drug particles size is too large to pass through the
bronchi and reach the alveoli.
62
Absorption of Drugs
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
63
Drug Distribution
Transfer of drug from systemic circulation to tissues
Capillary endothelium cells
Blood – plasma
Interstitial fluid
Intracellular
64
Drug Distribution
1. Factors that affect drug distribution
1) Regional blood flow
2) Capillary permeability
3) Rate of transfer from interstitial fluid into tissues
4) Binding to plasma proteins
2. Barriers to drug distribution
65
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 brain
Moderate: muscle and skin
Low: 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.
66
Drug Distribution
Blood perfusion rates in adult humans
Tissue
Perfusion rate
(ml/min/100g tissue)
Lung
400
Kidney
350
Muscle
5
Skin
5
Adipose tissue
3
67
Drug Distribution
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 potential
Brain: smaller fenestrae – lower capillary permeability
Liver – slit junction
Brain – tight junction -blood-brain barrier
68
Drug Distribution
Blood-brain barrier
Liver
Brain
Large fenestrae
Tight junction
Slit junction
Lipid soluble drugs
Drugs
Small fenestrae
Passive diffusion
Carrier-mediated
transport
Endothelial cells
MEMBRANE
MEMBRANE
69
Drug Distribution
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
70
Drug Distribution
3) Rate of transfer from interstitial fluid into tissues
Passive diffusion, active transport and endocytosis.
Passive diffusion - the most common and quickest means
Blood – plasma
Interstitial fluid
71
Drug Distribution
4) Binding to plasma proteins - reversible
Capillary endothelium cells
A + P = AP
Blood
Interstitial fluid
Cells and tissues
72
Drug Distribution
4) Binding to plasma proteins
a. Consequence of drug binding to plasma proteins:
Cannot go to its receptor at the site of action
Cannot 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 body
Surmin – trypanosomiasis – A single IV injection may be effective for three months.
Warfarin – 97% bound to plasma proteins and 3% free.
73
Drug Distribution
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.
74
Drug Distribution
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.
75
Drug Distribution
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
76
More plasma proteins
Less free drug available
77
Drug Distribution
2. Barriers to drug distribution:
1) Blood-brain barrier
CNS
Tight junction
Small fenestrae
Interstitial fluid
Tight junction
Endothelial cells
passive diffusion
Carrier-mediated transport
Lipid soluble drug
Polar or ionized
X
MEMBRANE
78
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 barrier
Regulates the passage of steriods
Prevents chemotherapeutic agents from reaching the testis
79
Excretion of Drugs
Drugs are removed from the body or drugs are transferred
from the internal to the external environment
80
Excretion of Drugs
1. Sites for drug excretion:
1)
2)
3)
4)
5)
Kidney - Urine
Liver – Bile
Skin
Lung
Milk
81
Glomerular
filtration
Excretion of Drugs
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
Passive
•
•
Active
secretion
Reabsorption
(unionized, lipid soluble)
82
Glomerular
filtration
Excretion of Drugs
2. Renal excretion
1)
Glomerular filtration
2)
Active secretion
•
Active transport systems:
Organic acids/Anions
Organic bases/Cations
•
Relatively non-specific
Anion/acid system – penicillins, phenobarbital, uric
acid, et al.
Cation/base system – morphine,
catecholamines, histamine, et al.
•
•
Active
secretion
Passive
Reabsorption
(unionized, lipid soluble)
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
83
Glomerular
filtration
Excretion of Drugs
2. Renal excretion
1)
2)
3)
Glomerular filtration
Active secretion
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
Active
secretion
Passive
Reabsorption
(unionized, lipid soluble)
84
Excretion of Drugs
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.
Acids
b. Bases
c.
Neutral compounds
d. Bile acids
Lipid insoluble or ionized drugs – excretion
Enterohepatic cycling: Liver Bile
intestine
a.
b.
c.
Lipid soluble – reabsorption from intestine to bile – transport back to the liver
Prolong drug action
Conserve endogenous substances – VD3, B12, folic acid, estrogens.
85
Excretion of Drugs
4. Pulmonary excretion
Gasses and volatile liquids
Simple diffusion from the blood into the airway
86
Excretion of Drugs
5. Sweat and saliva
Drugs or drug metabolites
Passive diffusion
Drug taste after i.v. administration
Side reaction of the skin
87
Excretion of Drugs
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
88