Transcript Drug interaction of plasma protein binding

Drugs and the Kidney
Jin Wang
Institute of Pharmacology
School of Medicine
Shandong University
[email protected]
Introduction
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Renal dysfunction may affect clearance
and distribution of drugs.
eg. phenobarbital
Drugs may directly influence renal
function.
eg. dopamine
Eeffect of renal impairment
on drug excretion
The Processes of Drug in the Body
receptor
B
tissue
free
F
bound
circulation
absorption
excretion
Free drug
Bound drug
metabolism
metabolites
The Drug Processes in the Body
The Classifications
Absorption吸收
Distribution分布
Metabolism代谢
Excretion排泄
Disposition处置:transportation and transformation
Elimination消除:metabolism and excretion
First-order Elimination Kinetics
一级消除动力学
The character of first-order kinetics is that the
rate of elimination is directly proportional to
the drug dose (linear relationship), here the
half-life time keeps constant and has nothing
to do with the amount of drug in the body.
Most drug are eliminated with this kind of
kinetics in their metabolism capacity.
Zero-order Elimination Kinetics
零级消除动力学
The character of zero-order kinetics is that
the rate of elimination is constant, i.e.,
independent of drug doses, and that the halflife time is positively relates to the drug doses.
When the concentration of drug exceeds the
capacity of the metabolism of the body, the
drug is eliminated with zero-order kinetics.
And then turn to the first-order kinetics
elimination.
Minimum effective concentration (MEC)
The concentration inducing the minimal effect.
Minimum toxic concentration (MTC)
Elimination half-life time(t1/2): The time
required for any given drug concentration in
plasma to decrease by half.
Time–Concentration (effect) Curve
时–量（效）曲线
Transportation of Drug Molecules
Modes of transportation转运方式
(1) Filtration滤过
(2) Simple diffusion简单扩散 (down hill)
Passive transport被动转运
No need for energy, carrier.
No saturation limited.
No competitive inhibition.
Passive Transport by Factors
Affected by properties, areas of membrane,
concentration between memb., and properties of
drug: molecular size, lipid solubility, polarity.
Ion trapping(离子障):
non-ionic drug is free to penetrate while ionic drug is
limited to one side of the biomembrane.
Transports of weak acidic and weak basic
drug by Handerson-Hasselbalch Equation
Weak acidic drug weak basic drug
HA ≒ H+ + ABH+ ≒ H+ + B
Ka = H+A-/HA
Ka = H+B/BH+
pKa = A-/HA
pKa = H+B/BH+
pKa = pH - logA-/HA pKa=pH-logB/BH+
pH–pKa=logA-/HA pK –pH=logBH+/B
when pH = pKa, A- = HA B = BH+
Transports of weak acidic and weak basic
drug by Handerson-Hasselbalch Equation
pH–pKa=logA-/HA
[HA]/[A-] = 10pka-pH
[A-]/[HA] = 10pH-pka
pK – pH=logBH+/B
BH+/B = 10pka-pH
question
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Aspirin PKa=3.5， PH (Stomach）
=1.5，PH（blood）=7.5 ，PH （urine）
=6.5
The extent of dissociation in stomach?
The extent of dissociation in blood?
(Drug in blood) /(drug in stomach)?
(Drug in blood) /(drug in urine)?
Absorption
The movement of a drug from its site of
administration into the blood circulation.
The pathways of absorption
Gastroentestinal pathway
Steps：gastric stasis，gastric acidity，
concurrent treatment drugs
Distribution
Conception
The process by which a drug leaves the blood
circulation to enter the extracellular fluids and
the tissues of the body.
Parameters of kinetics
Apparent volume of distribution (表观分布容积,
Vd)
Vd means that the ratio of in vivo drug quantity
verses concentration in plasma when the drug
reaches the dynamic equilibrium in the body.
Vd = A/C0 = A/AUC x Ke(L)
Apparent volume of distribution
For instance, if the Vd of a drug is about 3-5L,
this drug may mainly distribute in the blood.
If the Vd of a drug is about 10-20L, the drug
chiefly distributing in plasma and extacellular
fluid. And if a drug has the Vd of 40L, the
drug could distribute in extra-cellular and
intracellular fluids, indicating its widespread
distribution in whole body.
Importances of Vd
Vd: 5L(plasma), 10~20L(systemic fluid),
> 40L(tissue and organs), >100L(concentrate in
some organ or large area of tissue)
a 70kg male, blood volume is 5.5L, plasma 3L ,
extracellular fluid is 12L, total body fluids about
42L, Vd of aspirin is 11L, diazepam 80L,
morphine 230L.
Factors Affecting Drug Distribution
a. Plasma protein binding血浆蛋白结合
Acidic drug-albumin, basic drug-albumin,
lipoptrotein, and 1 acidic glycoprotein.
D ≒ D + P ≒ DP
Free drug
bound drug
Plasma Protein Binding Rate(PPBR)
The fraction of drug binding to plasma protein to
amount of drug in the body:
The extent of combination of drugs with plasma
protein differs, which is usually expressed by the
ratio of the concentration of bound drug over
total drug in the body, i.e., PPBR.
Plasma Protein Binding
Reversibility
Inactivation
Molecule bigger
Unmetabolized
No transmembrane
Capacity-limited protein binding
Replacement
Drug interaction of plasma protein binding
Drug A: 1000 molecules
+
Drug B with 94% bound
99.9% bound
1 molecules free
90.0% bound
100 molecules free
100-fold increase in free pharmacologically active
concentration at site of action.
Effective
TOXIC
Plasma Protein Binding
Replacement
Anticoagulant warfarin with PPBR of
99%, an anti-inflammatory agent,
phenylbutazone with PPBR of 98%,
when the two drugs are used at the
same time, the replacement may occur,
and eventually bleeding tendency due
to the high free warfarin.
Organ blood flow
The more blood flow of tissue and organ,
the more drugs go to these tissues or
organs. Such as liver, brain, kidney and lung.
Organ blood flow
Some higher lipid-solubility drug first go to
the abundant blood flow tissue or organ and
then go to the much poor blood flow tissue or
organ, such as thiopental first go to brain,
and then go to muscle or other lipid tissue to
form new equilibrium called redistribution.
The properties of drug and physical pH
The pH of body fluid may influence the
extent of dissociation of drugs and thus
affect the distribution and transport of
drugs in the body.
The properties of drug and physical pH
The pH of cellular fluid is 7.0 and that
of extracellular fluid is 7.4 under
physiological circumstances, so the
concentration of weak acidic drugs in
extracellular fluid is higher than that in
cellular fluid.
The properties of drug and physical pH
Reducing the pH of the blood can transfer
weak acidic drugs into cells, while decreasing
the pH of the blood can cause right-about
transfer of acidic drugs. The situation for
weak basic drugs is opposite.
The properties of drug and physical pH
Pentobarbital is a weak acidic drug,
when it is used overdose and
intoxication, the sodium bicarbonate
may used to base the blood and urine to
increase the excretion of pentobarbital
and to anti-toxicant.
Metabolism
(Biotransformation)
The process in which drugs result in chemical
changes, that may lead to the termination or
alternation of biological activity. it is also
called biotransformation of drug in the body.
The metabolism and excretion of drugs are
generally called elimination.
Cytochrome P450 (P450)
Enzyme induction
Enzyme inhibition
Enzyme inducer: phenobarbital, rifampin,
carbamazepine, phenytoin sodium, dexamethasone
Enzyme inhibitor: chloramphenicol,
ketoconazole, cimetidine
Excretion of Drug
The process in which of their prototype
and their metabolites transferred from
the internal to the external environment
of body.
The pathways of excretion includes: renal
peptic, respiratory and milk excretion.
The pathways of excretion
Kidney肾脏
Glomerular filtration: accumulation
Active tubular secretion:
Probenecid丙磺舒 – penicillin
Passive tubular reabsorption
phenobarbital – sodium bicarbonate
MTC
MEC
稳态 约经5个半衰期达
 到STEADY STATE
血
药
浓
度
稳态浓度
 与给药间隔和剂量相关
 与生物利用度和清除率相关
时间（半衰期）
靶浓度（target concentration）
有效而不产生毒性反应的稳态血浆药物浓度（Css）
Css-max < MTC
Css-min > MEC
Characteristics of drugs that predict that a
dosage adjustment should be made in renal
disease
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Primary urinary excretion of the parent
drug or active metabolites
>50%
Low therapeutic index
Therapeutic index (TI) ＝ LD50/ED50
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High protein binding
Small volume of distribution of the drug
Renal impairment induced by drugs
Antipyretic-analgesic and antiinflammatory drugs
non-steroidal anti-inflammatory
drugs (NSAIDs)
Aspirin-like drugs
Membrane phospholipids
PLA2
Arachidonic
acid
NSAIDs
PGG2
glucocorticoid
COX
PGH2
PGI2
PGF2
PGE2
TXA2
(vascular (bronchial (vascular dilation; (vascular
dilation;
constriction) GI protection;
constriction;
platelet
pain,fever)
thrombosis)
disaggregate;
pain)
lipoxygenase
LTs
LTC4/
D4/E4
Bronchial
constriction ;
Alteration of
vascular
permeability
LTB4
chemotaxis
COX-1
Production
Function
Constitutive
Physiological function
gastric protection
platelet aggregation
COX-2
Inducible
Pathological function
facilitate inflammation
cause fever and pain
peripheral vessel regulation
renal blood distribution
NASIDs effects unwanted side effects
therapeutic effects
Nephrotoxicity
worsening of renal function，
hypertension，fluid retention，
hyperkalaemia
necrosis of renal papillae, interstitial
nephritis, renal failure etc.
-caused by the inhibition of renal
cox-1 by NSAIDs(eg. fenoprofen)
Appendix:
Treatment aim
①relieve the acute
Acute
gout
chronic
gout
gouty arthritis
attack
②control the
hyperuricemia
reduce the serum
level of uric acid
Drug
Mechanism
(-)
colchicine
NSAIDs
Indometh
acin
allopurinol
probenecid
inflammatio
n
(-)
inflammation
↓uric acid
synthesis
↑uric acid
excretion
Appendix:
allopurinol
purine
xanthine oxidase
uric acid
probenecid
excretion
hyperuricemia
NSAIDs
joints
kidney
Other
tissues
arthritis
Kidney
damage
Other tissue
damages
Indomethacin
colchicine
Drugs-induced interstitial nephritis
Drugs-induced glomerular pathology
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A relatively uncommon condition which is
characterised by inflammation of the renal
tubules, glomeruli and surrounding tissue.
Interstitial nephritis is usually be temporary
and often associated with the use of a
particular medication. Chronic and
progressive forms do exist.
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Drugs that have been associated with
interstitial nephritis include penicillins,
ampicillin, cephalosporins, sulpha
drugs, non-steroidal anti-inflammatory
agents, furosemide and thiazide
diuretics. May result in mild kidney
dysfunction or acute renal failure.
Treatment may be with corticosteroids.
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Glomerular pathology is less common
than tubulointerstitial injury in druginduced nephrotoxicity. Prognosis.
eg. NSAIDs
Important causes of nephrotoxicity
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Gentamicin
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Aminoglycosides
Pharmacokinetics
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Absorption: po poorly, im, iv
Distribution :
low concentration in most tissue except
renal cortex
 Can pass placental barrier, ×BBB
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Excretion: in unchanged form by
glomerular filtration
Adverse reactions
Dangerous factors:
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Using continuously more than 5 days
High dose
Eldly and children
Renal insufficiency
Concurrent use with loop diuretics or
other nephrotoxic drugs
cyclosporin
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Cyclic undecapeptide isolated from Tolypocladium
inflatum, that has potent immunosuppressant activity on
both humoral and cellular systems. The use of cyclosporin
has made transplant surgery(eg.renal transplantation) much
easier, although the long term consequences of suppressing
immune function are not yet clear.
Used widely as an an antirejection drug in transplant
surgery and to prevent and treat rejection and graft-versushost disease in bone marrow transplant patients by
suppressing their normal immune system.
How cyclosporin nephrotoxicity is
manifested
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Long term usage of Cyclosporin
generally may results in Cyclosporin
Nephrotoxicity
Short term usage at high dosages can
also cause Cyclosporin Nephrotoxicity
Characterised by:
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Renal dysfunction
Reduced GFR,Reduced renal blood flow,
Rise in serum creatinine
Decrease in renal clearance
Rise in RAS, arteriolopathy of afferent
arteriole vascular dysfunction and elevated
BUN
Non-prescription medicines
eg.NSAIDs compound preparation
Contrast agents
eg.iodinated radiological contrast agents
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Nephrotoxicity
Principle for treatment of renal damage
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early discovery, early diagnosis, timely
withdrawal, timely treatment
prevention first
Diuretics
Diuretics are a family of drugs that act on kidney
and promote the excretion of urine (including water
and electrolyte). (mainly used in edema)
Classification of Diuretics
Ⅰ. Loop (high efficacy diuretics) diuretics
Ⅱ. Thiazide (moderate efficacy ) diuretics
Ⅲ. Potassium-sparing (low efficacy) diuretics
Ⅳ. Carbonic anhydrase inhibitors
Ⅴ. Osmotic diuretics (dehydrants)
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