Plasma Protein Binding and Tissue Distribution of Drugs Flashcards
Binding of Drugs to PP
Extensive Binding
Oral Anticoagulants, Oral Antidiabetics, NSAIDs, Loop
Diuretics, CV drugs (amidarone, digitoxin, prazosin)
Benzos (diazepine and midazolam), Montelukast
Barely Bind
Aminoglycosides, Codeine, Ethanol, ISH, Metformin,
Metoprolol, Lisinopril, Lithium
Intermediate Binding
Aspirin, Paracetamol, Phenytoin, Carbamazepine,
Theophylline
Extent indicated by % of unbound and % of bound drugs
Strength of binding indicated by binding affinity
(= association constant Ka)
Plasma Proteins that Bind Drugs
Albumin
High concentration therefore has high binding capacity
Preferentially binds acidic drugs (ex loop diuretics,
NSAIDs)
Also binds some basic drugs
Is a - acute phase protein
Decreased in: chronic liver failure, nephrotic syn, burns
a1 Acid Glycoprotein
Lower concentration-> lower binding capacity
Preferentially binds basic drugs (phenothiazines,
propanol, local anaesthetics)
Also binds neutral drugs (ex steroids)
+ acute phase protein
Decreased in: end stage liver disease, nephrotic syn,
Post treatment with steroids
Others Lipoproteins: Amphotericin B, Probucol SHBG Thyroxine Binding Globulin Transthyretin: thyroxine, retinol Transcobalamin: vitB12 Transferrin: Fe3+
Binding Characteristics
Low energy
Saturable
Reversible
Competitive
Delays elimination of drugs as only free molecules can be eliminated
Amount of drug bound to protein depends on:
Conc. of free drug
Affinity for binding site
Conc of protein
If bound and unbound fractions of drug are in equilibrium -> drug can leave plasma and be readily taken up by tissues. Bound dissociates when unbound leaves plasma to maintain equilibrium
Example: Donepezil
If drug not taken up extensively or has strong PPB-> plasma binding retains drug mainly in plasma
Example: Warfarin, sulfadoxine
Consequences of Extensive Plasma Protein Binding
Plasma proteins represent a silent binding site for drugs
Bound drug is inactive
As long as it’s bound it also can’t be eliminated
Changes in free drug fractions are only significant for extensively bound drugs
If decrease in binding by 5%-> significant increase in
free concentration
1) Delayed onset of effects
Examples: Fluoroquinolones
Acetlydigitoxin
2) Prolonged effect and delayed elimination
(slow release from PPB)
3) Competitive displacement by other drugs
-> increases elimination; therapeutic and toxic doses
Example: Amiodarone, furosemide displace warfarin
4) Competitive displacement of endogenous compounds
Example: Sulfonamides displace bilirubin
Ibu displaces uric acid-> benefitial
5) Changes in PP level influences effect of extensively
bound drugs (decrease level increases effect)
Ex: Hypoalbuminuria: lasartan may have increased
effect
6) Extensively bound drugs can’t be removed by
hemodialysis
Increase of dose is not proportionate to increase in free concentration as binding site can saturate
Binding of Drugs to RBC
Some lipid soluble drugs enter RBC and bind to IC proteins
-> high RBC to plasma concentration
Example: Cyclosporin, tacrolimus, sirolimus
Distribution of Drugs to Tissues
Factors Affecting Distribution
Chemical
Molecular Weight
Extremely large-> decreased distribution, stay in
plasma
Large remain in EC space; can be used in pregnancy
Ex: Heparin
Binding to Plasma Protein
Solubility
Lipophilic: readily diffuse to tissues
Biological
Blood Flow
Distribution initially determined by blood flow
Later distribution altered by tissue affinity-> redis
All IV GA, Chloroquine, lead
Capillary Porosity
Fenestrae
Distribution of Drugs to Specific Tissues
Liver
Many drugs reach liver in high conc initially
Sinusoids: slow blood flow-> longer residence time
Fenestrated endothelium
Membrane specialised for uptake; cont.
microvilli
Numerous transporters: GLUT2, NTCP, OATP..
Some drugs accumulate and are stored here
Examples: Lipid soluble vitamins, cationic amphiphilic
drugs (chloroquine, TCADs)
Methotrexate: as is plyglutamate with - charge
Distribution of Drugs to Specific Tissues
Lungs
Exposed to many drugs due to largest blood flow
Parenterally given drugs pass lungs first
–> anticancer drugs can cause fibrosis
Cationic amphiphilic drugs are retained
Examples: Heroin, Tetracaine
Bind to - charge of surfactant; entrapment in - interior of mitochondria, entrapment in acidic interior of lysosomes
Heroin can cause ARDS
Amiodarone may cause pulmonary fibrosis
Distribution of Drugs to Specific Tissues
Adipose Tissue
Highly lipid soluble drugs accumulate and are stored in fat.
Limited by low blood supply
Examples
Amiodarone, Probucol, ergocalciferol, terbinafine
Halothane
Testosterone cypionate
Distribution of Drugs to Specific Tissues
Bone
ECM contains sodium apatite
Some drugs ex Tetracyclines bind to this
Inorganic ions can be incorporated
ex: bisphosphonates instead of phosphate ions
Distribution of Drugs to Specific Tissues
Skin
Keratophilic drugs are those with high affinity to skin
Can be advantageous for antimycotics
Examples
Itraconazole, Terbinafine
Distribution of Drugs to Specific Tissues
Thyroid Gland
Follicular cells accumulate iodide via Na/I Symporter
NAI131 uptake significance:
Used for radiotherapy of hyperthyroidism
NAI123 uptake significance:
Can be used for scintigraphy
Methimazole and PTU accumulate here
Distribution of Drugs to Specific Tissues
Brain
BBB restricts entry
Extreme stress can increase permeability of BBB
BBB No fenestrae Tight junctions Astrocytes, pericytes Exporters: Pgp, BCRP, MRP
Lack of BBB at area postrema-> vomiting
Mechanism of Entry
Diffusion
Carrier Mediated via LAT1 and MCT1
R Mediated Endocytosis via R for ex Insulin
Drugs that can enter
Lipid soluble/amphiphilic: GA, antipsychotics,
antidepressants, hypnotic and anxiolytics, centrally
acting sympathimimmetics
Little lipid soluble durgs with low m.w and low PPB
Paracetamol
Those carried by transporters
LAT1: L-DOPA, methyldopa, gabapentin
MCT1: lactate, pyruvate, ketone bodies
Overcome BBB
Osmotic opening by Mannitol
Distribution of Drugs to Specific Tissues
Placenta
Rough placental structure:
Trophoblast
Endothelial cells
Interstitial c.t.
Is an effective barrier against highly charged and hydrophilic drugs (ex. Heparin), also against strongly PB drugs (ex thyroxine)
Moderately effective against drugs that are exported from placenta-> maternal blood via transporters
1ary active transporters: Pgp: digoxin, taxol
BCRP2: prazosin, dantrolene, mitoxantrone
MRP2: benzylpenicillin
OCT3-MATE: cimetidine, clonidine, amiloride, quinidine
Ineffective against lipophilic drugs; placenta only delays
passage
Example: Atropine; no protection from chronic exposure
Mechanism for placental transport
Diffusion
Carrier Mediated ex MCT and PEPT
R Mediated ex folic acid
Classification of Drugs based on Risk to Fetus
A
No risk; supported by evidence
Ex: Heparin
B
No risk; human studies
Ex: Paracetamol, penicillins, macrolides
C
Risk can’t be ruled out
Ex: Aspirin, Beta Lactamase AB
D
Evidence for risk +; given if benefit>risk
Ex: Antitumor drugs
X
NEVER give
Ex: ACE inhibitors, coumarins
