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Transcript
DISTRIBUTION OF DRUGS
A. BINDING OF DRUGS TO BLOOD-BORN ELEMENTS
I. BINDING OF DRUGS TO PLASMA PROTEINS
1. FEATURES OF PLASMA PROTEIN BINDING
a. Drugs binding to plasma proteins: high – intermediate – low binding
b. Plasma proteins that bind drugs: albumin, α1-acid glycoprotein (AGP),
others: TBG, SHBG, transcobalamin, lipoproteins
c. Binding characteristics
2. CONSEQEUENCE OF STRONG PLASMA PROTEIN BINDING
a. General rules
b. Specific consequences of strong plasma protein binding:
• Delayed onset of effect
• Delayed elimination
• Competitive displacement of other drugs
• Competitive displacement of endogenous compounds
• Decreased protein level increases, increased protein level decreases the effect
II. BINDING OF DRUGS TO RED BLOOD CELLS
1. CHLORTHALIDONE (a thiazide diuretic) – binds to carbonic anhydrase
2. CYCLOSPORINE, SIROLIMUS, TACROLIMUS (immunosuppressive drugs) bind to immunophilin
B. DISTRIBUTION OF DRUGS TO TISSUES
I. FACTORS AFFECTING DRUG DISTRIBUTION
1. Chemical factors: molecuar weight; binding to plasma proteins; solubility
2. Biological factors: blood flow to tissues; capillary porosity
II. DISTRIBUTION OF DRUGS TO SPECIFIC TISSUES
1. LIVER – many drugs reach high concentrations in liver (reasons; some accumulate in liver)
2. LUNG – 1st pass uptake after inj; transient uptake, yet cationic amphiphilic drugs may be retained
3. ADIPOSE TISSUE – highly lipid soluble drugs; drugs esterified with LC fatty acids (depot drugs)
4. BONE – bind to Ca-apatite (tetrac); incorporate into Ca-apatite (substitute Ca++, PO43-, or –OH)
5. SKIN – keratophilic drugs (itraconazole, terbinafine, griseofulvin)
6. THYROID GLAND – iodide, I131-iodide uptake by NIT
7. BRAIN
a. Mechanisms of drug entry into the brain
b. Influencing factors for entry of drugs into brain
• Chemical factors
• Biological factors: the blood-brain barrier
- The constituents of BBB
- Drugs excluded from brain: ionized drugs; e.g. prot-bound drugs; Mdr, Mrp, Bcrp substrates
- Areas lacking BBB – area postrema
- Overcoming the BBB: osmotic opening; tight junction openers, exporter inhibitors
8. PLACENTA AND FETUS
a. Placental layers: trophoblast cells (ST, CT) – interstitial connective tissue – endothelial cells
b. Mechanism for placental transport of drugs – diffusion, fac. diffusion, sec/tert active transport
c. The placenta as a barrier for some drugs, but not for others
d. Drug-induced adverse effects in the fetus:
• Transplacental carcinogenesis: DES (vaginal clear cell adenocarcinoma)
• Teratogenesis (fetal malformations): - thalidomide, retinoids, cumarins, ACEI, ATII-inhibitors
fetal hydantoin sy., fetal alcohol sy.
e. Classification of drugs based on risk to the fetus: A, B, C, D, X
DISTRIBUTION OF DRUGS
The absorption processes deliver drugs into the blood.
Blood-borne drugs may:
A. Bind to blood-borne elements, namely
I. Plasma proteins,
e.g., albumin, α1-acid glycoprotein (AGP) – this occurs commonly
II. Intracellular proteins in blood cells, especially RBC
e.g., carbonic anhydrase, immunophilin – significant binding is exceptional
B. Leave the blood and may be taken up into tissues
A. BINDING OF DRUGS TO BLOOD-BORN ELEMENTS
I. BINDING OF DRUGS TO PLASMA PROTEINS
1. FEATURES OF PLASMA PROTEIN BINDING:
a. Drugs that bind to plasma proteins:
Drugs EXTENSIVELY bound (>90%)
Drugs BARELY bound (<10%)
Oral anticoagulants: warfarin
Oral antidiab.: glimepiride, glipizide, glyburide
Lipid lower. drugs: gemfibrozil, statins
NSAID: indomethacine, phenylbutazone
ibuprofen, naproxen, diflunisal, diclophenac
Loop diuretics, e.g. furosemide
Antihypertensives: diazoxide, losartan
Cardiovasc: amiodarone, prazosin, felodipine,
nicardipine, digitoxin, ticlopidine
Antiinfectives: ceftriaxone, nalidixic acid,
ketoconazole, itraconazole, suramin, nelfinavir
Benzodiazepines: diazepam, midazolam
Others: montelukast, zafirlukast, entacapone
leflunomide
aminoglycosides, e.g. gentamycin
flucytosine, fluconazole
isoniazid
ifosfamide
metformin
codeine
metoprolol, tocainide
ouabain (strophantin)
lisinopril
lithium
ethanol
Drugs with INTERMEDIATE binding – examples:
phenytoin (89%), carbamazepine (74%), phenobarbital (60%), theophylline (60%),
hydrochlorothiazide (58%), aspirin (50%), paracetamol = acetaminophen (20%)
b. Plasma proteins that bind drugs:
• Albumin:
- Has high concentration (4 g/dL) → high binding capacity
- Binds acidic drugs preferentially (NSAID, loop diuretics), but also basic drugs
- Is a negative acute phase protein (↓
↓ in inflammation, cancer, tissue injury)
- Decreased in - chronic liver disease, malnutrition (decreased synthesis)
- nephrotic sy (loss into urine), burns (loss through the skin)
• α1-Acid glycoprotein (AGP):
- Has lower concentration (50-150 mg/dL) ) → lower binding capacity
- Binds basic drugs (e.g. phenothiazines, TCAD, propranolol, local anesthetics,
alfentanyl, atracurium) with high affinity (e.g. for thioridazine 1000-fold higher
than albumin) and neutral drugs (e.g. steroids)
- Is a positive acute phase protein (↑
↑ in inflammation, cancer, tissue injury)
- Decreased - endstage liver disease, in nephrotic sy
- after treatment with estrogens
• Rarely others:
- SHBG (Sex hormone-binding globulin): testosterone, dihydrotestosterone, estradiol
- TBG: thyroxine;
- Transthyretin: thyroxine, retinol
- Transcobalamin: vitamin B12
- Lipoproteins: amphotericin B, probucol, fulvestrant
c. Binding characteristics:
• low energy (apolar and ionic interactions)
• reversible (equilibrium between the bound and unbound fractions)
• saturable (at high concentration)
• competitive (→
→ competitive displacement)
2. CONSEQEUENCES
OF STRONG PLASMA PROTEIN BINDING
a. General rules:
Rule 1:
Plasma proteins represent silent binding site (depot) for drugs:
• the BOUND drug is inactive,
• the FREE, UNBOUND drug can leave the blood and act and can be acted upon.
As long as a drug is bound to plasma protein, it
• cannot act (as it can not reach the site of action)
• cannot be eliminated (as it can not reach enzymes and transporters, and
can not be filtered at the glomeruli).
Rule 2:
Only for extensively bound drugs,
can changes in the FREE (active) drug fraction be significant.
Examples to illustrate rule 2:
• Drug with intermediate plasma protein binding:
Decreased binding causes insignificant increase in free concentration
BOUND (%)
50
45
FREE (%)
50
55
→ only 10% increase
in the free fraction
• Drug with extensive plasma protein binding:
Decreased binding causes significant increase in free concentration
BOUND (%)
95
90
FREE (%)
5
10
→ 100% increase
in the free fraction
b. Specific consequences of strong PPB:
1. Delayed the onset of effect
Extensive PPB delays and restricts distribution of the drug to the target, therefore it
delays the onset of effect, or (in extreme case) may even prevent the systemic effect.
Examples:
• Acetyldigitoxin: highly bound → delayed onset of effect after iv injection
Strophantin:
barely bound → rapid onset of effect after iv injection
• Nalidixic acid:
PPB ~95% → the free conc < MIC
→ no systemic antibiotic effect (used only for urin. tract infect.)
Fluorokinolones: PPB ~ 40% → the free conc > MIC
→ systemic antibiotic effect → useful for systemic infections
2. Delayed elimination
Extensive PPB restricts distribution of the drug to the organs of drug elimination
(biotransformation and excretion) and thus delays the elimination of the drug.
Examples:
• digitoxin (90% bound)
– T1/2 = 7 days (for strophantin the T1/2 = 20 hrs)
• teicoplanin (95% bound)
– T1/2 = 4 days
• thyroxine (99.7% bound)
– T1/2 = 7 days (for T3 the T1/2 = 2 days)
• leflunomide (>99.4% bound) – T1/2 = 14 days
• suramin (99.97% bound)
– T1/2 = 50 days
3. Competitive displacement of other drugs
Extensively protein-binding drugs
• are prone to displace other drugs bound to plasma proteins,
• are prone to be displaced by other extensively binding drugs.
Consequence of „COMPETITIVE DISPLACEMENT”:
a. the displaced drug moves into tissues
→ higher tissue conc. → increased therapeutic (and toxic) effect
b. the displaced drug is filtered in the kidney and moves into tissues,
→ increased elimination by excretion and/or biotransformation
(e.g. furosemide → propranolol displacepent → ↑elimin of propranolol)
Note: effect „b” counteracts effect „a”!
Therefore, increased effectiveness/toxicity is
generally transient and self-limiting.
However, marked increase in effectiveness/toxicity occurs
if elimination becomes capacity-limited!
Examples: • amiodarone → glyburide: excessive hypoglycemia!
• phenylbutazone, amiodarone or furosemide → warfarin: bleeding!
4. Competitive displacement of endogenous compounds
Extensively protein-binding drugs are prone
• to displace endogenous compounds bound to plasma proteins,
• to be displaced by extensively binding endogenous compounds.
Examples: • sulfonamides, ceftriaxone → bilirubin: Kern icterus in neonates!
• ibuprofen → uric acid: ↑ uric acid excretion (beneficial)
• endog. compounds in uremic plasma → larger Vd for many drugs
5. Decreased protein level will increase,
increased potein level will decrease
the effect of extensively protein-binding drugs.
• In hypoalbunemia:
diazoxide or losartan → increased hypotensive effect!
• In patients with ↑AGP concentration (e.g. acute phase reaction):
- alfentanyl → decreased analgetic effect
- atracurium → decreased muscle relaxant effect
II. BINDING OF DRUGS TO RED BLOOD CELLS
Exceptionally, some lipid-soluble drugs enter RBC and bind to proteins in RBC,
forming a depot in these cells – Examples:
1. Chlorthalidone (a thiazide diuretic)
Chlorthaidone binds to carbonic anhydrase in RBC strongly → RBC : plasma
~70 ! → delayed elimination (T1/2 = 50 hrs) – its T1/2 correlates with the amount of
carbonic anhydrase in RBC
2. Cyclosporine, tacrolimus, sirolimus (=rapamicin)
These immunosuppressive drugs bind to immunophilin that is also present in
RBC. Therefore, these drugs accumulate in RBC → RBC : plasma ~15-60 !
Chlorthalidone (a thiazide diuretic) binds to carbonic anhydrase in RBC strongly
and accumulates in RBC 70 fold over plasma
Chlorthalidone is relatively lipophilic and thus it can diffuse into RBC. As thiazides in
general, chlorthalidone can also bind to carbonic anhydrase. Strong binding of this
drug to RBC-carbonic anhydrase enzyme has been demonstrated by X-ray
crystallography (see below, left; Temperini et al., J. Med. Chem. 52: 322-8, 2009).
RBC contain ~90% of the total carbonic anhydrase content in the body. For
chlorthalidone, the RBC represents a depot site. This explains why chlorthalidone has
a long elimination half-life (T1/2 = 20-70 hrs). Moreover, interindividual variation in the
T1/2 of chlorthalidone correlates with the activity (amount) of carbonic anhydrase in the
RBC of patients (see below, right).
O
NH
Chlorthalidone
O
O
S
NH2
OH
Cl
O
O
H
H
Asn67
H
O
O
H
N
H
W146
O
H
NH
O
H
H
O
Thr200
O
HN
Thr199
12
NH2
H
W161
Cl
S
O
NH
Zn
O
2+
His119
H
His94
His96
Carbonic anhydrase activity
in blood (x1000 U/ml)
W142
11
10
9
8
7
6
5
4
25
50
Elimination T1/2 (hrs)
75
B. DISTRIBUTION OF DRUGS TO TISSUES
I. FACTORS AFFECTING DRUG DISTRIBUTION
1. Chemical factors:
a. M.w.: • very large molecules stay in the plasma – dextran (up to 2000 kDa)
• large molecules remain in the extracellular space – heparin (5-30 kDa)
b. Binding to plasma proteins: restricts distribution – nalidixic acid
c. Solubility:
• Hydrophilic, ionized drugs – may distribute in the extracellular space
- acids: EDTA, deferoxamine
- bases: aminoglycosides, succinylcholine
• Lipophilic compounds readily diffuse into tissues (have ↑Vd)
Extremely lipid soluble compounds accumulate in the adipose tissue.
2. Biological factors:
a. Blood flow:
- initially, distribution is dictated by blood flow
(lung: 14, kidneys: 4, heart: 1, brain: 1, liver (a+v): 1 ml/min/g)
- later, distribution may be modified by „tissue affinity”
examples for redistribution:
thiopental → muscle, fat; chloroquine → liver; lead → bone
b. Capillary porosity:
CAPILLARY BED
Hepatic sinusoids
Renal peritubular capillaries
Renal glomerulus
Muscle
Brain
PORE SIZE (nm)
50-200
(fenestrae)
7-8
5-6
0
PORE PERMEABLE FOR
Protein-bound drugs
Protein-unbound drugs only
None
II. DISTRIBUTION OF DRUGS TO SPECIFIC TISSUES:
1. LIVER
• Many drugs reach high concentration in the liver, because
- drugs given orally pass the liver first
- in the hepatic sinusoids:
• the blood flow is slow → residence time is long
• the endothelium is fenestrated + lacks basement membrane
- the sinusoidal membrane of liver cells contains microvilli + transporters
e.g.: GLUT2: glucose; NTCP: bile acids; OATP2: pravastatin, fexofenadin,
methotrexate; OCT1: metformin, cimetidine; TC-II rec: vitB12-TC complex
• Some drugs accumulate and are stored in the liver:
- Cationic amphiphilic drugs, e.g. chloroquine, TCAD (lysosomal pH-entrapment)
- Metotrexate – entrapped as polyglutamate → may cause cirrhosis
- Lipid soluble vitamins (in fat storing parasinusoidal cells = perisinusoidal cells)
2. LUNG
The lung is exposed to many drugs, at least transiently, because
• the lung has the largest blood flow (14 ml/min/g)
→ drugs may be taken up rapidly (but also washed out rapidly)
• drugs given parenterally pass the lung first
→ cytotoxic anticancer drugs may cause pulmonary injury (fibrosis)
e.g., bleomycin, busulfan, carmustin, mitomycin
Cationic amphiphilic drugs may be retained in the lung by
• by binding to negative charges of the surfactant
• by entrapment in the negative interior of mitochondria
• by entrapment in the acidic interior of lysosomes (in alveolar macrophages)
Cationic amphiphilic drugs (amines, alkaloids with pKa >8):
Local anesthetics: tetracaine, bupivacaine; phenothiazines, TCAD;propranolol
Heroin (→
→ ARDS!); amiodarone (→
→ pulmonary fibrosis!)
3. ADIPOSE TISSUE
Accumulates and stores highly lipid soluble drugs/chemicals:
- Amiodarone, probucol, ergocalciferol (Vit D2), terbinafine, fulvestrant
- Halogenated hydrocarbons, halogenated ethers:
e.g.: halothane, (methoxyflurane)
DDT (dichloro-diphenyl-trichloroethane)
- Drugs esterified with long-chain fatty acids (depot drugs, prodrugs!):
e.g.: pipothiazine palmitate
testosterone cypionate (cypionate = cyclopentano-propionate)
4. BONE:
Contains calcium-apatite: Ca10 [(PO4)6 (OH)2],
• to which some drugs (with affinity to calcium) may bind (by adsorption):
tetracyclines (deposition into growing bone) → discoloration of teeth
• into which some ions may be incorporated:
♦In place of calcium ions:
- Sr2+: strontium ranelate → ↓bone resorption,↑
↑bone formation → for osteop.
3+
- Ga : gallium nitrate → ↓bone resorption → ↓se Ca++ in osteolytic tumor
- Pb2+ → stored in bone (increasingly mobilized during pregnancy → fetus!!!)
- Bone seeking radioactive metal ions: 226Ra, 90Sr, 144Ce, 239Pu → osteosarc.
♦In place of phosphate ions:
Bisphosphonates → ↓osteoclast function → treatment of osteoporosis
♦In place of hydroxide ions:
Fluoride - low intake: stimulates osteoblasts → treatment of osteoporosis
- overdose: formation of exostoses
formation of mottled enamel (dental fluorosis)
5. SKIN: Drugs with high affinity to the skin are called keratophilic.
The antimycotic drugs itraconazole, terbinafine and griseofulvin are keratophilic.
Their distribution to skin and skin appendages is an advantage for them in
treatment of the fungal skin infections (e.g., tinea, onychomycosis).
6. THYROID GLAND: accumulates iodide (I–) by the Na-iodide symporter (NIS)
Significance of NaI131 uptake (I131 emits β and γ radiation, T½ = 8 days):
• used for thyroid diagnostics – detected by γ radiation
(uptake kinetics; scanning of I131 above the gland)
used for radiotherapy of hyperthyroidism (its β radiation destroys the thyroid)
•
• may be released in nuclear accidents (Chernobil)
→ may cause hypothyroidism (!) - can be prevented by iodinated salt
7. BRAIN
a. Mechanisms of drug entry into the brain:
• Carrier-mediated transport: for some drugs
e.g.: amino acid transporter: L-DOPA
• Diffusion: for most drugs
b. Influencing factors for entry of drugs into the brain:
• Chemical factors:
♦ Lipid solubility: gen. anesthetics (halothane, thiopenthal), donepezil, heroin!
♦ Ionization: - atropine vs methylhomatropine
- physostigmine vs neostigmine
• Biological factors: the blood-brain barrier (BBB)
♦Constituents of BBB:
- Tight junctions between capillary endothelial cells (EC)
- Lack of fenestration in ECs
- External fortifications of ECs: basement membrane + astrocytes
- Exporters in the ECs (P-gp, BCRP, Mrp-transporters)
♦Drugs that are excluded from the brain by the BBB:
(1) Highly ionized compounds: tubocurarine, neostigmine, aminoglycosides
(2) Highly plasma protein-bound drugs:
- Diflunisal: not antipyretic (unlike aspirin), only anti-inflammatory
- Suramine: is not useful against trypanosomia in brain (→
→ melarsoprol)
Yet, donepezil (an anti-Alzheimer drug) is 96% PPB, but easily crosses the BBB
and its Vd is 12 L/kg! Explanation: Donepezil is lipophilic and PPB is an
equilibrium process: the free drug leaves the plasma and diffuses into the brain.
♦Drugs that are excluded from the brain by the BBB (continued):
(3) Drugs that are substrates for multidrug resistance transporters localized
in the luminal membrane of brain capillary endothelial cells, such as
- P-gp substrates: digoxin, cyclosporine, vinca alkaloids, doxorubicin,
opioids without CNS effect (e.g. domperidone), non-sedating antihistamines
- Bcrp substrates: pazosin, dantrolene, mitoxantrone (DHEA-sulfate – model c.)
- P-gp and Bcrp joint substrates: imatinib, topotecan
- Mrp-substrates: benzylpenicillin, cephalexine (but NOT ceftriaxone, imipenem
→ these are used in meningitis)
GLIA
BRAIN CAPILLARY
ENDOTHELIAL CELL
Pgp
Glucose
GLUT
BCRP
MCT
Valproate
Lactate
Ketone b.
MRP1
MCT =
monocarboxylate
transporter
(H+ - carboxylate
cotransporter)
NEURON
Brain to plasma concentration ratio of some drugs that are substrate for
P-glycoprotein (mdr1a) in control mice and in mdr1a-knockout mice.
Drug
BRAIN: PLASMA
mdr1a(+/+)
mdr1a(-/-)
Cyclosporin A (immunosup.)
0.276
3.296
Digoxin (cardiotonic)
0.060
1.67
Ivermectin (anthelminthic)
0.0938
2.52
Loperamide (antidiarrheal opioid)
0.308
2.07
Quinidine (antiarrhythmic)
0.087
0.773
Vinblastine (antineoplastic)
1.67
18.7
Data indicate that Mdr1 transporter (P-gp) significantly reduces the entry of
P-gp-substrates into brain. This explains why the synthetic opioid loperamide
exerts neither analgetic nor respiratory center depressive effect, but only a
peripheral antidiarrheal effect. P-gp also prevents the entry of vinblastin into
brain, making this antitumor drug ineffective in treatment of brain tumors.
Quinidine (Q) coadministration with loperamide (L) may result in respiratory
depression because Q increases the entry of L into the brain by competitively
inhibiting the export of L from the brain capillary ECs back to the blood via P-gp.
♦Lack of BBB at some areas:
e.g. at the area postrema (near the chemoreceptor trigger zone)
→ drugs may induce nausea or emesis (morphine, apomorphine, digitalis)
by acting on the chemoreceptor trigger zone.
♦Overcoming the BBB to promote drug entry:
- Clinically used procedure: “osmotic opening”:
intracarotid infusion of 1.4 M mannitol
+ the drug i.v. (e.g. methotrexate, cyclophosphamide)
- Experimental procedures:
• Tight junction opener endogenous substances:
TNF, endothelin-1, bradykinin, histamine
• Exporter inhibitors (poorly-transported substrates):
- Inhibitors of P-gp: cyclosporin, quinidine, verapamyl
valspodar (a cyclosporin analogue, which lacks the
immunosuppressive effect of cyclosporine)
- Inhibitors of Bcrp: pantoprazole
- Inhibitors of Mrp: probenecid
8. ACROSS THE PLACENTA INTO THE FETUS
Placenta: there are 3 layers between the maternal and fetal blood (25 µm):
• Trophoblast cells (ST and CT) – BB membrane facing the maternal blood
• Interstitial connective tissue
• Endothelial cells of the fetal blood vessels
A schematic representation of the maternal-fetal interface in the placenta
(ST: syncytiotrophoblast, CT: cytotrophoblast, FV: fetal blood vessel)
Mechanism for placental transport of drugs:
a. Diffusion: for many drugs, e.g. atropine, phenytoin, ethanol
b. Carrier-mediated transport:
- Facilitated diffusion, e.g. by the nucleoside transporter (ENT): cytarabine (!)
- Secondary/tertiary active transport: by the
• Monocarboxylate transporter (MCT; H+-coupled): salicylates
• Peptide transporter (PEPT; H+-coupled): ACE inhibitors (!)
• Organic cation trp (OCT2; potential-driven): quinidine, glibenclamide, TCAD
c. Receptor-mediated endocytosis: folic acid, methotrexate (!)
The barrier function of the placenta – only for:
a. Charged and highly hydrophilic drugs – e.g. heparin
b. Highly albumin-bound drugs: e.g. thyroxine (99.97%).
c. Drugs that are exported from the placenta back to the maternal blood by
transporters in the brush border membrane of trophoblast (ST) cells:
• Primary active transporters (limit, but not entirely prevent transfer into the fetus):
- P-gp: digoxin, taxol, vinca alkaloids
- Bcrp: pazosin, dantrolene, mitoxantrone
- Mrp2: benzylpenicillin
• MATE (an organic cation/H+ antiporter): cimetidine, clonidine, amyloride
The placenta is an inefficient barrier for lipophilic diffusible drugs:
• It only delays passage, e.g. i.v. atropine test:
maternal tachycardia - in 1 min
fetal tachycardia
- in 15 min
• It does not protect from chronic exposure!
Drugs taken during pregnancy may cause adverse effects in the fetus:
1. Transplacental carcinogenesis: DES
→ vaginal clear cell adenocarcinoma (Observed in Massachusetts General
Hospital, Boston, 1966-69)
2. Fetal malformations (teratogenesis):
• Thalidomide:
phocomelia, amelia
• Retinoids (isotretinoin, Acutan®):
cardiac, craniofacial, CNS defects
• Coumarins:
CNS and eye defects, bleeding
• ACE inhibitors, AT-II rec inhibitors: Fetal (and neonatal) hypotension
and anuria
→ oligohydramnion
→ limb contractures
craniofacial deformities
calvarial hypoplasia
pulmonal hypoplasia
i.u. growth retardation, death
• Antiepileptics (Fetal hydantoin sy): growth + mental retardation
cardiac and bone defects
• Alcohol (Fetal alcohol syndrome):
craniofacial signs
growth defect
immune deficiency
low IQ
Classification of drugs based on risk to the fetus by FDA:
CLASS DEFINITION
A
No risk,
supported by evidence from human studies
B
No evidence for risk from human studies
C
Risk can not be ruled out
D
Positive evidence for risk;
These drugs may be given only if B > R
X
Positive evidence for risk with R > B.
These drugs must never be given to
a pregnant woman!
EXAMPLES
heparin
Paracetamol, benzodiazepines,
penicillins, cefotaxim, macrolides,
loperamide
salicylates, penicillins+β
β-lactamase
inhibitors, rifampin, paroxetine
antitumor/antiviral drugs,
antiepileptics, tetracylines
isotretinoin, ACE-inhibitors,
AT-II receptor inhibitors,
coumarins, penicillamine,
leflunomide, bosentan