pharacology (pharmacokinetics, pharmacodynamics, teratogenesis) Flashcards
4 phases of human drug clinical testing?
phase I
- studied in normal volunteers
phase II
i. in target population
ii. vs control drug
phase III
i. like phase 2 but in large groups
ii. vs control drug
phase IV
- post marketing surveillance
what is the definition of bioavailability?
= the amount of drug that reaches the systemic circulation unchanged
what is the definition of volume of distribution (VD)?
= the theoretical volume of water in which the amount of drug would need to be uniformly distributed to produce an observed blood concentration
(fat soluble drugs have huge volumes of distribution and may have prolonged duration of action as they can have a reservoir in fat tissue)
drug elimination - renal and hepatic
p394
factors that may affect need for drug monitoring: (4)
- narrow therapeutic window
- intrinsic toxicity of drug/ how severe SE are
- impaired renal/ hepatic function
- special circumstances affecting pharmacodynamics e.g. breastfeeding, pregnancy, extremes of age
important physiological changes in pregnancy that affect pharmacodynamics: (6)
- increase in circulating volume (40-50%)
- increase renal blood flow and glomerular filtration
- increased 3rd space availability (amniotic fluid and peripheral oedema)
- relatively increased fat content
- reduced albumin and other binding proteins due to overall plasma dilutional effect
- progressive insulin resistance
p 395 –> results of this
drugs that do NOT cross the placenta: (3)
HIT
heparin (unfractioned or LMWH)
insulin
tubocurarine
known teratogens:
“all the As”
- Anticonvulsants
- Antibiotics
- Anticoagulants
- Antimetabolites
- Antipsychotics
- Androgens
- Acne drugs (“A-Vitamin”)
- Alcohol
teratogenic effects of drug according to timing of exposure:
i. <20 days
ii. day 20
iii. day 34
iv. day 36
v. day 42
vi. day 84
i. <20 days –> limb defects
ii. day 20 –> anencephaly
iii. day 34 –> transposition of great vessels
iv. day 36 –> cleft lip
v. day 42 –> VSD, syndactyly
vi. day 84 –> hypospadias
drugs that may result in miscarriage: (4)
MMET
- misoprostol
- mifepristone
- ergotamine
- thrombolytics
FDA pregnancy risk categories
A
- no foetal risk in pregnancy
B
- animal studies have failed to demonstrate a risk to foetus
- no adequate studies in pregnant women
C
- animal studies have shown adverse effects on foetus
- no adequate studies in pregnant pts
- benefit > risk
D
- evidence of risk of human terategenicity
- benefit >risk
X
- evidence of risk of human teratogenicity
- risk >benefit
drugs not excreted in breast (2)
warfarin
aminoglyclasides e.g. gentamycin
AGONISTS
give examples for agonists of following receptors:
i. B1 and B2 adrenergic
ii.a2 adrenergic
iii. a1 adrenergic
iv. muscarinic
v. GABA
vi. u-opiod
vii. dopamine
i. salbutamol
ii. methyldopa
iii. phenylephrine
iv. pilocarpine
v. diazepam
vi. mrophine
vii. cabergoline
ANTAGONISTS
give examples for agonists of following receptors:
i. β1 adrenergic
ii. α1, β1 adrenergic
iii. α1 adrenergic
iv. Muscarinic
v. Histamine (H2)
vi. Testosterone
vii. Dopamine
i. atenolol
ii. labetalol
iii. doxasozin
iv. tolteridone
v. ranitidine
vi. Cyproterone acetate
vii. metoclporamide
examples of drugs that inhibit enzymes.
which enzyme is inhibited by the following drugs?
i. Diclofenac
ii. Ramipril
iii. neostigmine
iv. Zidovudine
v. Acyclovir
vi.Warfarin
vii. Methotrexate
i. COX
ii. ACE
iii. anti-cholinesterase
iv. reverse transcriptase
v.HSV-specific thymidine kinase inhibition
vi. Vitamin K epoxide reductase inhibition
vii. Dihydrofolate reductase inhibition
sodium channel blockers examples:
lignocaine
amiloride
examples of antibiotics that affect metabolic processes:
anticonvulsants
i. % of epileptic mothers who have normal pregnancies?
ii. risk of teratogenicity:
A. in normal pregnancy
B. with epilepsy
C. with epilepsy + on rx
iii. what else increases risk?
i. 90%
ii.
A 2-3%
B 4%
C 6-8%
iii. polypharmacy i.e. >1 anti-epileptic
which anti-epileptic has highest risk?
sodium valproate
also has dose-related effect on verbal IQ
how many x do anti-convulsants increase risk of teratogenicity
3x
features of foteal anti-convulsant syndrome:
- cleft lip/ palate
- microcephaly
- cardiac anomalies
- mental retardation
- urogenital defects
- neonatal coagulopathies
^^ with phenytoin
with carbamazepine also:
- neural tube defects
teratogenicity risk reduction:
(4)
- 5mg folic acid pre-conception for 3/12
- avoid polypharmacy
- use lowest dose required
- vitamin K from 36 weeks (and im to foetus) to reduce risk of PPH and neonatal haemorrhage
which anti-epileptic is safest in pregnancy?
carbamazepine
antibiotics to AVOID in pregnancy (2)
- tetracyclines
- sulphonamides
tetracyclines
i. example
ii. why to avoid?
i. doxycycline
ii. dental discolouration
chelate calcium - impair bone growth from in utero to age 7
sulphonamides:
i. how do they work?
ii. cx to foetus
ii. examples
i. inhibit folate metabolism
ii. displace bilirubin from protein and so can cause kernicterus in neonate
ii. trimethoprim
sulfasalazine (probs safe xo)
antibiotics to use with caution (3)
+ which antihistamine?
- aminoglycosides
- quinolines
- nitrofurantoin
- chloramphenicol
aminoglycosides
i. e.g.
ii. SE
i. gentamycin
ii. nephrotoxic (cause tubular destruction
CN VIII damage (vestibular component
quinolones
i. e.g.
ii. SE
i. ciprofloxacin & other -floxacins
ii. arthropathy
nitrofurantoin
SE to foetus
neonatal haemolysis
SE to foetus with chloramphenicol if given close to term
Grey baby syndrome
(cardiovascular collapse)
but local rx e.g. eye drops is okay as systemic absorption is minimal
which 3 groups of abx are considered pregnancy safe?
penicillins
cephalosporins e.g. cephalexin, cefuroxime, ceftriaxone
erythromycin
in addition to treating maternal infection, what is an additional benefit of penicillin?
as 70% of maternal serum levels are also present in foetus foetal infection e.g. syphilis can also be treated
what may the neonate be at risk of following maternal macrolide use?
neonatal cholestatic jaundice
does heparin cross placenta? why?
what are the maternal risks associated with heparin therapy?
no, too large
- haemorrhage
- heparin-induced thrombocytopenia
- local skin reaction/ bruising
warfarin
- considered teratogenic until which gestation?
- what does it cause in foetus?
- does it cross placenta?
- is there a relationship between maternal and foetal INR? thus what is there risk of to foetus?
- 12 weeks
- multiple craniofacial and skeletal abnormalities (ConradiHunnerman syndrome)
- yes
- no link, risk of fetal intracranial haemorrhage
anti-metabolites (anti-neoplastic drugs)
i. when are they CI
ii. when else should they be avoided?
i. 1st trimester & breast feeding
ii. avoid within 2-3 weeks of delivery to allow marrow suppression to recover in mother
(most agents safe in 2nd &3rd trimester)
drugs CI in breast feeding:
- Cytotoxics
- Mood stabilisers - lithium
- Sedatives - Benzodiazepines, barbiturates
- Amiodarone
- Antibiotics – tetracyclines, metronidazole,
chloramphenicol - COCP (reduced milk)
- Theophylline (irritability)
- Aspirin (Reyes syndrome)
drugs administered to mother to treat foetal conditions:
i. betamethasone
ii. corticosteroids
iii. felcainide
iv. amioderone
v. salbutamol
vi penicillin
i. reduce RDS and IVH between 26-32 weels
ii. prevent masculinisation of female fetuses in CAH
iii. foetal tachycardia
iv. resistant foetal tachycardia
v. hydrops fetalis due to congenital heart block
vi. congenital syphilis
