Pharmacokinetics, Pharmacodynamics, and teratogenesis Flashcards
Define bioavailable
The amount of drug that reaches the systemic circulation unchanged
IV drugs = 100% bioavailability
Oral drugs loose a lot of bioavailability because of first pass metabolism
Define volume of distribution
The amount of water the drug would need to be dissolved into in order to make it same conc as in blood
Fat soluble drugs = V large volume of distribution since little of it is in blood.
Water soluble drugs = Little volume of distribution
Describe phase 1 of hepatic metabolism, Also describe the 3 types of production you can end of after phase 1 of hepatic drug metabolism
Phase 1 = Metabolis in liver by reduction/oxidation/hydrolysis with the cytochrome p450 enzyme complex
There are 3 types of products drugs can become after this first phase
1) Inactive = Vast majority of drugs will be this. Biologically inert
2) Active = The metabolism itself turns the drug active. Like enalapril and diazepam
3) Toxic = Rare. Some drugs turn toxic and require an additional step to be broken down. So can cause problems in overdose, like paracetamol.
Describe phase 2 of hepatic metablicm and the 3 different conjugation agents that can be used
Phase 2 = The chemical breakdown drug is made more soluble with conjugation to another compound
Three examples
1) Glucoronate = For basic drugs like paracetamol and morphine
2) Acetate = For acidic drugs like hydralazine, procainamide, ioniazide
3) Sulphate = For oral contraceptive.
What determines whether drug is excreted in urine or liver
Urine = Most things filtered from afferent blood flow and go out in urine
Bile = If molecular weight greater then 300Da goes into faeces.
Describe enterohepatic circulation, and an example drug
If excrete in faeces through bile = Some drugs can be reabsorbed through lower GI tract before final excretion
Example = COCP
Describe the 2 processes by which drugs are filtered within the nephrons of kidney
1) Can be active in the PCT = This relies on transporters
- Anion transporters = For acidic drugs
- Cation transporters = For basic drugs
2) Or passive = In descending loop of Henle.
How are highly protein bounded drugs different in terms of their renal excretion and why
These drugs are bound to negatively charged protein carriers.
They therefore are slightly repelled by the glomerular basement membrane. So they are filtered less overall in kidneys.
Describe 6 ways in which pharmacokinetics are altered in pregnancy.
1) Large 40-50% increase in circulating volume
2) Concomitant large increase in renal blood flow and consequent GFR
3) Increased third space = Amniotic fluid and peripheral oedema
4) Relatively increased fat content as laying down maternal fat. This effects Vd
5) Reduced albumin and other binding proteins due to overall plasma dilutional effect
6) Progressive insulin resistance
Describe how clearance of most drugs changes in pregnancy and give 3 classes of drug that commonly need their doses changed as a result
There is increased clearance of must drugs.
1) Anticonvulsants often need higher drug doses
2) Mood stabalisers = Esp like lithium where close titrations of levels are needed
3) Thyroxine
Most drugs in pregnancy will have reduced levels because of the Pk changes described earlier. But 2 types of drugs may not, or be affected less. What are these
1) Highly protein bound drugs = Because the active conc is affected less. This is because of reduced albumin levels, so less binding. Example is warfarin
2) Fat solubel drugs = because there is increased fat reservoir in pregnancy and can be stored there. Example is chloroquine.
How does ampicillin cause drug interactions? Esp with COCP
It alters bacterial gut flora = Meaning reduced entero-hepatic recirculation of oestrogens
Therefore can impair effect of COCP
Name some enzyme inhibitors
Valproate (all other antiepileptics are inducers).
Also Sulphonamide drugs = like sulphonylureas, certain diuretics, and antiretrovirals
Name some enzyme inducers
Phenytoin and other barbiturates, carbemazepine, rifampicin, spirnolactone
Give some general rules for using medication in pharmacy
1) Avoid drugs in the first trimester wherever possible
2) Use smallest effective dose as possible. And use drugs for the shortest time possible
3) Choose drugs with the most extensive experience in human pregnancy
4) Avoid polypharmacy where possible
The FDA has a drug categorisation for the teratogenicity of drugs in pregnancy, what are the categories and what do they mean
A = No risk in controlled human studies. Adequate human studies B = No risk in other studies = No risk in animal studies OR risk in animal studies, but no risk in human studies. C = Risk not ruled out = Animal studies show risk. But potential benefits may warrant use of drug despite these risks D = Positive evidence of risk = Positive human evidence of risk. But again benefits may outweight risks X = Contraindicated in pregnancy = Cannot use. Risks always overweigh benefits N = Not yet classified by FDA
When is the ‘all or nothing’ effect in regards to teratogenicity and when is it
Pre-embryonic stage up to day 17 = All of conceptus is totipotent cells
So here you either get = Death or survival.
So if there is drug exposure here and pregnancy continues = Can reassure mum
How long can retinoids last before you can get pregnancy
2 years
How long can methotrexate last before you can get pregnant
3 months
At what point during pregnanct is there the most risk of teratogenesis and why
The embryonic stage from day 18-55 = Organogenesis is occuring here from weeks 2-8.
Biggest potential for structure damage.
The earlier the exposure the more marked the damage is likely to be
What sort of teratogenic effects occur in the post-embryonic period and when is this
Post-embryonic period = From 8 weeks on
Effect = Often causing IUGR eg. beta blockers.
Also some organs are still developing like kidneys = So ACE-I cause reduced renal function
What is the way to remember the main classes of teratogens. There are 8 of these name them
ALL THE A’S = There are 8 groups
Anticonvulsants Antibiotics Anticoagulants Antimetabolites Antipsychotics Androgens Acne drugs ( or Vitamin A) Alcohol
There are 4 types of drugs that may result in miscarriage what are these
1) Ergotamine = Vasoconstrictor for migraines/cluster headaches
2) Misoprostol = Prostoglandin used in termination and to start labour
3) Mifepristone = Antiprogesterone use with misoprostol in terminations
4) Thrombolytics = Like alteplase as a tissue plasminogen activator
Which antiepileptic to use in pregnancy? and why
Lamotrigine = Shows no extra risk above baseline.
What extra things should you be doing in management of mothers taking antiepileptics
Give them high dose 5mg folic acid starting pro-conception
Give Vitamin K routinely to mothers from 36 weeks. And give IM to babies to reduce risk of neonatal haemorrhage.
How does phenytoin have its teratogenic effect?
Through anti-folate mechanisms
What are the features of the foetal anticonvulsant syndrome
These occur with things like phenytoin and carbamazepine and valproate
1) Cleft lip/palate
2) Microcephaly
3) Cardiac abnormalities
4) Mental retardation
What effect does tetracyclines have on baby
1) Permanent discolouration of teeth
2) Can caused impaired bone growth in utero and up to 7 years (because they chelate calcium)
What is a sulphonamide. What are the sulphonamide antibiotics. How do these have teratogenic effect, and what effects do they have?
Sulphonamide = Any drug containing the sulphonamide chemical group.
Including co-trimoxazole, sulphasalazine.
Teratogenic = As they inhibit folate metabolism.
Sulphonamides also displace biliurubin from protein = And may cause kernicterus in neonate
Describe the 2 steps in folate metabolism, and what drugs effect each step
1) Benzoic acid to folate = Inhibited by sulphonamides
2) Folate to tetrahydrofolate = Inhibited by trimethoprim.
Name some aminoglycosides, and their effect in pregnancy
Examples = Gent + Amikacin used in urosepsis.
Effects
1) Nephrotoxic in foetus (duh)
2) Cause 8th CN damage = deafness
Outcome = Use only if essential, and monitor levels
Name some quinolones and what is the teratogenic effect
Examples = Ciprofloxacin
Evidence = Permenant arthropathy in animals. Data is too limited in humans
Outcome = Better alternatives are usually available
What teratogenic effect does nitrofuratoin have
Associated with neonatal haemolysis.
Do not use
What teratogenic effect does chloramphenical have, and can it be used?
effect = Can cause cardiovascular collapse if given close to term (grey baby syndrome)
Local eye drops = Fine, as limited systemic absorption
Can penicillins and cephalosporins be used in pregnancy?
Yes. Both are safe.
Cephalosporins = Often used first line as limited other options
Can you use macrolides in pregnancy? Give examples of macrolides and the effect they can cause
Examples = Erythromycin, azithromycin
Effect = Small risk of neonatal cholestatic jaundice
Outcome = Appear safe, can use.
Can heparin be used in pregnancy? Why? Give 3 side effects of heparin
Both unfractionated + LMWH very large, do not cross placenta = Safe to use.
Maternal side effects
1) Haemorrhage
2) Herpain induced thrombocytopaenia
3) Local skin reaction + bruising
Is and when is warfarin CI in pregnancy? Can it ever be used?
Warfarin is contraindicated between = 6-12 weeks.
UNLESS = In cases there thrombo-embolism risk is very high like in metalic heart valves.
Between 12-36 weeks = Not teratogenic and therefore can be used here.
BUT warfarin crosses placenta = So increased risk of foetal intracranial haemorrhage. Maternal INR has no correlation with foetal INR
Intracrnial haemorrhage risk in foetus is more likely to occur near labour = So can actually swop to LMWH here before labour
When and why are antimetabolics contraindicated in pregnancy.
All anti-neoplastics = Teratogenic at some stage
Contraindicated in first trimester and during breastfeeding.
Avoid = 2-3 weeks before delivery to allow maternal marrow supression to recover.
How can the type of breastfeeding effect drug transfer in breastmilk
The molecule size and lipid solubility affect how well it passes through breastmilk.
The volume of milk = The hind milk actually contains more lipids, so deeper and longer suckling will contain more of the drug.
Name 8 classes of drug that are contraindicated in breastfeeding mothers
1) Cytotoxics
2) mood stabilisers = Lithium (small size)
3) Sedatives = Benzos, barbiturates
4) Amiodarone
5) Antibiotics = Tetracyclines, metronidazole, chloramphenicol
6) COCP = reduced milk
7) Theophylline = Irritability
8) Aspirin = Reyes syndrome
You can actually give mothers drug to pass onto the foetus = This is known as foetal pharmaco-therapy. Give 6 examples of drugs used in this manner
1) Betamethasone = Proven to reduce RDS and IVH between 26-32 weeks
2) Corticosteroids = used to prevent masculinisation of a female foetus in CAH
3) Flecanide for foetal tachycardia
4) Amiodarone for resistant foetal tachycardia
5) Salbutamol for hydrops fetalis due to congenital heart block
6) Penicillin for treatment of congenital syphilis.
