ADME Flashcards
What is the BBB?
Extreme form of lipid barrier with:
- few intracellular pores
- numerous tight junctions
- surrounded by glial cells
What drugs are able to penetrate the BBB? Give examples, and how it is manipulated for therapy.
- Lipid soluble drugs penetrate (exerting CNS effects)
- Water-soluble/polar drugs have limited access
E.g.
• H1 antagonists - sedating antihistamine (Chlorphenamine); crosses BBB thus has central effects. BUT, non-sedating (Loratadine) is polar; thus no sedating (central) effects = good.
• BBB is less effective in meningitis; can given antibiotics that do not normally pass through to kill bacteria etc. around inflamed meninges (benzylpenicillin)
How do Domperidone and Metoclopramide vary as anti-emetics WRT the BBB?
- Both DA receptor antagonists
- Metoclopramide is more lipid soluble and penetrates BBB; can cause drug-induced Parkinsonism
»> Domperidone does not (more charged)
Why is Domperidone dece as an add-in therapy in Parkinson’s?
- Anti-emetic (DA antagonist) that does not penetrate the BBB due to polarity
- Thus can effectively treat Levodopa-induced N&V; which hits peripheral DA receptors as well as in the brain
»> Thus antagonises peripheral DA receptors whilst still maintaining Levodopa efficacy in the brain
What cautions must be taken w/intrathecal anticancer therapy?
- Access to the CNS is normally tightly regulated by the body
- Drugs can be injected into the CSF to achieve anticancer drug access to the CNS
- BUT, if Vincristine is given in place of MTX = FATAL
(AVOID)
How does the single compartment model for PO and IV differ?
PO
- Initial rise in plasma concentration, then linear negative elimination phase
IV
- Linear elimination line all the way, starting from high
Describe Thiopental and its onset of action.
- Induction anaesthetic given by IV infusion, then replaced with a maintenance anaesthetic (usually gas; volatile liquids)
- Highly lipid-soluble
- Unconsciousness occurs within 20 seconds, lasting for 5 - 10 minutes (rapid induction phase; cancels out excitatory phase)
- Elimination half-life = 10 hours; even though unconsciousness wears off after 10 minutes
Describe the two compartmental model of the general anaesthetic, Thiopental.
Alpha Phase
- First 5-10 minutes; conc. required for induction WRT surgical anaesthesia
- Concentration starts high but plasma conc. rapidly declines (wide U shape) as the drug redistributes into tissues (muscle/fat)
Beta Phase
- Tissues act as reservoir for thiopental; drug slowly moves back into the plasma for slow elimination (hence half-life = 10 hours)
- Thus ‘hangover effect’; large volume, long half-life
»> Inhalation anaesthetics have no Beta Phase thus no ‘hangover effect’
How does a patient regain consciousness after general anaesthetic w/thiopental?
- There is rapid induction of anaesthesia initially due to rapid entry of thiopental into the brain
- Then re-distribution of thiopental to tissues pulls thiopental from the brain; recovery of consciousness due to redistribution
What kinetics (elimination) do most drugs show?
- First order kinetics
- Rate of elimination usually proportional to [drug]
What are zero order kinetics, why do they occur and which drugs display them?
- When rate of elimination no long is proportional to [drug]
- Small changes in dose rate lead to disproportionate increases in [drug]
- Due to the enzymes metabolising the drug becoming saturated; rate of elimination is no longer linear
E.g. phenytoin, ethanol (why you get drunk)
What does Vmax and Km stand for WRT Michaelis-Menten?
Vmax:
- Max rate of reaction/elimination
Km:
- Michaelis-Menten constant; [conc.] at which 50% enzymes are saturated
How does phenytoin demonstrate zero-order kinetics?
- Patients will each have a different Vmax; different levels of metabolising enzyme in each individual
- When said enzymes are saturated, there is a disproportionate rise in [drug]
- E.g. patients w/more metabolising enzyme (thus a higher Vmax) will require a higher dose rate to achieve the same [Conc]; but have a slightly bigger therapeutic window at higher dose ranges
How should anti-epileptics be taken during pregnancy/what cautions are associated?
- Many have teratogenic properties
E.g. Phenytoin, Valproate = AVOID - NICE (2004) recommends Lamotrigine (newer agent)
- Carbamazepine was preferred previously
> > > But, better to be medicated than to go without (weighing up risks; preventing seizures are a priority)
- Continuation of treatment preferable; counselling
- Or planned discontinuation (titrate down over time, checking if seizure-free)
Why is Phenytoin avoided in women of child-bearing age/pregnant women? Why is Carbamazepine now avoided too?
- Craniofacial abnormalities (cleft palate/lip)
- Hypoplasia of distal phalanges
- Growth deficiency
- Mental deficiency
> > > Carbamazepine safer, but still run the above risks (previously recommended therapy)
Why is Valproate avoided in women of child-bearing age/pregnant women?
- Associated with neural tube defects (spina bifida = paralysis below)
- Learning difficulties
What is given to pregnant women to reduce neural tube defects?
- 5mg folic acid (instead of 400 micrograms)
|»_space;> Pertinent in Valproate (associated w/NTD)
What antiepileptic is currently first line in pregnancy, and the caveat?
- Lamotrigine first line in generalised tonic-clonic seizures (avoiding teratogenic/interacting drugs)
- BUT, PK is altered in pregnancy, making it more difficult to use (plasma conc. drops; adjust dose accordingly)
How should antidepressants be used in pregnancy?
- Affects 20% of women in pregnancy
- Danish study; SSRIs (esp. Citalopram and Sertraline) associated w/cardiac septal defects (finite risk)
- Increased risk in 1st trimester
»> TCAs safer in pregnancy
What is foetal alcohol syndrome, and what advice does it lead to?
Drinking in pregnancy can lead to:
- Thin upper lip
- Short palpebral fissures (eye holes)
- Flat nasal bridge
- Short nose
- Mental retardation
> > > NO alcohol during pregnancy.
What may sedation from CNS acting drugs be enhanced by?
- Alcohol
- Counsel e.g. w/TCAs
What are some common drug interactions of CNS medications? What action is taken?
Some antiepileptics are enzyme-inducers:
- Oral contraceptives; CYP450 inducers can lead to a failure in contraceptive therapy e.g. w/phenytoin, carbamazepine, phenobarbital
»> Accelerates oral contraceptive metabolism
> > > Favour non-inducing agents or use alternative contraception
How do lamotrigine and PO contraceptives interact?
- Oral contraceptives can reduce plasma conc. of lamotrigine
- Thus may need to increase dose of lamotrigine to compensate
What is serotonergic syndrome?
- SSRIs and 5-HT1 agonists (triptans; migraines) lead to increased 5-HT levels
- Too much 5-HT activation
- Leads to various symptoms
What are the clinical features of serotonergic syndrome?
- Headache
- Confusion
- Nausea
- Twitching
What is St John’s Wort? What does it do/common interactions?
- SSRI-like actions
- Thus can cause Serotonergic Syndrome if used w/SSRIs
- Enzyme inducer, can affect:
• Oral contraceptives
• Anti-HIV drugs (could lead to AIDs)
• Ciclosporin (immunosuppressant; prevents organ rejection etc.)
What is Lithium used for? How must it be monitored, and why?
- Stabilising agent in bipolar disorder
- Narrow therapeutic window; thus plasma conc. determined by eGFR and electrolyte balance (caution w/diuretics)
- TDM: 0.4 - 1 mmol/L
> Underdose = not managing behaviour
> Overdose = toxic (unpleasant)
