ADME (Randall MD Prof) Flashcards
What is the function of the Blood Brain Barrier?
Protection
What cells regulate the BBB?
Glial cells
What is the BBB?
Very impermeable; extreme form of lipid barrier with few intercellular pores, numerous tight junctions, surrounded by glial cells.
What kind of drugs penetrate the BBB?
Lipid soluble
What kind of access do water soluble / polar drugs have through the BBB?
Limited access
What kind of examples show the BBB penetration of drugs?
Sedating v non-sedating antihistamines
Loratidine is polar and does not penetrate the BBB, Chlorphenamine must therefore have greater lipid solubility.
Both H1 receptor antagonists but differ in their BBB penetration
What conditions make the BBB less effective?
Meningitis
How can meningitis be treated if drugs do not cross the BBB?
Can give antibiotics that do not normally cross the BBB< but due to the meningitis can now penetrate. Meninges are inflamed and BBB compromised.
Benzylpenicillin (high dose)
What are the differences in side effect profile of Domperidone and Metoclopramide? Why?
Both are anti-emetics working as dopamine receptor antagonists.
Metoclopramide can cross the BBB and cause drug induced Parkinsonism whereas Domperidone does not.
Why does Domperidone not penetrate the BBB?
It is more charged than Metoclopramide and so cannot penetrate.
Given the information regarding Domperidone v Metoclopramide which drug is preferal when treating nausea caused by L-DOPA in Parkinson’s Disease?
Domperidone should be used - if Metaclopramide was given then it would penetrate the BBB, make L-DOPA less effective by antagonism of dopamine receptors and also cause Parkinsonism.
How is the BBB bypassed in some administration of chemotherapy drugs?
Intrathecal administration route to achieve drug access to the CNS.
What kinetic model(?) does Thiopental follow?
Two compartment model
Induction anesthetic given by IV infusion, then replaced with a maintenance anesthetic
Highly lipid soluble drug so can penetrate the BBB and unconsciousness occurs within 20 seconds and lasts for about 5-10 minutes. Elimination half life is 10 hours.
How is Thiopental distributed throughout the body when used in anesthetics?
Rapid entry into the brain across BBB upon induction of anesthesia - referred to as the alpha stage.
In the beta stage the drug distributes out into tissues (Vd increases) - distribution quickly into muscle and then to fat. Recovery of consciousness would then take place if it were not for the introduction of a maintenance anesthetic.
Hangover effect is due to the long elimination half life of 10 hours.
What are the most common order kinetics for drugs?
1st order kinetics where rate of elimination is proportional to the concentration of drug.
When can zero order kinetics arise?
When enzymes become saturated, the rate of elimination is no longer proportional to the concentration of drug i.e. phenytoin or ethanol (no longer linear, hence drunk.)
What is the Km value according to the Michealis-Menten equation?
The Km value is the value at which 50% of the enzymes active sites are occupied.
What is Vmax?
The maximum rate of elimination via enzyme
In zero order kinetics can Vmax be predicted?
No, a small change in dose can lead to disproportionate change in drug concentration because the enzyme has become saturated.
Which drug is recommended in pregnancy as an anti-epileptic? Or in women of child-bearing age*
Lamotrigine
Why is Phenytoin avoided in pregnancy?
It can cause craniofacial abnormalities, hypoplasia of distal phalanges, growth deficiency, mental deficiency.
Why is Sodium Valproate avoided in pregnancy?
Associated with neural tube defects (spina bifida) and learning difficulties.
Why is Carbomezapine avoided in pregnancy?
Similar risks to Phenytoin but less severe.
How is anti-epileptic ideally managed in pregnancy?
Continuation of treatment is preferable, or planned discontinuation
Carbamazepine is preferred (over Phenytoin or SV)
5mg folic acid is given to reduce chances of neural tube defects.
NICE recommends Lamotrigine can be used in tonic-clonic seizures to avoid teratogenic / interacting drugs.
How are the pharmacokinetics of Lamotrigine altered as a result of pregnancy?
Plasma concentration of Lamotrigine is reduced by the increased levels of estrogen in pregnancy.
When is the greatest risk of harm as a result of anti-depressants in pregnancy?
1st trimester
Which SSRIs are associated with problems in pregnancy?
Citalopram and Sertraline
Cardiac septal defects
Which class of antidepressants is preferable if necessary?
Tricyclic anti-depressants
Amitriptyline
Nortriptyline etc
What are some of the hallmarks of Fetal Alcohol Syndrome (FAS)?
Thin upper lip, short palpebral fissures, flat nasal bridge, short nose.
Microencephaly
Mental retardation
What is an everyday interaction that is common with long term CNS drugs?
Long term CNS medication often increases sedation which is enhanced by alcohol.
What kind of drug interactions are caused by Carbamazepine?
It is a CYP450 enzyme inducer and therefore can cause increased metabolism of oral contraceptives, resulting in a failure of their therapy.
Which anti-epileptic drugs are enzyme inducers?
Phenytoin
Carbamazepine
Phenobarbital
*Favour non inducing agents or use alternative methods of contraception.
What is serotonergic syndrome?
Clinical features: headache, confusion, nausea, twitching
It is a concern when using SSRIs, the increased serotonin can lead to reaction. 5-HT1 agonists (triptans) can also lead to the increased 5HT and this syndrome.
How does St John’s Wort act? What problems can it cause?
If used with SSRIs it can cause serotonoergic syndrome.
It is an enzyme inducer; can affect oral contraceptives, anti-HIV drugs, ciclosporin.
What is a problem with Lithium?
Narrow therapeutic window, plasma concentration is determined by eGFR and electrolyte balance TDM: 0.4 -1 mmol/L
As a stabilising agent for bipolar disorder it is hard to avoid unpleasant toxicity and sub-therapeutic doses.
