ADME (Randall MD Prof)

Question 1

What is the function of the Blood Brain Barrier?

Answer 1

Protection

Question 2

What cells regulate the BBB?

Answer 2

Glial cells

Question 3

What is the BBB?

Answer 3

Very impermeable; extreme form of lipid barrier with few intercellular pores, numerous tight junctions, surrounded by glial cells.

Question 4

What kind of drugs penetrate the BBB?

Answer 4

Lipid soluble

Question 5

What kind of access do water soluble / polar drugs have through the BBB?

Answer 5

Limited access

Question 6

What kind of examples show the BBB penetration of drugs?

Answer 6

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

Question 7

What conditions make the BBB less effective?

Answer 7

Meningitis

Question 8

How can meningitis be treated if drugs do not cross the BBB?

Answer 8

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)

Question 9

What are the differences in side effect profile of Domperidone and Metoclopramide? Why?

Answer 9

Both are anti-emetics working as dopamine receptor antagonists.
Metoclopramide can cross the BBB and cause drug induced Parkinsonism whereas Domperidone does not.

Question 10

Why does Domperidone not penetrate the BBB?

Answer 10

It is more charged than Metoclopramide and so cannot penetrate.

Question 11

Given the information regarding Domperidone v Metoclopramide which drug is preferal when treating nausea caused by L-DOPA in Parkinson’s Disease?

Answer 11

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.

Question 12

How is the BBB bypassed in some administration of chemotherapy drugs?

Answer 12

Intrathecal administration route to achieve drug access to the CNS.

Question 13

What kinetic model(?) does Thiopental follow?

Answer 13

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.

Question 14

How is Thiopental distributed throughout the body when used in anesthetics?

Answer 14

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.

Question 15

What are the most common order kinetics for drugs?

Answer 15

1st order kinetics where rate of elimination is proportional to the concentration of drug.

Question 16

When can zero order kinetics arise?

Answer 16

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.)

Question 17

What is the Km value according to the Michealis-Menten equation?

Answer 17

The Km value is the value at which 50% of the enzymes active sites are occupied.

Question 18

What is Vmax?

Answer 18

The maximum rate of elimination via enzyme

Question 19

In zero order kinetics can Vmax be predicted?

Answer 19

No, a small change in dose can lead to disproportionate change in drug concentration because the enzyme has become saturated.

Question 20

Which drug is recommended in pregnancy as an anti-epileptic? Or in women of child-bearing age*

Answer 20

Lamotrigine

Question 21

Why is Phenytoin avoided in pregnancy?

Answer 21

It can cause craniofacial abnormalities, hypoplasia of distal phalanges, growth deficiency, mental deficiency.

Question 22

Why is Sodium Valproate avoided in pregnancy?

Answer 22

Associated with neural tube defects (spina bifida) and learning difficulties.

Question 23

Why is Carbomezapine avoided in pregnancy?

Answer 23

Similar risks to Phenytoin but less severe.

Question 24

How is anti-epileptic ideally managed in pregnancy?

Answer 24

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.

Question 25

How are the pharmacokinetics of Lamotrigine altered as a result of pregnancy?

Answer 25

Plasma concentration of Lamotrigine is reduced by the increased levels of estrogen in pregnancy.

Question 26

When is the greatest risk of harm as a result of anti-depressants in pregnancy?

Answer 26

1st trimester

Question 27

Which SSRIs are associated with problems in pregnancy?

Answer 27

Citalopram and Sertraline | Cardiac septal defects

Question 28

Which class of antidepressants is preferable if necessary?

Answer 28

Tricyclic anti-depressants Amitriptyline Nortriptyline etc

Question 29

What are some of the hallmarks of Fetal Alcohol Syndrome (FAS)?

Answer 29

Thin upper lip, short palpebral fissures, flat nasal bridge, short nose. Microencephaly Mental retardation

Question 30

What is an everyday interaction that is common with long term CNS drugs?

Answer 30

Long term CNS medication often increases sedation which is enhanced by alcohol.

Question 31

What kind of drug interactions are caused by Carbamazepine?

Answer 31

It is a CYP450 enzyme inducer and therefore can cause increased metabolism of oral contraceptives, resulting in a failure of their therapy.

Question 32

Which anti-epileptic drugs are enzyme inducers?

Answer 32

Phenytoin Carbamazepine Phenobarbital *Favour non inducing agents or use alternative methods of contraception.

Question 33

What is serotonergic syndrome?

Answer 33

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.

Question 34

How does St John's Wort act? What problems can it cause?

Answer 34

If used with SSRIs it can cause serotonoergic syndrome. | It is an enzyme inducer; can affect oral contraceptives, anti-HIV drugs, ciclosporin.

Question 35

What is a problem with Lithium?

Answer 35

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.