Physiochemical requirements for CNS activity

Question 1

what is required in the blood brain barrier

Answer 1

1. neuronal signalling requires higher level of homeostasis
2. cerebral capillary endothelial cells
   - constitute the main BBB
   - provide blood supply to brain cells
   - have tight junctions between cells

Question 2

what is the function of the BBB

Answer 2

1. controls the ingress of systemic substances
   - ions
   - neurotransmitters
   - macromolecules
   - nutrients
   - neurotoxins
2. levels of these are different in brain fro general circulation

Question 3

describe what is used in protection against neurotoxins

Answer 3

1. adult CNS doesn’t have significant regenerative capacity if damaged
2. ABC energy dependent efflux transporters pump many agents out of brain
   - endogenous molecules
   - xenobiotics ingested in diet

Question 4

describe the differences between intestinal and BBB diffusion

Answer 4

1. poor correlation between comparative diffusion studies
2. differences in epithelium structure
   - tight junction preclude para cellular diffusion
   - few pinocytic vesicles
3. metabolising enzymes in BBB epithelium
4. efflux mechanisms in BBB epithelium

Question 5

describe the passage of drugs across BBB

Answer 5

1. polar molecules have generally poor CNS activity
   - unless actively transported
2. moderately lipophilic drugs can cross by passive diffusion

Question 6

describe the decarboxylation of L dopa

Answer 6

1. actively transported across BBB
2. L-dihydroxyphenylalanine is decarboxylated to dopamine
3. occurs during transit through endothelial cells

Question 7

what are the factors affecting BBB diffusion

Answer 7

1. size
2. shape
3. functional groups
   - polar surface area
   - hydrogen bonding
4. ionisation state

Question 8

describe how ionisation state affects BBB diffusion

Answer 8

1. equilibrium exists between ionised and unionised form of drug
2. log P= log of partition coefficient when all the drug is in unionised state
   - pKa 4-10 optimal

Question 9

what is Lipinskis rule of 5

Answer 9

poor oral absorption and permeation are more likely when the drug molecule has:
1. >5 H bond donors, expressed as sum of all OH’s and NH’s
2. Molecular weight >500
3. log P>5
4. >10 H bond acceptors (sum of all Ns and Os)
- substrates for biological transporters are exceptions

Question 10

what does CNS activity require

Answer 10

1. greater lipophilicity
2. smaller RMM
3. fewer H bonding heteroatoms

Question 11

what is the filtering rule for CNS activity

Answer 11

CNS penetration is likely if
1. RMM<400
2. logP<5
3. H bond donor <3
4. H bond acceptor <7
5. PSA <90A

Question 12

compare the penetration of morphine and heroin

Answer 12

1. acetylation of morphine removes H bond donor properties of 2 OH groups
2. increases CNS penetration

Question 13

how does polar surface area affect BBB diffusion

Answer 13

1. SA occupied by nitrogen and oxygen atoms and polar hydrogens attached to them
2. reflective of H bond capacity
3. high PSA values compromise oral permeability
4. tPSA >90 compromise BBB permeability

Question 14

what does concentration at site of action depend on

Answer 14

1. dose administered
2. apparent volume of distribution
3. ADME factors
   - rate of penetration to organs
   - rate of removal from organs

Question 15

why is diffusion concentration dependent

Answer 15

1. concentration of available drug
2. plasma protein binding can affect available drug concentration
3. more lipophilic= higher protein binding

Question 16

what are ABC transporters

Answer 16

1. ATP binding cassette transporters
2. family of proteins involved with homeostasis of solutes
3. require energy from ATP to translocate substrates
4. found throughout body ad largest family of transmembrane proteins
5. 7 subfamilies, designated A to G

Question 17

what is P-glycoprotein or ABCB1 (Pgp)

Answer 17

1. most important transporter for drugs
2. broad substrate specificity
3. found throughout body in gut and brain
4. many drugs that are substrates for cyp3A4 are substrates

Question 18

describe the drug to drug interactions for PgP

Answer 18

1. some drugs are Pgp inhibitors
   - erythromycin, clarithromycin
2. digoxin is a substrate for Pgp
   - important mechanism for excretion
3. co administration with digoxin can lead to elevated plasma levels

Question 19

give examples of EPSEs

Answer 19

• tremor
• slurred speech
• akathisia
• dystonia
• dyskinesia
• caused by dopamine blockade or depletion in basal ganglia

Question 20

what is the possible mechanism of EPSE

Answer 20

imbalance between dopaminergic and cholinergic neurotransmission

Question 21

describe the use of atypical antipsychotics

Answer 21

1. clozapine had fewer EPSEs
2. has heterogenous receptor binding activity
3. mainly D2 and 5HT2 activity
4. combination of activity thought to lower EPSE incidence

Question 22

give examples of metabolic side effects of antipsychotic drugs

Answer 22

1. weight gain
2. T2DM
3. CV disease
4. associated with classic and atypical antipsychotics
5. associated with H1 receptor blockade