PHARMACOLOGY - Pharmacokinetics and pharmacodynamics

Question 1

What factors affect diffusion coefficient? (3)

Answer 1

1. Lipid solubility
2. Ionization
3. Molecular size

The more lipophilic/hydrophobic or unionizd the drug, the faster they diffuse across membranes.

Question 2

What is Fick’s Law?

Answer 2

rate of diffusion = diffusion coefficient x concentration gradient / membrane thickness

Question 3

What happens to drug absorption with increased blink rate?

Answer 3

Reduces by increasing clearance

Question 4

What effect does acidity/alkaninity have on a drug?

Answer 4

1. More unionised and so more lipid soluble to increase corneal absorption
2. Causes irritation/lacrimation –> drug clearance

Question 5

What does Phase 1 drug metabolism involve?

Answer 5

oxidation, reduction, hydrolysis reactions (carried out by cytochrome P450) –> allows the drug to become inactive, or its metabolites become active (original substance known as prodrug)

Question 6

What do Phase 2 drug metabolism involve?

Answer 6

conjugation reactions (addition of glucuronate, glutamine and acetate groups) which makes drug/metabolite more water soluble for excretion

Question 7

What are the most important factors on rate and extent of ocular absorption (6)

Answer 7

PRE-corneal factors
1. Tear volume (7-30ul)
2. Tear turnover time (-.5-2.2ul/min)
3. Blink rate (15-min)

all these factors limit drug time in conjunctival sac to 3-5 minutes on average

4. Corneal thickness
5. Conjunctival:corneal surface area (17:1)
6. Any pre-existing corneal damage

Question 8

What is the greatest barrier in the cornea for ocular drug penetration?

What route do lipophilic drugs go by?
What route do hydrophilic drugs go by?

Answer 8

Corneal epithelium (lipophilic layer)

Lipophilic drugs –> intracellular route
Hydrophilic drugs –> paracellular route

Question 9

What compounds are most likely to penetrate the cornea to reach the anterior chamber (ie biphasic - both hydrophilic and hydrophobic) (3)

Answer 9

1. Acetate (most)
2. Alcohol
3. Phosphate (least)

Question 10

What is the difference between lipid soluble and water soluble drugs? (3)

Answer 10

1. Lipid soluble enter BBB so have more CNS effects
2. Water soluble are easier to clear
3. Hepatic drug metabolism converts lipid soluble drug into a water soluble drug

Question 11

Which drugs accumulate in the cornea? (2)

Answer 11

1. NSAIDs
2. Pilocarpine

Question 12

What is bioavailability?

Answer 12

The amount of oral dose that reaches systemic circulation and is available to the site of action

Question 13

What are the factors affecting first-pass metabolism? (5)

Answer 13

1. Gut motility.
2. Intestinal pH, bile salts
3. Intestinal blood flow
4. Intestinal microflora
5. Enterohepatic circulation

Question 14

Why do ocular drugs have higher bioavailability?

Answer 14

They are absorbed by the nasal mucosa and so bypass first pass metabolism.

Question 15

Whats the difference between first order and zero order drug kinetics?

Answer 15

First order: proportional linear increase in rate of drug consumption with concentration of drug

Zero order: saturation occurs at high drug concentrations (eg when liver enzymes are at full capacity)

Question 16

Which type of drugs are able to pass the blood-retinal barrier?

Answer 16

Lipophilic (lipid soluble) drugs

Question 17

What is the EC50?

Answer 17

The amount of ligand required to achieve 50% of full capacity binding

(relationship between a ligand and its receptor)

Question 18

What is a partial agonist?

Answer 18

Has both agonist and antagonist qualities - at high concentrations, exerts antagonist activity by blocking TRUE agonists

Question 19

Where is the most common site for topical administration?

Answer 19

Inferior fornix

Question 20

What is the conjunctival sac capacity?
What is the average amount of eyedrop?
Where is the drop lost to?

Answer 20

1. 15-30microL
2. 50-100microlitresL
3. Most is lost via overspill and tear turnover

Question 21

Which substances can increase viscosity which in turn increases time of drug in the conjunctiva?

Answer 21

Polyvinyl alcohol
Hydroxypropylcellulose

Question 22

What layer can preservatives be toxic to?

Answer 22

Precorneal tear film and epithelium

Question 23

What are the main properties of surfactant preservative benzalkonium chloride? (3)

Answer 23

1. Toxic to cornea
2. Bactericidal by rupturing cell walls
3. Most effective at pH 8
4. Inactivated by salts like magnesium and calcium

Question 24

How is VEGF upregulated?

Answer 24

Hypoxic state –> increase in hypoxic inducible factor –> release of VEGF –> breaks down inner blood retinal barrier and increases capillary permeability

Question 25

What is the mechanism of action of anti-VEGFs?

Answer 25

Bind to soluble VEGF and block its activity by preventing its binding to VEGF receptors (VEGF-1 and VEGF-2)

Question 26

What type of receptors are VEGF-1 and VEGF-2?

Answer 26

Tyrosine kinase receptors

Question 27

What is the mechanism of action of Ranibizumab (Lucentis)

Answer 27

Monoclonal recombinant human Fab against VEGF - targets all VEGF-A receptors and its products (isoforms 110, 1221, 165) Lacks an Fc region and so is very small and easily penetrates the retina

Question 28

What is the mechanism of action of Bevacizumab?

Answer 28

recombinant humanized antibody but is full sized and has two antigen binding domains rather than one - lasts longer

Question 29

What is the mechanism of action of Aflibicept?

Answer 29

A recombinant fusion protein which acts as a VEGF receptor decoy - it traps all VEGF with greater affinity so prevents binding to other VEGF receptors.

Question 30

What is the difference between pharmacogenetics and pharmacogenomics?

Answer 30

genetics - study of how genetic variation influences drug efficacy and toxicity but focus in on single genes Genomics - study of how individuals genome affects drug response

Question 31

Whats the difference between pharmacokinetics and pharmacodynamics?

Answer 31

dynamics: study of mechanism of action, biochemical and physiological effects on biological system (DOWNSTREAM) pharmacokinetics - how the drug is absorbed, distributed, metabolised and excreted

Question 32

Which factors can increase bioavailability in the cornea? (4)

Answer 32

1. increased lipid solubility 2. mild alkaninity of topical medication 3. high viscosity, increasing drug retention 3. isotonicity of topical medication

Question 33

Whats the difference between phase I and phase II metabolism?

Answer 33

Phase I - oxidative reactions by cytochrome p450 Phase II - conjugation reactions (addition of groups) to make molecules more water soluble for excretion

Question 34

How do you calculate the volume distribution of drug administration?

Answer 34

DOSE / PLASMA concentration at time of administration.

Question 35

What is the plasma concentration a function of/relationship between which two variables?

Answer 35

the rate of administration and the rate of elimination

Question 36

What are the main methods of drug penetration through cells (4)

Answer 36

1. Lipid diffusion (lipid solubility) 2. Aqueous pore difficusion 3. Via carrier molecules 4. Pinocytosis (type of endocytosis, or process for bringing substances into a cell, where the cell membrane folds to create small pockets that capture fluid and dissolved substances)

Question 37

Which two pathways are responsible for drug excretion? (2)

Answer 37

1. Renal excretion - glomeular filtration, tubular secretion and reabsorption 2. Biliary excretion - conjugated drugs concentrate in bile and delivered to intestine - the drug can be released and re-absorbed in the entero-hepatic circulation.

Question 38

What are the subunits of G-proteins? (3) How does it work?

Answer 38

1. Alpha (GTPase) 2. Beta (attach protein to membrane 3. Gamma (attach protein to membrane) alpha unit dissociates on binding of agonist and converts GDP to GTP.

Question 39

What are examples of G protein coupled receptors? (2)

Answer 39

1. Muscarinic ACh receptors 2. Adrenergic receptors

Question 40

Which clinical condition is associated with reduced G-protein activity?

Answer 40

pseudo-hypoparathyroidism (Albright's hereditary osteodystrophy)

Question 41

What are examples of ligand gated ion channels (3)

Answer 41

1. Nicotinic ACh receptors - main receptor at NMJ and autonomic ganglia 2. GABA A receptors 3. 5HT3 receptors

Question 42

What are the factors affecting conjunctival topical delivery ? (4)

Answer 42

1. Tear film instability - affects conjunctival residence time of drug 2. Altered tear film pH affect drug ionisation and diffusion capacity ----> purely ionised drugs do not penetrate an intact cornea ----> more unionised if more acidic/alkaline --> more lipid soluble and increases corenal absorption ---> acidity/alkaniity can cause irritation and lacrimation and increase drug clearance 3. Environmental temperature and humidity 4. Blink rate increases drug clearance.

Question 43

Which drugs accumulate in the retina?

Answer 43

chloroquine

Question 44

Which drugs accumulate in the iris? (2)

Answer 44

Ephedrine and atropine (to melanin in the iris)

Question 45

Diagram of all Anti-VEGFs

Answer 45

Question 46

What is the primary target of pegcetacoplan?

Answer 46

Targets C3 and C3b complement pathway