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PART ONE REVISION. > PHARMACOLOGY - Pharmacokinetics and pharmacodynamics > Flashcards

PHARMACOLOGY - Pharmacokinetics and pharmacodynamics Flashcards

1
Q

What factors affect diffusion coefficient? (3)

A
  1. Lipid solubility
  2. Ionization
  3. Molecular size

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

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2
Q

What is Fick’s Law?

A

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

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3
Q

What happens to drug absorption with increased blink rate?

A

Reduces by increasing clearance

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4
Q

What effect does acidity/alkaninity have on a drug?

A
  1. More unionised and so more lipid soluble to increase corneal absorption
  2. Causes irritation/lacrimation –> drug clearance
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5
Q

What does Phase 1 drug metabolism involve?

A

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)

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6
Q

What do Phase 2 drug metabolism involve?

A

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

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7
Q

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

A

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

  1. Corneal thickness
  2. Conjunctival:corneal surface area (17:1)
  3. Any pre-existing corneal damage
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8
Q

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?

A

Corneal epithelium (lipophilic layer)

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

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9
Q

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

A
  1. Acetate (most)
  2. Alcohol
  3. Phosphate (least)
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10
Q

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

A
  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
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11
Q

Which drugs accumulate in the cornea? (2)

A
  1. NSAIDs
  2. Pilocarpine
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12
Q

What is bioavailability?

A

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

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13
Q

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

A
  1. Gut motility.
  2. Intestinal pH, bile salts
  3. Intestinal blood flow
  4. Intestinal microflora
  5. Enterohepatic circulation
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14
Q

Why do ocular drugs have higher bioavailability?

A

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

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15
Q

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

A

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)

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16
Q

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

A

Lipophilic (lipid soluble) drugs

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17
Q

What is the EC50?

A

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

(relationship between a ligand and its receptor)

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18
Q

What is a partial agonist?

A

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

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19
Q

Where is the most common site for topical administration?

A

Inferior fornix

20
Q

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

A
  1. 15-30microL
  2. 50-100microlitresL
  3. Most is lost via overspill and tear turnover
21
Q

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

A

Polyvinyl alcohol
Hydroxypropylcellulose

22
Q

What layer can preservatives be toxic to?

A

Precorneal tear film and epithelium

23
Q

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

A
  1. Toxic to cornea
  2. Bactericidal by rupturing cell walls
  3. Most effective at pH 8
  4. Inactivated by salts like magnesium and calcium
24
Q

How is VEGF upregulated?

A

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

25
Q

What is the mechanism of action of anti-VEGFs?

A

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

26
Q

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

A

Tyrosine kinase receptors

27
Q

What is the mechanism of action of Ranibizumab (Lucentis)

A

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

28
Q

What is the mechanism of action of Bevacizumab?

A

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

29
Q

What is the mechanism of action of Aflibicept?

A

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.

30
Q

What is the difference between pharmacogenetics and pharmacogenomics?

A

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

31
Q

Whats the difference between pharmacokinetics and pharmacodynamics?

A

dynamics: study of mechanism of action, biochemical and physiological effects on biological system (DOWNSTREAM)

pharmacokinetics - how the drug is absorbed, distributed, metabolised and excreted

32
Q

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

A
  1. increased lipid solubility
  2. mild alkaninity of topical medication
  3. high viscosity, increasing drug retention
  4. isotonicity of topical medication
33
Q

Whats the difference between phase I and phase II metabolism?

A

Phase I - oxidative reactions by cytochrome p450

Phase II - conjugation reactions (addition of groups) to make molecules more water soluble for excretion

34
Q

How do you calculate the volume distribution of drug administration?

A

DOSE / PLASMA concentration at time of administration.

35
Q

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

A

the rate of administration and the rate of elimination

36
Q

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

A
  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)
37
Q

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

A
  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.
38
Q

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

A
  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.

39
Q

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

A
  1. Muscarinic ACh receptors
  2. Adrenergic receptors
40
Q

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

A

pseudo-hypoparathyroidism (Albright’s hereditary osteodystrophy)

41
Q

What are examples of ligand gated ion channels (3)

A
  1. Nicotinic ACh receptors - main receptor at NMJ and autonomic ganglia
  2. GABA A receptors
  3. 5HT3 receptors
42
Q

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

A
  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

  1. Environmental temperature and humidity
  2. Blink rate increases drug clearance.
43
Q

Which drugs accumulate in the retina?

A

chloroquine

44
Q

Which drugs accumulate in the iris? (2)

A

Ephedrine and atropine (to melanin in the iris)

45
Q

Diagram of all Anti-VEGFs

A
46
Q

What is the primary target of pegcetacoplan?

A

Targets C3 and C3b complement pathway

47
Q
A

PART ONE REVISION. (78 decks)

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