PHARMACOLOGY - Pharmacokinetics and pharmacodynamics Flashcards
What factors affect diffusion coefficient? (3)
- Lipid solubility
- Ionization
- Molecular size
The more lipophilic/hydrophobic or unionizd the drug, the faster they diffuse across membranes.
What is Fick’s Law?
rate of diffusion = diffusion coefficient x concentration gradient / membrane thickness
What happens to drug absorption with increased blink rate?
Reduces by increasing clearance
What effect does acidity/alkaninity have on a drug?
- More unionised and so more lipid soluble to increase corneal absorption
- Causes irritation/lacrimation –> drug clearance
What does Phase 1 drug metabolism involve?
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)
What do Phase 2 drug metabolism involve?
conjugation reactions (addition of glucuronate, glutamine and acetate groups) which makes drug/metabolite more water soluble for excretion
What are the most important factors on rate and extent of ocular absorption (6)
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
- Corneal thickness
- Conjunctival:corneal surface area (17:1)
- Any pre-existing corneal damage
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?
Corneal epithelium (lipophilic layer)
Lipophilic drugs –> intracellular route
Hydrophilic drugs –> paracellular route
What compounds are most likely to penetrate the cornea to reach the anterior chamber (ie biphasic - both hydrophilic and hydrophobic) (3)
- Acetate (most)
- Alcohol
- Phosphate (least)
What is the difference between lipid soluble and water soluble drugs? (3)
- Lipid soluble enter BBB so have more CNS effects
- Water soluble are easier to clear
- Hepatic drug metabolism converts lipid soluble drug into a water soluble drug
Which drugs accumulate in the cornea? (2)
- NSAIDs
- Pilocarpine
What is bioavailability?
The amount of oral dose that reaches systemic circulation and is available to the site of action
What are the factors affecting first-pass metabolism? (5)
- Gut motility.
- Intestinal pH, bile salts
- Intestinal blood flow
- Intestinal microflora
- Enterohepatic circulation
Why do ocular drugs have higher bioavailability?
They are absorbed by the nasal mucosa and so bypass first pass metabolism.
Whats the difference between first order and zero order drug kinetics?
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)
Which type of drugs are able to pass the blood-retinal barrier?
Lipophilic (lipid soluble) drugs
What is the EC50?
The amount of ligand required to achieve 50% of full capacity binding
(relationship between a ligand and its receptor)
What is a partial agonist?
Has both agonist and antagonist qualities - at high concentrations, exerts antagonist activity by blocking TRUE agonists
Where is the most common site for topical administration?
Inferior fornix
What is the conjunctival sac capacity?
What is the average amount of eyedrop?
Where is the drop lost to?
- 15-30microL
- 50-100microlitresL
- Most is lost via overspill and tear turnover
Which substances can increase viscosity which in turn increases time of drug in the conjunctiva?
Polyvinyl alcohol
Hydroxypropylcellulose
What layer can preservatives be toxic to?
Precorneal tear film and epithelium
What are the main properties of surfactant preservative benzalkonium chloride? (3)
- Toxic to cornea
- Bactericidal by rupturing cell walls
- Most effective at pH 8
- Inactivated by salts like magnesium and calcium
How is VEGF upregulated?
Hypoxic state –> increase in hypoxic inducible factor –> release of VEGF –> breaks down inner blood retinal barrier and increases capillary permeability
What is the mechanism of action of anti-VEGFs?
Bind to soluble VEGF and block its activity by preventing its binding to VEGF receptors (VEGF-1 and VEGF-2)
What type of receptors are VEGF-1 and VEGF-2?
Tyrosine kinase receptors
What is the mechanism of action of Ranibizumab (Lucentis)
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
What is the mechanism of action of Bevacizumab?
recombinant humanized antibody but is full sized and has two antigen binding domains rather than one - lasts longer
What is the mechanism of action of Aflibicept?
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.
What is the difference between pharmacogenetics and pharmacogenomics?
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
Whats the difference between pharmacokinetics and pharmacodynamics?
dynamics: study of mechanism of action, biochemical and physiological effects on biological system (DOWNSTREAM)
pharmacokinetics - how the drug is absorbed, distributed, metabolised and excreted
Which factors can increase bioavailability in the cornea? (4)
- increased lipid solubility
- mild alkaninity of topical medication
- high viscosity, increasing drug retention
- isotonicity of topical medication
Whats the difference between phase I and phase II metabolism?
Phase I - oxidative reactions by cytochrome p450
Phase II - conjugation reactions (addition of groups) to make molecules more water soluble for excretion
How do you calculate the volume distribution of drug administration?
DOSE / PLASMA concentration at time of administration.
What is the plasma concentration a function of/relationship between which two variables?
the rate of administration and the rate of elimination
What are the main methods of drug penetration through cells (4)
- Lipid diffusion (lipid solubility)
- Aqueous pore difficusion
- Via carrier molecules
- 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)
Which two pathways are responsible for drug excretion? (2)
- Renal excretion
- glomeular filtration, tubular secretion and reabsorption - Biliary excretion
- conjugated drugs concentrate in bile and delivered to intestine - the drug can be released and re-absorbed in the entero-hepatic circulation.
What are the subunits of G-proteins? (3) How does it work?
- Alpha (GTPase)
- Beta (attach protein to membrane
- Gamma (attach protein to membrane)
alpha unit dissociates on binding of agonist and converts GDP to GTP.
What are examples of G protein coupled receptors? (2)
- Muscarinic ACh receptors
- Adrenergic receptors
Which clinical condition is associated with reduced G-protein activity?
pseudo-hypoparathyroidism (Albright’s hereditary osteodystrophy)
What are examples of ligand gated ion channels (3)
- Nicotinic ACh receptors - main receptor at NMJ and autonomic ganglia
- GABA A receptors
- 5HT3 receptors
What are the factors affecting conjunctival topical delivery ? (4)
- Tear film instability - affects conjunctival residence time of drug
- 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
- Environmental temperature and humidity
- Blink rate increases drug clearance.
Which drugs accumulate in the retina?
chloroquine
Which drugs accumulate in the iris? (2)
Ephedrine and atropine (to melanin in the iris)
Diagram of all Anti-VEGFs
What is the primary target of pegcetacoplan?
Targets C3 and C3b complement pathway
