OPTOM 345 Flashcards
What is a drug
Chemical substance that produces a biological effect and interacts with Receptors, Ion channels, Carriers and Enzymes
What is Pharmacokinetics
How drug moves in body and how well it reaches parts of the body
What is pharmacodynamics
The effect the drug has on the body
Name the axis on a Dose Response Curve
X axis = Drug Concentration
Y axis = Drug Response
What does a dose response curve tell us
Measures how well a drug binds to a receptor, and the point where it reaches maximum effect
What is maximum effect
The point where increasing drug concentration does not increase drug response
What is affinity
Drug interaction strength at the target site
What is Potency
Drug concentration needed for 50% maximal effect
Efficacy
The ability of the drug to produce a response once bound to a target site
When to use Bioequivalence
Used to determine which drug is better to use when compared to each other
How do we compare drugs
Risk v Benefit ratio
How does the risk v benefit ratio work
Uses the Toxic dose and Effective dose to calculate a therapeutic index
How to calculate the therapeutic index
TI = TD50 / ED50
The higher TI the safer the drug
What is the toxic dose
The toxic dose in 50% of the population
What is the effective dose
The effective dose in 50% of the population
What is the Therapeutic window
The dose range where the drug effect has minimal adverse effect
Different between specificity and selectivity
Specificity is where the drug targets in the body
Selectivity is how exclusive the drug is to certain receptors
Important of binding specificity
A drug must be specific for certain cells and tissues but in reality, no drug is completely specific.
Importance of binding selectivity
important for drugs to bind exclusively to certain receptors to reduce unwanted effects
What happens if we increase drug dose
It decreases drug specificity resulting in adverse effects
How do we make a drug more selective
By changing its size or having stereoisomerism where a drug has a different geometric structure so it will be selective to certain receptors increasing the potency for that receptor
What do Bioassays do
compare new drugs to existing drugs
What are the requirements for an assay
Should be reproducible, reliable indicator of its response and able to effectively comapre two or more drugs/formulations
Describe In-Vitro, Ex-Vivo and In-Vivo
In-vitro = Outside of body in Petri dish
Ex-vivo = Extract tissue from living organism
In-vivo = Perform study inside living organism
Explain the Transgenic animal models
They are use genetic manioulation to inactivate individual genes, mutate genes to pathological genotypes, introduce new genes and to over express genes such as parkinsons with increased synuclein expression
What is a requirement for animal models
Should be similar to human disease model where the pathophysiological phenotypes, causation and response to the treatment are similar
Why do many drugs fail clinical trials
Due to lack of clinical efficacy unmanageable toxicity, poor drug like properties, lack of commercial interest and poor strategic planning
What are clinical trials
Research studies that see if a medical strategy, treatment or device is safe and effective for humans
Briefly explain the procedures in clinical testing
Preclinical testing, 4 phases of clinical research and final data analysis with followups
What occurs in Phase 1 trial
Determine drug safety in healthy volunteers
What occurs in phase 2 trials
Pharmaco-kinetic/dynamic studies in healthy volunteers. There is also intital assessment of efficacy and continued assessment of safety in volunteers
What occurs in phase 3 trials
Assess longer-yerm efficacy and safety of the drug in the patient
What occurs in phase 4 trials
Post-marketing surveillance, ongoing assessment of safety and the likelihood of approval
What is a biomarker
Something that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process or pharcologic response to a therapeuti intervention
What do biomarkers do
Indicate the prognosis of disease and monitor clinical response to an intervention
What do we measure in Bioassays when comparing drugs
The drugs efficacy, not potency
Strategies to avoid bias in drug testing
Controlled, Randomised and Double-blind testing
What is controlled testing
Compare A with B ( B is a control or placebo )
What is randomised testing
Patients assigned to group A or B randomly
What is double blind testing
Common in Phase 1-3 and sometimes 4, here neither participants or researchers know which participants belong to the control or test group. This minimises subjective bias
What is simple randomisation
When patients are assigned randomly to each group
What is stratified randomisation
When you divide participants into smaller group, then randomise each group with both the treatments and allocated similar overall demographics
What is Pharmacogenomics
Study the role of genes in drug response
Why do we do Pharmacogenomics
People of different ethnics have different genetic backgrounds that changes how the drug is metabolised and varies its efficacy
How to calculate Risk and Odds in a test
Risk for patients = Number of affected divided by the total number of paticipants
Odds for patients = Number of affected divided by the difference between the total number of participants and the affected
How to calculate relative risk ( RR )
Ratio of risk in treatment group and the risk in the control
How to calculate relative risk reduction ( RRR )
1 - RR
How to calculate Absolute Risk Reduction ( ARR )
Control risk - Treatment risk
How to calculate the number needed to treat ( NNT )
1/ARR
What is the number needed to treat ( NNT )
Number of people needed to treat to show the given effect of the drug
Lower NNT is more valuable
A drug that halves a mortality from 50% to 25% is more valuable than a drug that halves a mortality from 5% to 2.5%
What is the null hypothesis
States that there is no effect between comparisons
What is the P-Value
The probability that the null hypothesis is true. A statistically signficant P value is a value less that 0.05. When significant, we can reject the null hypothesis ( Ho )
What is the confidence interval
Range of values where the true parameter falls in, usually at 95%
What is Type 1 error
Rejection of a null hypothesis when it is true in the population
What is Type 2 error
Accepting null hypothesis when it is false in the population
What is power in statistics
The probability of detecting a difference when present where a larger sample size gives more power
What is the goal in a statistical tests regarding the number of participants
Recruit the minimum number of subjects to reject the null hypothesis ( usually 80% power )
How to calculate the power of a study
1 - Beta
Beta is the probability of a type 2 error
What does sample size of a study depend on
Power, magnitude of the difference you want to see and the statistical tests you plan to run
What are the 4 main targets for drugs
Receptors, Ion Channels, Carriers and Enzymes
Function of a receptor
Recognise and respond to endogenous chemical signals known as ligands and are found on cell surfaces
What happens when a receptor is bound
It activates and causes downstream effects
How do GPCRs work
Ligand binds giving conformational change in the GPCR causing the Alpha subunit to exchange GDP for GTP resulting in the alpha subunit and the beta-gamma dimer to dissociate and regulates the target proteins. Then the GTP hydrolyses to GDP and the cycle continues
How do Receptor Tyrosine Kinases work ( RTKs )
These have two receptors, when both are bound they come together forming one receptor causing the tyrosine residue to phosphorylate causing downstream effects
Name the 4 receptor types
Ligand gates ion channels, GPCRs, Kinase linked receptor and Nuclear receptors
How quickly do Ligand gated ion channels act
Milliseconds
How quickly do GPCRs act
Seconds
How quickly do Kinase linked receptors act
Hours
How quickly do nuclear receptors act
Hours
Why do nuclear receptors take so long to act
They are intracellular receptors so the ligand has to diffuse into the cell membrane to bind to the receptor
Function of ligand gated ion channels
When bound, the gate open or closes which either increases or decreases permeability to select ions. When membrane potential is changed by depolarisation or hyperpolarisation
Function of GPCRs
In eurkaryotes with 7 transmembrane domains coupled with G proteins which bind to GDP or GTP. These are also Muscarinic ACH receptors. It is for therapeutic drugs and causes downstream activation of other membrane targets
Structure of GPCRs
These are heterotrimeric so it has 3 subunits known as alpha, beta and gamma subunits which interact with GDP and GTP
Function of Kinase Linked Receptors
Includes RTKs, and Cytokine receptors. When bound is cuases phosphorylation of the intracellular domain and signals downstream processes
Also mediates growth factors, cytokines and hormones. The effects are exerted at the gene transcirption level and controls cell division, growth, differentiation, inflammation, immune responses, tissue repair and apoptosis
Function of Nuclear receptors
Found in cytoplasm ( Class 1 ), Nucleus ( Class 2 ) and Endocrine system ( Hybrid class ) known as steroid receptors
Activated by cell-permeating or lipophilic molecules and leads to the signalling cascades affecting gene expression
What is affinity and what does it depend on
The tendency of the drug to bind to a receptor, it depends on the Van der waals forces, hydrophobic, ionic, hydrogen and covalents
What is an agonist
acts as ligand and can activate or deactivate receptors
What is an antagonist
Acts as ligand and binds to receptor and causes no change in activity as it stops other molecules binding to the receptor but does not interact with active site
What is a partial agonist
Has an intermediate efficacy when bound even when all receptors are occupied
What are full agonists
Has full efficacy
What are inverse agonists
Drug that shows selectivity for resting states instead of activation of a receptor
What are antagonists
Have affinity but zero efficacy
Classes of Antagonists
Competitive reversible, Competitive irreversible and Non-competitive
What are competitive reversible antagonists and its effect on the dose respone curve
Competes with agonist, whichever concentration is higher will be favoured
Curve shifts to the right as more agonists needed to displace antagonist
What are competitive irreversible antagonists and its effect on the dose response curve
Competes with agnostic but has higher affinity for receptor so it requires new receptors to reverse its effects. Increasing concentration of agonist does not reverse its effect
Shifts curve to the right and reduces efficacy on the curve
What is a non-competitive antagonistm and its effect on the dose response curve
Does not bind to active site, binds to allosteric site
Shifts curve to the right and decreases efficacy
What are secondary messengers
Have receptors for ligand gated ion channels. When bound it causes a conformational change in the channel and ions move down their concentration gradients causing hyper or a depolarised state giving a cellular effect
Name the two ligand gated ion channels
Nicotinic acetylcholine receptor and the GABA receptor
What is the Nicotinic Acetylcholine receptor
ACH or Nicotine bnids giving influx of sodium which depolarises the cells increasing the chance of an action potential
What are GABA receptors
GABA binds causing influx of chloride ions into the cell and hyperpolarises the membrane reducing chance of an action potential
Name the types of GPCRs
Adenylyl Cyclase, Phospholipase C, Ion Channels, Rho A / Pho Kinase and Mitogen-Activated Protein Kinase
What is Adenylyl cyclase
Enzyme for cAMP formation
What is Phospholipase C
Enzyme for Inositol Phosphate and DAG formation
Ion channels
Calcium and Potassium channels
What are Rho A and Pho Kinase
System regulating activity of signal pathways for cell growth, proliferation, motility and smooth muscle contraction
What are Mitogen activated Protein Kinases
System controlling cell functions like cell division, and also a target of several kinase linked receptors
Name the subunits in G Proteins
Gas, Gai, Gao, Gaq and Ga12/13
What does Gas do
Stimulate Adenylyl cyclase increasing cAMP formation
What does Gai do
Inhibit Adenylyl cyclase decreasing cAMP formation
What does Gaq do
activate phospholipase C increasing production of secondary messengers and releases Ca2+ form its stores
What goes Ga12/13 do
Activate Rho and thus Rho kinase
What does adenylyl cyclase do and its downstream effects
Produce cAMP which activate protein kinase inreasing lipolysis, reduced glycogen synthesis and increased glycogen breakdown. It also phosphorylates other enzymes for sugnalling cascades
What does Phospholipase C do
Cause IP3 to be released resulting in IP3 gated calcium channels in the smooth endoplasmic reticulum to open which activates protein kinase C and binds to DAG
What does DAG do
Remains in cell membrane and activates membrane bound protein kinase C that catalyses the phosphorylation of intracellular proteins
How does GPCR control channel function
With G-protein via activation of effector proteins like adenyly cylclase or phospholipase C
What do enzyme linked receptors do
Govern action of protein mediators like GF, cytokines and hormones
Receptors like RTKs and cytokine receptors
What do nuclear receptors do
regulate gene transcription where ligands are lipophilic like hormones and fatty acid class 2
Characteristics of Ion Channels
Polar molecules cannot penetrate the lipid bilayer unless there is an ion channel or transporter
Ion channels are water filled pores across the lipid membrane where the rate and direction of ion omvement is dependent on the electrochemical gradient for the ion
What are ion channels selective for
Cations or Anions
What does Phenytoin do
Blocks sodium channels to prevent excessive firing of neutrons during seizures
What does phenobarbital do
Activates GABA receptors which opens chloride channels and reduces chances of action potentials
What do blockers do
Block permeation of ions
What do Modulators do
Increase or decrease the opening probability of a channel
Ways enzymes can be inhibited
Competitive or non-competitive drugs
What is a false substrate
A substrate that produces an abnornal response
What is a competitive inhibitor for acetylcholinesterase and what is its acting duration
Neostigmate and is a medium duraton inhibitor
What does Neostigmate do
Improves muscle tone in people with MG and reverses effects of non-depolaring muscle relaxants after surgery
Which drug needs to be metabolised to be converted to an active state
Codeine
What effect does Neostigmate have on muscles
It prolongs the effects of muscarinic and nicotinic receptors as it stops ACH from binding and also prevents the degradation of ACH
How is codeine metabolised and to what
Metabolised to morphine by CYP2D6 when codeine reaches the liver
Why is drug activation like codeine good
It reduces the interaction with opioid receptors in the GI tract and used for mild moderate pain with minimal side effects
Methods of transporting molecules across membranes
Facilitated diffusion, Active transport, Na/K/Cl co transporters and Na/K ATPase
How does Na/K ATPase work
Pumps Na to extracellular side and K to the intracellular side
What is co-transport
Transports two things together in the same direction
What are anti-porters
Transports two things in opposite directions
How is pharmacokinetics measured
With ADME
What is ADME
Absorption, Distribution, Metabolism and Elimination
Why do we study pharmacokinetics
To see how much and how often we should supply a drug to maintain drug efficacy
Why should we keep a drug in the therapeutic range
Otherwise it could get too toxic or the drug may not work well
Methods of absorption
Oral, Parenteral ( IV ), Inhaled and topical
What does absorption depend on
Membrane properties, drug characteristics and dosage form
Characteristics of the Cornea regarding drug penetration
A mechanical barrier where drugs smaller than molecular weight of 5kDa can pass.
The corneas epithelium and endothelium is lipophilic and the stroma is hydrophilic
What does Drug distribution depend on
The drugs characteristics, plasma protein binding and the patients weight. Other factors include permeability of barriers and the binding capacity of the drug.
At what conditions do most drugs penetrate the lipophilic epithelium
pH 7 with drug in unionised form
When more than pH7 the ionised drug can easilt diffuse through the hydrophilic stroma
What does drug metabolism depend on
The first pass, the enzyme inhibition and inducton, and drug activation.
What drugs are more lipophilic and what does it mean for it
Ester prodrugs are more lipophilic so they are better at being absorbed and penetrates the cornea from the activation of esterases
Where does metabolism mainly occur
In the liver and either activates or inactivates the drug
Where does Elimination of drugs occur
In the kidneys in the GFR
Describe the kinetics in elimination of a drug
Starts with first order or zero order where drugs decrease in concentration by half in the same time peroid, or has decreased reduction in concentration in the same time period
What does washout mean
Tear fluid turnover after eyedrop application
What is reflex tearing
From irritation from pH or foreign body sensation
Where do most eyedrops drugs leave
In the nasolacrimal duct
Where do most absorption of eyedrop drugs occur
In the nose where there is a high surface area and blood supply, this gives side effects which is a type of elimination we want to reduce
Name the main routes of drug administration
Oral, sublingual, transdermal, rectal, inhalation, intranasal and parenteral
What is bioavailability
The fraction of the administered dose that reaches the systemic circulation
Oral administration characteristics
At least 80% drugs use this as its convenient and economical. Drug absorbed in stomach or intestines and enters the hepatic portal circulation into the liver for first pass. Then enters to general circulation giving longer onset of action and lower bioavailability
Sublingual Administration characteristics
Drug dissolves under toungue and absorbs through mucous membranes into
blood stream, here there is no first pass. This makes it convenient and
economical and this method isnt suitable for all drugs
Transdermal administration characteristics
Drug absorbed through skin, no first pass. Drug dosage here is continuous
and long acting. This is expensive and causes local irritation sometimes.
Rectal administration characteristics
Drug absorbed through the mucous membranes. Suitable for children,
unconscious or vomiting patients. BUT there can be incomplete or irregular
absorption. This method has some First Pass
Inhalation administration characteristics
Drug inhaled as gas to act in lung, so no first pass. This has a rapid onset of
action but can irritate lung tissue
Intranasal administration characteristics
Drug absorbed through nasal mucous so no first pass, rapid onset of action
and this isnt suitable for all drugs. Drugs like Tyrvaya which increases tear
production
Parenteral administration characteristics
( IV, IM and SC )
( Intravenous/muscular and
subcutaneous )
Bioavailability ( IV > IM > SC ). This gives more rapid response and avoids
unpredictable absorption processes in the GIT and is useful in unconcious or
uncooperative px. BUT must be sterile to prevent infection, drug cannot be
retrieved once injected, more expensive vs other routes and pain at the
injection site so px compliance goes down
Types of ocular routes for drug administration
Intravitreal, intraocular, topical, periocular and systemic
How do tonical eye drops work
Direct application to target site, a smaller dose is required and has rapid onset of
action. This method can have contamination and has limited corneal absorption
and fast nasolacrimal elimination giving systemic absorption giving side effects
How do intravitreal injections work
Injection close to target site, a smaller drug doe required and has rapid onset of
action. This is an invasive procedure giving complications, also limited volume of
injection and has a short half life
Compare solid and liquid dose drugs
Either way the drug needs to be in a solution for it to be absorbed. Solid excipents determine the tablet disintegration
What do smaller particles mean for drugs
Higher surface area giving faster dissolution
How do drugs get extended release formulations
Enteric coating
Describe dosage forms as a solution
It is a homogenous mixture composed of only one phase where the solute is dissolved in the solvent
Name examples of solution doses for ophthalmic formulations
Beta blockers and alpha agonists
Pros and Cons of drugs as a solution
Pros –> Good stability, easy to prepare and low cost
Cons –> Fast drainage, low drug permeability through cornea and low drug bioavailability
Describe dosage forms as a suspension
It is a heterogenous mixture composed of two phases where it has an internal solid phase which is dispersed throughout the external liquid phase such as steroids
Pros and Cons of drugs as a suspension
Pros –> Reduced drainage as particles remain in lower lid, prolonged residence time giving higher drug availability
Cons –> Higher cost, larger particle size giving foreign body sensation and that suspensions need to be shaken before use
Name the types of drug properties
Molecular weight, Partition coefficient and the acid dissociation constant
Name the characteristics of class 1, 2, 3 and 4 drugs
Class 1 –> High solubility and permeability
Class 2 –> Low solubility and high permeability
Class 3 –> High solubility and low permeability
Class 4 –> Low solubility and low permeability
Where does a drug need to be in order to be absorbed in regards to solubility
In a solution
What dictates solubility
The solid state properties and the affinity for the solvent where like dissolves like
What is the Henderson-Hasselbalch equation
pH = pKa - Log (Unionised)/(Ionised)
Regarding permeability, explain the path for a drug to get to its site
Drug must penetrate the enterocytes lining the GIT
What dictates permeability in passive diffusion
The drugs molecular weight, lipophilicity and the ionisation
Which transport mechanism is more important for drug
Passive diffusion where it is driven by the concentration gradient
What does active transport require
Energy as it transports things against its concentration gradient
What does the rate of passive diffusion depend on
Concentration gradient between the GIT and the plasma, Surface area, thickness of the membrane and the diffusion coefficient of the molecule
Rate of diffusion equation
((Cg - Cp) x A x D ) / d
What is first pass metabolism
Occurs before the drug reaches the systemic circulation, mainly in the liver
How to calculate oral dose
(Drug mass administered ) / (Bioavailability of that drug)
How to ocular bioavailability increased in suspensions
Shaking the bottle before use and applying one drop into the lower lid pocket and close eyes, obstruct duct so the cornea can absorb it
How long should we wait before applying another drop
5 minutes
Why do we wait 5 mins before applying a second drop
Washout effect takes 5 mins for the drug to clear
What does less washout mean
Higher absorption of drug
How to increase compliance of px when multiple eye drops needed
Use a product that has a combination of both drugs in the same eye drop
How is corneal permeability increased
By using penetration enhancers, prodrugs, colloidal delivery systems and increasing the contact time with the ocular surface by using viscosity enhancing
Requirement for two pharmaceutical drugs to be bioequivalent
Both drugs need to be pharmaceutically equivalent and have the same bioavailability
What is pharmaceutical equivalence
Same amount of same active form in same dosage for the same route of administration
Are two different drops of the same drug bioequivalent
no
Why arent the two drops bioequivalent
May have different pH giving different solubility and permeation, the particle size of the drug in the suspension can change its drainage and solubility. The addition of preservatives can vary the corneal penetration and absorption
Where do drugs go
Places like blood, fat, intracellular and extracellular fluids
What does drug absorption depend on
Drug properties, plasma protein binding and the disease state / age
What is volume distribution ( Vd ) and how its calculated
Its a constant value for a drug in the average person. Here the total amount of drug absorbed is divided by the plasma concentration
It depends on Drug properties, plasma protein binding and the disease state / age
What does a low plasma concentration mean for Volume distribution
A higher volume distribution, and vice versa.
What decreases volume distribution
Increased molecular weight and plasma protein binding
What increases volume distribution
Increased LogP and lipophilic drugs
How is LogP and lipophilic drugs related
Higher LogP the more Lipophilic the drug is
Compare Chloroquine and Warfarin
Chloroquine has longer half life as Warfarin binds to proteins like albumin
They have similar LogP and Molecular Weight
What is the loading dose ( LD )
The amount of drug needed to achieve target concentration
How to calculate loading dose ( LD )
LD = (Desired steady state concentration) x (Volume Distribution)
How does increased age affect the drug in the body
Less plasma proteins in older people so more free drugs and possible increase in volume distribution. Diseases also increases permeability of capillary walls increasing volume distribution
What does volume distribution affect
The time for a drug to reach a steady state and the time for the drug to be completely eliminated
What is steady state ( Css )
The rate where drug administration equals drug elimination
How to calculate steady state of a drug
Css = ( Maintanence dose rate ) / CL
CL = Clearance of drug
Can use to calculate Maintanence dose rate ( MDR ) where MDR = Css x CL
What does does a higher volume distribution mean for Steady state
Longer time to reach steady state concentration ( Css )
What does increasing the loading dose mean for Steady state
Decreases the time to the steady state concentration ( Css )
What is Clearance ( CL )
The volume of plasma irreversibly cleared of drug per unit time.
Can be excretion of unchanged drug and metabolic conversion
How are most drugs removed
Urinated out
How does Renal clearance of a drug occur and how to calculate excretion
Drugs filtered into the bowmans capsule and then some components are reabsorbed and secreted
Excretion = Filtration - Reabsorption + Secretion
What is the glomerular filtration rate ( GFR )
Total volume of filtrate produced per unit time by all functioning nephrons
Explain the two phases in Hepatic clearance
Phase 1 –> Modification by oxidation, reduction, hydrolysis
Phase 2 –> Conjugation by sulphates, amino acids and Gluathione Acetylation
What can occur in hepatic clearance
Can be eliminated by renal elimination of if drug goes through the hepatic circulation then that is not good for the liver
How to calculate CLtotal
CLrenal + CLhepatic + CLother
What affects GFR ( Glomerular filtration rate )
Renal diseases and failure reduces clearance
How is GFR measured
By the creatinine clearance ( Multiply 0.85 for females )
How to calculate creatinine clearance
[(140 - age in years) x Body mass in kg] / 814 x serum creatinine
Which order kinetics do most drugs get eliminated
First order, where decline is constant over time
What drugs are zero order kinetics regards to rate of elimination
Aspirin, Phenytoin and Ethanol
What is a first order elimination
Exponential, where it is the amount of drug eliminated per unit time is proportional to a constant % of drug is eliminated per unit time
In other words, it is the constant fraction of drug eliminated per unit time
What is a zero order elimination
A constant amount of drug is eliminated per unit time and is seen as a straight and declining line
Characteristics of Zero order elimination
Metabolism dependent on enzyme saturation, more easily overdoes and the half life is not constant
What is t 1/2
The time taken to eliminate 50% of the drug
How to calculate the half life of a drug
t1/2 = (0.693 x Vd) / CL
or 0.693 / Ke
How long does it take to eliminate a given drug dose
4-5x the half life of that drug , this is where 95% of the drug is out
How long does it take to reach a drugs Css ( Steady state concentration )
Also 4-5x the half life of that drug
Which equation is more relevant for drugs with higher half lifes
LD = Desired Css x Vd
Which equation is more relevant for drugs with lower half lifes
MDR = Desired Css x CL
What is the half life of most drugs
8-24 hours, hence dose is 1-3x per day
Why do we do all these pharmaceutical calculations for drugs
To prevent no response and unwanted response and aim for desired response
We want the drug effect to be therapeutic, not toxic or sub-therapeutic
