WEEK 1 - PHARMACOLOGY Flashcards
List the target sites for drug action
- Enzymes (e.g. ACE inhibitors, aspirin, neostigmine)
- Carrier Molecules (e.g. flavonoid – Pgp antagonist, digoxin)
- Ion channels (e.g. verapamil - L-type calcium channel antagonist)
- Receptors (e.g. benzodiazepine – GABA receptor agonist, adrenoceptor agonists and antagonists )
- Structural proteins (e.g. Taxol – Tubulin “agonist”)
- DNA (e.g. anti cancer agents like Doxorubicin)
What are receptors?
Protein molecules whose function is to recognise and respond to endogenous chemical signals.
What is meant by dose-response curve?
Dose response curves are typically used to plot the concentration of a drug (usually log) against its “response”
What is an agonist?
Molecule/drug that binds and activates the receptor
What is an affinity?
The tendency of a drug to bind to the receptor
What is Efficacy?
The tendency of a drug to activate the receptor once bound.
What is the difference between a partial agonist and a full agonist?
- If the activation is 100%, namely each time a drug interacts with its target there is a response then the agonist is said to be a “full agonist”
- If the activation is <100%, the agonist is said “partial agonist”. Partial agonists have lower efficacy than full agonists – even with maximal occupancy of receptors.
What is EC50?
Effective concentration. The dose required for an individual to experience 50% of the maximal effect
What is ED50?
Effective dose. The dose for 50% of the population to obtain the therapeutic effect.
What is Potency?
Amount of drug required to produce 50% of its maximal effects.
What is Efficacy?
The maximum therapeutic response that a drug can produce (example: morphine vs buprenorphine)
What is specificity?
Describes the capacity of a drug to cause a particular action in a population
What is Selectivity?
Relates to a drugs ability to target only a selective population i.e. cell/tissue/ signalling pathway, protein etc in preference to others.
What is an antagonist?
Molecule/drug that binds a receptor without activation
What are the main types of antagonism?
- Competitive
- Non-competitive
- Irreversible
What is competitive antagonism - describe this?
- Competitive agonists compete with agonists for the receptor binding site.
- The chemical structure of the agonist and competitive antagonist are often similar (lock and key hypothesis).
- Antagonist binds to receptor in such a way as to prevent agonist binding
- Competitive antagonism is surmountable – additional agonist can overcome the receptor blockade.
What effects does a competitive antagonist have on a dose-response curve?
Addition of a competitive antagonist shifts the dose response curve of the agonist to the right
What is non-competitive antagonism - describe this?
Non-competitive antagonists either bind to a different receptor site
OR
Block the chain of events “post” binding - acting “downstream” of the receptor.
What is irreversible antagonism - describe this?
- Antagonist dissociates from the receptor only very slowly or not at all.
- The antagonist forms covalent bonds with the receptor.
- Irreversible antagonism is insurmountable – additional agonist cannot overcome the receptor blockade.
What is an Inverse agonist?
Drug that reduces the activation of a receptor with constitutive activity (example: GABAA receptor)
Can be regarded as drugs with negative efficacy.
What is IC50 and what is it used for?
- Concentration of antagonist to inhibit 50% of the agonist maximal effect.
- Used to measure antagonist drug potency.
What is Tachyphylaxis (“rapid protection”)?
Reduction in drug tolerance which develops after a short period of repeated dosing (decrease in response). Not common. Often due to a lack of a co-factor.
What is Self-Antagonism?
When a drug becomes antagonistic to its own effects
What are Drug-drug interactions?
“Altered pharmacologic response to one drug caused by the presence of a second drug”
What are the 3 different mechanisms of Drug-drug interactions?
Pharmaceutical – related to physiochemical properties and formulation (chemical or physical incompatibility/interaction)
Pharmacokinetic – related to interactions within ADME (absorption, distribution, metabolism, and excretion)
Pharmacodynamic – related to interactions within receptor signalling (antagonism, synergisms)
What is Summation?
When two drugs are administered together the effect seen is equal to the sum of the individual effects of each drug
What is Potentiation?
When a drug or food increases the effect of another drug, but has no effect when administered alone
What is Synergism?
When two drugs are administered together produce effects that are greater than would be produced if either drug were administered individually or would be seen with summative (additive) effects.
E.g. sulphonamide-trimethoprim (enhanced)
Toxicity: aminoglycosides and furosemide
What is Ki?
( dissociation constant for inhibitor binding)= indicator of enzyme affinity for inhibitor
What are the effects of a competitive enzyme inhibitor?
Increases Km
No effect on Vmax
Amount of inhibition depends on Ki
Example: Captopril-angiotensin converting enzyme inhibitor (treatment of hypertension)
What are the effects of a non-competitive enzyme inhibitor?
No effect on Km
Decreases Vmax
Example:Aspirin-cyclo-oxygenase (anti-inflammatory, analgesic, antipyretic)
How does a competitive enzyme inhibitor affect Ki?
For a competitive inhibitor, the lines converge above the x axis, and the value of [I] where they intersect is -Ki
How does a non-competitive enzyme inhibitor affect Ki?
For a non-competitive inhibitor, the lines converge on x axis, and the value of [I] where they intersect is -Ki
What is Pharmacokinetics (PK)?
What the body does to the drug
What is Pharmacodynamics (PD)?
What the drug does to the body
What are the Enteral routes (directly in the gastrointestinal tract) of drug administration?
- Sublingual
- Swallowing
- rectal
What are the Parenteral routes of drug administration?
- Topical
- Intradermal
- Subcutaneous
- Intramuscular
- Intravascular
- Inhalation
How are drugs absorbed when administered by enteral routes?
- Along the length of the GI-tract
- interaction between gastric juice/physicochemical properties of drugs will decide whether drugs are absorbed in acidified (e.g. stomach) or ~neutral/alkaline (e.g. intestine) compartments (drug design to help the dissolution in high or low pH)
What are the characteristics of drugs that are rapidly absorbed via enteral routes of administration?
a. Low degree of ionization
b. High lipid/water partition in the non ionized form
c. Relatively low Molecular Weight < 1000
d. A biological affinity with transporters/facilitated diffusion (e.g. cephalporins are absorbed by a transporter for dipeptides).
In general which compounds are not absorbed by enteral routes and why?
a. High degree of ionization (ions need specific channels/transporters: Na+ vs. Mg2+)
b. Low lipid/water partition in the non ionized form (flows with the peristaltic mvt & eliminated or needs transporter e.g. glucose)
c. Too large (e.g. chemicals forming precipitate flows with the peristaltic mvt & eliminated).
d. Degraded by specific enzymes (e.g. insulin, epinephrine, histamine,…)
What is first pass metabolism?
If a drug is metabolised BEFORE it reaches the systemic circulation
Where do enzymes act in the liver?
In the liver, enzymes act in the smooth endoplasmic reticulum of Liver Cells (hepatocytes)
What is Entero-hepatic circulation?
Parent drug or metabolites may recycle several times before entering the systemic circulation (the drug follows bile salts)
Which group of enzymes oxidate the drug in phase I metabolism?
CYP450
What are the 4 different types of Metabolite activity?
- Detoxification
- Similar activity to drug
- Different activity
- Toxic metabolites
Where are CYPs found in the body?
The majority of CYPs are found in the liver, but certain CYPs are also present in the cell wall of the intestine.
Where are Mammalian CYPs membrane bound?
Mammalian CYPs are membrane bound to the endoplasmic reticulum.
There are many variables between individuals (notion of bioavailability) in enteral routes of drug administration such as???
- e.g. amount of food eaten (age related)
- e.g. peristaltic movement (age related)
- e.g. metabolic rates/organs function (age and size related)
How does age effect drug absorption for enteral routes of administration?
- more chronic illness = more chance to have an adverse reaction
- Elderly: Less proteins & water in the body
- Infant (human): >77% of water (human adult average ~70%)
- pH of the GI-tract may change with age
How does temperature effect drug absorption for enteral routes of administration?
Cold blood animals (e.g. fish)… variable metabolism…depending on the season
What is the advantage of Parenteral routes of drug administration in terms of drug absorption?
The clear advantage is that the first pass metabolism is bypassed.
Describe drug absorption via Topical admin.
- Skin: Local slow & sustained effects (hours to weeks, e.g. patches).
- Eye drops: local effect to renew frequently (washed away rapidly).
- Nasal instillation local systemic effect.
Describe drug absorption via Intradermal admin.
Between skin layers: slow absorption
Describe drug absorption via Subcutaneous admin.
- Faster absorption but fat layer may trap lipid soluble compounds
- Massage increases blood flow and absorption.
Describe drug absorption via Intramuscular admin.
- Very fast absorption
- Physical activity/massage increases absorption.
- Absorption: liquid>suspension>emulsion.
Describe drug absorption via Intravascular admin.
- Mostly used when need to accurately control the body concentration of drugs. Typically used when compounds have narrow margins of safety between therapeutic and toxic index (e.g. doxorubicin/anticancer drugs).
- Drawback:
- Drug injected cannot be recalled (whereas stomach pump or emetics can be used for enteral routes & other means exist to delay dermal/muscular injections).
- A slow administration is needed to avoid side effects.
Describe drug absorption via Inhalation
- Gas and aerosols:
- Rapid systemic effect but dependent on:
1- the tidal volume
2- the size of the aerosol particle (not true for gas). The smaller the more likely to reach alveolar ducts and sacs. Otherwise get stacked in bronchi.
What are the main routes of drug excretion?
- Kidneys
- Hepatobiliary system
- Lungs (volatile compounds e.g. GAs)
What are the secondary routes of drug excretion?
- Milk
- Sweat
What is the equation for Net Renal Excretion?
Filtration + Secretion – Reabsorption
What is the equation for Filtration Excretion?
- Filtration Excretion = GFR x fu
- Where fu = drug plasma free fraction = 1-fraction of drug bound to plasma
What happens if renal excretion > GFR x fu?
Secretion
What happens if renal excretion < GFR x fu?
Net reabsorption
Why would metabolic acidosis/alkalosis affect drug excretion?
Must be neutral to cross the membrane (if too charged they would associate with many other molecules which would impair their ability to diffuse).
What happens if pH urine
- protonated form dominates in urine which implies:
(a) Trapping of basic drug in urine therefore increased renal excretion
(b) Greater reabsorption of acid drug therefore reduced renal excretion
What happens if pH urine>pH blood?
Protonated form dominates in blood which implies:
(a) Trapping of acid drug in urine therefore increased renal excretion
(b) Greater reabsorption of basic drug therefore reduced renal excretion
What are Drug interactions?
“Altered pharmacologic response to one drug caused by the presence of a second drug”
What are Pharmaceutical drug interactions?
Interaction prior to administration
What are Pharmacokinetic drug interactions?
Tissue/plasma levels of one drug altered by another one
What are Pharmacodynamic drug interactions?
Action of one drug is altered by a second one
What are the possible outcomes of drug interactions?
- Action of one or more drugs is ENHANCED
- Development of totally NEW EFFECTS
- INHIBITORY effects of one drug on the other
- NO CHANGE
What are the Pharmaceutical mechanisms of interactions - provide examples?
- Chemical or physical incompatibility/interaction
- Sodium bicarbonate and calcium
- Insulin is denatured by glucose
- Diazepam binds to plastics
What are the Physical incompatibilities Pharmaceutical mechanisms of interactions?
Insolubility e.g. amphotericin B precipitates in electrolyte solutions
What are the chemical Pharmaceutical mechanisms of interactions?
- pH
- Stability of drugs is often pH dependent E.g. penicillin G is inactivated by alkaline sulphonamide
- Oxidation/reduction e.g. tetracyclines are oxidised by riboflavin
- Complex formation
What does CYP3A induction lead to?
- An increased metabolism of the administered substance due to upregulated enzymes.
- This can cause adverse reactions, like inflammation of the liver (hepatitis).
What are the Pharmacodynamic interactions at receptor sites?
- Agonist/antagonist negate an effect
- E.g. Organophosphate with pralidoxime OR vitamin K
with coumarin anticoagulant
- E.g. Organophosphate with pralidoxime OR vitamin K
- Agonist/antagonist induce a harmful effect
e. g. a2 antagonist and a2 agonist - Synergistic effects
- Drug combinations produce a therapeutic or toxic
- effect greater than sum of each drug’s action
- E.g. sulphonamide-trimethoprim (enhanced)
- Toxicity: aminoglycosides and furosemide
What is Summation?
When each drug has an independent action in the absence of the other e.g. midazolam lowers the dose of propofol needed for anaesthesia.
What is Potentiation?
When a drug on its own does not have an effect but may affect/be affected in combination with another drug e.g. probenecid reduces penicillin excretion in urine and increases effectiveness of penicillin.
What is Synergism?
- Drug combinations produce a therapeutic or toxic effect greater than sum of each drug’s action
E.g. sulphonamide-trimethoprim (enhanced)
Toxicity: aminoglycosides and furosemide
What is Quantitative Pharmacokinetics (PK)?
Changes in plasma/tissue drug concentration
with time
What is Quantitative Pharmacodynamics (PD)?
Changes in biological response with time
What is the Drug Absorption Rate?
The Amount of Drug Absorbed from Administration Site to Measurement Site per Unit Time
What are the units for the Drug absorption rate?
Mass or Moles per time
What is the Absorption rate from bolus intravenous administration?
Absorption rate from bolus intravenous administration can be considered instant
What is the Absorption rate from infusion administrations?
Absorption rate from infusion administrations eg intravenous infusion, transdermal patch etc follow zero order kinetics.
What is the Absorption rate from diffusion type administrations?
Absorption rate from diffusion type administrations eg oral,intramuscular etc tend to follow first order kinetics
What is zero order Drug Absorption Rate Kinetics?
- Absorption rate from infusion administration = Infusion Rate (IR)
- Rate is independent of the Amount of drug (zero order)
What is first order Drug Absorption Rate Kinetics?
Absorption rate from oral administration tends to be proportional to amount of drug (first order)
What is the relationship between Amount of drug at administration site and rate of absorption?
Amount of drug at administration site decreases with time therefore, rate of absorption decreases
What is the Drug Elimination Rate?
The Amount of Parent Drug Eliminated from the Body per Unit Time
What is Elimination rate defined with respect to?
Elimination rate is defined with respect to irreversible removal of parent drug and does not include metabolites
What is Volume of Distribution (Vd)?
A proportionality constant relating the Blood/plasma concentration to the amount of drug in the body
What is the equation for Vd?
Amount of Drug in body at time (t) = Volume of distribution at time (t) x Blood/plasma concentration at time (t)
What is the volume distribution of total body water?
TBW is approx 0.6L/Kg
What is the volume distribution of Extra Cellular Fluid?
ECF is approx 0.1-0.3L/Kg
What happens if Vd is in the order of 0.1-0.3L/Kg?
Most likely it is water soluble and distributes mainly to the ECF
What happens if Vd is in the order of 0.6L/Kg?
Most likely the drug distributes mainly to both ECF and ICF?
What happens if Vd is in the order of 0.6L/Kg?
Most likely the drug distributes mainly to both ECF and ICF?
What happens if Vd is high (in the order of 2L/Kg)?
The drug is probably accumulating at a particular site.
What is Total Body (Blood) Clearance?
The volume of blood/plasma cleared of parent drug per unit time
What is the rate of elimination equation?
Rate of Elimination = Blood/Plasma Clearance x Blood/Plasma Concentration
What is the equation for Total Body (Blood) Clearance?
CLtotal = Clhepatic+Clrenal+Clpulmonary
What is Blood/Plasma clearance is determined from?
- Blood/Plasma clearance is determined from the area under the blood/plasma
- Concentration versus time curve (AUC) from an IV administration
What is the equation from determining clearance after IV dosing?
CL=Dose/AUC
What is Bioavailability (F)?
- Measure of extent of absorption from administration site to measurement site
- fraction or percentage of administered dose that reaches the plasma
What is the equation for Bioavailability (F)?
F = (Dose IV/Dose Oral) x (AUC Oral x AUC IV)
What is the Elimination Rate Constant (k) of Drug?
A constant relating the rate of elimination to the amount of drug in the body
What is the equation for the Elimination Rate Constant (k) of Drug?
elimination rate constant k = Clearance / Vd
What are Non-compartmental Pharmacokinetic Models?
- No specialised software required
- No assumptions on disposition of drug
- Can not use to simulate PK for different dosing regimens
What are compartmental Pharmacokinetic Models?
- Assumes disposition of drug into compartments
- Way of predicting and extrapolating drug PK
Describe Elimination following a One Compartment IV Model
- Single Exponential Decay
- For a single (mono) exponential decay; clearance, volume of distribution (Vd) and half-life are constant
How do you calculate Vd for a single (mono) exponential decay?
Volume of distribution (Vd) = initial volume (Vi) = Dose/C0
What is the Half-Life of a drug?
The time for the concentration of the drug to halve
What is the equation for Half-Life?
(0.693xVd)/CL
How does a Two compartment model, first order elimination and distribution, IV administration work?
Drug distributed instantaneously throughout compartment 1 (ECF and rapidly perfused tissues) and slowly throughout compartment 2 (poorly perfused tissues)
What happens in a Drug concentration versus time Two compartment IV Model?
- Two half-lives, alpha and beta
- Implies volume of distribution initially increases
Describe the Volume of distribution (Vd) from
Bolus administration?
Volume of distribution is related to kinetics of drug elimination:
- Phase I: the drug partitions into tissues
- Phase II: the drug is slowly cleared from tissues
What is the calculation for Average Concentrationss
Average Concentration(ss) = (Therapeutic Dose x F)/(CL x Dosing Interval)
What is a loading dose?
A loading dose is an initial higher dose of a drug that
may be given at the beginning of a course of treatment
before dropping down to a lower maintenance dose
What is a loading dose useful for?
A loading dose is most useful for drugs that are
eliminated from the body relatively slowly, i.e. have
a long systemic half-life
What is the equation for loading dose?
Loading Dose = (Theraputic Css x Vss)/F
What is Allometric Scaling?
The mass specific (per gram) metabolic rate* needed to sustain an organism decreases with body weight (BW) to the 1/4 power
What is the Application of Allometry to Drug Clearance?
- Mass specific Blood flow (Q) to eliminating organs decreases with weight
according to an allometric 1/5 power law - Plasma clearance is dependent upon blood flow to eliminating organ
- Therefore the clearance of a drug is expected to be greater for a smaller species compared to a larger one based upon blood flow alone (in units of flow per kg of bodyweight)
What is Intrinsic clearance?
Intrinsic clearance (CLintrinsic) is the enzyme-mediated clearance that would occur without physiological limitations (e.g. hepatic blood flow)
How do you calculate intrinsic clearance?
CLintrinsic = Vmax/Km
What are in vitro methods used for?
Prediction of Hepatic Metabolic Clearance
Drug Plasma protein binding (PPB) can vary for several reasons - what are they?
- Elderly and neonates have a lower concentration of plasma proteins compared to healthy adults
- Disease states can affect concentration of plasma proteins
- Drugs may be displaced from plasma proteins by other drugs that have a higher affinity (high PPB) leading to a change in their PPB
What will a decrease in PPB do to the total and free
pharmacokinetics?
- Both volume of distribution and clearance move in the same direction when there is a change in the PPB and therefore half-life does not change
- Total drug concentration changes upon a change in PPB but NOT Free drug concentration
What are the three main exceptions to the general rule for which drug binding interaction has no clinical meaning?
- Rapid bolus IV injection
- Parenteral administration of displaced drug with a high organ extraction ratio
- Therapeutic drug monitoring and drug displacement from the plasma binding site
What happens to the free drug concentration when a rapid IV bolus is given?
If the displacing agent is given rapidly (IV bolus), the free concentration could increase dramatically due to rapid displacement of the displaced drug before the compensatory mechanism (redistribution) takes place
What are the advantages of Controlled Release (CR) Drug Delivery?
- Similar kinetics to intravenous infusion (zero order)
- Reduced risk of breaching therapeutic window
- Drug delivery period can be over several months from single administration
How does the Paratect® bolus morantel system work?
- Delivers morantel tartrate for up to 90 days in gastrointestinal Roundworms in cattle
- Controlled release through porous end discs (Depot effect)
How do Spot-on anti-parasitic drugs (e.g. fipronil or imidacloprid) work?
- Oil-based spot-on administered to skin behind the neck distributes over the skin gradually for 30 days
- Drugs are sequestered by sebaceous glands, which release drugs together with sebum onto skin over the therapeutic period at a level above that required to kill parasites
- Drugs act noncompetitively and with high potency to inhibit flea glutamate-gated chloride channels and with lower potency to inhibit GABA-gated ones
How does PRID® (progesterone releasingintra-vaginal device) work?
- Management of ovarian dysfunction in postpartum dairy cows
- High-temperature injection mould process is used to cure a drug-impregnated silicone matrix over a nylon spine
- Can help get cycling and non- cycling cows and heifers pregnant faster
How does Osmotic Ruminal Therapeutic System (IVOMEC-SR® bolus) work?
- Delivers ivermectin for up to 135 days for parasite treatment
- Contact with water swells capsule via osmosis which pushes flow moderator and releases agent
How does Drug delivery via Aerosol work?
- Standard human MDI connected to cat/dog specific aerosol chamber for the treatment of asthma and allergies
