Pharmacology Flashcards
What is phamacodynamics and pharmacokinetics?
Pharmacodynamics is the effect of the drug on the body
Pharmacokinetics is the effect of the body on the drug (ADME)
What is druggability or ligandability?
The ability of a protein target to bind small molecules.
How well a biological target can impacted by a drug.
What are the four kinds of receptor which may be druggable?
Ligand gate ion channels
G protein coupled receptors
Kinase-linked receptors
Cytosolic/nuclear receptors
What is a GPCR made of and how do they work?
Ligand binds to a receptor site among the 7 transmembrane proteins.
This activates a G protein which alpha subunit (attached to the transmembrane proteins) binds GTP turning it on.
This releases the beta-gama dimer along the plasma membrane which activates adenyl cyclase etc.
When ligand is removed, GTP is hydrolysed to GDP and the beta-gamma dimer returns to the alpha subunit
Name 2 common enzymes which G protein activate
Adenylyl cyclase - cAMP
Phospholipase C - IP3
How do kinase linked receptors work?
Ligand binds to extracellular part
This allows phosphorylation of the intracellular domain
This causes intracellular cascade
How do nuclear receptors work?
Ligand passes into nucleus to ligand binding domain
Causes transcription of certain proteins which act as transcription factors on other parts of the genome.
For a receptor agonist, what is EC50?
Effective dose 50 - what amount/concentration of a drug will give 50% of the maximum response
Describe potency?
What makes a drug more potent than another?
This relates to whether a drug is strong or weak
If drug A causes a greater response at the same dose of drug B, then drug A is more potent.
What is a full agonist?
An agonist which can reach a 100% response - even if a very large dose is required.
What is a partial agonist?
Where no matter how much agonist we give, it cannot reach 100% response. The maximum it reaches is called Emax.
What is Emax of a partial agonist?
The maximum response of a partial agonist
What is efficacy? What would make a drug more efficacious?
This relates to how effective the drug is, independent of dose. If drug A has a higher Emax than drug C, it is more efficacious.
What is the difference between efficacy and potency?
Potency relates to whether a drug is strong or weak. If we need double dose for same effect, it is half as potent.
Efficacy is do to with how effective a drug is - can you get a maximal response or not?
What is the intrinsic activity of a compound?
Intrinsic activity is a measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity.
It is similar to efficacy
What is the calculate for intrinsic activity (of drug X)?
Intrinsic activity = Emax of partial agonist (X) / Emax of a full agonist
What is affinity?
This describes how well a ligand binds to the receptor. This is property shown by both agonists and antagonists
What 2 “tissue related” factors govern drug effect?
Receptor number - other drugs can completely block receptors
Signal amplification - the amplitude can vary greatly.
What 2 receptor related factors govern drug affect?
Affinity of receptor
Efficacy of receptor
What is receptor reserve?
When an agonist only needs to activate a small fraction of existing receptors to produce a maximal response, there will be spare receptors.
As such, if you give irreversible antagonists there may not be any affect at low doses as you are just blocking the receptor reserve.
What is allosteric modulaton?
Where you activate or block a receptor using a different site to where ligands bind.
What is inverse agonism?
When a drug binds to the same receptor as an agonist but causes the opposite response - like a form of antagnoism
What is tolerance?
Drug tolerance
Repeat exposure to a drug means the receptors become desensitised and you do not get the same response.
What is densitisation?
Give 3 ways desensitisation occurs
Where receptors stop producing a great affect. Receptors can be
Uncoupled to enzymes
Internalised (conformation changes)
Degraded
You need a greater dose for the same response.
Are drugs specific or selective?
Selective - no compound is every truly specific and will act on a few receptors.
We are trying to change this
Pharmacokinetics Absoprtion:
What are four ways a drug can corss a membrane?
1) Passive diffusion across lipid bilayer (rate is proportional to concentration gradient, area and permeability (IVP to thickness))
2) Diffusion through ion channels - limited to small molecules
3) Carrier mediated transport, example of carrier is ATP-binding Cassette
4) Pinocytosis
Where are weak acid and weak base drugs best absorbed each?
Weak acids - stomach
Weak bases - intestine
Each will be unionised making them more lipid soluble so they can cross the phospholipid bilayer
How can we make Aspirin overdose be cleared quicker from the urine?
Alkalise urine.
Aspirin is a weak acid, hence by alkalising urine we can assure that it is ionised, and so will remain in urine
What 5 things do we need to consider when evaluating how well a drug reaches circulation from oral administeration?
1) Drug structure - lipid soluble improves. Also not being pH sensitive or targetted by digestive enzymes in SI
2) Drug formulation - A tablet that dissolves quickly?
3) Gastric emptying - can be slowed
4) Enzymes in intestinal lumen/wall
5) First pass metabolism
What is first metabolism and why can it be a problem/yield higher drug doses?
Where a drug is absorbed in the intestine, enters portal (venous) circualtion, is taken to the liver and is metabolised.
We lose drug if it is metabolised in the liver before reaching the systemic circulation
What kind of drugs can be absorbed transcutaneously?
Lipid soluble drugs. Also potent, non-irritant. E.g. Fentanyl patch
Why do we inject a drug subcutaneously?
It is absorbed more slowly than injected into a vein (e.g. long term contraceptive implants)
Also useful for local effects (e.g. anaesthetics)
What is a depot IM injfection?
Where a drug is made lipophilic before injected intramuscularly, this causes the drug to be absorbed into the blood slowly over weeks if necessary.
What required quality of a drug limits inhalational administeration?
We cannot deliver non-volative drugs (needs to be a gas).
Alternatively we can give them as a gas.
How does drug distribution change overtime when injecting IV?
(hint: osmolarity)
1) Initially there is a high plasma concentration of the drug, it moves out by osmosis, particularly to well perfused tissue such as the brain, liver and lungs
2) The drug continues to enter less well perfused tissues lowering plasma concentration
3) The high concentrations in well perfused tissues acts as a resevoir and drug moves back into blood by osmosis.
How can protein binding act as a drug depot?
If a drug binds reversibly to a plasma protein (commonly albumin) then when plasma concentration decreases, drug can release from protein
Note any drug irreversibly bound is effectively eliminated
Which kind of drugs can cross the placenta?
Small molecules - even these rarely reach feotal circulation as placenta blood flow is quite low.
What does the body (liver) try to do with lipid soluble drugs?
Tries to make lipid soluble soluble drugs more hydropholic so they can be excreted in urine.
Sometimes this can increase biological activity if a pro-drug is given.
Describe Phase 1 reactions/metabolism in the liver
Makes the drug more polar by unmasking or adding functional groups.
Oxidation is most common, usually catalysed by CYP450s (exceptions are alcohol dehydrogenase)
Describe Phase 2 reactions/metabolism in the liver
This is conjugation, adding a polar molecule via a covalent bond to make the molecule much more water soluble.
Name 3 different routes drugs can be excreted?
1) Fluids - urine, bile, sweat, tears, breast milk. Important for low molecular weight polar compounds
2) Solids - Important for high molecular weight compounds. Taken by hepatocytes and excreted in bile (note some can be reabsorbed in enterohepatic circulation)
3) Gases - important for volatiles
What is first order kinetics?
When considering how drug plasma concentration decreases
When the change in concentration of a drug is proportional to the concentration of the drug.
There will be an inverse exponential decrease (starts of decreasing fast, levels then slow)
What is zero order kinetics? When may it occur?
When considering how drug plasma concentration decreases
The change in concentration per unit time is fixed and independent of drug concentration.
This may occur if the enzyme system which removes a drug is saturated (occurs with alcohol DH)
When considering drug absorption (pharmacokinetics), what is bioavailability (F)?
“The fraction of the administered drug that reaches the systemic circulation unaltered”
What is the bioavailability (F) of:
1) IV drugs
2) Oral drugs
1) 100%
2) F<1. This can occur if they are incompletely absorbed or undergo first pass metabolism.
Why do we need to consider bioavailability (F) when chosing a drug dose?
If F<1 for oral route, we will need to give a greater dose than if we administered IV.
If F=0.5, then we would need double oral dose compared to IV dose.
When considering drug distribution, what determines:
1) Water soluble drugs
2) Lipid soluble drugs
Rate of distribution
1) Rate of passage across membranes
2) Blood flow to tissues
What is “volume of distribution” (Vd)?
The volume (litres) that the drug would occupy if it was distributed through all compartments as if they were all plasma.
What is the calculation for volume of distribution?
Vd = Total amount of drug in body / concentration of drug in plasma.
What does it mean if Vd is:
1) High
2) Low
1) If high then it suggests the drug may be distributed in total body water and is lipophilic (can leave blood)
2) If low then it suggests that the drug may be confined to the circualtory volume
Why is Vd often very large?
We only measure the plasma concentration and assume it is all in the plasma.
When a drug is injected it is taken up by organ systems and blood concentration will decrease. Thus when you calculate Vd, it will be much more
What is the definition for clearance?
The volume of blood or plasma cleared of a drug per unit time.
Describe the relationship between Vd and clearance.
If a drug has a high Vd (low plasma concentration/lipophilic) then it will have a low plasma concentration so the rate of eliminaton is inversely proportional to Vd. As such:
K = Cl/Vd
Describe the relationship between Vd, half-life and clearance.
t1/2 = 0.693 Vd/CL.
This is just showing that half-life is inversely proportional to clearance and directly proportional to the volume of distribution.
What is drug steady state (Css)?
When we are giving repeat drug doses we have reached a point where drug intake has reached elimination and the desired concentration remains constant.
How will having a slow drug elimination (long t1/2) affected time to reach Css?
It will take a long time to reach steady state as the drug will accumulate high plasma concentrations before elimination rate rises to match drug infusion.
Note t1/2 is directly proportionally to Vd and inversley proportional to Cl
What is a loading dose (when trying to achieve steady state)?
Where if a drug has a long t1/2 it takes a long time to reach a steady state, instead we give a high initial dose of a drug which loads the system and shortens the time taken to reach the steady state.
What are the 2 types of enzyme inhibitors?
Irreversible and reversible inhibitors
Give 2 examples of enzyme inhibiting drugs?
Statins - inhibit enzymes in the cholesterol synthesis pathway
ACEi
Name 5 patient risk factors for drug interactions
Polypharmacy Old age Genetics Hepatic disease Renal disease
Name 3 drug risk factors for drug interactions
Narrow therapeutic index Steep dose/response curve Saturable metabolism (where drug breakdown is not linear - it "peaks" at high concentrations)
Can food interact with drugs?
Yes - grapefruit juice and avocados for instance can inhibit CYPs enzymes leading to increased bioavailability.
What are the 3 types of pharmacodynamic effects of drugs?
Receptor based effects
Signal transduction - blocking intracellular cascades
Physiological systems - beta blockers work on heart, blood vessels and the lungs
What are the 2 ways a drug (agonist/antagonist) can elicit its effects?
Competitive
Non-competetive (allosteric)
Why do you need a high dose of oral opioids compared to IV/SC?
Opioids taken orally have low bioavailability since liver metabolises about 50% on first pass.,
How do opioids elicit analgeisa?
They are receptor agonists for opioid receptors. These activate naturally occuring pain modulation pathways (descending pathways).
Physiologically, these pathways use endorphins and enkephalins.
What is the antagonist to morphine?
Naloxone - you would give this if someone has overdose on morphine.
Name 5+ side-effects of opioids
Respiratory depression Sedation Nausea/vomitting Constipation Itching Immune suppression Endocrine effects
What is codeine and how is it metabolised?
Codeine is a weaker form of morphine, it is metabolised by CYP2D6 into morphine to work.
Note some people can have deficinecies in this enzyme
Name some stronger and weaker than morphine opioids
Stronger - oxycodone
Weaker - codeine, tramadol
What are the receptors in the sympathetic nervous system? Are post-ganglionic fibres long or short?
Preganglionic -> nicotinic receptor (ACh) -> Postganglionic -> adrenergic (NorA)
Postganglionic nerve fibres are long
What are the receptors in the parasympathetic nervous system? Are post-ganglionic fibres long or short?
Preganglionic -> nicotinic receptor (ACh) -> Postganglionic -> muscarinic (ACh)
Postganglionic nerve fibres are short
Name 1 organ only controlled by:
1) Parasympathetic innervation
2) Sympathetic innervation
1) Bronchial smooth muscle
2) Blood vessels smooth muscle
What kind of receptors are nicotinic, muscarinic and adrenergic?
All 7 transmembrane GCPRs
Name a muscarinic agonist and antagonist
Agonist - Pilocarpine - stimulates salivation (side-effects=slow heart)
Antagonist - Hyoscine - reduces secretion
Where can M1,2,3,4,5 muscarinic receptors be found?
M1 - brain
M2 - Heart, activation slows the heart
M3 - Bronchial smooth muscle, activation causes constriction
M4/5 - CNS
We can agonise/antagonise any of these.
Name the relationship between dopamine, noradrenaline and adrenaline?
Dopamine is converted to noradrenaline which is converted to adrenaline
What do these receptors do/where are they found?
1) Alpha 1
2) Alpha 2
3) Beta 1
4) Beta 2
1) Contracts smooth muscle in non-essential blood vessels and pupils
2) Mixed effects
3) Chronotropic (HR) and inotropic heart effects
4) Relax smooth muscle in airways and essential blood vessels
Name an alpha 1 agonist and antagonist and what can they be used to treat
Agonist: Noradrenaline, Septic shock, it activates A1 receptors causing vasoconstriction.
Antagonist: Doxazosin, lower blood pressure by antagonising A1 receptors
What is adrenergic A1 receptors and B2 receptors preferred ligands?
A1 - Noradrenaline
B2 - Adrenaline
Name a beta antagonist (blocker) and what can it be used to treat?
Atenolol - B1 receptor blocker decreasing heart and lowering blood pressure
The side-effect of this is bronchoconstriction
What is an ADR?
Adverse Drug Reaction defined as: Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug.
What is the difference between an ADR and side-effects?
Side effect is any unindented effect, can be positive or negative or minor.
An ADR is always negative and usually more severe.
What are the 3 situations we can get with an ADR?
Hypersusceptibility - ADR when drug is below therapeutic range
Collateral effects - within therapeutic range
Toxic effects - when the drug is above the therapeutic range
What are the 6 types of ADR classified by Rawlin and Thompson?
Type A, B, C, D, E, F
Rawlin and Thompson classification of ADR:
What is type A?
Augmented pharmacological - predictable, dose dependent and common.
This is what you’d expect, bradycardia with propanolol etc.
Rawlin and Thompson classification of ADR:
What is type B?
Bizarre/idiosynchratic - not predictable or dose dependent.
Can be an allergy or type 1 (anaphylactic) hypersensitivity reaction
Rawlin and Thompson classification of ADR:
What is type C?
Continuous - for example steroids causing osteoporosis
Rawlin and Thompson classification of ADR:
What is type D?
Delyaed - for instance teratogenesis (thalidomide in pregnancy)
Rawlin and Thompson classification of ADR:
What is type E?
Ending of use - withdrawal symptoms and others
Rawlin and Thompson classification of ADR:
What is type F?
Failure - where a drug doesnt work
What is DoTS way to classify ADR?
Dose relatedness (toxic, hypersusceptibility), Timing and patient Suscepticibility
What is the yellow card scheme?
A BNF document for recording ADRs
What is a black triangle drug?
A medicine undergoing additional monitoring maybe due to new medicine, has been approved exceptionally etc.
Describe type 1 hypersensitivity pathophysiology with reference to drug acute anaphylaxis
First exposure with drug sensitises causing IgE antibodies to be formed and attached to mast cells/leukocytes
Rexposure causes rapid mast cell degranulation and release of inflammatory mediators into systemic circulation causing anaphylaxis
Name symptoms of anaphylaxis
Rash/urticaria Bronchoconstriction/SOB or wheeze Angio-oedema in face, lipds etc. Hypotension (anaphylactic shock) Cardiac arrest
Name some drugs which often cause anaphylactic/hypersensitivity reactions
Aspirin, NSAIDs, Penicillin’s and aneasthetics
How does adrenaline help with anaphylaxis?
Stimulates A1 adrenergic receptors causing vasoconstriction
Stimulates B1 adrenergic receptors causing positive inotropic and chronotropic effects on the heart
Both increase BP, reduce peripheral oedema
On a small molecule drug, what is the function of a sulphonamide nucleus?
It is unreactive and rigid, making drugs more stable.
Why do we have to consider drug stereoisomers?
Because despite the same molecular formula, they can have very different biological activities.
What suffix denotes monoclonal antibodies?
"-mab" E.g. "-omab - derived from mice "-ximab" - derived from multiple species (chimeric antibodies) "-zumab" - humanised antibodies "-umab" - human antibodies
Name 3 ways we can eliminate TNFa
Chimeric antibodies against TNFa - infliximab
Fusion proteins (receptor antagonist) - etanercept
Human antibodies - adalimumab
What 2 pharmacokinetic principles do we need to consider when dealing with antibodies?
Immunoglobulin are large hence no filtered by kidney
Monoclonal antibodies do not react with FcRN receptor hence long half-life
