Pharmacology Flashcards
What is the definition of a receptor?
The cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response
What is the definition of potency?
Potency is the concentration (EC50) or dose (ED50) of a drug to produce 50% of the drugs maximal effect
What is the definition of relative potency?
A variant where instead of using units to describe the dose required to reach a certain end point, one ends up using a ratio of equivalent doses
What is the definition of efficacy?
E(max) is the maximum effect which can be expected from the drug. (When this magnitude is reached, increasing the dose will not increase the magnitude of the effect)
What is the definition of intrinsic activity/maximal agonist effect of a drug?
The maximal efficacy as a fraction of the maximal efficacy produced by a full agonist of the same type acting through the same receptors in the same condition
What actually is a ligand?
Usually a small molecule, but they range from ions and small peptides to dissolved proteins
What actually is a receptor?
A large protein with a 3D structure
What does it mean that a ligand and a receptor have molecular complementarity?
The shape and chemical properties of their binding sites are matching to permit high-affinity selective binding
What are the chemical bonds that make up ligand and receptor binding and give four examples?
- Van de Waals forces - monoclonal antibodies and their targets
- Hydrophobic attraction - suggamadex and rocuronium
- Hydrogen bonding - local anaesthetic to a voltage gated sodium channel
- Electrostatic attraction - acetylcholine and its receptor
What is a pharmacophore?
The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target
Think systematically
List the different drug-receptor interactions and give some examples
Extracellular
- Soluble extracellular enzymes (dabigatran, perindopril)
Cell Surface
- Cell surface molecules (abciximab)
- Transmembrane non-enzymes (cytokines, interferon gamma)
- Transmembrane proteins with active domains eg receptor kinases (insulin)
- Ligand-gated ion channels (nicotine, suxamethonium)
- Voltage-gated ion channels (lignocaine, verapamil)
- G-protein coupled receptors (dobutamine, metoprolol)
Intracellular
- Soluble intracellular enzymes (GTN)
- Nuclear receptors (corticosteroids, thyroxine)
- Nucliec acids (azithromycin)
What are ion channels?
They are pore-like transmembrane proteins that alter the local permeability of the cell membrane to ions. Typically, these are fairly selective to which ion they open for
How do ligand-gated ion channels work?
The binding of a ligand opens the pore, and without the ligand the channel is closed.
Classic examples are acetylcholine and suxamethonium.
Endogenous ligands include serotonin, GABA, glycine and glutamate
How do voltage-gated ion channels work?
The channels are closed and undergo a conformational change when the transmembrane voltage difference reaches some threshold voltage.
How do G-protein coupled receptors work?
The G-protein coupled receptor is bound to a GTP-ase protein, which hydrolyses GTP into GDP. When bound to GTP, these proteins become activated, which then allows them to regulate the activity of second messenger systems and amplify the signal of receptor activation
A G-protein is a receptor with seven transmembrane regions, which have their extracellular domain as the receptor. They are made of seven helix domains that stretch back and forth across the membrane
How do nuclear receptors work?
These receptors, when activated, will bind directly to some sort of ‘response elements’ in the promoter regions of their specific genes. Once it binds to the ligand, the receptor will usually undergo a conformational change which recruits other proteins into a huge multimeric complex, or instead destabilises and deactivates such a complex
These are usually hormone receptors, and their role is to regulate gene transcription. They work slowly.
What are the two different types of nuclear receptors and how do they work?
Steroid
Generally found in extranuclear cytoplasm, when bound to an agonist they move intranuclear and do their work
Non-steroid
Often intranuclear, found in a heterodimer (bound to other intranuclear receptors and transcription factors)
What is an agonist?
A ligand that binds to a receptor and alters the receptor state resulting in a biological response
What are the 3 different types of agonist?
Full agonist
reaches the maximal response capability of the system
Partial agonist
does not reach the maximal response capability of the system even at a full receptor occupancy
Inverse agonist
a ligand that by binding to the receptors, reduces the fraction of them in an active conformation
Note: A partial agonist acts as an antagonist in the presence of a full agonist (if they compete for the same receptors)
What does an allosteric modulator do?
Increases or decreases the action of a primary agonist whilst having no effect on its own
What are spare receptors?
They are receptors that exist wherever a full agonist can cause a maximal response when occupying only a fraction of the total receptor population
What is an antagonist?
A drug that reduced the action of another drug
What are the 5 different types of antagonist?
Competitive antagonist
competes for the same binding site with an agonist, their binding is mutually exclusive
Non-competitive antagonist
can prevent the action of an agonist without any effect of the binding of the agonist to the receptor
Insurmountable antagonist
can reduce the maximum effect of the agonist, and this inhibitory effect is not affected by increasing agonist concentration
Irreversible antagonist
is insurmountable but it does not have to be non-competitive
Physiological antagonist
non-competitive but it does not have to be insurmountable e.g. something that depresses what the agonist is trying to illicit
How does a competitive antagonist effect efficacy and potency?
The efficacy is not affected but the potency is increased
What is the Schild equation used for?
It has some relevance to quantifying the affect of the competitive antagonist on the agonist’s potency. If you plot in as the Schild plot on a graph it can help determine whether one drug is acting as a competitive antagonist against another one
What is the Schild equation?
C’/C - 1 = [B]/Kb
C’ is concentration of the agonist in the prescence of competitive antagonist
C is concentration of the agonist in the absence of competitive antagonist
[B] is the concentration of the competitive antagonist
Kb is the equilibrium dissociation constant describing the combination of the competitive antagonist with the receptor
What is a second messenger?
An intermediate molcule for an intracellular signal transduction cascade, which is used to transmit and amplify the signal between an extracellular stimulus and an intracellular effector
What are the characteristic features of a second messenger?
- The drug receptor or receptor-ligand interaction often does not result in the direct action of the intracellular effector
- The intermediate molecule created is synthesised or released in response to the receptor-ligand interaction, and then degraded afterwards
- The rate of synthesis or degradation of this molecule is tightly regulated to control the magnitude of response to receptor activation, and this regulation can be used to amplify or dampen the response
Where can a second messenger act?
It can act locally or it can diffuse distally to convey the signal to a multitude of targets; and multiple secondary messenger systems can interact to produce complex responses to receptor-ligand binding
What are the 5 broad types of second messengers?
- Hydrophobic molecules such as DAG and phosphatidylinosotols which do most of their work from the intermembrane space
- Hydrophilic molecules such as cAMP, cGMP and IP3 which diffuse freely into the cytosol
- Ions such as ionised potassium, calcium, and sodium
- Gases such as nitric oxide and carbon monoxide which diffuse easily through lipid and water
- Soluble proteins such as JAK/STAT, NF-kB
What is cAMP?
Cyclic adenosine monophosphate is a cyclic nucleotide secondary messenger
How is cAMP produced and degraded?
It is produced when G-protein activates adenylyl cyclase.
It is degraded by phosphodiesterases
What is cAMPs main targets?
Its main downstream targets include protein kinase A (PKA), EPAC and cyclic nucleotide-gated ion channels
What is the main action of cAMP?
It plays an important role in mediating the response to catecholamines, glycogenelysis, insulin secretion, vision and olfactory sense
What are nucleotides made of?
- a phosphate group (or two or three)
- sugar (classically a pentose sugar such as ribose)
- a nitrogenous nucleobase
What are the observable effects of cAMP?
- mobilisation of stored energy eg. glycogenolysis
- vasopressin-mediated water retention
- parathyroid hormone mediated calcium homeostasis
- response to catecholamines (beta-adrenergic)
What is cGMP?
Cyclic guanosine monophospate is a cyclic nucleotide secondary messenger
How is cGMP produced and degraded?
- cGMP is produced when guanylyl cyclase is activated by nitric oxide or by a naturetic peptide and this make cGMP from GTP
- cGMP is degraded by phosphodiesterases
What are the main downstream targets of cGMP and briefly tell me their effects?
Protein kinase G (PKG) activation
* smooth muscle relaxation by decreased intracellular calcium availability
* negative inotropic effect by reduction of myofilament calcium responsiveness
* increased angiogenesis
cGNP-gated ion channels
* mainly unselective cation channels in retinal and olfactory neuroepithelium and in nephrons
cGMP-modulated phosphodiesterase
* cGMP can bind to phosphodiesterases which increase their activity against both cGMP and cAMP, resulting in the inhibition of both secondary messengers
What does PKG do and how does that affect the net effect of cGMP?
- PKG decreases IP3 activity, densisitises myofibrils to calcium, and decreases intracellular calcium availability by several other mechanisms
- The net effect of cGMP is smooth muscle relaxation
What are the clinically relevant effects of cGMP?
Mainly related to its activation by nitric oxide, leading to increased calcium ion uptake into sarcoplasmic reticulum and a decrease in intracellular calcium, and therefore smooth muscle relaxation
Describe the points on the graph including the axis labels, what each line represents and what the dotted lines represent
The y-axis is response (% of maximal)
The x-axis is drug concentration (log)
The red line is a full agonist
The blue line is a partial agonist
The outer dotted line is Emax
What do the lines on this graph represent?
The blue one is a full agonist
The green one is a full agonist with a non-competitive antagonist
The red one is a full agonist with a competitive antagonist
What is the definition of volume distribution?
The apparent volume into which a drug disperses in order to produce the observed plasma concentration
It is the parameter relating the concentration of a drug in the plasma to the total amount of drug in the body
What is volume distribution used for?
To calculate loading doses, much as clearance is used to calculate maintenance dose
How do you work out the volume distribution?
Dose / Plasma concentration
What are the units of volume distribution?
It can be expressed as Litres (L), or indexed to body mass L/kg
What is V-initial/Vc? What affects V-initial?
V-initial - Vd of the central compartment (from the rapid distribution phase)
Is often affecting by the degree of protein binding - highly protein-bound drugs with have a high V-initial
What is V-extrap? What is it used for?
V-extrap - Vd of the tissue compartment (from the elimination phase)
Not used for much!
What is V-area?
V-area - Vd extrapolated from the area under the curve of the concentration curve
How do you calculate Varea?
What is V-ss? How do you work it out?
V-ss - Vd in a steady state model, often the most useful in calculating the loading dose
Vss = amount of drug in the body in equilibrium conditions/steady state plasma concentrations
What are the main molecule factors that influence the volume distribution?
Major determinants are drug properties which affect protein binding and tissue binding:
* molecule size
* charge
* pKa
* the lipid/water partition coefficient
What are the main patient features that affect volume distribution?
- age
- gender
- body muscle/fat proportion
- level of hydration
- water distribution (oedema, ascites, APO, pregnancy)
- extracorpeal sites of distribution (circuit, filters, oxygenation)
How do these things affect Vd?
* Molecule size
* Molecule charge
* pKa
* Lipid solubility
* Water solubility
- Molecule size - large the molecule, harder it is to move, lower Vd
- Molecule charge - highly ionised molecules, higher water solubility, less likely to move, lower Vd
- pKa - determines ionisation and lipid solubility
- Lipid-solubility - highly lipid soluble molecules have a high Vd due to low fat content of the blood stream
- Water-solubility - difficult to penetrate lipid bilayer, smaller Vd
What is the definition of half life?
(t 1/2) is the time required to reduced the concentration of a drug by a half
What is the equation for half life?
t 1/2 = 0.693 x Vd/CL
0.693 is the logarithm of 2, it represents the exponential rate of elimination
How is half life related to Vd and clearance?
An increase in Vd causes an increase in half life
A decrease in the clearance causes an increase in half life
How many half lives does it take for a drug to be roughly 97% eliminated?
5!
(50% -> 75% -> 87.5% -> 93.75% -> 96.875)
How would doubling the dose of a drug affect the half life?
It will usually increase its duration of action by one half-life (because it’s clearance is a logarithm function)
How does first or zero order kinetics affect half life?
First order kinetics drugs have a constant half-life regardless of concentration
With zero order kinetics drugs, the term becomes meaningless, one instead refers to a dose or concentration removed over time
What is first order kinetics vs zero order kinetics?
First order elimination kinetics - a constant proportion (e.g. percentage) of a drug is eliminated per unit time
Zero order elimination kinetics - a constant amount (e.g. milligrams) of a drug is eliminated per unit time
How does concentration affect first order and zero order kinetics?
First order kinetics is a concentration dependent process (the higher the concentration, the faster the clearance)
Zero order elimination rate is independent from concentration
What is the pharmacology of first order kinetics?
This is a logarithmic function. All enzymes and clearance mechanisms are working at well below their maximum capacity, and the rate of drug elimination is directly proportional to drug concentration
What does this graph show?
What equation can you use to estimate the concentration of the drug at any given time using the semi-logarithmic concentration/time graph?
What is the pharmacology mechanism behind Michaelis Menten elimination kinetics?
There is a limit on how much enzyme activity there can be before the system becomes saturated.
At low concentrations, the more substrate you give, the faster the reaction. At higher concentrations, the rate of the reaction stays the same because all the enzyme molecules are busy
What is the equation of Michaelis Menten kinetics?
How does Michaelis Menten elimination kinetics affect the doses we give to patients?
When receiving relatively high doses of drugs, a small change in dose will create a disproportionately large change in concentration
How is Michealis Menden elimination kinetics relevant to therapeutic index? At what value does it become a narrow index?
The drugs at higher doses will have a narrow therapeutic index.
If the drug concentration required to have a useful effect is above 50% of Vmax, the drug will have a narrow therapeutic index
How do you achieve maintenance dosing in continuous infusions? How long does this take?
The drug accumulates gradually. Steady state is achieved when the dose rate and clearance rate are equal.
This takes 3-5 half lives.
How do you achieve maintenance dosing in regular dosing? How long does it take?
Steady state is achieved in steps, but eventually the dose rate and clearance are equal.
It takes about 5 half-lives
Why do you need loading dose?
A loading dose rapidly achieves the peak concentration nessecary to equal the clearance, so the desired effect is achieved and maintained sooner.
How does oral vs IV administration affect dosing?
- All the loading and maintenace doses have to be adjusted to bioavailability (higher if low bioavailability)
- The slower instestinal absorption of the drug has a ‘smoothing’ effect on the peaks of concentration, which decreases the concentration-dependent adverse effects
How is bioavailability measured?
Bioavailability is measured using the area under the concentration-time curve (Dost’s Law). The ratio of AUCs is the bioavailability value.
Bioavailability (F) = AUC (oral) / AUC (IV)
Biotransformation reactions can be split into two phases. Phase I and Phase II.
Phase I reactions convert the drug to a more polar environment via oxidation, reduction or hydrolyses
If it is not polar enough, phase II reactions take place, in which an endogenous substrate such as glucuronic acid, sulphuric acid or an amino acid combine with the drug to form a higher polar conjugate
What two key enzymes are important for oxidative drug metabolism? What do they need to do it?
NADPH-cytochrome P450 oxidoreductase
and
Cytochrome P450
Microsomal oxidations require P450, P450 reductase, a reducing agent (NADPH) and an oxygen molecule
What happens in the oxidation reaction?
- Oxidised (Fe3+) P450 combines with a drug substrate to form a complex
- NADPH donates an electron to the flavoprotein P450 reductase, which reduces the oxidised P450-drug complex
- A second electron is donated from NADPH via the same P450 reductase, which reduced oxygen, forming an ‘activated oxygen’-P450-drug complex
- This complex transfers activated oxygen to the drug substrate to form the oxidised product
What is the classification of anti-arrhythmics called? What are it’s groups? Give examples for each
Vaughn Williams Classification
1. Sodium channel blockers - a) quinine - b) IV lidocaine - c) flecainide
2. Beta blockers - metoprolol, esmolol, bisoprolol
3. K+ channel blockers - amiodarone, sotalol
4. Ca+ channel blockers - verapamil, diltiazem
How do class 1 antiarrhythmics work? What are the subclasses of class 1? - Give an example for each
- Class 1 action is a sodium channel blocker
- Subclasses of this action reflect effects on the action potential duration (APD).
- Class 1a drugs prolong the APD and dissociate from the channel with intermediate kinetics - quinine
- Class 1b drugs shorten the APD in some tissues of the heart and dissociate from the channel with rapid kinetics - IV lidocaine
- Class 1c drugs have minimal effects on the APD and dissociate from the channel with slow kinetics - flecainide
How do class 2 anti-arrhythmics work? Give an example
Class 2 action is sympatholytic. Drugs with this action reduce beta-adrenergic activity in the heart - beta blockers - metoprolol, esmolol, bisoprolol
How do class 3 anti-arrhythmics work? Give an example
Potassium channel blockers manifest as prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectified potassium current. An example is amiodarone
How do class 4 anti-arrhythmics work?
Calcium channel blockers slow conduction in regions where the action potential upstroke is calcium dependent, e.g. the SA and AV nodes. Examples include verapamil and diltiazem
What are the cardiac effects of amiodarone?
- It markedly prolongs the action potential duration (and the QT interval on ECG) by blocking the potassium channels.
- The APD is prolonged uniformly over a wide range of heart rates, amiodarone does not have a reverse use-dependent action
- It also significantly blocks inactivated sodium channels. Its action potential prolonging action reinforces this effect.
- Amiodarone also has weak adrenergic and calcium-channel blocking actions.
- Consequences of these actions include slowing the heart rate and AV node conduction
What are the pharmacodynamics of digoxin?
- It inhibits the Na/K+ATPase pump in the cell membranes (that transports sodium)
- Mechanical effects - increases cardiac contraction (positively inotropic) by increasing the free calcium concentration. It does this by: 1) increasing intracellular sodium concentration by inhibiting the Na/K+ATPase pump and 2) relatively reducing calcium expulsion from the cell by the sodium calcium exchanger caused by the increased intracellular sodium.
- Electrical effects - causes an early, brief prolongation of the action potential, followed by a shortening. This is probably from the increased potassium conductance caused by high intracellular calcium. At low doses, is has cardioselective parasympathetic effects by sensitising the baroreceptors, causing central vagus stimulation, and facilitation of muscarinic transmission at the nerve ending-myocyte synapse
What happens during digoxin toxicity?
- Resting membrane potential is reduced as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarising afterpotentials appear following normally evoked action potentials.
- When afterpotentials reach threshold, they elicit action potentials (premature depolarisations ‘ectopic beats’) that are coupled to the preceding normal action potentials.
- If afterpotentials happen regularly in the Purkinje system, bigeminy will be seen
- With further toxification, after each of these action potentials there will be a suprathreshold afterpotential, and a self-sustaining tachycardia, which may go onto develop AF or VF.
What receptors does adrenaline bind to? What effect does this have?
- It is an agonist for both alpha and beta receptors. It is therefore a very potent vasoconstrictor and cardiac stimulant.
- It is positively inotropic and chronotropic (predominantly beta 1 receptors) and causes vasoconstriction in many vascular beds (alpha receptors).
- It also activates beta 2 receptors in some vessels, leading to their vasodilation and therefore decreasing peripheral vascular resistance, explaining the transient hypotension that can follow administration
What are the tissues where alpha 1 receptors are and the actions they produce?
- Most innervated vascular smooth muscle - contraction
- Pupillary dilator muscles - contraction
- Pilomotor smooth muscle - contraction (erects hair)
- Prostate - contraction
- Heart - increases contraction
What are the tissues where alpha 2 receptors are and the actions they produce?
- Post-synaptic neurons - probably multiple actions
- Platelet - aggregation
- Adrenergic and cholinergic nerve terminals - inhibits transmitter release
- Some vascular smooth muscle - contraction
- Fat cells - increase lipolysis
What are the tissues where beta 1 receptors are and the actions they produce?
- Heart - inotropic and chronotropic
- Juxtuglomerular cells - increases renin release
What are the tissues where beta 2 receptors are and the actions they produce?
- Respiratory - promotes smooth muscle relaxation
- Uterine - promotes smooth muscle relaxation
- Vascular smooth muscle - promotes smooth muscle relaxation
What are the tissues where beta 3 receptors are and the actions they produce?
Bladder - relaxes detrusor muscle
What are the pharmacokinetics of nitrates?
- The liver contains a high-capacity nitrate reductase that ultimately inactivates the drug, therefore oral bioavailability is low (<10-20%)
- The sublingual route is preferred as it avoids the first-pass effect. Both nitroglycerin and isosorbide dinitrate reach therapeutic blood levels within a few minutes via this route
- The duration of effect is 15-30 minutes.
- Other routes include oral, transdermal and buccal absorption.
- Once absorbed, the half-life is only 2-8 minutes
- The bioavailability of isosorbide mononitrate is 100% and it is metabolised to isosorbide dinitrate
- Excretion is largely by the kidney
What is the pharmacodynamics of nitrates mechanism of action in smooth muscle?
- The drug must be bioactivated with the release of nitric oxide
- Nitroglycerin can be denitrated by glutathione S-transferase in smooth muscle and other cells
- A mitochondrial enzyme, aldehyde dehydrogenase isoform 2 (ALDH2) and ALDH3 appears to be key in the activation and release of nitric oxide from nitroglycerin and pentarythritol tetranitrate.
- Free nitrate ion is released, which is then converted to NO. NO combines with the heme group of soluble guanylyl cyclase, activating it and causing an increase in cGMP.
What are the nitrate effects in angina of effort?
- Decreased venous return to the heart and resulting reduction of intracardiac volume are important beneficial haemodynamic effects of nitrates
- Arterial pressure also decreases.
- Decreased intraventricular pressure and left ventricular volume are associated with decreased wall tension and decreased myocardial oxygen requirement.
- IV or sublingual nitrate administration consistently increases the caliber of the large epicardial coronary arteries except where blocked by concentric atheromas.
- Coronary arteriolar resistance tends to decrease, though to a lesser extent
- The reduction in oxygen demand is the major mechanism for the relief of effort angina
What are the nitrate effects in variant angina?
Relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm
