3. Agonists and enzymes Flashcards
What are pharmacodynamics?
study of a drug’s molecular, biochemical, and physiologic effects or actions
What is the equation for a reversible drug/receptor reaction?
D + R <=> DR (drug receptor complex)
What is the law of mass action?
The rate of a chemical reaction is proportional to the concentration of the reacting substrates
What is KD and how do we derive it?
It’s the dissociation constant for a drug/receptor reaction. It is when the drug concentration at which half of the receptors are occupied.
See equation derivations page 1.
What is KA in relation to KD?
What does it describe?
The affinity constant. It is the reciprocal of KD e.g. 1/KD
It describes the affinity of a drug to its receptor
What is the rule with any thing and it’s reciprocal?
If we double the number, the reciprocal will halve.
What is the equation for drug receptor occupancy?
r= [DR]/ [RT]
r = fractional occupancy
RT = total number of receptors e.g. the sum of bound and free receptors.
What is the fractional occupancy if KD is equal to the drug concentration?
0.5
How can we plot a drugs KD on an affinity graph?
KD = D R / DR
At equilibrium, half of the receptors are full therefore, R = DR and so they cancel each other out. Meaning that KD = D.
So an affinity graph has % of receptor occupied as y and drug concentration on x, then the concentration of drug can be plotted as 50% occupancy on the graph.
If we plot a graphical representation of affinity, what shape do we get?
Hyperbolic curve
What happens to KD as drug affinity changes?
KD = D R / DR
If drugs have a high affinity, the DR side of the equation will be favoured. If DR is high D R will be low and so KD will be low.
Higher affinity = lower KD and vice versa.
What is the difference between full and partial agonists?
Full agonist = drugs that provide a maximum response (E) - an intrinsic activity of 1.
Partial = below maximal response - intrinsic activity between 0-1.
How does the dissociation constant (KD) relate to full agonists?
It is the concentration of full agonist producing a half maximal response
On a graph KD is the same as EC or ED50
What is an inverse agonist?
They have the opposite effect on a receptor
What shape is an enzyme simulation graph showing Km?
Hyperbolic
Look at the two Km tables on page 2 of graphs
What is Km?
The Michaelis constant, which is the concentration of substrate that means the velocity of the reaction is half of the Vmax.
What is the michaelis menten equation and what does it tell us?
V = Vmax [S] / (Km + [S])
It predicts the rate of a biological reaction according to substrate concentration and enzyme characteristics e.g. Km and Vmax.
What are the three ways that drugs can increase enzyme activity?
Direct positive allosteric modulation: increases the Vmax or Km e.g. insulin or tyrosine kinase
Indirect increase via intermediate messengers e.g. GCP receptor agonists coupled with adenylate cyclase i.e. H2 D1 and b receptors.
Enzyme induction (increasing concentration): the cyp450 enzymes metabolise many drugs and chronic exposure induces them, meaning increased drug clearance. Some iso forms metabolise several drugs.
List the important drug interactions we must know, for enzyme inducers?
For Vec, warfarin, ciclosporin, steroids.
If we stopped the enzyme inducers suddenly, what would happen to the other drug?
phenytoin and carbemazepine reduce the duration of vec
rifampicin or carbemazepine reduce the efficacy of warfarin
Rifampicin reduces the efficacy of ciclosporin
barbiturates reduce the efficacy of corticosteroids
Stopping g the enzyme inhibitors suddenly causes increase of other drugs.
What ways can drugs reduce enzymes?
Direct inhibition via reduction of Km or Vmax
Indirect via intermediary messengers
Either reversible or irreversible
What is the role and structure of acetylcholinesterase?
What are the three different kinds of inhibitors?
AChE causes ester hydrolysis of ACh at the NMJ.
Contains: (Diagram pharma 3 page 27)
anionic site (negatively charged) attracting a positive quarternary ammonium ion.
Esoteric site: ester hydrolysis to form choline and acetic acid.
Inhibitors:
Short acting: edrophonium binds to anionic site
Medium: neostigmine and pyridostigmine - bind to both sites.
Long acting: organophosphates - phosphorylates the esteratic site (acts like carbamylators). The drug enzyme complex becomes aged with time and inhibition becomes irreversible.
What are the two classes of reversible AChE inhibitors and what do they do?
Carbamylators (e.g. -igmines)
Carbamylated enzyme (usually acetylated), reacts more slowly with water, reducing the rate of ACh breakdown allowing cleft buildup.
Anionic site (edrophonium).
Short acting competitive used for diagnostic purposes.
What can toxic levels of anticholinesterases cause?
This can cause a cholinergic crisis involving:
Salivation
Lacrimation
Urination
Defeacation
GI upset
Emesis
Plus: weakness, bradycardia and respiratory paralysis.
What is the treatment for organophosphate poisoning and how does it work?
Pralidoxime can be given in the first 36-48h before ageing occurs.
It displaces phosphate from the esteratic site until the poison can be eliminated.
Alternatively, new ACHe synthesis can take place if death has not occurred already.
What do phosphodiasterase inhibitors do?
Types?
Examples?
Phosphodiasterases degrade the phosphodiester bond in cGMP and cAMP making them inactive.
Active gCMP can lead to smooth muscle relaxation and alteration of platelet function.
cAMP leads to glucose and lipid metabolism and calcium release.
Non-selective e.g. aminophylline and theophylline, mainly effect bronchial smooth muscle but can also cause, vasodilation, positive inotropy and inhibition of platelet aggregation.
Selective:
PDE-3 is similar to cAMP and is predominantly in the heart, producing positive inotropy. Enoximone and milrinone selectively inhibit this.
PDE-V, causes platelet aggregation. Dipyridamole and sildenafil inhibit this.
What kind of isomer mixture is warfarin?
Racemic
How does warfarin work?
Clotting factors 2, 7, 9 and 10 need vitamin K as a cofactor
Vitamin K is recycled with vitamin K epoxide reductase (VKOR)
Warfarin inhibits VKOR
VKOR genetic variants exist
What warfarin isomer is more potent?
How is it metabolised?
S-entantiomer is the most potent.
CYP2C9 is responsible for metabolism (subject to genetic variation)
What do allopurinol, methyldopa and methotrexate inhibit?
Allopurinol inhibits xanthine oxidase
Methyldopa does dopa decarboxylase
Methotrexate does dihydrofolate reductase
What might giving verapamil/diltiazem with beta blockers cause?
AV block and bradycardia hypotension and asystole
What enzymes are used as drugs and why?
Streptokinase, urokinase and altepase can be used as fibrinolytics to convert plasminogen to plasmin to degrade fibrin.
Hyaluronidase breaks down hyaluronic acid - added to ophthalmic LA
What is KD?
KD is the molar concentration of a drug at which half of the available drug receptors are occupied at equilibrium.
What is ED50 and EC50?
ED = median effective dose, which is the dose of a drug required to achieve the desired effect in 50% of the population
EC = minimum effective concentration, which is the concentration of the drug required to achieve half of the maximal effect.
How are EC50 and ED50 related to potency?
The lower the EC/ED 50, the more potent it is.
What is the equation for observed response of a drug?
E = er
Response = intrinsic activity x fractional occupancy
Fractional occupancy = r = DR/Rt (rt = total)
Intrinsic activity = Emax of drug/Emax of full agonist
In terms of affinity and intrinsic activity (efficacy), what is the difference between a full agonist, a partial agonist, an inverse agonist and an antagonist?
Full = affinity and and IA of 1
Partial = affinity and IA 0-1
Inverse = affinity and IA between 0 and -1
Antagonist = affinity but no IA
What are the different types of antagonists and how does this relate to partial agonists?
Either competitive: reversible or non reversible.
Or non-competitive: different binding site.
Partial agonists can act as antagonists of full agonists as they compete for binding site and cause a lesser response.
What is constitutive receptor activity?
Receptors being activated in the absence of agonist.
What is functional selectivity of receptors?
When one drug can have a range of actions at the same receptor, via different effectors. Can be an agonist, an inverse agonist and an antagonist all at the same time.
What is the median lethal dose?
LD50
The dose that will be lethal in 50% of the population
What is ED95?
The dose where 95z of people will experience desired effect
What is the therapeutic index and how is it calculated?
The balance between useful effects and toxic effects.
LD50/ED50
What is affinity?
Efficacy?
Potency?
Affinity = how avidly a drug binds to its receptor.
Efficacy = the magnitude of the effect once a drug receptor complex is formed.
Potency = quantity of drug required to produce a maximal effect.
What is first order kinetics?
At low substrate concentrations, not all receptors are saturated and so rate of reaction is dependent on substrate concentration.
What is zero order kinetics?
High substrate concentration. Enzymes fully saturated and so rate independent of further substrate concentration changes.
What does the michaelis menten equation do?
Michaelis–Menten equation predicts the rate of a biological reaction according to the concentration of substrate and the specific enzyme characteristics
What type of drug is cyanide and how does it work?
Non competitive enzyme inhibitor
Inhibits cytochrome oxidase in the electron transport chain, reducing ATP.
What are the 3 cox isoenzymes and what do they do?
1: forms GI mucosa, gastric and renal blood flow, vasodilation and platelet function via thromboxane
2: tissue trauma = prostaglandin release = cardinal features of inflammation
3: ? CNS pain perception
What are the different types of mono amine oxidases?
Where are they found?
What do they do?
Deanimate neurotransmitters. Found in the liver, so also process foods.
MAO- A: serotonin and catechaolamines
B: tyramine and phenyethanine
Both do dopamine
What does carbonic anhydrase do?
Changes H2O and CO2 to H2CO3
How do streptokinase, urokinase and altepase work?
Why is altepase a preferential drug?
They convert plasminogen to plasmin which causes fibrin lysis.
Altepase (TPA) is only activated when bound to fibrin so has less systemic effects.
What might giving Amiodarone with warfarin cause?
Increased bleeding
What food should not be given with ciclosporin?
Grapefruit juice
Can cause ciclosporin toxicity
What can SSrI’s and NSAIDs cause?
Increased bleeding
What antibiotic shouldn’t be given terfenadine and why?
Clari
Can cause torsades
What can Ketoconazole giving with buprenorphine cause?
Increased plasma buprenorphine
