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30 Cards in this Set
- Front
- Back
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Why is it important to consider drug concentration in molarity?
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1L of a 1M solution will contain 1 mole of molecules.
Mass/ molecular weight = moles 100mg/L of different drugs will contain different numbers of molecules. |
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Define affinity and efficacy
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Drug binding is termed affinity – KD is a measure of affinity
• Drug effect is termed efficacy • Agonists require both affinity and efficacy whereas antagonists only require affinity as there action is to block agonists which is do just by binding |
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How does number of receptors impact drug action
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• The number of receptors directly affects the ability of the drug to create a response.
• If there are not enough receptors available a drug may not be able to create a full response i.e. partial agonist no matter what the drug concentration is. o KD = EC50 – 50% receptor occupancy needed for 50% response – no spare receptors • However if there are more receptors than needed to create the maximum response a maximum response can be created with spare receptors left over o EC50<KD – 50% receptor occupancy is NOT required for 50% response – spare receptors |
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What is KD, EC50 and LD50?
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KD – the concentration of drug needed to bind 50% of receptors, the smaller the KD the higher the affinity of the drug
EC50 –the concentration of drug needed to give 50% of the maximal response, the smaller the EC50 the more potent the drug When spare receptors are present KD may be greater than EC50. LD50 – lethal dose to 50% of the population. Therapeutic index is calculated by LD50/ED50 - max tolerated dose/ minimum effective dose |
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Describe the difference between drug affinity, efficacy and potency
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• Affinity = The ability of a drug (agonist or antagonist) to bind to a receptor site. Kd is a measure of affinity ( low kd = high affinity – concentration of drug needed to bind 50% of the receptors)
• Efficacy = The ability of a drug to elicit a response once binding has occurred • Potency = The strength of the drug which is determined by both affinity and efficacy, the stronger each one of these the more potent the drug as it can generate a more effective and larger response. EC50 ( Effective concentration giving 50% of the maximal response) is a measure of potency, smaller EC50 the more potent the drug. Potency is also determined by number of receptors – if reduced a full agonist may become a partial agonist. |
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Draw 2 graphs to show affinity and efficacy of a drug. How would you calculate the level of receptor occupancy necessary to cause 50% of the maximal response?
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In order to find the level of receptor occupancy needed to cause 50% of the maximal response, the value for EC50 would be applied to the graph of proportions of receptors bound against drug concentration. Usually Kd > EC50 so fewer receptors than 50% would be needed.
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Describe what is meant by the term agonist, partial agonist and antagonist
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• Agonist = A ligand which can elicit a full response in a cell
• Partial agonist = A ligand which cannot even at full occupancy cause the maximal response in a cell/tissue (maybe a full agonist in a different tissue where more receptors are available etc) – It has a low efficacy, so it needs more receptors to have a full response. It has a lower intrinsic activity - amplitude of response. • Antagonist = A molecule which blocks the action of an agonist by binding at the receptor site or a site further down the cascade |
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What adaptive changes can occur in receptor populations when exposed to agonists and antagonists
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• Receptor populations can be down-regulated when stimulus is persistent. For example if a cell doesn’t need a certain substance it will stop creating receptors needed for that substance to be absorbed and so a full response may not be possible anymore.
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Appreciate whole body considerations of drugs reaching their sites of therapeutic action.
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• Depends on administration – enteral, parenteral, ocal
• Absorption by the gut may be slow and affected by pathology or food or the characteristics of the drug itself. Bioavailability can be measured by the amount or the rate. The amount which gets into the circulation can be determined by the area under a plot of blood drug level against time. the rate can be measured by peak height and rate of rise of drug level in blood. • First pass metabolism (oral) - The guts blood supply is linked to the portal circulation and so the first pass is the liver which is primarily responsible for metabolising drugs and so the bioavailability may be reduced massively by this so oral administration is not best for some drugs. • Drug-protein binding interactions - Only free concentrations of the drug cause an effect. So if a drug is highly bound to albumin you need to consider its free effective concentration o Important considerations Drug binds more than 90% to albumin/protein Drug has a low therapeutic index (LD50(maximum tolerated)/ED50(minimum effective dose)) Other drugs that bind in similar sites and administered in higher concentration dissociating more lethal low therapeutic window drugs. • rate of excretion by the kidney and whether that is the main way of removal of the drug – renal disease prolongs half life. |
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Describe drug bioavailability.
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Drug bioavailability is the proportion of the dose, administered any way except IV, that reaches the systemic circulation unchanged. Bioavailability can be expressed by:
- Amount – the area under the curve of concentration of drug in blood against time. Depends on GI absorbtion and first pass metabolism. - Rate – calculated by the peak height and the rate of rise of drug in blood. The rate is affected by pharmaceutical factors and rate of gut absorption. |
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describe the role of the kidneys in drug inactivation and elimination
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Inactivation and elemination can be done by the kidney.
- Only the free unbound drug is filtered at the glomerulus - Drugs can be actively secreted by kidney tubules eg penicilin Passive reabsorbtion of lipid soluble unionised drug depends on pH of urine and pK of drug (ph at which half of it is ionised and the other half is unionised). - Weak bases – acidic alkaline will ionise the drug and so increases excretion - Weak acids (aspirin)– alkaline urine will make the drug ionised and so increases excretion, |
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Describe the role of the liver in drug inactivation and elimination.
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Liver metabolism
Phase I - Oxidation, reduction and hydrolysis – add or expose reactive group - Carried out by mixed function enzymes with low substrate specificity - NAPDH cytochrome P450 reductase - Affinity for lipid soluble drugs - Inducible and inhibitable Phase II - Conjugation (glucuronide, acetyl, methyl, sulphate (makes it more excretable) |
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When are drug interactions in metabolism likely to matter clinically?
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- Drugs with low therapeutic ratio ( small therapeutic window so increased conc can be toxic)
- Drug is being used at minimum effective concentration eg oral contraceptive pill - Drug metabolism follows zero order kinetics |
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Give examples of an enzyme inducer and inhibitor of oxidases in liver microsomes.
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Enzyme inducer = rifampacin -> affects oral contraceptive
Enzyme inhibitor = cimetidine -> warfarin |
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What is the affect of alchohol on warfarin?
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Alcohol is a warfarin potentiator and inhibits its metabolism so it stays is circulation longer.
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What is the affect of aspirin on warfarin.
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Aspirin displaces warfarin from plasma protein increasing free concentration of warfarin. It also reduces platlet aggregation which supports warfarin in preventing clot formation.
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What is the effect of broad spectrum antibiotics on warfarin?
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Broad spectrum antibiotics are potentiators of warfarin and reduce vitamin K synthesis by bacteria in the gut.
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What are the roles of barbituates and rifampacin on warfarin?
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Barbiturates and rifampacin are Inhibitors of warfarin by inducing liver metabolising enzymes
Maintenance dose is given and a steady state of plasma concentration will be reached in 5 half lives. - Loading dose – if an immediate dose is required eg atrial fibrillation, maintenance dose would take too long so a higher dose of the drug eg digoxin is given, which is determined by volume of distribution. bioavailability and factors affecting this |
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Describe the principle of drug formulation and administration,
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• Formulation - Molar concentrations in a liquid form, moles in solid.
o Simple routine - Better compliance o If solid how fast does it dissolve and what is the drugs acid tolerance |
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List sites of administration of drug and which would be best avoided to prevent first pass effect?
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Administration
o Enteral - Oral - Sublingual - Glycerine trinitrate - Rectal o Parenteral - SC, IM, IV - Transdermal - Inhalation o Ocal – Eye |
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Define different ways in which drugs may interact
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• Class I drugs (object drugs) - used at a concentration less then available binding sites
• Class II drugs (precipitant drugs - aspirin) - Used at concentrations higher then available binding sites • Therefore if a class I and II are used together the class II will competitively displace the class I effectively raising its free concentration (which could push it into a toxic range if the therapeutic index ( small therapeutic window, otherwise toxic) is low like in warfarin’s case). • If a drug is an inducer or inhibitor of cytochrome P450 reductase and other drug metabolising enzymes, it may stop the drug being effective as half life falls in inducers case or make toxic in inhibitors case and concentration raises. |
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Understand the differences between zero and first order kinetics
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• First order the rate of elimination is proportional to the concentration of the drug
o Enzymes that obey the Michaelis-Menton kinetics o Log drug level against time is a straight line o Vmax[c]/Km + [c] o If [c] is less then Km then Vmax[c]/Km o Half life can be defined o Low doses zero order o Vmax[c]/[c] = Vmax o High doses – constant elimination, independent of drug dose as enzymes are saturated o Eg alcohol o Half life cannot be defined but rate of elimination can from drug level against time. o Drug level against time is straight line |
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Describe the graph plotted for a zero order drug with rate of elimination against dose.
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The rate of elimination would increase until all enzymes are saturated and then there will be a horizontal straight line as elimination will be unaffected by drug eg alcohol.
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Define axontomesis.
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Axontomesis is the loss of continuity in the axon and myelin sheath with wallerian degeneration of distal part but the supportive connective tissue is not damaged so regeneration of axon can occur at 2mm per day and restore continuity.
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Define neuropraxia
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Neuropraxia is the temporary loss of motor and sensory functions due to blockage of nerve conduction. There is damage to the myelin sheath but the nerve remains intact so there is no wallerian degeneration. There is a rapid and complete recovery of motor and sensory function when nerve contact is restored.
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Define neurotmesis.
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In neurotmesis the nerve and the nerve sheath are damaged so that although partial recovery may be possible, complete recovery isn’t.
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Define volume of distribution.
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Volume of distribution is the theoretical volume into which drug is distributed if this occurred instantaneously. It is obtained by extrapolation of plasma levels to zero time. It used to calculate loading dose.
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In liver and renal disease describe the changes on drugs that should be carried out.
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Liver disease – be careful with drug with a low therapeutic window due to cellular dysfunction, portasystemic shunts, reduced blood flow and reduced albumin.
Renal disease – if the drug is excreted as its main route of elimination, half live is prolonged. Therefore maintenance dose must be lowered - It takes 5 half lives to reach equilibrium every time dose is changed - Loading dose is the same if the volume of distribution is not changed - Protein binding of drugs is altered, |
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Distinguish between reversible competitive and irreversible antagonism
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• Competitive antagonists can be out competed by increasing the agonist concentration and so they effectively shift the drug action curve to the right.
• Irreversible competitive antagonism (binding is permanent or dissociation is very slow) cannot be out competed by increasing drug concentration and so it effectively reduces the number of available receptors, including spare receptors, and so a full response may not be possible in its presence. • Non-competitive antagonism is when the binding is allosteric or post-receptor – Same effect as above |
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List the factors affecting oral bioavailibility.
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- formulation
- first pass metabolism - gut absorbtion |
