Clinical Pharmacology Flashcards
in most drugs in clinical use the active agent of a drug is…
a small molecule
Why are small molecules the active agent of a drug
- more easily enter the body
- reach there site of action before being metabolised or cleared
What is the advantages and disadvantages of medicines using anitbodies and gene therapies
Advantge
- designed to have greater specificity than small molecules
Disadvantage
- can be more difficult to deliver to their targets
What are the usual sites of drug action within the body
- usually on proteins
- protiens are key and ubiquitous functional elements in the body
What is an affinity of a drug
- the affinity of a drug for its receptors is a measure of how well it binds a chemically sensitive site or receptor
- drugs bind to receptors at a rate proportional to the drug concentration
What is the proportion of receptors occupied by a drug equal to
p = [D]/[D] + Kd
- square brackets are short hand for concenration
- Kd is ratio K-/K+
- K+ is the foward rate constant
- K- is the reverse rate constant
increasing competitive antagonist concentration causes …
right shift in the relationship between drug concentrations and receptor binding so there is a lower proportion of receptors bound at a higher drug concentration due to the antagonist effects
What is an agonist
- An agonist is a chemical that binds to its target to increase its activity
What is an antagonist
An antagonist is a chemical that opposes the action of another chemical
- this means that antagonists have no action on their targets in the absence of an agonist
How can an antagonist act without an agonist
- in the body it is common for an endogenous agonist to be continuously present so antagonists like propranolol will cause physciological effects by themselves
What does the effect of an antagonist depend on
- Depends on the level of activation of the target by the agonist which can vary with the physiological state
What are the two main classes of antagonists
- Competitive
- non competitive
What are competitive antagonists
- the binding of the antagonists prevents the binding of the agonists usually by comepting for the same binding site
increasing competitive antaognist concenration..
right shifts the curve, decreasing binding for a fixed agonist concentration
What is the efficacy of a drug
- this is a term that is used to define how well an agonist achieves a response, it can encompass a complex pathway
two drugs acting on the same target can have identical affinities…
but very different efficacies, producing different clinical effects for the same concentrations
- therefore different drugs acting at the same receptors can be given at very different concentrations to achieve the same effect
What drug target most commonly used for drugs
G protein coupled receptors
what kind of drug measures the concentration of the drug and the response in percentage
- logarthmic scale
What is the potency of the drug
- this is the input output relationship - how much goes in and what do you get out
- potency of a drug is often described by the concentration (or dose) that is able to elicit 50% of the maximal response (ED50)
- a drug that has a higher potency achieves that size of response at a lower concentration
A drug that has a higher potency achieves …
that size of response at a lower concentration
What is a partial agonist
- A partial agonist is a drug that has a lower maximal response resulting from lower efficacy
Describe an example of how parital agonists can be used
- Many of the beta blockers are actual partial agonist
- this property means that they can compete with endogenous full agonists blocking their effect but nevertheless partially stimulating the receptors to avoid the symptoms that can arise from complete loss of receptor stimulation
What are allosteric modulators
- The bind to proteins at sites other than the binding site for the principal agonists
How do allosteric modulators work
- Alter the affinity of binding site for its agonists
- change the efficacy of the response when the agonists binds
Action can be:
- positive (to increase the potency of the agonists)
- negative (to decrease the potency of an agonist)
What is advatnages for allosteric modulators
- they dont directly activate (or inactivate) cell signalling but rather they change the set-point for normal activity
Members of the same drug class can have…
Different potencies
What is desensitisation
This it the process that diminishes a response by a drug after repeated exposure to it
Drugs can have longer term effects…
- that are different from their initial action at receptors which can result in altered levels of the drug or its target thereby changing its potency
Describe how patches cause plasma concentration
- patches - supply a relatively steady, sustained rate of nicotine delivery
- a fall is ot predicted to occur during a constant rate of drug delivery
agonists can differ in their efficacy …
even if they have the same receptor affinity
peripheral desensitisation to the effect of drugs…
does not require that the activity of the receptors change
- there are other ways that the response can desensitise such as the adaptation of hte intracellular second messenger pathways or changes outside
What is tolerance
Tolerance is a person’s diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug.
What is tachyphylaxis
- this is a general term that describes a decline in the response to repeated doses of an agonist but doesnt imply a particular mechanisms
How is tolerance associated with the long term use of opioid drugs
- Tolerance associated with the long term use of opioid drugs is a biochemical response that involves increased production of mediators in the pathway affected by the drug
Name two drugs from the same drug class that have different lipid solubility
- Simvastatin = lipophilic
- Pravastatin = Hydrophilic
describe how the chemical structure of drugs in the same class can have a major effect on how they are metabolised and excreted
- for example not all statins are metabolised by the cytochrome P450 enzyme system in the liver therefore drug interactions can be different for different statins
What are the two main types of ion channels
- voltage dependent
- ligand gated
describe voltage dependent ion channels
- enable a cell to be excitable and to generate action potentials
- named according to what ion they conduct
- open in response to depolariation of the cell membrane
What is the pore forming subunit in voltage dependent ion channels
- the pore forming subunit is called the alpha subunit
Describe the structure of calcium voltage dependent ion channels
- 10 different alpha subunit genes
Describe the structure of potassium voltage dependent ion channels
- 40 different alpha subunits and because the channel is assembled from 4 subunits different subunits can form channels with different properties producing complexcity
- very few drugs that target this channel type
Describe the structure of sodium voltage dependent ion channels
- 9 different alpha subunit genes
- targeting sodium channels is clearly important for local anaesthetics, antidysrhythmic and antiepileptic agents
What do calcium voltage dependent calcium channels do
- in neurones they are invovled in the release of neurotransmitter at a synapse
- in smooth and cardiac muscle cells, the increase in intracellular caclium leads to contraction
What calcium channel is targeted in cardiac and vascular smooth muscle
- L type channel
Name dihydropyridine calcium channel blockers
- Nifedipine
- amlodipine
What are dihydropyridine calcium channels blockers use for
- vasodilators and are prescribed for the treatment of hypertension adn prophylaxis of angina
What part of the calcium channel do dihydropyridine calcium channel blockers bind to
- bind to the alpha subunit of L type calcium channels, reducing calcium channel opening
- lowering intracellular caclium leads to relaxation of smooth muscle and vasodilation
Where is the Cav1.2 variant expressed
- It is exporessed in both vascular smooth muscle and cardiac muscle but there are molecular differences
What part of the calcium channel does verapamil and dilitiazem bind to
- Bind to the L type calcium channels, but these drugs act on the Cav1.2 splice variant expressed in cardiac muscle
- thereofre it has a more ionotropic effect on the heart and is useful for the treatment of angina
Name some monoamine transporter molecules at the synapse
- Noradrenaline
- 5-HT
- dopamine
Each monamine has there own …
transporter
- DAT (dopamine)
- NET (nroadrenaline)
- SERT (serotonin)
What inhibits NET and DAT
- cocaine
What activates NET, DAT, SERT
- amphetamines are actually substrates for all three transporters
- cause the release of monoamines at the synapse
What drug is more selective for SERT
- Ecstasy (MDMA)
What are the euphoric effects of the drugs of abuse
- they are due to the increased levels of doapmine at the synapse
Why dont antidepressants lead to abuse
- many antidepressant drugs inhibit the transporters (tricyclics, selective serotonin reuptake inhibitors) but they have little abuse potential probably because they have little effect on DAT
what does methylphenidate inhibits
- inhibits both DAT and NET
- used for the treatment of narcolepsy and attent deficit hyperactivity disorder
What is the drug modafinil used for
= has some amphetamine like effects
- thought to act on mnay targets including DAT and has been used for the treatment of narcolepsy and other sleep disorders but its use is not widespread
Describe the mechanism of action of TCAs
- inhibit both NET and SERT
- side effects of the TCAs can result from antagonism of muscarinic ACh receptors causing cardiac dysrhythmias, dry mouth, blurred vision and constipation
Describe the mechanism of action of SNRIs
- Venlafaxine
- non selective for NET and SERT
- do not have antimuscarinic effects
Describe SSRIs
- most commonly prescribed antidepressant in the UK -
- effectivness in itreating moderate depression is not different from TCAs but they do not have antimuscarinic effects
What are the types of enzyme inhibition
- Competitive = the drug binds to the same site on the enzyme as the substrate
- Non-competitive - the drug-bound enzyme can still bind the substrate
can also be
- Reversible
- Irreversible - causing permanent loss of function
Describe the mechanism of action of aspirin
- irreversible, non competitive inhibitor of COX
- COX is an important enzyme involved in the formation of prostaglandins and thromboxanes which are important mediators of the inflammatory response
Describe the mechanism of action of captopril
- reversible
- competitive inhibitor of ACE
- prevents the formation of angiotensin II, this acts to retain fluid and cause vasoconstriction
- example of rational drug desgin where the drug has a similar chemical structure ot that part of the normal substrate that binds to the enzyme
describe the different areas that enzymes can be affected by drugs in
- Intracellular - e.g. COX usually requiring that the drugs are lipid soluble
- Extracellular such as ACE - enzyme can be membrane bound or fully extracellular
some drugs require…
enzyme action for their activity
- for example zidovudine (AZT) and other nucleoside reverse transcriptase inhibitors must be activated by host cell kinases to produce the triphosphate form
How else can enzymes be used with drugs
- antoher therapeutic approach is to provide novel enzyme susbtrates for the correction of faulty metabolic pathways
- for example in dopamine beta hydroxylase deficiency the faulty synthesis of noradrenaline can be corrected by supplying a synthetic substrate for a different enzyme giving dihydroxyphenylserine (L-DOPS) which increases noradrenaline synthesis wihtout the need for the dopamine beta-hydroxylase enzyme
How do statins reduce the risk of heart attacks and strokes
- they reduce the risk by reducing cholesterol levels and thereby reducing atherosclerosis and thrombus formation
What do statins inhibit
- they inhibit the enzyme HMG-CoA reductase that catalyses the rate limiting step in liver cells for synthesis of cholesterol
When are statins more beneficial
- the enzyme HMG-CoA reductase are more active at night and therefore statins with a shorter half life are most benefiical when given at bedtime
What tool is used to assess the formal CVD risk for the primary prevention of CVD
- QRISK 3
What drugs act on receptors that are located in the nucleus
- steroid hromones act on receptors that are located in the nucleus
what drugs act on things inside the cell
- lipophilic receptors
What are the concerns regarding gene therapy
- induction of immune response by viruses
- cancer caued by random insertion of a replacement genes into the genome
Name a disease that can be targeted by monoclonal antibodies
- antibody against TNF alpha can be used in rhumatoid arthritis
