Basic Principles Flashcards
What is pharmacology?
the study of the effects of drugs on the function of living systems
What is a drug?
a substance of known chemical structure which when administered to a living organism produces a biological effect
What is pharmacodynamics?
the study of how drugs work
What is the general principle of a drug?
A drug will not work unless it is bound
What can drugs target?
receptors, enzymes, ion channels, transporters and other miscellaneous targets i.e. DNA
How might a drug target a receptor?
It may be an agonist - which initiates a biological response
It may be an antagonist - which has no effect but blocks the endogenous modulator
How might an agonist work on a receptor?
Directly or Indirectly
How might an agonist work directly on a receptor?
Ligand binding ion channels
Enzyme activation or inactivation
How might an agonist work indirectly on a receptor?
Through transduction mechanisms
Through ion channel modulation
DNA transcription
How might a drug target an ion channel?
Blockers- blocking the ion channel
Modulators - increasing or decreasing the permeability of an ion - i.e. NMDA receptor is blocked by MK-801
How might a drug target enzymes?
Inhibition - inhibiting the normal reaction
False substrate - causing an abnormal metabolite to be produced
Pro-drug - drug is administered in an inactive form and the active form is produced by the enzyme
Give an example of a drug which targets an enzyme
Monoamine Oxidase Inhibitor B - Selegine
MAOs metabolise monoamines such as dopamine, serotonin and noradrenaline
MAO-B Inhibitor is used in the treatment of Parkinson’s to prevent the metabolism of dopamine and phenylethylamine
How might a drug target transporters?
Inhibitors can attack the same site or an allosteric site blocking transport
Give an example how a transporter might be blocked and how it might be used
Uptake 1 inhibitors - the re-uptake of neurotransmitter is known as uptake 1 and may be blocked, such as in anti-depressants to maintain higher levels of neurotransmitter in the synapse
What is a receptor?
Any cellular assembly (target molecule) that a drug molecule binds to in order to elicit a specific response
What is the difference between affinity and efficacy?
Affinity is the ability of the drug to bind to a receptor
Efficacy is the ability of the drug to elicit a biological response once bound - agonists only
What is a full agonist?
A full agonist has maximal effects and high efficacy
What is a partial agonist?
A partial agonist has sub maximal effects and medium efficacy
What is an antagonist?
Antagonists have no efficacy and do not exert an effect on the receptor other than to block it
What is agonist potency?
How strongly an agonist can exert its effects can be used in comparison to other agonists when choosing drugs
What kind of antagonists are there?
competitive - binds to same site as agonist
non-competitive - binds to an allosteric site
reversible - binds non-covalently
irreversible - binds covalently
Give an example of a reversible competitive antagonist and its actions
Propanolol (decreases BP, B-blocker) is an antagonist of isoproterenol (increases HR and works on B-adrenoceptors)
The maximum response is not changed however there is a shift right in the dose-response curve as more agonist is needed.
Give an example of an irreversible competitive antagonist and its actions
Naloxone is used in opioid overdose
The EC50 is not affected however the maximal effects are as an increase in agonist will not overcome this.
Give an example of a reversible, non-competitive antagonist and its actions
Ketamine is an antagonist to NMDA by blocking the ion channel of the glutamate receptor
The maximum response is reduced but there is no change in the EC50
Give an example of a irreversible non-competitive antagonist and its actions
Phenoxybenzamine blocks the effects of noradrenaline on a-adrenoceptors on vascular sm. muscle
What are the other methods of antagonism?
Physiological - two drugs producing opposing effects i.e. NA and adrenaline
Chemical - drug reduces concentration of an agonist by forming a chemical complex i.e. protamine sulphate(+ve) binder to heparin(an anticoagulant)(-ve) preventing heparin from working
Pharmacokinetic - one drug affects the absorption, metabolism or elimination of another i.e. phenobarbital-induced enzyme induction increases the metabolism of the anticoagulant coumadin
What kind of receptor families do you get?
Ion Channels
GPCRs
Tyrosine Kinase
Nuclear Hormone Receptors
How might drugs affect ion channels?
agonist binding results in a conformational change in the receptor and may cause the ion channel to open
How might drugs affect GPCRs?
activation results in a stimulation of a second messenger signalling cascade
How might drugs affect tyrosine kinase receptors?
these receptors mediate the first steps in transduction of signals by insulin and growth factors
How might drugs affect Nuclear hormone receptors?
they may cause transcriptional changes in the DNA and hence change gene expression
What is the pathway of drugs in the body?
absorption > distribution > metabolism > excretion
How might the absorption of drugs be influenced?
Route of administration - how quickly it reaches the bloodstream and its bioavailability
If to be absorbed in the GI tract it must be lipid soluble and able to cope with changes in pH - stomach is acidic and intestines are alkaline
How might drug dissolution be affected?
The presence of food, the availability of HCl and the availablility of pancreatic/intestinal secretions
What is the first-pass effect?
Where the liver is able to metabolise and inactivate drugs before they are distributed about the body i.e. heroin can be converted to morphine
What may affect drug metabolism?
Liver metabolising enzymes may be induced or inhibited by other drugs - drug-drug interactions
What are bioassays designed to do?
To see how one drug works against a standard on a dose response curve
What are the parameters against which drugs are checked?
IC50 - antagonists - how well they can block agonists and enzymes at a 50% of max effect
EC50 - 50% of the maximum effect of an agonist
ED50 - the minimum dose required to show effect in 50% of the tested population
LD50 - the dose required to kill 50% of the population after x time
The therapeutic index - LD50/ED50
How many phases of drug trials are there and what happens during them?
Phase I - hospital, v.controlled, safety checking
Phase II - checking for efficacy and how well it works
Phase III - confirm the findings in large populations
Phase IV - testing the long term safety 2-3 years
