Introduction to Pharmacology Flashcards
define pharmacology
- Pharmacology Is the study of substances that interact with living systems through chemical processes
how do drugs interact
- They usually interact by binding to regulatory molecules and activating or inhibiting normal body processes
- they try to restore a natural homeostatic state
define what a drug is
- Any substance that interacts with a molecule or protein that plays a regulatory role in living systems,
what are the types of drugs
- Hormones (neurotransmitters) these are endogenous drugs
- Poisons are drugs that have exclusively harmful effects but can be beneficial, such as chemotherapy can stop cell process but needed to kill a cell off
- Toxins are positions of biological origin usually synthesised by plants or animals, therefore they are naturally occurring such as taxanes
- Enzymes
- Transcription factors
- many drugs we use mimic endogenous drugs but allow us to moderate the body process for example hormone replacement
define what a receptor is
- A specific molecule, usually a protein, that interacts with a specific chemical this causes a change in the receptor that produces a regulated function
what type of receptors are there
- Ion channelled linked
- G protein coupled receptors
- Enzyme linked (receptor tyrosine kinase)
- Intracellular hormone receptors
define what an agonist is
- An agonist is any drug that binds to the receptor and activates the receptor it mimics the natural ligand
describe what an agonist does
- When the ligand leaves the receptor this usually deactivates the receptor and stops the effect
- Some receptors are permanently activated even after the ligand has gone – there is a covalent change in receptor
- Can bind to another site in the receport and amplify the effect of the endogenous ligand while it is bound to it, this gives a positive effect - this is an allosteric activation, can cause ligand to stay there for longer
describe an example of a covalent change in receptor by an agonist drug
- Aspirin makes covalent change in receptor that keeps anti-platelet action on for life of that platelet (3 months)
- electron stays not the aspirin, therefore it is permanently activated
give example of ion channel linked receptors
- nitontinic acetylcholine
- sodium
- potassium
describe G protein coupled receptors
- larger category
- only need one agnosit and this can multiple the activity
describe receptor tyrosine kinase channels (enzyme linked)
usually dimers that phosphorylated and use signal molecules inside the cell to activate cell signalling
describe intracellular hormone receptors
nuclear receptor
- uses hydrophobic hormones as they are lipid soluble
- activates transcription and translation of DNA inside the cell
define a partial agonist
- A partial agonist binds to the receptor at the active site but is unable to cause the maximal response even if all receptors are occupied as they have a low affinity for the receptor so do not bind as strongly
what does a full agonist do
- give same effect of the natural endogenous ligand, giving the same activity and affinity
what are partial agonists only partial
- don’t not bind as well to the receptor as they have a low affinity therefore do not have as greater of an affect
describe an example of a partial agonist
- Buprenorphine
- Has a high affinity but low intrinsic activity at the mu opioid receptor and will displace methadone, morphine and other full agonists from the receptor
- So at analgesic doses buprenorphine is 20 times more portent an analgesic that morphine
- Because of its low intrinsic activity at the mu receptor, at increases doseases, unlike a full opioid agnostic, the agonist effects will reach a maximum and do not increase linearly, this is called the ceiling effect
why can you not get an overdose of an partial agonist
this is due to the ceiling affect as the maximal response is never met therefore you are less likely to cause a fatal respriatory depression than what a full agonist would cause
Describe the consequences of having a lower affinity for the receptor means in partial agonists
- They don’t bind as strongly as a full agonist
- Therefore they have reduced intrinsic activity as they don’t bind fully
- only give half the effect
- Occupies receptors prevents other agonists from binding therefore they can regulate the system without having overdose effects so they are safer to give to the patient
define an inverse agonist
- It produces a response below the baseline response, this is negative efficacy and it give the opposite effect to the agonist
describe how an inverse agonist works
- Acts on unoccupied receptors to produce an affect opposite of an agonist therefore it shifts the equilibrium towards the inactive state, only seen in systems that are active without any binding of ligand/agonist
- Give the opposite effect too the agonist
describe examples of inverse agonists
- Autonomic nervous system
- Anti-histamines certirizine,
- ioratodaine stabilise the receptor in the inactive state
whats a pharmogloical antagonist
- any drug that binds to a receptor and prevents the activation of the receptor
What are the 4 types of antagonist
- chemical antagonist
- physiologic antagonist
- competitive antagonist
- non competitive antagonist
describe how a competitive antagonist works
compete for the binding site, does not activate it reduces agonist potency
describe how a non competitive antagonist works
– binds to a differnet site, modulates receptor function, it reduces agonist efficacy
describe examples of chemical antagonists
- heparin
- protamine – this bind to heparin and inactivates it
- 1mg of protamine neutralises 100 units of heparin activity
describe chemical antagonist
- binds directly to an agonist an prevents it binding to a receptor
describe physiologic antagonist
- when 2 substances have opposite actions (cancel each other out) but act via differnet pathways
describe an example of physiologic antagonists
- histamine and adrenaline have opposite effects on smooth muscle in the bronchials and blood pressure but work via different pathways so adrenaline given to treat allergic reactions does not block the histamine and does not counteract the histamine receptors
but it bind to beta 2 receptors leading to the bronchioles dilating which is opposite to the bronchonconstiction caused by histamine H1 receptors - glucagon and insulin on blood sugar levels is another example
what do drugs need to work
ADME
- absorption
- distribution
- metabolism
- elimination
what kind of acid and bases do drugs tend to be
- drugs tend to be either weak acids or weak bases
what are the forms of drugs
- the undissociated form is a lipid soluble (uncharged, pronated) - can go through the membrane more easily
- the dissociated form is water (charged and proton has been lost) - cannot go through the membrane
describe the example of aspiring of weak acid and weak base in the body
- Aspirin is C8H7O2COOH
- The R-COOH is converted to R-COO- + H+
- R-COOH – uncharged, lipophilic, pronated
- R-COO- and H+ - ionic aspiring hydrophilic and unpronated
what happens to drugs in acidic conditions
- More hydrogen ions in the water
- Pushes the equation to the left so more uncharged RCOOH produced in order to reduce hydrogen ions in solution
- Lipid soluble and absorbed in the stomach
what happens to drugs in alkali conditions
- More OH ions
- More COO- NAD H+ formed in order to increase hydrogen ion concentration
- Hydrolysed by alkaline secretions in small intestine
define pKa
- pH at which the drug is completely balanced between uncharged (lipid soluble) and charged (water soluble form)a
why does most of the absorption of aspirin happen happens in the stomach
ph is 3 so 99% of it is in pronated form in stomach and most absorption of aspirin happens here
pH affect on drug eliminations
- all drugs are filtered by the glomerulus which in the kidney (in water)
- pronated form of a weak acid is more lipid soluble
- a pronated drug passing through the kidney will be reabsorbed back ito the blood
- therefore a weak acid excreted is faster in alkaline urine as more of it is in the unpronated form
- this is the opposite effect for weak bases
How deal with an overdose of tricyclic antidepressant overdose (weak acid)
- weak acid
- alkalinize the blood with sodium bicarbonate causes TCA to dissociate to its charged form
- does not diffuse back inot the blood from the renal tubules
and can be excreted
how to deal with an overdose of amphetamine which is a weak base
- amphetamine excretion can be speeded up by acidifying the urine by administration of ammonium chloride
how do you work out the drug of pronated form versus drug of unprompted form
Henderson hasslebalch equation
- all based on this equation
- log RH/R = pKa – pH = this means log of drug in pronated form over drug in unpronated form equals pKa-pH
pH = pKa + log [A-]/[HA]
what is specificity of a drug
- this is the which organ a drug works on and the range of actions produced by a drug
what is a selectivity of a drug
- this is what receptor a drug binds to produce an effect and is a binding dependent drugs
- This means it acts on a particular target but not another
what do both selectivity and specificity of a drug do
both consider the efficacy of a drug
what is the affinity of a drug
- how tightly the durg binds to the receptor and how good of a fit it is
drugs often ….
act on multiple receptors
what are receptors responsible for
- they are responsible for the selectivity of drug action
describe allosteric interactions
- do not act directly on the receptor,
- they affect the efficacy of binding affinity
what are the two types fo allosteric interactions
allosteric activators
allosteric inhibitors
describe allosteric activators
- increase the activation of the receptor
- binds stronger and keeps it there for longer
describe allosteric inhibitors
- decrease the activity of the receptor
- changes the binding so it may change the active site shape and make the agonist unable to bind fully or not at all
describe allosteric inhibitors
- decrease the activity of the receptor
- changes the binding so it may change the active site shape and make the agonist unable to bind fully or not at all
- non competitive
How do drugs bind to receptors
- covalent - very strong and usually irreversible
- electrostatic - fairy strong ionic groups and hydrogen bonds
- lipophilic - weak
- van der Waals - very week
- most drugs use a combination of these drugs
what are pharmokinetics
action of the body on the drug
- relates to ADME
what are pharmodyanmics
action of the drug on the body
- relates to the activity of the drug, dose response, relationship and intrinsic activity
describe an example of pharmcokinetics
- propranolol is metabolised and eliminated by the liver and kidneys
describe an example of pharmoacodynamcis
- propranolol lowers blood pressure and heart rate
as the dose increases
the response usually increase in portion to the dose
as dose increases…
response increment diminishes as it heads to the maximal response
what is the maximal response
this is when there is no further increase in response
what is half the maximum response
EC50 (ED50-dose)
• ED50 - the dose required to achieve 50% of the desired response in 50% of the population
• Median effective dose
what is TD50
- TD50: the dose required to get 50% of the population reporting the specific toxic effect
- Median toxic dose
what is LD50
- LD50: the dose required to achieve 50% mortality from toxicity
- Median lethal dose
describe the competitive antagonist response curve
- For competitive antagonist you Need to add more drugs to get EC50
- When enough agonist is added it wins the competition and so the drugs maximal affect can be achieved
- Shifts to the right of the agonist curve as it is competiting
describe the non competitive antagonist curve
- maximal affect is reduced, EC50 is the same dose as for agonist alone
- it binds at another site of the receptor and prevents the action of the receptor so will not reach maximal effect as no matter how much agonist added it cannot activate any more of the receptors
why do you get maximal response
- don’t use all receptors and you have spares
- all receptors do not have to be occupied to produce a full response
relationship between receptor occupancy and response is not..
linear
what do the spare receptors do
- spare receptors increase both the sensitivity and speed of a tissues responsiveness to a ligand
what is the competitive antagonist effect on spare receptors
- competitive antagonist effectively removes the spare receptors this is irreversible
- shifts curve to the right but maximal affect can still be achieved by agonist interactive with spare receptors
what is efficacy
it is the magnitude of response a drug causes when it interacts with a receptor
- the effect of the drug
- the more the effect the more efficacious the drug
- sometimes called intrinsic activity
what is potency
- refers to concentration of a drug needed for that effect
- have the same efficacy
- the concentration of the drug producing 50% of the maximum effect (EC50) is usually used to determine potency
what happens when the receptor is activated
- The interaction causes a change in the receptor which produces a regulated function
- A receptor is said to be activated only when its specific ligand is attached
what is the process of absorption
this is the transfer of a drug from the site of administration ot the blood stream, the rate and extent of absorption depend on the environment where the drug is absorbed the chemical characteristics of the drug, the route of administration
what is the process of distribution
The process by which a drug leaves the blood stream and enters the extracellular fluid (drugs administered IV, absorption is not a factor), depends on cardiac output, local bloodlfow, capillary permeability, tissue volume
what is the process of metabolism
as soon as a drug enters the body the process of elimination begins, - 3 major elimination routes these are hepatic, bilary and urinary elimination, most of the drugs are lipid soluble and without chemical modification they diffuse out of the tubular lumen, to minise this drugs are modified in the liver into more polar substances
what is the process of elimination
remove of the drugs via the kidney and intestines
what are the 3 major elimination routes
- hepatic
- bilary
- urinary elimination
what does strong acid/base mean
strong means it has dissociated fully in water
what does weak acid/base mean
weak means it partially dissociates in water
what happens once the aspirin is in the cell
Once the asprin is in the cell it changes to the water soluble form, and in the body it is metabolised to salicyclic acid which at ECF pH 7.4 is water soluble so remains in the ECF to have an affect, it remains highly unpronated
How does pH affect absorption
The concentration of the permeable from of the drug at its absorption site depends on two things
- the pH at the site of absorption
- strength of the acid/base this is represented by pKa
The concentration of the permeable from of the drug at its absorption site depends on two things….
- the pH at the site of absorption
- strength of the acid/base this is represented by pKa
the lower the pKa…
the more acidic
the higher the pKa,….
the more basic
what is a distribution equilibrium
this is achieved when the permeable form of the drug achieves an equal concentration in all water spaces
what an example of pKa
- drugs weak acids or bases because small changes in pH are required to shift between lipid (easily pass through with transport)and water soluble (does not pass through with transport)
No drug is truly specific….
but many have selective action on one type of receptor
why is it rare to find a drug that is specific and selective at the same time
For example, a drug binds on a particular receptor-target (so its selective), but that target may be expressed in different tissues and thus may exert different biological effects (so no-specific).
describe the potency curve
• As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).
• Plotting the magnitude of response against increasing doses of a drug produces a graded dose–response curve
• The curve can be described as a rectangular hyperbola, which is a familiar curve in biology because it can be applied to diverse biological events, such as enzymatic activity, and responses to pharmacologic agents.
• Two important properties of drugs, potency and efficacy, can be determined by graded dose–response curves.
C is more potent than D (it has a lower EC50
Value)
what is absorption
this is the transfer from administration site to the blood stream
what are the mechanisms of absorption
- passive diffusion
- facilitated diffusion
- active transport
- endocytosis and exocytosis
what are the influencers affecting absorption
- pH
- surface area
- blood flow to the site – the intestine receives more blood flow that the stomach so absorption from the intestine is favoured over the stomach
- contact time
