Foundations of Medicine Block 1 Week 4 Flashcards
What is Pharmacology ?
The branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the effects of drugs on the function of living organisms.
What is a drug ?
Broadly defined as any man-made, natural, or endogenous (within the body) chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.
A drug is a chemical applied to a physiological system that affects its function in a specific way
What is a ligand ?
Ligand is a molecule which produces a signal by binding to a site on a target protein.
Generally, drugs are considered to bind to receptors and any chemicals that bind to receptors are usually termed ligands (e.g. drugs).
Which target proteins do drugs act on ?
- receptors
- enzymes
- carriers (across cell membranes )
- ion channels
How is the term receptor used when talking about drugs ?
The term receptor is used in different ways. In pharmacology, it describes protein molecules whose function is to recognise and respond to endogenous chemical signals (permanently or transiently). Other macromolecules with which drugs interact to produce their effects are known as drug targets.
Describe the specifity of drugs ?
Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognise only certain classes of drug.
No drugs are completely specific in their actions. In many cases, increasing the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side effects.
Specificity: the degree to which the effects of a drug are due to the one pharmacological action.
Give examples of receptor target drugs and non- receptor target drugs ?
Scope of pharmacology ?
Choosing the receptor allows drugs to target specific tissues
Choosing the receptor allows drugs to target specific tissues
What is pharmacokinetics ?
Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion .
Questions which Pharmacokinetics answer:
The effect the drug has on the body
How does the drug get into the body?
What does the body do to the drug?
How does the body get rid of the drug?
What are the 4 stages/things that happen as part of pharmacokinetics ?
- absorption (how drug gets into the body)
- distribution (where the drug goes to in the body)
- metabolism (how the body chemically modifies the drug)
- excretion (how the bod gets rid of the drug)
ADME
These are 4 things we need to consider when talking about the pharmacokinetics of certain drugs.
What is affinity ? (drug)
Affinity (ease of binding): The strength of noncovalent bonds between drug and receptor (DR), as measured by the dissociation constant (Kd) of the DR complex.
The smaller the KD value, the greater the binding affinity of the ligand for its target.
What is dissociation constant (Kd)
Dissociation constant (Kd): the concentration at which half of the drug is bound to the receptor at equilibrium. Note not all drugs dissociate.
The other half of the drug is ‘swimming free in the system’.
Kd = (concentration of ligand)x(concentration of receptor) / (concentration of receptor -ligand complexes)
kon= concentration of receptor-ligand complexes
koff = (concentration of receptors) x (concentration of ligands)
What is pharmacodynamics ?
Pharmacodynamics is the study of the biochemical and physiologic effects of drugs.
The study of drug-receptor interactions is called pharmacodynamics.
Questions answered by Pharmacodynamics?
What does the drug do?
What effects does it have?
Describe drug receptor interactions
- Receptors are macromolecules involved in chemical signaling between and within cells; they may be located on the cell surface membrane or within the cytoplasm.
- Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity)
-Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have relative selectivity.
What is selectivity when it comes to drugs ?
Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors
What is the affinity of a drug ?
A drug’s ability to affect a given receptor is related to the drug’s affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response). A drug’s affinity and activity are determined by its chemical structure.
What is residence time ? (drug)
The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug’s toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity.
What is an Agonist ?
A drug that produces a positive effect (boosts) when bound to a receptor.
Agonists activate receptors to produce the desired response. Conventional agonists increase the proportion of activated receptors.
What is an Antagonist ?
A drug that reduces the effect of an agonist at a given receptor.
Antagonist: A drug that reduces the effect of an agonist at a given receptor.
Antagonist can increase and decrease the effects of cellular function
Antagonists prevent receptor activation. Preventing activation has many effects. Antagonists increase cellular function if they block the action of a substance that normally decreases cellular function. Antagonists decrease cellular function if they block the action of a substance that normally increases cellular function.
Receptor antagonists can be classified as reversible or irreversible. Reversible antagonists readily dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly permanent chemical bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists slowly dissociate from their receptor
What is competitive antagonism ?
binding of the antagonist to the receptor prevents binding of the agonist to the receptor.
What is non - competitive antagonism ?
Agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the action of the agonist.
A non-competitive antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor.
It changes the shape of the binding site
You can keep adding agonist but it wont improve binding. Useful in certain conditions.
What is reversible competitive antagonism ?
A reversible antagonist binds non-covalently to the receptor, therefore can be “ washed out”.
Examples of irreversible binding ?
Aspirin irreversibly inhibits cyclooxygenase (COX) by acetylation of an amino acid serine residue, and thus blocks the subsequent biosynthesis of prostaglandins and thromboxane.
Pharmacokinetics graph explained ?
C - max: is the maximum concentration of the drug in the body.
T-max: is the time at which maximum concentration occurs.
To find the half life of a drug. Find half the c-max then go across to find half the t-max.
Binding is not 100% specific
Not all ligands bind to the receptor (specific), some bind to other things eg. plasma globules (non-specific).
First graph: At low concentrations very little drug is bound. At higher concentrations more drug is bound.
The difference between total and non-specific tells us what a particular receptor does.
Second graph: The specifically bound drug-receptor increases as we increase the concentration of the drug, until a plateau is established this is because the number of receptors is the limiting step.
Third graph: is known as a semilog plot. As the concentration of the drug increases so does the specificity.
What are Inverse agonists ?
Inverse agonist: A drug that produces negative (Ie: inhibitory) effect when bound to a receptor.
Will occupy the same binding areas as ligands but cause the opposite effects.
What is the drug effect spectrum?
A drug which produces a 100% response is called a Full Agonist
Super Agonist is a molecule which can boost the function of agonist. Eg, endogenous opiates )100% agonist) and manufactured opiates (produce an even more effect over 100%).
Partial Agonist - when bound to an agonist partially boost the agonist
Silent Antagonist - bind to agonist but do nothing and do not induce any effect. They just occupy binding site so that nobody else can bind. Hey reduce binding from 100% to 0%
Full Inverse Agonist - will reduce binding from 100% to -100%. Will mirror full agonist.
Partial Inverse Agonist - Partially block
What is the drug effect spectrum?
A drug which produces a 100% response is called a Full Agonist
Super Agonist is a molecule which can boost the function of agonist. Eg, endogenous opiates )100% agonist) and manufactured opiates (produce an even more effect over 100%).
Partial Agonist - when bound to an agonist partially boost the agonist
Silent Antagonist - bind to agonist but do nothing and do not induce any effect. They just occupy binding site so that nobody else can bind. Hey reduce binding from 100% to 0%
Full Inverse Agonist - will reduce binding from 100% to -100%. Will mirror full agonist.
Partial Inverse Agonist - Partially block
What is the dose -response curve ?
What are the main types of receptors?
4 main types:
- ligand-gated ion channels
- G - protein coupled receptors
- receptor kinases
- nuclear receptors
What are ligand - gated ion channels ?
Ligand gated ion channels are usually found in the cellular membrane. They transfer ions in and out of the cell.
Main effector is ion channel
There is direct coupling
Examples: nicotinic, acetylcholine receptor, GABA receptor
What are receptor kinases ?
Found in the cell membrane
Main effector is protein kinases
The coupling is direct
Examples: Insulin, growth factors, cytokine receptors
What are nuclear receptors ?
Found in intracellular (inside cells)
Effector is Gene Transcription
The coupling is via DNA.
Examples: Steroid Receptors
Receptors: The effects they produce ranges from milliseconds to hours.
What is the structure of ligand gated ion channels ?
ligand gated ion channels:
ion selective domain
transmembrane domain
gating domain
pore - when the pore is open certain ions can enter and leave the cell.
What happens when ligand bind to receptor:
Upon binding of agonist their is a conformational change of the different subunits.
Sodium which is positively charged enters
As a result the cell becomes depolarized and is excitable so contraction can take place.
By knowing what ion binds to the receptor we can predict the effect it will have on the cell.
What are the multiple drug binding sites on a receptor (ion channel) ?
CHANNEL BLOCK (from outside)
BLOCK OF INACTIVATION (stop the pore from closing) sodium is constantly pumped into cell. This is lethal to the cell.
CHANNEL BLOCK (from the inside) - how local anesthetics work
ALTERED GATING
What are GPCRs ?
Within the GPRC superfamily there are 5 major families, name them ?
G protein coupled receptors
GPCRs are helical transmembrane receptors complemented by functional extracellular and intracellular loops (4). Within the GPCR superfamily, there have been five major families identified.
rhodopsin (family A), secretin (family B), glutamate (family C), adhesion and Frizzled/Taste2.
The ligand is the gold structure in the image at the extracellular end. There is no pore except the G-protein is cleaved and phosphate groups are available to phosphorylate several other proteins or second messenger, cellular biological response.
There are subunits of GPCRs.
Ga subtypes
What is the associated receptors and main effectors of Gαs (G alpha s subunit) ?
Associated receptors: Many amine and other receptors (e.g. catecholamines, histamine, serotonin).
Main effectors: Stimulates adenylyl cyclase, causing increased cAMP formation.
Ga subtypes
What are the associated receptors and main effectors of Gai (G alpha i) and Gao ( G alpha o) ?
Gai associated receptors: As for Gas (g alpha s ), also opioid, cannabinoid receptors.
Gao associated receptors: As for G (g alpha s), also opioid and cannabinoid receptors.
Gai main effectors: Inhibits adenylyl cyclase, decreasing camp formation.
Gao associated factors: Limiting effects of a (alpha) subunit (effects mainly due to By (beta) subunits
Ga subtypes
What are the associated receptors and main effectors of Gaq (G alpha q) ?
Gaq associated receptors : Amine, Peptide and prostanoid receptors
Gaq main effectors: Activates phospholipase C, increasing production of second messengers inositol trisphosphate and diacylglycerol.
When a agonist binds to a g-protein coupled receptor the following pathways/cascades can be triggered ?
Convergence: multiple G-proteins affect one target
Divergence: single G-proteins affect multiple targets
To design specific drugs that target G protein coupled receptors is challenging.
Drugs which can be prescribed to target these receptors are limited.
Give an example of B-adrenoreceptor, Gas ?
What are kinase - linked receptors ?
Kinase-linked receptors (KLRs) are one of the main cell surface receptors that function similar to other transmembrane receptors.
KLRs are able to autophosphorylate.
Mainly used in controlling cell growth and differentiation and act indirectly by regulating gene transcription.
2 main pathways of KLRs are:
MAP kinase pathway
Jak/Stat pathway
What are nuclear receptors ?
Are the most commonly prescribed receptors
Nuclear receptors are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various other lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone
There are 2 types of nuclear receptor:
- cytoplasmic
-nuclear
Once the ligand receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting co-activator or co-repressor factors.
Only when the ligand is bound to the nuclear receptor can the receptor exert its biological effect.
What is tolerance of a drug ?
When a drug is administered over a longer period of time again and again, this biological response becomes weaker and weaker.
The concept of tolerance is caused by homeostasis.
Even if the drug is bound to the receptor the biological response becomes weaker and weaker. In the long run you need larger and larger doses to achieve the same response you had initially to the drug.
What is tolerance and dependence (physical and psychological)
The cell has set a new homeostasis point in the presence of a drug.
So when you stop administration of a drug the symptoms decrease below initial levels, you have a drastic withdrawal, that would be worse than the initial state of the patient when they first came to see you.
Withdrawal effects get milder over time.
If you administer anti-epileptic drugs over a certain period of time you cannot simply remove them from the patient otherwise they will suffer massive seizures.
Abuse of opiates shows a strong psychological dependence
How can we treat dependence ? (pharmacologically)
There are two strategies to treat dependence. One is to administer a drug (agonist) which will give a similar effect to the drug of abuse but more mild side effects. The other is to administer drug (antagonist) which will stop you getting the buzz from that drug and target the psychological part of the dependence.
Abstinence syndrome - when you withdraw from drugs.
- When a patient is experiencing drug withdrawal e.g. the drug is unavailable, they will go through a drug withdrawal. During the drug withdrawal there is a negative reinforcement mechanism, the patient experiences abstinence syndrome. You can administer an agonist like methadone. Methadone is an agonist to heroin.
So methadone is an agonist to the drug of abuse (aka heroin) but is going to have milder side effects. It is the better of two evils.
- When a patient has purchased the drug of abuse because they know they will feel brilliant after taking the drug of abuse. By administering an antagonist they don’t feel brilliant, they don’t get the buzz they used to by the drug of abuse. So you target the psychological dependence. However the compliance is the main problem that challenges this pharmacological strategy.
What is adverse reactions ?
Adverse drug reaction: an appreciably harmful or unpleasant reaction resulting from an intervention related to the use of a medicinal product
Adverse drug reactions can be classified into two groups:
- ADR related to pharmalogical property
- ADR unrelated to pharmalogical property
