Pharmacodynamics/ Pharmakinetics - 2 Flashcards
Define pharmacology. What are drugs?
- Studies of drugs and their effects on living organisms
>A 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
What are the 5 targets of drugs? (All protein or multi protein complexes)
- Receptors
- Targets capable of binding specific molecules called ligands
-Exterting or mediating one or more multiple cellular effects in response to binding of ligand - Enzymes
- Catalysts in chemical modifications of metabolites and other biomolecules - Ion channels
- Channels/aqueous passages through phospholipidic-membranes for ions with various degrees specificity and mechanisms - Transporters/ Carriers
- Transporters/carriers through phospholipidic-membranes for ions, metabolites or other biomolecules with various degrees specificity and mechanisms - Non-protein and other targets
-Including chemical and physical mechanisms; DNA/RNA, glucidic and lipid molecules: targets immune-therapeutics: some nano-therapies
What is EC50? What is its importance?
-The effective concentration of ligand giving half of the maximum possible response
>Compares efficiencies of different drugs
>More efficient drug will have a lower EC50 value
Antagonistic drug vs agonistic drug?
1) Agonistic effect : Both molecules acting cooperatively on the same target, reach biological response at lower concentration than ligand alone
>EC50 that is much lower
2) Antagonistic effect : Both molecules with opposite effects on the same target
>EC50 will be higher than ligand alone as drug interferes with ligands capability to produce an effect
What is LC50?
> Concentration at which drug causes cell mortality in 50% of individuals
- Unwanted effects as the drug interacts less efficiently with many other proteins
- Check whether cells are viable at the concentration of drug I am using
Can drugs be toxic? When are toxic effects more common?
-Yes, drugs have therapeutic effects and side effects. Some are toxic and lethal
Toxic effects > Higher concentrations than the therapeutic effect - % of the population that will give us a given wanted biological effect?
What is the ED50, TD50, LD50 ?
-Median effective dose - dose at which 50% of the treated individuals present the desired therapeutic effect
-Median toxic dose - dose at which 50% of the treated individuals present undesired and to be avoided toxic effect
-Median lethal dose - dose at which 50% of treated individuals die
What is therapeutic index? What is margin of safety?
- How far away TD50 is from ED50. The greater the better. TD50/ED50
> A patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect. - TD1/ ED99
>higher is the ratio, safer is the drug we are using.
What is therapeutic window?
- Dosage of the drug up to TD1
-Good drug : therapeutic window reaches ED99 and the wanted response in the majority of the population before TD1
Why do we have issues with this drug?
-ED50 and TD50 are far apart - (Therapeutic index)
- However effective dose for majority of the population ED99
-20% population suffers from toxic effect
Why is this drug good?
-Therapeutic index is not toxic as TD1 dosage doesn’t overlap with ED99
- Good therapeutic window , safer drug
How are receptors a target for drugs? What are the 3 types?
- Exert one or
multiple effects in response to binding to specific molecules
1) Membrane receptors - associated with phospholipid bilayer
2) Cytoplasmic receptors
3) Nuclear receptors
What is the difference between the 2 membrane receptors?
- Ionotropic receptors
“Ion channels” (open, inactive or closed) govern ion membrane permeability by responding to an extra-cellular stimulus
.. fast, specific, depends on electrochemical gradient, magnitude dependent on :
-time channel open, quantity of receptors , receptor sensitivity - Metabotropic receptors
They convert an extra-cellular stimulus to a specific intracellular signal, second messenger… slower
e.g. - Coupled to protein Gs (GPCR)
e.g. Coupled to enzymes
(… there are also receptors coupled to other mediators)
What are the positive and negative effects of 2 molecules interacting with an effector protein?
1) Agonistic effect : each of the molecules contributes to the effect, appearing as augmenting the overall response
2) Antagonistic effect one or both of the molecules inhibits the effect of the other, appearing as diminishing the response of one of both drugs
3) Positive and Negative Allosteric effects
one of the molecules, by interacting on a secondary binding site at the effector protein, respectively, potentiates or diminishes the effect of the other
4) Neutral (or Silent) Allosteric effect : drug binds to allosteric site and prevents binding of anything else
What are cytoplasmic receptors?
-These receptors are in the cell cytoplasm and are part of the cellular innate immune response
What are Nuclear receptors?
-modify the gene-transcription program of cells in consequence of a received stimulus (ligand)
> Their target is in the nucleus, where they directly (or indirectly) bind the DNA and regulate the transcription of the genes adjacent to the site of binding
How are enzymes targets for drugs directly?
-Enzymes control many chemical reactions drugs interfere with these
Drugs can directly interfere with enzymes by acting as any of these:
1. Metabolite or cofactor : Agonist drug
2. Direct Inhibitors : Antagonistic drug
3. Allosteric activators : PAM
4. Allosteric inhibitors : NAM
How can drugs indirectly inhibit enzymes?
- by inhibiting the formation of enzymes
- by interfering with its association to other key
components or its trafficking - by making less available the substrate or the
cofactor
How do drugs target transporters?
-Normal compounds : replacement of molecule if deficient
-Inhibitors : Inhibitors prevent the transport of the physiological target of the transporter.
-False substrates: out-competing the natural ligand for the carrier protein because they cannot be fully metabolized into an active product.
How are ion channels drug targets?
- Direct binding to the channel protein itself
❖ Activator ❖ Inhibitor - Indirect interaction with Intracellular signaling molecules which produce their effects on the channel.
How do drugs interact acellular ?
Give 2 examples
- Do not interact with cells to cause effect
- e.g. antacids neutralise stomach
e.g. monoclonal antibodies present substrate binding to receptor
How do drugs target genes and proteosomes?
- Inhibit proteasome .. inhibits NF-KB… inhibits gene transcription
What is pharmacokinetics? Bioavailability?
- Processes that affect the bioavailability of a drug to its target ADME :
‒ Absorption from the site of administration
‒ Distribution within the body, rapid in vascularised organs
‒ Metabolism
‒ Excretion
> Bioavailability indicates the fraction (F) of an administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and local metabolic degradation.
How can drugs be administered?
- Entereal : Oral, sublingual , rectal
- Parenteal : . Intramuscular (IM) , Subcutaneous (SC), Intravenous (IV)
- Other : Epithelial, transdermal, inhalation
How are drugs absorbed in the GI tract?
- Facilitated diffusion , Simple diffusion, Active transport, Endocytosis
Most drugs are reversibly bound to plasma proteins. What does this mean?
- Unbound drug is pharmacologically active.
- Extensive protein binding slows drug elimination.
- Competition between drugs for protein binding can lead to drug interactions.
Are drugs uniformly distributed?
-No
How are drugs metabolised from the body?
- Metabolism in the liver = lipophillic drug more water soluble and therefore more easily excreted in the urine.
- Metabolism of drugs is less crucial in polar drugs, which are typically excreted in the urine in an unchanged state.
How are drugs eliminated from the body?
What are some extra - renal routes ?
-Excretion via kidney
