lecture 1 and 2 Flashcards

Question

What is a quantal dose response curve? What are the two ways to represent this?

Answer 1

Quantal dose response curve – indicates sensitivity of a given population to the doses of a drug for a given effect Different doses of a drug are given to a group of people and a defined response is noted – e.g. induction of sleep Frequency distribution Each bar shows the number of people responding to that dose – at 100 mg 21 people respond, excludes people responding to lower doses Cumulative frequency – each bar shows the number of people responding to that dose and to lower doses – at 200 mg all 100 people respond

Answer 2

Therapeutic index = TD 50 / ED50 = 350 / 150 = 2.3 ED50 Effective dose working in half the population TD50 Toxic effect or concentration used to induce toxic effect in 50% of the population.

Answer 3

lethal dose in 50% of people. supposedly the therapeutic index = TD50 or LD50/ED50. The higher the ratio, the safer the drug.

Answer 4

Therapeutic Window reflects a plasma concentration range that provides efficacy without unacceptable toxicity. Therapeutic window is the difference between the minimum effective concentrations for a desired response and an adverse response Anti cancer drug has a TI of 1 because they’re effective and toxic.

Answer 5

A dose-(concentration)-response curve shows graded responses in a single individual, produced by increasing concentrations of a given drug A quantal dose-response curve shows a specific response (quantal – all or none, either present or absent) in a group of individuals (population) produced by a drug (shows sensitivity of the population to a drug for a given effect – so different doses may be required for the same response in different individuals)

Answer 6

Drug – receptor interaction - produces a response The events involved in this response are known as signal transduction Common responses in the body - Transient increase in intracellular free calcium levels - Muscle contraction - Activation of enzymes for various biochemical reactions - Neurotransmission - Secretion of neurotransmitters and hormones

Answer 7

4 fundamental mechanisms or types 1. G-protein coupled receptor systems (GPCRs, metabotropic receptors) Half of all known drugs work through GPCRs 2. Ion-channel receptors (Ionotropic receptors) Ion-channel receptors - Has a central channel in it that allows ions to travel in and out. Fastest acting signal transduction. 3. Enzymes as receptors – tyrosine kinase, serine/threonine kinase 4. Nuclear receptors

Answer 8

``` Inactive receptor (G protein coupled receptor) has the inactive G-protein bound to GDP and there is for example an inactive adenylyl cyclse. In the agonist binding, the activated receptor GPCR is bound to GTP and it becomes GDP as it phosphorylates the activated enzyme adenylyl cyclase. ```

Answer 9

Three major second messengers activated by GPCRs: cAMP (cyclic adenosine monophosphate) IP3 (inositol trisphosphate) to increase calcium DAG (diacyl glycerol) leads to protein and kinase C. Adenylyl cyclase converts ATP to cAMP which then leads to protein kinase A.

Answer 10

The receptor consists of a pair of protein molecules (monomers) that are separate when inactive. An agonist causes them to interact and form a dimer. The interaction phosphorylates tyrosines in the intracellular region of the receptor and the receptor becomes an active enzyme. The active receptor enzyme then activates a number of other enzymes that interact with the active tyrosine of the receptor. e.g. insulin receptor, growth factor receptors

Answer 11

The receptor is a protein with a channel in the centre. An agonist causes the channel to open and allows specific ions to cross the cell membrane to the other side. e.g. Nicotinic acetylcholine receptor – conducts Na+ ions – causes muscle depolarization and contraction (Fig. B) Gamma aminobutyric acid (GABA) receptor – conducts Cl- ions – inhibits neurotransmission

Answer 12

These receptors are in the cell cytosol. An agonist enters the cell and binds to the receptor. The drug-receptor complex then enters the nucleus and stimulates gene transcription. This leads to synthesis of new proteins and enzymes. This kind of signal transduction extends over hours to days. e.g. receptors for steroids, retinoids and thyroid hormones

Answer 13

Agonists tend to desensitize receptors – e.g. Very commonly, frequent stimulation of a receptor by its agonist results in a decreased response - desensitization of receptors. Several mechanisms have been proposed: e.g. Decreased receptor number (downregulation) or decreased signal transduction The desensitization is homologous when only a given receptor is desensitized The desensitization is heterologous when desensitization of one receptor by an agonist also causes desensitization of another receptor (e.g. when the signal transduction pathways of two receptors cross each other)

Answer 14

Antagonists tend to up regulate receptors – e.g. treatment with a β-receptor antagonist causes a withdrawal rebound effect when the antagonist treatment is stopped suddenly. This is because the receptor number has increased and when the antagonist is suddenly removed from the receptor, there are more receptors available for the agonist resulting in a rebound response. It is important to gradually decrease the dose of any antagonist to prevent such a rebound Prolonged treatment with an agonist drug can desensitize the receptor. Pinodol a partial agonist at B-receptors, will decrease the tachycardia caused by norepinephrine (because it is a partial agnoist acting like an antagonist). Suddenly stopping prolonged treatment with an antagonist drug can produce a withdrawl (rebound) response due to receptor upregulation. The lower the dissociation constant the more affinity the drug has for its receptor.

Answer 15

Drug absorption refers to the passage of drug from the site of administration into the general circulation (except for drugs that are applied directly to the target tissue) A drug that is injected intravenously is considered to be immediately and completely (100%) absorbed Absorption of orally administered drugs is incomplete for most drugs. At the same time it can vary for a given drug in a given patient. If changes are observed in the therapeutic effect of a drug used over a long-term, one should think about changes in factors affecting oral absorption or bioavailability of the drug.

Answer 16

Better absorbed - non-ionized - small molecules - lipid-soluble drugs Poorly absorbed or not absorbed - ionized - large molecules Lipid soluble drugs can go through a cell membrane. They can distribute to almost all the compartments of the body. They can cross the blood:brain barrier, the placental barrier and the skin. Therefore they can be applied as skin patches, but at the same time they can cause CNS or fetal toxicity.

Answer 17

They are destroyed by stomach acid or digestive enzymes (e.g Penicillin G, insulin) Chelated to components of food to form insoluble complexes (e.g. tetracyclines) So polar they won’t cross cell membranes (e.g aminoglycoside antibiotics) – streptomycin, gentamycin Undergo extensive metabolism (e.g. nitroglycerin, adrenaline, dopamine) Insulin is a peptide. All peptide drugs have the limitation that they cannot be given orally. The biggest challenge to treat type I diabetes is the development of an orally effective form of insulin. Drugs which get chelated to food components should be taken by the patient at least 2 hours before or after a meal. The aminoglycoside antibiotics are very effective to treat some serious infections, but they have to be injected because they are not absorbed orally. For drugs which undergo extensive first-pass metabolism, one solution is to give a very large dose so that the small fraction which is absorbed is therapeutic. This is why you sometimes have to tell patients to not eat before treatment or before some medicines. Because it can chelate to the food. The GI tract epithelium and the liver will metabolize nitroglycerin, adrenalin, and dopamine, if they are taken orally.

Answer 18

The pKa of a drug is defined as the pH at which half of the drug is ionized Most drugs are either weak acids or weak bases The Henderson-Hasselbach equation can be used to calculate the ratio of nonionized/ionized molecules: log[protonated form]/[unprotonated form] = pKa - pH Most drugs used clinically are either weak acids or weak bases. Therefore, when we put them in an aqeous phase they will become ionized. The pH of the solution will then determine how much of the drug becomes ionized and how much remains non-ionized. It is the non-ionized fraction which can cross cell membranes easily. This does not mean that the ionized fraction cannot go across a barrier at all. While the ionized molecule will not cross through a cell membrane it can still go through large gaps or channels between cells. Remember that in the capillaries of certain organs like the liver and the kidney glomerulus, there are large gaps between endothelial cells and thus almost all drugs will enter the liver or the kidney tubule from the circulation, even if they are ionized.

Answer 19

when a patient swallows aspirin for example, there are already a lot of hydrogen atoms ad so it will not be as ionized because it will shift back to the HA side of the HA H + A equation. Because the ionized side is H+ and A- So acidic drugs become more ionized in a basic medium and less ionized in an acidic medium. Basic drugs become more ionized in an acidic medium and less ionized in a basic medium. B + H HB and so if you put this weak base into an acidic solution with lots of hydrogen in it it will want to shift to the ionized side. Because it's actually BH+