Exam 2020-juni Flashcards
Overuse of receptor agonists could result in receptor desensitization. Describe two mechanisms for receptor desensitization (describe what happens on a cellular and/or molecular level). How is the pharmacological response affected? Motivate your answer.
Homologous desensitization: This mechanism occurs when the receptor itself becomes less responsive to its agonist. Chronic stimulation of the receptor by an agonist leads to the activation of intracellular signaling pathways, such as the activation of protein kinases. These kinases then phosphorylate the receptor, which reduces its affinity for the agonist and/or its ability to activate downstream signaling pathways. As a result, the pharmacological response to the agonist decreases. An example of homologous desensitization is the desensitization of beta-adrenergic receptors in response to chronic exposure to beta-adrenergic agonists such as isoproterenol. This can result in a reduced response to these agonists in the treatment of conditions such as asthma or heart failure.
Heterologous desensitization: This mechanism occurs when the desensitization of one type of receptor affects the responsiveness of another type of receptor. Chronic stimulation of a receptor can lead to the activation of intracellular signaling pathways, such as the activation of protein kinases or the release of intracellular messengers. These signaling molecules can then affect the activity of other receptors by altering their downstream signaling pathways or modulating their expression. As a result, the pharmacological response to multiple types of agonists can be affected. An example of heterologous desensitization is the desensitization of opioid receptors in response to chronic exposure to opioids. This can lead to a reduced response to other types of analgesics, such as nonsteroidal anti-inflammatory drugs, as a result of cross-tolerance.
Salbutamol is a drug commonly used in the treatment of obstructive airway diseases. Which of the following molecular actions most likely mediates the positive effects of salbutamol? Motivate your answer. (4p)
a. Increased phosphorylation of myosin light chain
b. Activation of myosin light chain kinase
c. Increased formation of the Ca2+ /calmodulin complex
d. Inhibition of cAMP-dependent protein kinase
e. Increased synthesis of cAMP
the mechanism of action of salbutamol involves binding to beta2-adrenergic receptors on airway smooth muscle cells, leading to activation of the cAMP-PKA pathway and inhibition of smooth muscle contraction. These effects contribute to the bronchodilatory and anti-inflammatory effects of salbutamol.
Activation of PKA by cAMP leads to a decrease in intracellular calcium levels, which is the main trigger for smooth muscle contraction. This occurs via two mechanisms:
Inhibition of myosin light chain kinase (MLCK): PKA phosphorylates and inhibits MLCK, which is the enzyme responsible for phosphorylating myosin light chains and initiating smooth muscle contraction. By inhibiting MLCK, salbutamol reduces the ability of smooth muscle cells to contract.
Activation of myosin light chain phosphatase (MLCP): PKA also activates MLCP, which is the enzyme responsible for dephosphorylating myosin light chains and promoting smooth muscle relaxation. By activating MLCP, salbutamol promotes smooth muscle relaxation.
Anti-inflammatory drugs could act on several pharmacodynamics targets eg receptors, enzymes or gene transcription.
Choose one drug for each target and;
a. describe the specific mechanism of action
NSAID (enzyme inhibitors), non-steroidal anti-inflammatory drugs. They are COX inhibitors. Irreversible Treo, reversible ipren.
Glucocorticoids binds to intracellular receptors, receptor ligand complex migrate to nucleus, that affect transcription of genes either up or down regulating.
Cyclosporine is an example of a immunosuppressive drug that inhibit production of IL-2 which results in decreased clonal proliferation of T cells. They wokr on the IL-2 receptor on the cell surface.
Anti-inflammatory drugs could act on several pharmacodynamics targets eg receptors, enzymes or gene transcription.
Choose one drug for each target and;
Identify a common Typ A side effect for each drug (drug group), motivate
Treo and Ipren has aisde effects on the gastic mucosa and platelets.
Glucocorticoids have metabolic effects, increase weight, proness to diabetes etc especially when not administrated locally.
Cycvlosporine increase risk of infections and tumors
Identify ONE pharmacological drug that inhibits the action of MORE THAN TWO of the molecules shown in the picture. Describe the mechanism of action of this drug. (It’s different targets for anticoagulant drugs)
Heparin, binds to the enzyme inhibitor antithrombin III (AT). The activated AT then inactivates thrombin, factor Xa and other proteases. This causes the drug to be an anticoagulant.
Some of the molecules in the picture below are targets for different drugs that have different mechanisms of action. Identify one such molecule in the picture and describe two different mechanisms of action for inhibiting this molecule. (It’s different targets for anticoagulant drugs)
Clopidogrel, The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible.
ASA (also anti-inflammatory drug), disrupts the production of prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
In relation to psychotic illness the term ”positive symptoms” is used. What does this term mean in relation to symptoms? (2p)
Also, schizophrenia can be treated using two groups of antipsychotics, typical and atypical, give a generic drug from each group. (1p)
Positive symptoms for psycotic illnesses include hallucinations which can be visual, audio halusionaitons or tactic hallunicaitons. It can also mean paranoia etc. It means symptoms that add something to the patients life it didn’t hvae before while negative symptoms mean a loss such as flattened mood, unable to take initiative, apathy etc the patient loses abilties it had prior.
Typical (first-generation): haloperidol
Atypical (second-generation): risperidone
You are looking into a novel treatment for a CNS disorder that seems to be dependent on neurotransmitter concentration in the synaptic cleft. Which process(es) or type of molecular target in the synapse, or the pre- and/or post- synaptic cell (neuron) may you want to target to possibly treat the disease?
Antidepressants for example that block seratonin and norephinierhine transporters so the substances are longer in the brain, adhd medication that blocks dopamine and nordadrenaline transporter etc.
When is nitroglycerin used clinically?
How is the drug administered? Motivate and explain why the drug is administrated the way you answered.
Nitroglycerin is a medication that is primarily used clinically to treat and manage chest pain (angina) and heart failure. It works by relaxing the smooth muscles in blood vessels, which leads to dilation of the blood vessels, increased blood flow, and reduced workload on the heart.
The most common and preferred route of administration for acute angina is sublingual. Nitroglycerin tablets are placed under the tongue, where they dissolve and are rapidly absorbed into the bloodstream. This route of administration provides quick relief of angina symptoms, typically within 1-2 minutes. It’s so it can have a fast acting effect since it’s a acute state that needs to be treated as quickly as possible.
Your colleague is fascinated by the sinoatrial node and asks for your advice on what type of pharmacological drug to use to reduce the heart rate (i.e. frequency of firing). Explain your preferred type of drug to achieve such an effect. Motivate your choice by explaining to your colleague the mechanism of action of your preferred type of drug in the sinoatrial node.
Beta-blockers work by blocking the beta-adrenergic receptors located in the heart and other tissues. These receptors are responsible for receiving signals from the sympathetic nervous system, which can increase heart rate and contractility. Specifacally Beta blockers -1 since it’s located on for example the SA node.
Some anti-arrhythmic drugs primarily affect cardiomyocytes that fire with abnormally fast heart rate. Describe the mechanism underlying this behavior of drugs.
Class IV anti-arrhythmic drugs, such as verapamil and diltiazem, block the calcium channels in the cardiomyocytes, reducing the influx of calcium ions into the cell. This action slows down the depolarization of the cell and the firing of the action potential, thereby decreasing the heart rate.
a) What are these two main groups of mitosinhibitors called?
b) Explain how the drugs affects the balance between free tubulin heterodimers and microtubule? If you add another drug that promotes/enhances microtubule formation, is the drug effect enhanced or decreased for the two groups of mitosinhibitors?
c) When treating the cells with each type of mitosinhibitors what is the result of the inhibition on the cells?
a) The two main groups of mitosis inhibitors are microtubule-destabilizing agents and microtubule-stabilizing agents.
b) Microtubule-destabilizing agents, such as vinca alkaloids (e.g. vincristine, vinblastine) and colchicine, bind to the beta subunit of tubulin and prevent the formation of microtubules. This results in an increase in the concentration of free tubulin heterodimers in the cytoplasm, which are unable to polymerize into microtubules. As a consequence, the balance between free tubulin heterodimers and microtubules is shifted towards the former, leading to a disruption of the mitotic spindle and arrest of the cell cycle in the metaphase.
On the other hand, microtubule-stabilizing agents, such as taxanes (e.g. paclitaxel, docetaxel) and epothilones (e.g. ixabepilone), bind to the microtubules and stabilize them, preventing their depolymerization. This results in the accumulation of microtubules in the cell, which interferes with the normal dynamics of the mitotic spindle and leads to cell cycle arrest in the metaphase.
If another drug that promotes/enhances microtubule formation, such as the microtubule-stabilizing agent, is added to the cells treated with microtubule-destabilizing agents, the effect of the mitosinhibitors is decreased. This is because the microtubule-stabilizing agent counters the effect of the microtubule-destabilizing agent by promoting the formation of microtubules.
c) When cells are treated with mitosinhibitors, their cell division is inhibited, leading to cell cycle arrest in the metaphase. This can ultimately lead to apoptosis or cell death if the cells are unable to exit the mitotic phase and complete the cell division process. Mitosinhibitors are widely used in cancer therapy, as cancer cells divide more rapidly than normal cells and are therefore more sensitive to mitotic inhibitors. However, these drugs can also affect normal cells that divide rapidly, such as cells in the bone marrow, gastrointestinal tract, and hair follicles, leading to various side effects.
