exam 2020-augsti Flashcards
Based on a effect/molar graph how can one see which drug has the highest potency?
It’s the one that gives the strongest effect at the smallest concentration
Based on a effect/molar graph how can one see if the drug is a partial antaognist?
It doesn’t reach Emax
Based on a effect/molar graph how can one see if two drugs differ in efficacy?
In pharmacology, efficacy describes the maximum response that can be achieved with a drug. SO the drug with the highest Emax has the highest efficacy.
competitive vs noncompetitive antagonist show up on a effect/molar graph?
For a competetive antagonist the potency lowers but not Emax and for a noncompetetive antagonist the Emax lowers.
Overuse of an agonist could result in receptor desensitization. How is the pharmacological response affected? Discuss scenarios with and without spare receptors.
Stimulation can trigger receptor desensitization where invaginations occur where the receptor proteins are on the cell surface. This doesn’t matter if the drug has high efficiency and spare receptors, but if there are no spare receptors this can become a big problem for partial agonists. Desensitization can be due to internalization of receptors ort decreased synthesis but also changes in receptor proteins, changes of transducer proteins or changes in second messenger systems.
You have a headache and therefore swallow a pill that contains paracetamol to relieve the pain.
a) Draw a curve that in general terms show how your plasma concentration of paracetamol changes over time. Motivate in writing why the curve looks the way it does. (2p)
It’s a curve that starts at 0 goes sharp up and sharp down and then flattens out a bit.
b) Assume that on another occasion you receive a continuous intravenous infusion of another drug. The drug is infused during a period of 10h. For the whole 10h, the infusion is added at the same constant rate. At time 4h the concentration is 40 mg / L and at this time steady state is reached. Draw a curve that shows how the plasma concentration of the drug changes over time. Start at 0h and end at 10h. Motivate in writing why the curve looks the way it does. (2p)
It will start at 0 then quickly go up to 40mg and then reach a steady state after a while where the curve flattens out
Terbutaline 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 terbutaline? Motivate why you exclude the other alternatives (5p)
a. Increased phosphorylation of myosin light chain
b. Increased synthesis of cAMP
c. Increased formation of the Ca2+ /calmodulin complex
d. Activation of myosin light chain kinase
e. Inhibition of cAMP-dependent protein kinase
Is a β2 adrenergic receptor agonist, which increases cyclic AMP. So b is the correct answer.
Anti-inflammatory and immunosuppressive drugs could act on several pharmacodynamic targets eg membrane receptors, intracellular receptors and enzymes. Choose one drug acting on each target and
a. describe the specific mechanism of action 6p
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 and immunosuppressive drugs could act on several pharmacodynamic targets eg membrane receptors, intracellular receptors and enzymes. Choose one drug acting on each target and
b. state a common Type A side effect for each drug (drug group), motivate 3p
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
Describe mechanism of action for drugs that affect ADP, thrombin and TXA2 on platelets
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 and TXA2 throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
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.
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? (6p)
Block the reuptake of dopamine and noradrenaline into the terminal by blocking dopamine transporter (DAT) and noradrenaline transporter (NAT), increasing levels of dopamine and noradrenaline in the synaptic cleft.
Inhibit CNS neuronal reuptake of serotonin.
You want to design a new drug that you will administer peripherally, for example intravenously, but that will have its effects in the central nervous system. What are the obstacles you need to consider and what properties of your drug can you modify to better circumvent this?
lood-Brain Barrier (BBB): The BBB is a selective barrier that prevents many drugs from entering the CNS. To overcome this, one can design a drug that can cross the BBB or use strategies that temporarily disrupt the BBB such as:
Lipophilicity: The BBB is composed of tightly packed endothelial cells, and lipid-soluble molecules can pass through the BBB more easily. Therefore, drugs that are lipophilic or have a high octanol-water partition coefficient (log P) are more likely to cross the BBB.
Molecular size: The BBB has restricted permeability to molecules larger than 500 Da. Therefore, drugs that have a low molecular weight and are smaller in size are more likely to cross the BBB.
Active transport: The BBB has transport mechanisms, such as carrier-mediated transport and receptor-mediated transcytosis, that allow specific molecules to cross the BBB. Designing drugs that can utilize these transport mechanisms can increase the drug’s ability to cross the BBB.
Chemical modification: Chemical modifications such as conjugation to lipophilic moieties, prodrug design, or PEGylation can increase a drug’s lipophilicity, solubility, and stability, thereby improving its ability to cross the BBB.
Drug stability: Drugs administered peripherally need to be stable enough to reach the CNS. They should also be able to resist degradation by enzymes or other molecules in the blood. One way to address this is to design a prodrug that can be activated once it reaches the CNS.
Selectivity: The drug should be able to target specific receptors or molecules in the CNS without affecting other areas of the body. This can be done by making the drug with high specificty for the sepcific receptor or enzyme we want to target.
Half-life: The half-life of the drug in the bloodstream must be long enough to allow sufficient time for it to reach the CNS. This can be achieved by modifying the chemical structure of the drug or by using sustained-release formulations.
Nodal cells in the heart have an action potential that differ in shape from the action potential of ventricular cardiomyocytes. Describe with your own words what is unique with the nodal action potential. Also, describe mechanistically what underlies the ability of nodal cells to fire spontaneously and act as “pacemakers” of the heart.
Nodal cells do not have a stable resting membrane potential but instead exhibit a slow depolarization due to the influx of sodium (Na+) and calcium (Ca2+) ions through specialized ion channels called funny channels (If). This phase gives the nodal cells their automaticity, meaning they can generate an action potential spontaneously without external stimulation.
Once the membrane potential reaches a threshold level, voltage-gated calcium channels (Ca2+) open, leading to a rapid depolarization of the cell membrane. This phase is responsible for the initiation of the action potential.
After reaching its peak, the membrane potential repolarizes slowly due to the opening of voltage-gated potassium (K+) channels and closing of the voltage-gated calcium channels. This phase prepares the cell for the next action potential.
Mechanistically, the unique ability of nodal cells to fire spontaneously and act as pacemakers is due to the presence of specialized ion channels and transporters. The main contributors to the spontaneous depolarization are the funny channels (If) that allow a slow influx of sodium (Na+) and calcium (Ca2+) ions during phase 4. The Na+/K+ ATPase pump maintains the ion concentration gradient necessary for the function of the cardiac cells. The rate of funny channel activation determines the rate of depolarization, which determines the heart rate.
In addition to the funny channels, nodal cells also have a variety of other ion channels that contribute to the action potential, such as voltage-gated calcium channels (Ca2+) and potassium channels (K+). The interplay between these channels determines the shape and duration of the action potential.
Upon a routine medical examination of a patient, which included taking an electrocardiogram, a prolonged QT interval was observed. You suspect that the prolonged QT interval is an adverse effect of one of the medical drugs the patient is taking. Which cardiac ion channel may the drug be acting on? Motivate your choice by explaining the role of this ion channel in the heart.
The drug in question may be acting on the Kv channels, as these channels are responsible for the repolarization of the ventricles during the QT interval. When a drug blocks the Kv11.1 channel, it impairs the repolarization of the ventricles and prolongs the QT interval.
