PHARMA YR2 Flashcards

Question

How can we asses druggability and what are the processes to keep in mind?

Answer 1

Sequence based: Predictions made based on the characteristic sequence of the target. Structure-base: Predictions made based on the 3D structure of the molecule or high-quality homologous models. Ligand based: Predictions made based on the likelihood of interaction between the natural ligand of the compound and the target molecule. Precedent based: Predictions based on proteins that already have been established and compounds that are undergoing clinical trials.

Answer 2

Target validation consists in a group of experimental activities to verify the therapeutic value of a biological target. For that we need to demonstrate that the target expression and anatomical distribution are consistent with the disease. The define the pharmacological profile needed to achieve this effect.

Answer 3

Blockage or reduction of the protein function —> to mRNA —> no protein —> altered phenotype —> to see the effects on the onset of disease.

Answer 4

Insert point mutations, distraction of transcription and deletion of exons. Ex. ShRNA Knockdown, creates a loop in the RNA that interferes with the translation of a target. CRISPR Cas 9 technology is a sort of precise surgery approach that tackles only a few bases of interest.

Answer 5

Tissue Specific: The genome of interest or the target protein, is not only expressed in the tissue where it is normally is, but it is also expressed and maintained in other regions. Time Specific: If we have a protein that is expressed only in a specific window of the lifetime of the animal. There are means by which we can inactivate them expression of that protein in that window of time. Inducible Knockdown: We can switch on to off the target protein depending on the experimental settings.

Answer 6

Biochemical/molecular bio markers: The first thing to do is to analyze its protein and mRNA expression. Histopathological analysis: we perform a histology, immunohistopathology and moprhometry analysis. Physiological analysis: Hemodynamics parameters, ECG, EEG Behavioral analysis: we must see hoe the modifications we induced modify the behavior of the subject.

Answer 7

Pharmacodynamic/Response biomarker: identify pharmacological response to treatment. Predictive biomarkers: identify which patients are likely to respond to a particular treatment. Safety biomarkers: monitor whether there is an adverse effect of the treatment. Susceptibility/risk/prognostic biomarkers: identify patients at risk of disease occurrence or progression in absence of treatment. Diagnostic biomarkers: determine the presence of the disease. Screening biomarkers: identify patients at risk of developing a disease. Monitoring biomarkers: already present at the begging of treatment and tell how things are going.

Answer 8

Type 0: correlation between levels and symptoms. Type 1: used to monitor target engagement. Type 2: correlates with core pathology of the disease. Considered surrogate endpoints.

Answer 9

Bc they are faster and easier to study, also bc they may be unethical. Ex. Surrogate endpoint for cancer can be tumor volume while the true endpoint might be death.

Answer 10

Therapeutic indication, pharmacokinetics and drug metabolism, toxicology and formulation.

Answer 11

Single blind: are clinical trials in which only the researcher knows the treatment. Double blind: are clinical trials in which neither the researchers nor the patient know the treatment.

Answer 12

Failure due to efficacy of the product, failure due to commercial considerations such as companies not willing to invest.

Answer 13

Spread financial risk, re do a phenotypic screening, drug repurposing.

Answer 14

Changing the dosing routes, changing the dosage regiments, targeting a different patient population and matching mechanism of action to disease.

Answer 15

Most abused psycho stimulant in the world. It is responsible for tobacco dependence increasing the dopamine in the nucleus accumbens. It increases alertness, relaxes muscles, nausea, tachycardia and hypertension.

Answer 16

Varenicline: partial agonist of nicotinic receptors Bupropion: antagonist of nicotine Rimonabant: antagonist of CB1 receptor of cannabinoids

Answer 17

Cocaine acts by blocking the reuptake of dopamine in the synaptic cleft. Furthermore, noradrenaline, serotonin and other monoamines reuptake is blocked and affected. There is a boost of the levels of dopamine.

Answer 18

MDPV is a derivative of MDMA. It was developed in the 60s as a drug for chronic fatigue and appetite suppression. The most common route of administration is intranasal. The effects are similar to methamphetamines, MDMA or cocaine. Since these compounds share the mode of action, it is a norepinephrine and dopamine reuptake inhibitor.

Answer 19

Mephedrone is ingested orally, inhaled or rectally. It is also a norepinephrine- dopamine reuptake inhibitor. Unlike MDPV, mephedrone has a much shorter half-life of about 45-60 minutes.

Answer 20

PCP, phencyclidine, was developed as a general anesthetic but because of the significant side effects (hallucinations, delirium, mania) it was discontinued as an anesthetic. Now ketamine has taken its place with a similar mode of action and less side effects. PCP is highly addictive. PCP has a different mechanism of action compared to the aforementioned drugs; it doesn’t really act on serotonin, dopamine, noradrenaline or other monoamines, but rather on glutamate ion-gated NMDA receptors.

Answer 21

Cannabinoids are terpenoids. They are highly lipophilic, as it can be inferred from their structure, so they are highly soluble in oil and only poorly soluble in water. In the plant, they are slightly acidic but after drying and heating they become neutral. The main psychoactive compound of cannabis is Δ9-tetrahydrocannabinol.

Answer 22

They interact with CB1 and CB2 receptors. CB1 are found in the CNS and CB2 are mostly found peripherally. CB1 is involved in learning, memory, cognition and motor control. CB2 are less studied but they are involved in inflammation, immune response, cell apoptosis and neural disorders. They bind also to PPARs which are important in cell cycle and division.

Answer 23

We produce endogenous cannabinoids that bind to CB1 and CB2 receptors. These endocannabinoids are derived from arachidonic acid, hence from membrane lipids. They are precursors in the membranes. There are two families of endocannabinoids: amides and esters. Endocannabinoids are "made on demand", meaning that they are produced when they are needed. The two main endogenous cannabinoids are anandamide and 2-AG. Anandamide is much more selective for CB1, while 2-AG binds to both CB1 and CB2.

Answer 24

Anandamide is synthesized by the enzyme PLD (NAPE-phospholipase D). Hence, we first have PE (phosphatidylethanolamine), which is then converted into NAPE (N-arachidonoyl phosphatidylethanolamine). This is then converted to anandamide. Finally, anandamide is converted to ethanolamine and arachidonic acid by FAAH (fatty acid amide hydrolase).

Answer 25

MAGL, monoacylglycerol lipase, breaks it down into glycerol and arachidonic acid.

Answer 26

Sativex is an oromucosal spray with a THC to CBD ratio of 1:1. It is used for MS spasticity as a muscle relaxant in order to relieve pain. It binds to the CB1 receptor present at glutamatergic synapses. This reduces the excitatory activity of glutamate (there is a boost of glutamate in these spasms).

Answer 27

Nabilone is an analogue of THC. It is administered in form of capsules. It is used for treating nausea and vomiting induced by chemotherapy.

Answer 28

Marinol is a synthetic THC. It is a highly potent agonist for CB1 and CB2. It is approved in the US and in Canada for appetite stimulation in AIDS patients and as an antiemetic in patients undergoing chemotherapy.

Answer 29

Cesamet contains nabilone, which is a THC analog. It is produced in form of capsules. It is an even more potent CB1 and CB2 agonist. It is approved in the US and in Canada as an antiemetic in patients undergoing chemotherapy.

Answer 30

The effects of THC are analgesic, anti-spasmodic, anti-tremor, anti- inflammatory, appetite-stimulating and antiemetic. These effects are mediated through activation of CB1 and CB2 receptors.CBD has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD counters some of the side effects of THC. Furthermore, it delays and reduces the intensity of intoxication by THC. We hence use a 1:1 ratio of THC to CBD because THC is more important for some of the effects but in order to counteract side effects, we need CBD.

Answer 31

CBD has little activity at the CB1 receptor but greater activity on the CB2 receptor. It targets are TRPV1 receptors and 5-HT1A receptors. It also inhibits the uptake and breakdown of anandamide.

Answer 32

Epidiolex is a purified cannabidiol from cannabis. In the US, it is authorized for orphan pathologies and under testing as an anticonvulsant for pediatric epilepsy. The Dravet and Lennox- Gastaut syndromes are orphan pathologies, which are very debilitating for children. There is no approved drug yet. Now, Epidiolex is tested for the treatment of these syndromes and it seems to work very well because it has an anti-seizure effect.

Answer 33

Because they produce their pharmacological effects by interacting with multiple molecular targets, and their pharmacological fingerprint can better match that of multi-factorial pathologies (e.g., depression, MS) than can be obtained with THC since it is much more likely that a drug with a multi-factorial activity is effective in such a disease as compared to a drug that only acts on one receptor.

Answer 34

Cancer related psychiatric, existential distress, addiction from tobacco, alcohol, Cocaine and opioids, major depression and anxiety disorders.

Answer 35

Generally, psychedelics are considered safe from physiological perspective. They are not associated with organ damage (unlike cocaine, amphetamine etc.) and do not display carcinogenicity or teratogenicity. During acute psychological distress or also called bad trip the patient experiences a dreamlike state and may feel depressed, anxiety, panic, agitation, fear and delirium.

Answer 36

Past LSD research shows that chances of psychosis lasting >2 days are relatively low: in normal volunteers 0.8 per 1000, in patients 1.8 per 1000. Despite these low numbers, we must keep in mind that administration of psychedelic will make some patients experience psychosis. In patients with psychiatric disorder suicide attempt was 1.2 out of 1000.

Answer 37

Psychedelics do not lead to addiction because they do not boost dopamine in reward pathways, thus they do not lead to any withdrawal symptoms even if the patient uses psychedelics for a long period of time.

Answer 38

Most importantly psilocybin seems to enhance brain’s capacity for change, also known as neuroplasticity. In many disorders brain appears to work in an abnormal way in comparison to a healthy individual. Hence these hyperactive/hypoactive parts of the brain could be targeted with psychedelics for treatment. • Psilocybin’s indole ring containing a nitrogen resembles the chemical structure of serotonin. That’s why it binds to 5HT-2A (serotonin) receptors and produces mind-altering effects.

Answer 39

Default mode network is a large-scale brain network responsible for controlling emotion, mood, and appetite. It’s composed of several regions. This region is controlled by serotonergic innervation. This network is active when the person is not focused on the outside world, when the brain is at wakeful rest (daydreaming/mind-wondering).

Answer 40

Cancer Psilocybin is used to treat psychological distress that may be present in cancer patients, which have a higher likelihood of developing depression or anxiety due to their medical condition. Depression/anxiety, this study uses Hamilton rating scale in which patients are asked questions and their answers have scores or 0, 1, or 2. For example, Hamilton score of 20 indicates depression of medium severity. The graph shows that after one high dose of psilocybin patients significantly reduced their Hamilton score (ex. a drop from 23 to 6 in HAM-D), which indicates a relief from depression symptoms. And even after the one low dose there is a significant improvement.

Answer 41

Participants had 3 psilocybin sessions over the course of 8 weeks. The graph shows that even after 3 years there is still a high percentage of participants (around 60%) that remained abstinent from nicotine after psilocybin administration. A similar trend is shown in the alcohol dependence pilot study which tested alcohol-dependent participants. All had to undergo motivational enhancement therapy and 2 psilocybin sessions. Results show that patients treated with psilocybin has significant reduction in number of heavy drinking days and effect was well-maintained over time.

Answer 42

Esketamine is S-enantiomer of the racemic ketamine. It is a non-selective, non-competitive antagonist of the NMDA receptor, an ionotropic glutamate receptor. Esketamine is levorotatory, but it’s administered as ketamine intravenously to reduce the depression symptoms. Also, it can be administered via nasal spray. It’s a potent drug for major depression as it seems to reduce suicidal behavior in the treatment-resistant depressed patients. It’s important to remember that esketamine can interact with other drugs

Answer 43

Beta 2 adrenergic receptor is a celle membrane receptor that binds adrenaline. Ultimately it increases heart rate, pupil dilation etc.

Answer 44

Tyr kinase inhibitor is a drug that inhibits tyrosine kinases which are responsible for the activation of many signal transduction pathways.

Answer 45

Agonist: is a chemical that activates a receptor to produce a biological response. Ex. Heroin Antagonist: is a chemical that binds to a receptor and causing a halt or blockage of something. Ex naltrexone which displaced opioids. Partial agonist: is a chemical that binds and activates a receptor but doesn’t have the full efficacy. Ex THC in both CB1 and CB2 receptor

Answer 46

Non Steroidal Anti Inflammatory Drugs are medicines that are used to relive pain, reduce inflammation and bring down a fever. Some ore over the counter such as Ibuprofen. Might have side effects such as indigestion, headache and drowsiness. The mechanism of action is the inhibition of the enzyme Cyclooxygenase, COX, as the inhibition stops it from converting archidonic acid into prostaglandins and prostacylines.

Answer 47

Aspirin is effective in the treatment and prevention of a variety of medical conditions. It has ‘analgesic’, ‘anti-pyretic’ and anti-inflammatory properties and so can be used in adults to treat pain, fever and inflammation. Aspirin in low doses (2-5 milligrams/kg) prevents the aggregation of platelets thereby preventing the formation of blood clots. It does this by inhibiting an enzyme called cyclo-oxygenase thereby preventing the formation of a substance called thromboxane which acts as a scaffolding for platelets to aggregate and form a blood clot.

Answer 48

Since aspirin inhibits COX therefore the production of prostaglandins and one of them specifically is PEG2. Prostaglandins in a pregnant woman is used for labor induction or termination of pregnancy.

Answer 49

DRA are a type of drug that block dopamine receptors. Most antipsychotics are DRA and used to treat schizophrenia and bipolar disorder. Typical aka first generation antipsychotics can cause extra pyramidal side effects such as; spasm, stiff muscles, involuntary facial movements. Atypical aka second generation antipsychotics are not only DRA but act of serotonin receptor 5HT2A. They cause less extra pyramidal side effects but have more metabolic side effects such as weight gain, high cholesterol, BP and blood sugar.

Answer 50

The dose of the drug divided the AUC which is calculated using the patient mass.

Answer 51

Urine pH is a great influence on whether a drug is excreted quickly or slowly and in some clinical situations is manipulated to control the excretion of certain drugs from the body. In alkaline urine, acidic drugs are more readily ionised. In acidic urine, alkaline drugs are more readily ionised. Ionised substances (also refered to as polar) are more soluble in water so dissolve in the body fluids more readily for excretion.

Answer 52

They all lead to psychomotor stimulation, euphoria, tachycardia, and increase confidence, energy and sociability. Cocaine works by blocking the reuptake of dopamine in the synaptic cleft. Meth and amphetamines effect the CNS by releasing dopamine, norepinephrine and serotonin.

Answer 53

Opioids like morphine, fentanyl or heroin tend to give miosis so a constricted pupil less that 2mm. Cocaine, ecstasy and hallucinogenic can cause mydriasis or in other words dilated pupils over 7mm.

Answer 54

They are used to treat anxiety and sleep disorders. Some known names are Xanax and Valium. Benzodiazepines act on GABA receptors specifically GABA A. When they bind they have an allosteric effect on GABA binding allowing an influx of negative charged chloride ions causing hyperpolarization and decrease le likely hood of an action potential.

Answer 55

First pass effect: orally taken drugs pass first through the liver before reaching systemic circulation, and since the liver metabolizes the drugs a lower percentage that what originally was taken is going to enter systemic circulation. Bioavailability is the percentage of the drug that reaches systemic circulation. For example IV route is 100% bioavailable.

Answer 56

Atropine: is used to treat low HR, before surgery for example. It is an anticholinergic, specifically anti Muscarinic. It inhibits effects of excessive vagal activation Scopolamine: It is used to treat motion sickness, postoperative nausea and vomiting. It is an anticholingergic

Answer 57

Lipophilicity since it needs to cross cell membrane and biological barriers. Ph difference with the drug in the stomach can readily ionize and make more soluble certain compounds. Surface area in the GI tract, Blood perfusion, presence of mucus.

Answer 58

Rectal administration can be useful when a patient is vomiting or has nausea but it can interrupt defecation and the patient may not accept this route.

Answer 59

It is the study of how a drug affects our body. Generally a drug will react with a protein aka a receptor. The Ligand that binds to the receptor and in essence turn the receptor on a evoking a conformational change and propagates a signal.

Answer 60

It is the amount of drug required to produce a particular effect, or the concentration required to produce 50% of maximal effect.

Answer 61

It is the maximum effect that can be achieved by a drug.

Answer 62

Ligand gated ion channels: the ligand binds to the receptor causing ions to flow across the membrane. G protein coupled receptors: 3 subunits know as the G protein. Alpha subunit has GDP attached and when the ligand binds GDP is displaced and GTP takes ita place. This causes the subunits to disassociate and interact or regulated a response. Enzyme linked receptors: mostly tyrosine kinase type which means that they display kinase activity and there is tyrosine involved. When the ligand binds it causes a conformational change bc the tyr regions get activated, ADP is displaced by ATP which phosphorylates the Tyr. Intracellular receptors: It is located entirely inside the cell.

Answer 63

Aka acetaminophen, has a central analgesic effect that is mediated through the activation of serotonergic pathways. It is a COX1, 2 and 3 inhibitor. COX 3 is specialty sensitive to paracetamol.

Answer 64

It is a muscarinic cholinergic agonist used on the eye to treat various types of glaucoma and to induce miosis.

Answer 65

Ex. Meclizine , cyclizine. They bind histamine receptors and inactive it. The first generation histamines had strong somnolence unlike the second generation which have a lower CNS penetration therefore less somnolence.

Answer 66

They are biological factors that act like local hormones. They modulate activity of smooth muscle, glands, nerves, platelets. Examples are eicosanoids, angiotensin, NO, histamine and serotonin.

Answer 67

It is a non selective beta adrenergic antagonist. It decrease HR.

Answer 68

They are a group a medicines that are used against migraines or headaches. They are agonists for serotonin 5HT1D receptors at blood vessels and nerve endings. Ex Naratriptan.

Answer 69

It is a compound or a chemical class that has a suitable pharmacological profile.

Answer 70

It is a compound or chemical class with a suitable profile both in vitro and in vivo.

Answer 71

Single compound with suitable pharmacological profile associated with proper develop ability features.

Answer 72

Small molecules in the range of 300-700 daltons bc they penetrate the cells.

Answer 73

HTS is the use of automated equipment to test rapidly thousands of samples for biological activity.

Answer 74

Focused: if we have already an idea of the target (of the hit). E.g., if we know that the hit is a GPCR, I might use a library that tests compounds already screened and designed for GPCR. Broad: if we have no idea. It samples everything we can think of in the chemical universe. This is much more expensive.

Answer 75

Computer algorithms developed to understand the proper structural requirement to maximize ligand target interaction.

Answer 76

Rigid docking: the internal geometry of both the receptors an the ligand is rigid and there are only 6 degrees of freedom. Flexible docking: flexible ligand binding into rigid target.

Answer 77

Sb: relies on the structure of the protein (that needs to be known). The basic assumption here is that there should be shape similarities between the molecules tested and the actual chemical compounds. Lb: no need for the structure of the molecule, but need the structure of the ligand. It used the information already known on active ligands on that target to device and design new molecules that could be much more effective.

Answer 78

Pros: fast, cheap. Cons: false positive rate, limited chemical space.

Answer 79

Generates a compound starting from a chemical fragment. This is a very powerful method to develop a potent small molecule starting from very big ones. The main advantage is to increase chemical diversity → we might get HITs that are suitable for different targets. Huge libraries are not needed, small portions are enough.