PHARMA YR2 Flashcards
What is addiction?
Addiction is a chronic, relapsing disorder characterized by craving, compulsive drug use. It can be characterized as a brain disease. 20/40% of people who experiment with drugs develop an addiction.
What circuits can a drug addiction affect?
- Reward: dopamine transmission is increased bc of the drug.
- Motivation
- Memory/learning
- Inhibitory control
What are some pathways in which dopamine is involved?
Mesolimbic pathway: associated with pleasure, reward and goal directed behavior.
Mesocortical pathway: associated with motivational and emotional responses.
Nigrostriatal pathway: involved in coordination of movement.
Tuberoinfundibular pathway: regulated secretion of prolactin by the pituitary gland.
What are the steps that lead to drug addiction?
Drug use: activating the reward system
Tolerance: increased doses needed to provide same effect
Dependence: withdrawal symptoms if i stop usage
Addiction: lost control of taking habits
How is alcohol metabolized?
It is metabolized mainly in the liver where it is oxidized by an enzyme called Alcohol Dehydrogenase to Acetaldehyde. It is then transported to the mitochondria where it is oxidized by Aldehyde Dehydrogenase into Acetic acid. Acetic acid is released in the circulation and it is eliminated though the kidneys.
What are some protein receptors alcohol binds with and what are the consequences?
GABA A receptors: the activation causes hyper polarization which in turn causes chloride ions to enter the cell. This is linked to sedative effects.
Glutamate Receptors: reduce excitation and is linked to memory deficit.
What are some effects of chronic intoxication of alcohol?
GI Tract: gastritis, damage to mucosa, problems with absorption.
Liver: oxidative stress, cellular necrosis, damage to hepatocytes, inflammation, liver cirrhosis.
Neurological: pellagra, tremors, seizures, Warnick’s encephalopathy.
Cardiovascular: cardiomyopathies, hypertension, chronic heart failure and stroke.
Hormonal: impotence, gynecomastia and infertility.
Fetus: cause birth defects like Fetal Alcohol Syndrome and others.
What are the four steps of alcohol’s pharmacokinetics?
- Absorption of alcohol: 10/20% absorbed in the stomach the rest in the intestine. Affecting absorption are factors like empty stomach and speed of consumption.
- Distribution of alcohol.
- Metabolism of alcohol.
- Elimination of alcohol: eliminated through, 98% urine, 2% sweat and breath.
What are some drugs to treat alcohol dependance?
Disulfiram, the first drug ever developed, Naltrexone, Acamprosate and Naltrexone Depot.
How does the drug Disulfiram work?
It is a drug prescribed to be taken before alcohol consumption which cause the patient to have adverse effects like headache and vomit. Now it is not used as patients simply stopped taking the drug instead of stop drinking. It worked by inhibiting Aldehyde Dehydrogenase which cause an accumulation fo acetaldehyde.
How does the drug Naltrexone work?
It is a competitive antagonist of opioid receptors and also reduces alcohol induced dopamine release. It was more efficient when coupled with psychological support. The adverse effects are nausea, diarrhea, fatigue and headache.
How does the drug Acamprosate work?
It is an NDMA antagonist, restores glutaminergic control and reduces alcohol self administration and reduces emotional response to object or situation that recall drinking. It still has adverse effects but less than naltrexone, which include diarrhea, irritability and fatigue.
How does the drug Topiramate work?
It is an allosteric modulator of GABA, Ca2+ channel inhibitor and Na+ channel modulator, therefore it restores normal excitability. It reduces dopamine release and self administration. It has one of the highest efficacy’s between these drugs. There are still some adverse effects like: somnolence, depression, anorexia.
How does the drug Gamma-Hydroxybutyrate work?
GHB is a GABA agonist and a “substitute” of alcohol. It is distributed illegally and used as a strength enhancer as people claim it helps metabolize fat and build muscle. There are reports of it being used as a date rape drug. It is only used sometimes in early treatments and has abuse potential, bradycardia, nausea and vomit as adverse effects.
What are the fundamental concepts to keep in mind about drugs and their administration?
Drug: it consists of the Active Pharmaceutical Ingredient.
Medicine: drug + excipients which are molecule that make the distribution of the drug in the body easier.
Dosage: appropriate API regiment plus timing to achieve the desired affect.
Pharmacological effect: effect of the drug on bodily functions.
Therapeutic effect: the positive effect you get depending on the dosage prescribed.
What are the different types of administration of a drug?
Enteral: through GI tract so oral, sublingual or rectal.
Parenteral: IV, Intrathecal, subcutaneous etc.
Topical: on the skin, eye etc.
What are the two fundamental parameters for drugs excretion?
Half life: time required for the plasma concentration to be reduced by 50%.
Clearance: rate at which the drug is removed form the plasma divided by the concentration of the same drug in plasma.
What are the four phases of clinal research of a drug?
Phase I: limited number of paid volunteers to test safety
Phase II: small number of patients to find optimal dosage of the drug.
Phase III: larger number of patients to see the efficacy of the drug, submission of data to FDA for example in USA.
Phase IV: Pharmacovigilance
What are Induced Pluripotent Stem Cells used for in drug research?
We start from a human sample (like fibroblasts) and we reprogram them into our cell of
interest. The advantage compared to animal models is that the reprogrammed cell will contain the human genome. They can be useful to assess a drug efficacy/toxicity or for cell replacement therapy.
How are Organoid realizations used in drug research?
They’re a simplified 3D version of an organ, they can derive from surgical specimens or from biopsy tissue. They have a lot of applications (drug modelling is among them).The advantage is that cells can interact among themselves in the matrix (collagen mostly) and even with other cell populations. It’s a miniature structure of the organ you’re dealing with.
What is phenotypic screening?
It consists in compounds being screened in cellular or animal disease models, in order to identify which is the compound that causes a desirable change in the phenotype.
What is the purpose of OMICS, cell tissue expression profile?
The function is to identify the target, in order to possibly create a specific drug for them. The OMICS are genomics, transcriptomics, proteomics and metabolomics.
What are Metabolomics? What are the different types?
Metabolomics studies metabolites that are modified inside the cell or tissue upon a pathological condition. Targeted Metabolomics are a process through which we go looking specifically for a metabolite, most of the time by using a radioactive compound. Instead, untargeted metabolomics are a broad analysis of how a pathologic condition is changing the profile of all the metabolites of the cell, tissue or organism. So, it is the simultaneous measurement of many metabolites, and it is very complex.
What is druggability?
Druggability is the likelihood of being able to modulate a target with a small-molecule drug. If there are drugs that can modulate the function of that target, that target is druggable.
How can we asses druggability and what are the processes to keep in mind?
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.
What is target validation?
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.
What does silencing a target of interest mean?
Blockage or reduction of the protein function —> to mRNA —> no protein —> altered phenotype —> to see the effects on the onset of disease.
What are the different means of silencing a gene?
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.
What are the two different types of gene knockdowns in mice?
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.
What are some endpoints used to design a drug?
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.
What are some types of bio markers and what are some examples?
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.
How can bio markers be classified?
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.
Why use a surrogate endpoint instead of a clinical endpoint?
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.
What are the four parameters considered when selecting a drug?
Therapeutic indication, pharmacokinetics and drug metabolism, toxicology and formulation.
What are single blind and double blind studies?
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.
What are some of the reasons why only 1 out of 3 drugs makes it through phase 1?
Failure due to efficacy of the product, failure due to commercial considerations such as companies not willing to invest.
What can you do if clinical trials fail?
Spread financial risk, re do a phenotypic screening, drug repurposing.
What approaches and changes can be used for drug repurposing?
Changing the dosing routes, changing the dosage regiments, targeting a different patient population and matching mechanism of action to disease.
Nicotine abuse:?
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.
What are some drugs used to treat nicotine abuse?
Varenicline: partial agonist of nicotinic receptors
Bupropion: antagonist of nicotine
Rimonabant: antagonist of CB1 receptor of cannabinoids
What is the mechanism of action of cocaine?
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.
