Med Chem Flashcards
Tell me about Nolvadex
What is the mechanism of action, dosage, and indications?
What are common side effects?
What is the PK profile (ADME)?
What are the contraindications?
What are the drug interactions?
10mg and 20mg oral solid dose tablet form.
20mg daily dose used to treat ER+ breast cancer and infertility.
Tamoxifen citrate works as a Selective Oestrogen Receptor modulator (SERM). The action differs between tissues- Breast tissue it acts as an antagonist where ER+ genes are inhibited. Endometrial tissue is an agonist.
Side effects- Endometrial cancer, Thromboembolism, Liver toxicity.
PK profile- Oral absorption in prodrug, metabolism CYP450 to 100% BA, Albumin bound. Plasma T1/2 5-7 days. Excreted in bile and Faeces.
Contra-indications: Pregnancy, hypersensitivity, DVT.
Drug interactions : Centred around CYP450 metabolism. Many drugs can impact the metabolism of pre-drug to active metabolite (SSRIs)
Tell me about Zoladex
What is the mechanism of action, dosage, and indications?
What are common side effects?
What is the PK profile (ADME)?
What are the contraindications?
What are the drug interactions?
10.8mg, 3.6mg depot formulation- subcutaneous injection.
1 monthly or 3 monthly dependent on dose.
Used to treat Metastatic prostate cancer, ER+ breast cancer and endometrial fibroids and used also in reproductive assistance.
Contains goserelin acetate, gonadotrophin releasing hormone agonist. Acts on pituitary gland to increase Luteinising hormone which increases androgens for 2-3 week period. Natural downregulation then occurs and stops LH activity- hormones then go to castration levels to starve tumour.
S/E- Initial Androgen ‘flare’- co-prescribe anti androgen to combat effect (Casodex). Headaches, hot flushes, bone pain, ED and Gynecomastia.
PK profile- Absorbed through Injection site dissolution of depot- 100% BA, T1/2 of 2-4 hours, Peak plasma within 2 hours. Excreted via Urine.
Contra-indications. Pregnancy and breastfeeding, hypersensitivity.
Drug interactions- QT prolonging drugs- Amiodarone.
Tell me about Zomig
What is the mechanism of action, dosage, and indications?
What are common side effects?
What is the PK profile (ADME)?
What are the contraindications?
What are the drug interactions?
5mg and 2.5mg doses for Nasal Spray.
Indicated for Acute Migraine attacks
Selective 5-HT (Serotonin) Agonist, causes vasoconstriction of intracranial blood vessels
Side effects- Increased BP and sedation
PK profile; Crosses BB for rapid onset. 40% BA, Metabolised via CYP450, T 1/2 3 hours. Renal elimination.
Contra-indicated in CV disease (BP increases)
Interactions: SSRIs- toxicity risk.
Top 5 drugs for AZ in 2023 were Tagrisso, Vaxzevira, Forxiga, Symbicort and Imfinzi- How do they work and what are they used to treat?
Tagrisso- Lung Cancer- Epidermal growth factor receptor
Vaxzevira- Covid 19, Local neutralising antibody
Forxiga- Diabetes, Sodium/Glucose transporter inhibitor
Symbicort- Asthma- Budesonide/fomoterol Steroid and LABA.
Imfinzi- Lung/Bladder cancer- PD-L1 binder- unmasks cancer cells.
What can you tell me about the autonomic nervous system?
Sympathetic NS- Fight/Flight
Parasympathetic- Rest/recover
Both systems contain synapses with neurotransmitters which can be chemically exploited. Ion channels also offer secondary messenger pathways as exploitation sites.
What are some examples of medicines that can affect blood pressure and heart rate?
Beta adrenoceptor antagonists (Propranolol, bisoprolol)
ACE inhibitors- Act on Renin angiotensin and angiotensinogen pathway as inhibitors of angiotensin converting enzyme preventing vasoconstriction (ramipril, enalapril)
Angiotensin 2 receptor blockers ( Candesartan)- prevent vasoconstriction.
Diuretics- Reduce circulating volume (Furosemide, Bendroflumethiazide)
Calcium channel blockers- block voltage gates in muscle tissue (heart)- Amlodipine.
What drugs can impact inflammation? How do they work?
Inflammation can be cell mediated or antibody mediated. Adaptive or immune. Inappropriate response leads to inflammation.
Cyclo-oxygenase pathway contains enzymes - COX1 and COX 2 which enable prostaglandin secretion via arachadonic acid. NSAIDs will inhibit COX and prevent cycle.
Glucocorticoids will inhibit Phospholipase 2 in the arachidonic acid /cox cycle and supress inflammation
DMARDS- disease modifying anti inflammatory drugs will act to suppress the immune response.
What are the impacts of excess or limited dopamine activity in the CNS? What pathways are involved and what drugs are available to treat this?
Dopamine acts on 2 pathways- Mesolimbic (cognition) and Nigrostriatal (Motor) pathways.
Increase dopamine in mesolimbic pathway leads to schizophrenia. Treated by antipsychotics (Seroquel, Lithium)
Decrease of dopamine (loss of receptors) in nigrostriatal pathway leads to Parkinsons. No cure, but increasing available dopamine (levodopa and carbidopa) will reduce symptoms.
What classes of drugs are available to treat anxiety and depression?
Anxiety- Benzodiazapines- secondary messenger GABA pathway to reduce 5-HT.
Depression;
Monoamine oxidase inhibitors: Prevent breakdown of Serotonin and NE. Tyramine effect if eat cheese with them (flushing)
Tricyclic antidepressants: Block Monoamine re-uptake. Amitriptyline (dry mouth S/E)
Selective Serotonin Reuptake Inhibitors: Prevent Serotonin reuptake, better S/E profile. Fluoxetine/ Citalopram.
What are the mainstay of cancer therapies?
Cytotoxic
Hormone
Growth factors- Genetic links
MABs
Antibody/Drug conjugates
Gene profiling for patient to determine most effective treatment.
What causes peptic ulcers? How do you treat them?
H-Pylori infection
H2 antagonist (Zantac)
PPIs- Omeprazole
Antibiotic treatments
What types of diabetes are there? What medications are used for each type?
T1, T2
Insulin for T1
T2:
Biguanides- Metformin (Reduce glucose absorption)
Sulphonylureas- Gliclazide (Stimulate insulin release)
Incretins - Exanetide (Increase insulin responsiveness)
DPP4 inhibitors - Saxagliptin (Prevents Glucagon like protein inhibition)
SGLT-2 inhibitor - Forxiga (Prevents glucose re-entry to bloodstream from urine)
What can impact Absorption? Distribution? Metabolism? Excretion?
Absorption;
Bioavailability of active
Formulation
Physicochemistry of drug
Absorption site
Concentration gradient
Dose/ Solubility
Weak acids will be associated in acidic conditions and therefore non-polar and will diffuse across mucosal layer.
Weak bases in acid will disassociate, become polar and soluble but not pass through barrier.
Stomach = Acid
Small intestine = Alkaline.
Distribution;
Compartment models
Plasma binding, Albumin binding
Metabolism;
Liver main site- CYP450
Natural process- 2 phases
Increase solubility and decrease activity
Excretion;
First order kinetics- Kidney
Billary excretion for high MW drugs.
What is bioequivalence?
When would you perform a BE study? What justification would you need not to perform a BE Study?
Where is the guidance for this?
No difference in rate/extent for API to be available at site of action when given at same dose under same conditions.
Consider a BE study for;
1. New drug substance
2. New product using existing active substance
3. MR preparations
Justification for not performing BE;
Need to demonstrate statistically no difference between new and reference material in PK parameters. IV/IV comparison study. Manufacturing changes may be invitro assessed.
In vivo study- human cross over trial.
EMA guidance available.
What is the difference between cleaning validation and cleaning verification?
Talk me through a cleaning validation protocol.
Cleaning validation- Cleaning operation can routinely meet pre-defined standards. Consistency of cleaning has been demonstrated
Cleaning verification- Consistency has not been demonstrated but can meet pre-defined standards on a single occasion.
Cleaning validation protocol;
Understand cleaning solution/method to be used.
Define worst case solubility and toxicity of products (PDE).
Determine visual standards of cleanliness
Consider materials of construction, length of pathway- Rinse samples
Hard to reach areas- trapping points, Swab samples
Determine rinse/ swab recovery efficiency (recovered/total spiked)- 95%Ci
Define maximum carry over limits and use as acceptance criteria for analytical method validation (LOD, LOQ, Specificity)
Determine Maximum clean and dirty hold times
Establish report with recommendations and SOP for cleaning if all acceptance criteria met.
