BMSC week 8: pharmacology and integration
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- What is an agonist?
- a ligand that binds to a receptor and alters the receptor state
- What is an antagonist?
- a drug that reduces the action of another drug
- How is the potency of a drug measured?
- it is the amount of the drug necessary to reach the ED50 (not very important)
- What is the efficacy of a drug?
- the efficacy refers to the response that a drug elicits
- What is desensitization?
- a spontaneous decline in the response to an agonist due to a change in receptor activation
- What is the difference between "fade" and "tachyphylaxis"?
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-fade refers to the decline in response to continued application of agonist
-tachyphylaxis refers to the decline in response to repeated applications of agonist - What is a full agonist?
- an agonist capable of producing the system maximal response in a tissue
- What is a partial agonist?
- an agonist that cannot elicit the maximum effect, compared to another agonist that acts through the same receptors.
- What are spare receptors?
- a system has spare receptors if an agonist does not need to occupy all the receptors to elicit the maximum response
- What is competitive antagonism?
- the binding of the agonist and antagonist is mutually exclusive
- What is noncompetitive antagonism?
- agonist and antagonist can be bound to the receptor simultaneously, but the antagonist prevents the action of the agonist
- What is the difference between pharmacokinetics and pharmacodynamics?
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pharmacokinetics: study of [drug/metabolite] in body fluids
pharmacodynamics: study of drug-target interactions - What factors determine drug response?
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-number of receptors
-receptor occupancy
-efficacy
-duration of drug exposure - How is the dissociation constant (Kd) measured?
- it is the [Dfree] present when 50% of the receptors are occupied
- What usually causes sensitization?
- prolonged exposure to antagonists (left shift in dose-response curve)
- What is one molecular explanation for partial agonists?
- the inactive drug-receptor conformation is more stable than the active conformation
- How can competitive and noncompetitive inhibition be distinguished on dose-response curves?
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in competitive inhibition, the maximum response can be achieved regardless of inhibitor concentration.
in noncompetitive inhibition, the possible response is dependent on inhibitor concentration - How is the therapeutic index calculated? What is it for?
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toxic dose for 50% population / effective dose for 50% population
-it measures safety → large TI = safe, small TI = not safe - What are some amino acid transmitters?
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-glutamate
-GABA
-glycine - What are some amine transmitters?
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-dopamine
-norepinephrine
-epinephrine
-serotonin
-histamine - What are some neuropeptides?
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-substance P
-vasopressin - What are the precursors of acetylcholine? What enzyme catalyzes this reaction and where?
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-acetyl-CoA and choline are precursors
-choline acetyltransferase catalyzes this reaction in the cytoplasm - What is the limiting factor in acetylcholine synthesis?
- availability of choline (provided by choline/Na+ cotransporter in presynaptic terminal)
- What terminates acetylcholine action?
- acetylcholinesterase in the synapse
- What is the precursor of norepinephrine, epinephrine, and dopamine?
- tyrosine
- What is the major regulatory step in the synthesis of biogenic amines? What enzyme catalyzes this step?
- hydroxylation of tyrosine by tyrosine hydroxylase to produce dihydroxyphenylalanine (DOPA)
- What is the immediate precursor of dopamine? What enzyme catalyzes its conversion into dopamine?
- DOPA; the enzyme is DOPA decarboxylase
- What is the immediate precursor of norepinephrine? What enzyme catalyzes its conversion into norepinephrine?
- dopamine; the enzyme is dopamine β-hydroxylase
- What is the immediate precursor of epinephrine? What enzyme catalyzes its conversion into epinephrine?
- norepinephrine; the enzyme is phenylethanol-amine N-methyl-transferase
- How is the action of biogenic amines terminated?
- reuptake by pumps in the presynaptic membrane
- What does monoamine oxidase (MAO) do? Where in the cell is it found?
- converts amine group into aldehyde in catecholamine metabolism; it is found in mitochondria
- What does catechol-O-methyltransferase do?
- converts a hydroxyl group into a methyl ether in catecholamine metabolism
- How does the amount of time per cell cycle differ in a cancer cell and a normal cell?
- it doesn't; cancer cells divide more often (more cell cycles) but each cell cycle takes the same amount of time as in a normal cell
- How many cancer cells must be present in order for the cancer to be clinically detected?
- 10^9
- At the time of host death from cancer, how many cancer cells are usually present?
- 10^12
- At what point in the cell cycle can the cell undergo death from differentiation?
- mitosis
- Which cells in a tumor are drug sensitive?
- clonogenic proliferating cells
- Which cells in a tumor are in G0?
- clonogenic nonproliferating cells
- Which cells in a tumor are "doomed" cells?
- nonclonogenic proliferating cells
- Which cells in a tumor are "end" cells?
- nonclonogenic nonproliferating cells
- What are some categories of cell cycle-specific agents? What is their general mechanism of action?
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-antimetabolites (interfere with synthesis)
-vinca alkaloids (destroy mitotic spindle)
-topoisomerase inhibitors (disrupt transcription and duplication) - What are some categories of cell cycle nonspecific agents? What is their general mechanism of action?
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-alkylating agents (covalently crosslink DNA)
-antibiotics (intercalation, DNA scission, block RNA production)
-platinum salts (inhibits DNA synthesis, DNA crosslinking) - What are the pathologic processes involved in rheumatoid arthritis?
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-inflammation
-synoviocyte proliferation → cartilage destruction
-angiogenesis
-matrix metalloproteinases → irreversibly degrade cartilage matrix
-chondrocytes → impaired cartilage synthesis - What is palliative treatment?
- treatment of symptoms rather than the cause
- What is the mechanism of action of gold salts?
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-block prostaglandin synthesis
-suppress mononuclear phagocytes
-inhibit lysosomal hydrolases - How do corticosteroids work?
- alter gene expression (downregulate expression of cytokines)
- How do antimalarials work?
- inhibit cyclooxygenase
- What DNA sequence is frequently methylated?
- 5'-CG-3' (C is methylated at position 5 of the pyrimidine ring)
- How does methylation regulate transcription?
- heavy methylation of CG-rich islands → low transcription of downstream genes
- How can methylation lead to mutations?
- methylated C can spontaneously deaminate to yield T
- What is Lepore hemoglobin?
- caused by fusion of δ and β genes and driven by the δ promoter (weaker)
- How are Alu repeats involved in familial hypercholesterolemia?
- aberrant recombination between Alu repeats causes a deletion
- What are transgenic mice? How are they generated?
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-mice which have had mutated/altered genes introduced into their genome
-foreign DNA is injected into fertilized mouse egg before male and female pronuclei fuse
-injected eggs are transferred to a foster mother
-offspring are selectively bred - What is gene knockout? How is it accomplished? What are the
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-a technique for selectively inactivating a gene by replacing it with a mutant allele
-mutant alleles are introduced into embryonic stem cell by homologous recombination
-embryonic stem cells with the mutation are introduced into a mouse embryo
-offspring are selectively bred - How do G16 and R16 variants of the β2 adrenergic receptor affect its interactions with agonist?
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-R16/R16 variant has full response to albuterol
-G16/R16 variant has 75% response
-G16/G16 variant has 50% response - How does N-acetyl transferase affect isoniazid metabolism? What happens to slow acetylators?
- Acetylation of isoniazid inactivates it. Slow acetylators have a greater risk for adverse side effects.
- What drugs (categories) are metabolized by CYP2D6?
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-beta-blockers
-tricyclic antidepressants
-anti-arrhythmic agents
-anti-psychotic agents and selective serotonin-reuptake inhibitors
-opioids - What happens to patients with serum cholinesterase deficiency?
- potentially fatal adverse reaction to the muscle relaxant succinyl choline → prolonged apnea requiring artificial respiratory support
- What is the most common enzyme deficiency in humans? Why? What is the mode of inheritance for this deficiency?
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-glucose-6-phosphate dehydrogenase deficiency
-confers resistance to malaria
-X-linked recessive - What happens to people with deficiency in glucose-6-phosphate dehydrogenase? Why?
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-decreased ability to dispose of oxidants because glutathione peroxidase activity is low (needs glutathione)
-things that increase oxidants are primaquine, xenobiotics, fava beans
-hemolysis - What does the ryanodine receptor (RYR1) do? What happens if it is mutated?
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-it is a calcium ion release channel in sarcoplasmic reticulum
-if it is mutated (dominant), inhalation anesthetics cause malignant hyperthermia → death (preventable with dantrolene sodium) - How is a retrovirus made?
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-start with RNA virus (usually Moloney murine leukemia virus)
-replace the genes that code for capsid, replication, and envelope with desired gene
- - What are the problems with using retrovirus gene therapy?
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-only works in dividing cells (useless in neurons for example)
-only ex-vivo currently possible
-gradual turn-off of gene over months
-transgene can interrupt another gene, or viral LTR can overexpress another gene - What is an adeno-associated virus?
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-small defective DNA virus
-needs adenovirus or herpes simplex virus
-in absence of helper virus, integrates into specific region of chromosome 19
-recombinant AAV rarely integrates - What are the problems with using recombinant AAV therapy?
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-small cloning capacity
-difficult to obtain high titer stocks
-immune response to viral capsid antigens - What is the problem with delivering DNA without a viral vector?
- it is inefficient
- Why was the treatment of SCID using retroviral vector halted?
- insertional mutagenesis caused 3 out of the 10 patients to develop leukemia (from LMO2 oncogene), and 2 died
- How is recombinant AAV used to treat hemophilia B? What were the problems with this therapy?
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-hepatic portal vein infusion
-destruction of transduced hepatocytes by immune system
-immunomodulatory treatment proposed - What are the targets of most antiarrhythmic drugs?
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-voltage-dependent Na+ channels
-voltage-dependent K+ channels
-voltage-dependent L-type Ca2+ channels - What is the target of one class of vasodilators?
- voltage-dependent L-type Ca2+ channels (inactive conformation)
- What is the target of local anesthetics?
- voltage-dependent Na+ channels (open conformation)
- What are the targets of many antiepileptic drugs?
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-voltage-dependent Na+ channels (slow recovery from "inactive" to "rest")
-voltage-dependent Ca2+ N-type or low-threshold channels - What are the two types of Ca2+ channel vasodilators?
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-nonselective
-vasoselective (preferentially bind "inactive") - What are the differences between cardiac and vascular smooth muscle cells?
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-cardiac cells have high resting membrane potential, vascular cells have low
-cardiac cells have an AP range of -70-100 → 0-25 mV, vascular of -50 → 0 mV
-cardiac cells have "open" channels more often, vascular have "inactive" more often - What is the difference between use-dependent binding and voltage-dependent binding?
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Use-dependent: binds "open" and "resting" preferentially
Voltage-dependent: binds "inactive" preferentially - What is an HMO? Where do their income and costs come from?
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Health Maintenance Organization; contracts with a primary care provider, group, or Independent Provider Association (IPA)
Income: patients
Costs:
-administration
-IPA
-pharmacy
-hospital
-risk pool - Where do the income and costs for an IPA come from?
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Income:
-HMO contract
-risk pool
Costs:
-management
-primary care physician fee
-specialists
-lab
-medical equipment
-x rays - What is a PPO?
- Preferred Provider Organization - network of physicians that agree to accept a guaranteed discounted fee
- What type of family makes up the majority of the uninsured population?
- more than 1 adult, no children, with worker(s)