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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"?
-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?
pharmacokinetics: study of [drug/metabolite] in body fluids
pharmacodynamics: study of drug-target interactions
What factors determine drug response?
-number of receptors
-receptor occupancy
-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?
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?
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?
What are some amine transmitters?
What are some neuropeptides?
-substance P
What are the precursors of acetylcholine? What enzyme catalyzes this reaction and where?
-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?
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?
At the time of host death from cancer, how many cancer cells are usually present?
At what point in the cell cycle can the cell undergo death from differentiation?
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?
-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?
-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?
-synoviocyte proliferation → cartilage destruction
-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?
-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?
-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
-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?
-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?
-tricyclic antidepressants
-anti-arrhythmic agents
-anti-psychotic agents and selective serotonin-reuptake inhibitors
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?
-glucose-6-phosphate dehydrogenase deficiency
-confers resistance to malaria
-X-linked recessive
What happens to people with deficiency in glucose-6-phosphate dehydrogenase? Why?
-decreased ability to dispose of oxidants because glutathione peroxidase activity is low (needs glutathione)
-things that increase oxidants are primaquine, xenobiotics, fava beans
What does the ryanodine receptor (RYR1) do? What happens if it is mutated?
-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?
-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?
-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?
-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?
-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?
-hepatic portal vein infusion
-destruction of transduced hepatocytes by immune system
-immunomodulatory treatment proposed
What are the targets of most antiarrhythmic drugs?
-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?
-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?
-vasoselective (preferentially bind "inactive")
What are the differences between cardiac and vascular smooth muscle cells?
-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?
Use-dependent: binds "open" and "resting" preferentially
Voltage-dependent: binds "inactive" preferentially
What is an HMO? Where do their income and costs come from?
Health Maintenance Organization; contracts with a primary care provider, group, or Independent Provider Association (IPA)
Income: patients
-risk pool
Where do the income and costs for an IPA come from?
-HMO contract
-risk pool
-primary care physician fee
-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)

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