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63 Cards in this Set
- Front
- Back
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Drug reactions to correctly prescribed medications kill how many in US/year?
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100K
6th most common cause of death |
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Prescription errors kill how many in US/yr
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1.5 million
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Concerns with Herbal Meds
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Contaminents
Components that interact with other drugs |
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Do drugs create physiologic effects?
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No, they modulate them.
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All drugs require?
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A receptor
Drugs are ligands for the receptors |
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Describe types of drug receptors
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Physiologic receptors (ones acted on by hormones, neurotransmitters, etc)
Non-physiologic: enzymes, structural proteins, transport protein, nucleic acids |
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Receptor specificity
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Ligand
Process initiated by ligand binding |
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Agonist
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Ligands that interact with a receptor and initiate a response
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Antagonists
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Occupy a receptor site but either do not initiate a response or inhibit the normal response
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GR
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Steriod receptor in nuclear receptor superfamily
GC hormones (and similar substances) are agonists that result in nuclear translocation of GR and transcriptional activation of hormone sensitive genes |
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Physioogic drug receptor mechanisms
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1. Transactivation (steriod receptor)
2. Ligand binding activates enzymatic intracellular domain (kinase) 3. Ligand binding activates coupled intracellular partner's enzymatic activity 4. Ligand binding opens ionic channel |
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Drug receptor chemical interactions
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Mostly hydrogen bonds and VDW interactions
Decrease w/ distance (VDW to 7th power) Covalent interactions -- some antagonists with irreversible effect Drugs are not usually charged |
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Drug-receptor association and dissociation
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Better the pocket fit the more stable the complex
All non-covalent complexes dissociate--terminating drug action |
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Frequency of drug association dependent on
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[drug]
[receptor] drug-receptor affinity |
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Magnitude of response is a fnc of
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Number of drug-receptor complexes
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Dose-response concept
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Degree of response is a fnc of the amount of drug administered to organism
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Quantal dose response curve
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All or none phenomenon
S-shaped curve for cumulative, gaussian distribution for incremental Response in % linear vs log of dose Give information about the population--not individual |
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ED-50
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Dose at which 50% of population responds
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LD-50
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Dose at which 50% of the population treated dies
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Probit
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Plotting dose-response data on a straight line
Easier to see ED50 and LD50 |
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Grade or continual dose response curves
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Individual response to increases doses of drug
Typically results in a sigmoidal log-linear Only informs about individual, although shapes of the curves are usually the same (receptor interactions) |
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Primary effect
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desired affect of therapeutic value
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Side effects or undesired effects
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non-target effects, not necessarily bad
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Toxic effects
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always bad
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Components of dose
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Amount
Duration and frequency Chemical form Physical Form Route |
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Relationships between therapeutic and toxic effects of drugs
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1. Single receptor, signal effector pathway leading to desired and undesired effects (difficult to separate)
2. Single receptor, multiple effector pathways (block toxic pathway downstream) 3. Two receptors (block toxic pathway or design new drug that is more specific) |
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OTC efficacy requirements
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Dose must be effective in 99% of people with no harm
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Degree of safety of a drug is determined by?
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Separation between therapeutic and toxic effects
Ideally max effective dose would be lower than beginning of lethal curve |
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Therapeutic index (TI)
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LD50/ED50
Should be greater than 1, bigger is better, ideally greater than 10 Does not tell you if the curves overlap |
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Organization of the autonomic NS
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Two neuron system --pre and post ganglionic
Exceptions -- Sympathetic direct innervation of adrenal Hormonal targets -- Non innervated Sympt -- bronchial smooth muscle (beta1) Para -- vascular endothelial cell M3, M5 |
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Preganglionic autonomic nerves
cell bodies? axons? neurostransmitter? |
Cell bodies in midbrain, medulla, or spinal cord
Myelinated axons to peripheral ganglia Neurotransmitter is ACh |
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Postganglionic autonomic nerves
Receptors? cell bodies? axons? |
Nicotinic cholinergic receptors
Cell bodies in peripheral ganglia Unmyelinated axons to all involuntary organ systems (adrenal medulla only is sympathetic only) |
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Nicotinic cholinergic receptors
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Ligand gated Na/K channels
Nn in peripheral ganglia Nm in skeletal muscle |
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Parasympathetic innervation structure
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Long preganglionic neuron w/ cell body in brain or lumbar spinal cord
Releases Ach recevied at Nicotinic receptor Short postganglionic neuron w/ cell body in peripheral ganglion Releases Ach Received at muscarinic Ach receptor on target organ |
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Muscarinic cholingergic receptor
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G-coupled protein
M1-M5 most target tissues express M3 M2 in heart M1 gastric parietal cells |
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Parasympathetic ganglia
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CNIII - ciliary ganglia - eye
CNVIII- pterygolpalantne -- lacrimal gland submaxillary - submaxillary/sublingual glands CNIX - otic - parotid CNX - lots S2-S4 - pelvic ganglia, pelvic organs |
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Organization of innervation of sympathetic system
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Short preganglionic outflow from thoracolumbar spinal cord
Release of AcH Received by nicotinic cholingeric receptor Long post ganglionic neuron in sympathetic ganglia Release usually norepi Received usually by adrenergic receptor Target tissues usually have multiple receptors |
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Sympathetic ganglia
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Superior cervical - eye, lacrimal and salivary glands
Inferior cervica/upper chain - lungs, heart Chain- vessles, sweat glands, piloercter muscles Celiac - GI to liver, small intestine, pancreas SM- large intestine IM -GU |
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Sympathetic cholinergic innervation
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Post ganglionic neurons release AcH
Tissues have muscarinic receptors Thermoregulatory (holocrine) sweat glands VSM of skeletal muscle |
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Sympathetic dopaminergic innervation
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Post ganglionic neurons release dopamine
Renal VSM Dopamine receptors are D1-5 Renal VSM mostly expresses D1 |
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Adrenal Medulla innervation
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Sympathetic preganglionic innervation
Chromaffin cells have nicotine cholingeric receptors Release epi and norepi into blood stream Neurohormonal actions |
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Sexual response
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parasympathetic -- sexual arousal
sympathetic - orgasm |
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Actions of epinephrine from adrenal medulla
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Dilates airways
Increases cardiac oupt Increases skeletal muscle contraction and efficiency Increases fatty acid release Increased mental altertness Increased ACTH and TSH Increased glycogenolysis Decreased intestinal motility |
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Resting state
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parasympatetic tone predominates
skeletal arterial VSM have resting sympathetic state Inhibitors of NE have little effect Inhibitors of ACh have major anti parasympathetic effects |
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In stressed state
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Sympathetic tone predominates
Inhibitors of NE have increased effect Skeletal arterial VSM are dilated via sympathetic B2 |
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Cholinergic Neurotransmission
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1. Transmitter release
AP, Ca influx, vesicle fusion, AcH release 2 Post release effects Post synaptic M, N receptor binding Presynaptic receptor binding (usually inhibitory) Degradation of acetylcholinesterase |
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Post degradation fate of ACh
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Choline uptake into nerve terminus
CHoline acetyltransferase makes ACh Transport into vescile |
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M3
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Muscarinc cholingergic receptor
In most tissues Gprotein coupled Uses Gq |
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M2
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Muscarinic cholinergic receptor
In Heart Gprotein coupled Uses Gi |
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M1
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Muscarinic cholintergic receptor
Gastric parietal cells Gprotein coupled Uses Gq |
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alpha and beta adrenergic receptors
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G protein coupled
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alpha 1 adrenergic receptors
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GPCRs
3 - A, B, D -- very similar always post ganglionic use Gq |
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alpha 2 adrengeric receptors
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GPCRs
3 -- A,B,C - very similar post and pre ganglionic uses Gi |
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beta adrenergic receptors
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GPCRs
3 - 2,3,4 Use Gs Most common is B2 Heart and JGA have B1 Fat has B3 |
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D1 and D5
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Dopamine receptors
Dopamine receptor GPCR Uses Gs Post synaptic Brain and renal VSM |
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D2
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Dopamine receptor
GPCR Uses Gi Pre and post synaptic highest in brain Modulates NT reelase |
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D3
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Dopamine receptor
GPCR Uses Gi Post synaptic Mainly in brain |
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D4
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Dopamine receptor
GPCR Uses Gi Post synaptic Brain and CV tissue |
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GPCR
structural features |
7 membrane spanning receptors
Extracellular side binds ligand Intracellular side binds Galpa, Gbeta, Ggamma complex Exchange Galpa(GTP_ and Gbeta, Ggamma complex Specificity mainly determined by Galpha |
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Galphas
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Gs -Stimulates adenylyl cyclase
Gi - Inhibits adenylyl cylclase Gq -Queer - stimulates phospholipase C |
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alpha1s, M1, M3
Signalling |
Use alpha q/11
open membrane Ca channels Increases activity of phospholipase C Effects through protein kinase C |
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Alpha2s, M2, D2
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Use g alpha i
Inhibits adenylyl cyclase Decreases cAMP (increases PLC, PLD, PLA2) effects through protein kinase A (and C) |
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Beta 1-3, D1
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Uses g-alpha s
Activates adenylyl cyclase Increases cAMP effects though protein kinase A |
