Final Flashcards
Routes of administration and characterization of each route
Oral (metabolism); intravenous (nonlipid, fast onset); intramuscular (lipid, slow, long release); inhalation (gas, lipid (gas exchange), Topical (lipid, slow, long release); subcutaneous (like IM); Intraperitoneal (rat stomach), intracranial (spinal cord)
phenomenon by which concentration of administered drug is greatly reduced before reaching circulation via _____
First pass effect, metabolism
how do orally administered drugs cross PPB of cell membranes?
achieve neutrality after metabolism
places drug can go from bloodstream
tissue reservoirs, proteins, tissues, metabolism and elimination
“bi-functional role of receptor” meaning and who?
Langley, “binding and transduction”
lock and key metaphor, who?
Ehrlich
Gs (short)
stimulates adenylyl cylase
Gi (short)
inhibits adenylyl cyclase
Gq (short)
stimulates PLC
Go (short)
couples directly to ion channels
Gs/Gi (whole sequence)
ligand binds, alpha subunit disconnects, activating adenylyl cyclase, converts ATP to cAMP, cAMP goes on to rearrange regulatory subunits and release catabolic subunits of PKA
Gq
ligand couples to receptor, stimulates PLC to phosphorylate PIP2 into DAG and IP3. DAG activates PKC and IP3 stimulates calcium calmodulin action
Go
ligand couples, receptor opens K+ pathways and they exocytose, leading to inhibition?
affinity
ability of drug to bind receptor
Kd
(affinity constant) concentration of drug at which 50% receptors are bound. (looks logarythmic, the one that is sharper slope is more effective (less concentration) (drug concentration vs %maximal binding)
IC50
(Competitor) concentration at which 50% of binding sites have now been taken over (like a backwards S, negative slope)
Efficacy
ability of a ligand to activate a receptor (full, partial, antagonistic)
Full agonist
intrinsic efficacy of 1
partial agonist
efficacy between 0 and 1
antagonist
bonds to receptor, intrinsic efficacy of 0
EC50
concentration of drug at which 50% of population exhibits response over certain time period (survey “has pain been relieved) (forwards s, sharper slope and smaller EC50 means better drug)
mechanisms of tolerance:
desensitization and downregulation
desensitization
when sudden, high concentrations of agonist and receptor become phosphorylated, inactivated, and internalized
Downregulation
when chronic levels of agonist, receptors become phosphorylated multiple times, inactivated, and internalized for degradation (may be way diabetes works with insulin detection / release?) not sure
what molecule flags for degradation?
B-arrestin
TD50
concentration of drug at which 50% of the population shows toxicity (S shape)
TD50-Ed50=______; (Larger = _____)
Therapeutic window; (larger=safer)
Metabolism types (4)
Oxidation, reduction, hydrolysis, conjugation
oxidation
R-CH2-CH3 —ctochrome P450)—> R-CH(OH)-CH3
reduction
R-NO2 —–> R-NH2
hydrolysis
R-CO2R’ —esterases—-> R-CO2H + R’OH
conjugation
R-OH + R’ —–> R-O-R’
example of the way enzymes responsible for metabolism are inhibited
Grapefruit juice contains furanocoumarins that inhibit cytochrome P450, leading to increased levels of circulating drug
Regulation of Choline Acetyltransferase amounts in the synapse (3)
End product inhibition
Neuronal Stimulation
Mass Action
negative feedback loop used to regulate production of a given molecule; prevents excess buildup of end-product
end-product inhibition
if a neuron is stimulated by depolarization from action potential, ACh will be released/used up, so choline acetyltransferase will become activated to produce more ACh and compensate for its use
Neuronal stimulation
principle on the equilibrium of a process (hypothetical)
mass action
terminates the action of acetylcholine action by breaking ACh into acetate and choline
Acetylcholinesterase
Two parts of acetylcholinesterase
anionic(bonding) site, (catabolic) esteratic site with serine as the “separator/transformer”
receptor type present in NMJ, allows fast, stimulatory influx of Na+
Nicotinic receptors
The types of muscarinic receptors that are stimulatory, and couple to Gq
M1 M3 M5
The types of muscarinic receptors that are inhibitory, and couple to Gi/o
M2, M4
scopolamine
Muscarinic drug that is M1 receptor antagonist that blocks input to brainstem vomition center (medulla?)
vesicare
muscarinic drug that is M3 receptor antagonist that decreases contractility of bladder smooth muscle
Axon of motor junction (presynaptic terminal) > NMJ > muscle fiber (postsynaptic membrane)
NMJ
Voluntary Muscle Contraction (5 steps)
• Depolarization causes release of ACh from pre-synaptic
motor neuron
• ACh binds nicotinic receptors on the muscle cell
membrane to depolarize the cell
• Depolarization causes the opening of voltage-gated Ca2+
channels and diffusion of Ca2+ ions out from the SR
• Calcium binds troponin which allows movement of
tropomyosin to reveal myosin binding sites
• Myosin globular heads can attach to actin filaments and
pull, causing contraction and shortening of the sarcomere
• Reversible = edrophonium chloride
• forms salt bridge in anionic site of enzyme but cannot be
hydrolyzed
• Slowly reacting substrates = physostigmine
• fits in the enzyme binding site and will be hydrolyzed
• Irreversible inhibitors = organophosphates
• Will form permanent bond with AChE causing total inactivation of
the enzyme within certain time frame
Acetylcholinesterase Inhibitors
reversible Ach Inhibitor
edrophonium chloride
physostigmine
slowly reacting substrate that blocks AChE
irreversible AChE inhibitor that forms permanent bond with AChE causing total inactivation of enzyme within certain time-frame
organophosphates
You might use AChE inhibtor clinically if (2)
Curare poisoning, myasthenia gravis
• Antagonistic blockade of nicotinic receptors at neuromuscular
junction causes paralysis
• Curare poisoning
• Antibodies to nicotinic receptors causes downregulation
• Myasthenia Gravis
Inhibition of AChE increases____
neurotransmissions at the
cholinergic synapse
Dopamine Synthesis
Tyrosine »_space;»»Tyrosine hydroxylase»»» DOPA »_space;»>amino acid decarboxylase»»> Dopamine (DA)
adrenergic receptor that couples to Gq = stimulatory action
• Expressed in blood vessels to mediate constriction
α1
adrenergic receptor that couples to Gi
/Go = inhibitory action
• Expressed primarily is pre-synaptic autoreceptor
α2
adrenergic that all couple to Gs = stimulatory action
β1, β2, β3
β1 expressed in heart to mediate increased HR
• β2 expressed in bronchial tubes to mediate relaxation
• In sympathetic response, contraction or relaxation of
smooth muscles occurs based on the ________
expressed in the muscle
types of receptors
smooth muscle contraction sequence
Smooth muscle is found mainly in walls of
hollow organs and vasculature
q Made up of thick and thin myofilaments
n Actin and myosin
q Not organized into distinct bands
q Does not contain troponin
n Contains calmodulin
q Calcium-calmodulin complex allows activation of myosin
q Contractions are elicited by a number of stimuli
n All result in increase in intracellular calcium
n Increased calcium in the smooth muscle cell
causes contraction
q Calcium may come from extracellular or
intracellular stores
n Calcium binds calmodulin
q Calcium activates calmodulin to allow it to
stimulate myosin light chain kinase (MLCK)
n MLCK phosphorylates myosin light chains
(MLC)
q Phosphorylation leads to cross-bridge formation
with actin filaments
q Causes
contraction
Smooth Muscle Physiology
n MLCK phosphorylates myosin light chains
(MLC)
q Phosphorylation leads to cross-bridge formation
with actin filaments
q Causes contraction
n Contraction is terminated after calcium is
removed from cytoplasm
q Calcium pumps may transport intracellular calcium
into sarcoplasmic reticulum or outside of cell
(simple) involuntary muscle contraction
Contraction continues until calcium removed
Phosphorylation promotes cross-bridge formation
MLCK phosphorylates myosin light chains
Calcium-calmodulin complex stimulates MLCK
Calcium binds to calmodulin
Increase in Ca2+ in smooth muscle cell
Serotonin synthesis
Tryptophan > Tryptophan
Hydroxylase>
5-HTP >Amino Acid
Decarboxylase> Serotonin
ANS neuron characteristic: 2 neuron pathway
preganglionic neuron with cell body in CNS –> postganglionic neuron with cell body in ganglion
Postganglionic axons are myelinated or unmyelinated?
unmyelinated. Pre are myelinated, I think
sympathetic activation targets
Preganglionic fibers exit through spinal cord ventral root Fibers pass through white ramus to reach ganglia Synapse in sympathetic chain ganglia with postganglionic cell body Spinal nerve route: synapse in chain on same level Sympathetic chain route: travel up/down chain before a synapse Travel through sympathetic ganglia, but no synapse until reaching collateral ganglia Travel through sympathetic ganglia, but no synapse; release ACh directly on adrenal medulla
Sympathetic activation characteristics: 3 things that cause widespread activation
sympathetic chain ganglia - connectivity
NE and Epi release from adrenal medulla
• Postganglionic terminal varicosities
only sympathetic response that affects posganglionic ACh
sweat glands
3 differences between SNS and PNS activation
• Spinal nerves: Lumbar and thoracic versus cranial and sacral • Ganglia location: Close to spinal cord versus close to effector • Neurotransmitter ACh and NE versus ACh and ACh
a-1 pathway mediates
Constriction of vasculature • Constriction of internal sphincter in bladder and colorectal pathway • Contraction of radial eye muscle for dilation • Release of glucagon from alpha cells of the pancreas
a-2 pathway mediates
Inhibition of NE release at
SNS terminals
• Inhibition of insulin release
from pancreas beta cells
β1 pathway mediates
Increased strength of
heart contraction
• Increased heart rate
β2 pathway mediates
Dilation of the bronchioles
• Dilation of blood vessels
that lead to heart and
skeletal muscles
_________ activation characteristics:
• ALL postganglionic parasympathetic neurons release ACh
• 75% of parasympathetic outflow through vagus nerve
• Effects at target tissue mediated by muscarinic receptors
parasympathetic
M3 pathway mediates
Constriction of bronchial tubes and the trachea • Contraction of detrusor muscle of bladder • Contraction of circular eye muscle for pupil constriction
M2 pathway mediates
• Decrease in heart rate
through action at SA and
AV nodes
How do SNS and PNS coordinate through synaptic level control?
presynaptic a2 receptor in sympathetic terminal. presynaptic m2 receptor in parasympathetic terminal
Sensory Receptor --> Sensory Neuron --> CNS (spinal cord) --> Preganglionic neuron --> Postganglionic neuron --> Effector Tissue
autonomic reflex arc
How do SNS and PNS coordinate through spinal level control?
autonomic reflex arc
3 locations of function of pancreas
beta cells, effector cells, and alpha cells
Function of pancreas: beta cells
inc blood glucose, inc ATP production, inhibit outward K+
channels, depolarization opens v-gated Ca2+, exocytosis of
insulin
Function of pancreas: effector cells
• insulin binds tyrosine kinase receptor, activates signal pathway, GLUT4 transporters translocate to cell surface
Function of pancreas: alpha cells
• dec blood glucose, release of glucagon
SNS synergistic activity at pancreas to increase blood glucose
NE binds α1 on alpha cells • Stimulates IP3 pathway • Increase Ca2+ promotes glucagon exocytosis
• NE binds β2 on alpha cells • Activates Gs, increase cAMP • PKA opens Ca2+ channels
NE binds α2 on beta cells • Simulates outward K+ current • Slow hyperpolarization inhibits insulin exocytosis
urinary bladder reflex on detrusor
Stretch receptors sense filling of bladder
- Sensory neuron projects to spinal cord
- Synapse on preganglionic neuron»_space;synapse on postganglionic neuron
- Release of ACh onto M3 receptors in detrusor
- Smooth muscle contraction via Gq pathway
Micturition (other than detrusor) (parasympathetic)
Relaxation of internal sphincter • Output from micturition center inhibits SNS smooth muscle activation α1 • Relaxation of external sphincter • Output from micturition center inhibits voluntary motor neuron activation
Bladder filling (sympathetic)
Relaxation of detrusor muscle • NE binds β3 to inhibit smooth muscle contraction • SNS inhibits PNS input • Constriction of internal sphincter • NE binds α1 to mediate smooth muscle contraction • Constriction of external sphincter • SNS output enhances voluntary motor neuron activity
Control of blood pressure
• Regulate cardiac output through: • Changes in heart rate • Changes in stroke volume • Regulate total peripheral resistance through: Changes in vasoconstriction • Regulate blood volume through (next section of the course): • Changes in RAS system • Release of aldosterone
how blood pressure decreases heart rate
• Increase in blood pressure • Firing frequency of baroreceptors increases • Activates NTS neurons that project to vagus nerve • Increase ACh release at SA node • M2 receptors cause hyperpolarization through K+ efflux • Decrease in heart rate
increase in heart rate
• Decrease in blood pressure • Firing frequency of baroreceptors decreases • Activates NTS neurons that project to RVLM • Increase NE release at SA node • β1 receptors cause depolarization through decreased K+ efflux • Increase in heart rate
increase in contractility
• Decrease in blood pressure • Firing frequency of baroreceptors decreases • Activates NTS neurons that project to RVLM • Increase NE release at SA node • β1 receptors cause depolarization through decreased K+ efflux • Increase in heart rate
vasoconstriction to increase TPR
NE binds a1 and etc happens
3 respiratory groups that regulate breathing
Venral, pontine, dorsal
• 1) Inhalation: Inspiratory neurons fire à project to diaphragm and
intercostal muscles
• 2) Exhalation: Expiratory neurons fire à inhibit inspiratory neurons
ventral respiratory group
• Inhibits inspiratory neurons à causes shorter respiration cycles,
increases respiration rate
• Important during breathing/exercising
pontine respiratory group
- Respond to activity of chemosensors:
- Central – most sensitive to H+
- Peripheral – most sensitive to changes in O2 and CO2
dorsal respiratory group
Peripheral chemosensation
• O2 level decreases • O2-sensitive K+ channels close • Depolarization and activation of fibers to DRG
• CO2 level increases • Intracellular acidity increases • Inhibition of K+ channels • Depolarization and activation of fibers to DRG
chemosensation arc
Chemosensors»_space;» DRG»_space;» VRG »_space;»>
Diaphragm/
InercostalMuscles
