Pharmacology Flashcards
What the key receptor types?
Ligand Gated Ion channel, GPCR, Transmembrane enzyme (tyrosine kinases), cytoplasmic/nuclear receptors
What the the key types of ligand gated ion channels?
Nicotinic Receptor ligands, Serotonin 5HT-3, Glutamate-AMPA, Glutamate NDMA, GABAa (inhibitory), Glycine
Azepam/azolam suffix meaning?
Benzodiazepines = allosteric activator of GABA receptors. Increases frequency of opening of GABAa-gated Cl- channels which enhance synaptic inhibition. Therapeutic index for diazepam is very good (~100)
Examples: Diazepam (Valium), Lorazepam (Atvian), Estazolam (Prosom), Clonazepam, Flurazepam, Alprazolam (Xanax), Clonazepam
What are setrons used for?
Drugs with -setron suffix (e.g. ondansetron, granisetron) are competitve inhibitors used to treat nausea and vomitting.
Tetrodotoxin (TTX)
Blocks voltage gated Na+ channels in nerve an muscle cells (TTX acts like a plug at the extracellular surface of the voltage-gated sodium potential
What do curoniums do?
Curoniums are nicotinic receptor blockers (rocuronium, vecuronium). They are used as non-depolarizing competitive inhibitors which relax skeletal muscles during surgery.
What is succinylcholine used for?
depolarizing blocker because it depolarizes the muscle before it blocks. used to relax airway during intubation.
What do stigmines do?
Cholinesterase inhibitors which inhibit the degradation of ACh, therefore increasing the concentration of ACh in the synaptic cleft -> enhances synaptic transmission.
Ex. neostigmine (reversible inhibitor). During surgery, vecuronium given as ACh receptor competitive inhibitor. After surgery, neostigmine given to increase ACh concentration, thus competing off the competive inhibition of vecuronium.
What is sarin and how does it work?
Sarin is an irreversible cholinesterase inhibitor. ACh so intensely activated due to large increase of ACh in synaptic cleft.
How does the parasympathetic nervous system slow the heart?
The post synaptic neuron releases Acetylcholine onto the muscarinic GPCR in the heart. The beta and gamma subunits of the activated G-proteins then bind to K+ channels on the membrane and HYPERpolarize the muscles, therefore decreasing the propagation of action potentials and slowing the heart.
What is the role of atropine?
Competitive inhibitor of parasympathetic muscarinic receptors on the heart. By competing with ACh for muscarinic receptors, atropine decreases the amount of inhibition of HR therefore INCREASING the HR.
What do tropiums do?
Block muscarinic receptors in the bronchioles. Muscarinic receptors in the bronchioles typically CONSTRICT the airways in the lungs. By blocking the muscarinic receptors, the bronchioles OPEN up more. Therefore, blocking muscarinic receptors with competitive inhibitors can be used to treat asthma/COPD/ other airway disorders.
Examples: ipratropium, tiotropium
How does the sympathetic nervous system act on blood vessels? Example of drugs?
The sympathetic nerve endings release norepinephrine onto the alpha 1 andrenergic receptors on blood vessels. These receptors (like all receptors for parasympathetic and sympathetic nervous systems) are GPCRs. These GPCR activate phospholipase C which converts PIP2 to IP3. IP3 then causes calcium to be released, leading to the constriction of blood vessels.
Example of drugs: Norepinephrine, phenylephrine
Phenylephrine also used to decrease nasal congestion
Where are beta 1 receptors located? What about beta 2 receptors? What happens when they are innervated?
Beta 1 receptors are located on the heart. Beta 2 receptors located on smooth muscles of blood vessels and bronchioles.
Beta 1 receptors: when innervated by norepinephrine, activate adenylyl cylase, which converts ATP to cAMP, which activates PKA -> phosphorylation of proteins which increase contractile force of heart
Beta 2 receptors also act in the same way except the result is the opposite. Smooth muscles RELAX in response to increases in cAMP
How to cardiac muscles respond to increases in cAMP? What about smooth muscle?
Cardiac muscles have increased contractility. cAMP INCREASE calcium entry into the cardiac muscle cell, therefore increasing contractility.
Smooth muscles relax. Increases in cAMP DECREASES calcium concentrations, therefore decreasing contraction -> relaxation
What are beta-1 blockers used for? How can you identify them?
-olol suffix (i.e. propranolol, metoprolol)
Used to treat hypertension, arrythmias caused by sympathetic nervous system, heart failure. Competitive inhibitors of norepi at beta -1 receptors.
What is difference between propranolol and metoprolol?
Metoprolol = beta-1 receptor selective
Propanolol = inhibits both beta 1 and beta 2 receptors
Significant because if a patient has asthma, you dont want to use propanolol. Propanolol will inhibit beta 2 receptors -> inhibit relaxation of bronchioles -> constriction of airways
What are the beta 2 agonists?
EROL suffix
Albuterol, salmeterol, formoterol
Since they activate beta 2 receptors, they DECREASE calcium concentrations in the smooth muscles of the bronchioles -> RELAX bronchioles. used to treat asthmas/COPD
What is sympathetic tone?
Tonic vasoconstriction of blood vessels due to tonic firing of sympathetic nerves innervating the vasculature. Increasing tonic firing of action potentials -> more constriction. Decreasing tonic fire -> less constriction.
What is equation for blood pressure?
What is cardiac output?
BP = CO * TPR
(similar to Ohm’s law V = I*R)
CO = HR * SV
HR = heart rate, SV = stroke volume
TPR = length * viscosity * constant / pi*(blood vessel radius) ^4
Therefore, INCREASING radius => greatly reduces TPR => lowers BP
What CYP is used in the metabolism of benzodiazepams?
CYP3A4 (remember the diazepine ring)
What CYP is used to metabolize metoprolol and opoids (codeine, hydrocodone)
CYP2D6
- key thing is remember is that CYP2D6 is responsible for more polymorphisms than any other CYPs. Therefore, if the questions involves polymorphisms, think CYP2D6
How do ethanol and acetominophen react?
Ethanol upregulates CYP2E1. CYP2E1 is reponsible for converting acetominophen to NAPQI, which is a toxic electrophile. Thus, people taking both acetominophen and alcohol are at risk for damaging their liver.
What factors contribute to the resting potential of a cell?
Leak channels and the Na/K ATPase
In particular, the K+ leak channel plays a large role in the resting potential of the cell. This is why the resting potential of the cell is closer to the K+ equillibrium potential.
What are graded potentials?
Local transient changes in membrane potential evoked by neurotransmitters. These occur in dendrites and cell bodies of neurons/neuromusclar junctions.
There are EPSP, IPSP, and end plate potentials (EPP)
What is summation? Why is it important?
Summation is the net outcome of all the EPSP and IPSP acting on a neuron. If the summation is large enough to exceed the threshold potential of a neuron, an action potential will be fired.
What do GABA receptors do?
What is unique about GABA?
They hyperpolarize the membrane by allowing Cl- to enter the cell.
GABA receptors are not always inhibitory. During neuron development, Cl- is actually higher in the neuron. Thus, opening GABA actually depolarizes the cell.
What is NKCC1?
What is KCC2?
NKCC1 stands for Na-K-2Cl transporter. During neuron development, NKCC1 pushes Cl- into the cell, thus making the concentraiton of Cl- higher in the cell than outside the cell. As a result, the membrane potential of chlorine is actually excitatory.
After neurons are developed, KCC2 transporters (K-Cl transporter) become active and export Cl form the cell. Thus, the concentration of Cl is higher outside the cell than inside the cell. As a result, Cl becomes inhibitory.
What are the steps of an action potential?
1) Graded potentials act on neuron and cause it to reach threshold
2) Na+ VGC open as a result of reaching threshold
3) Na+ enters the cell, rapidly increasing the voltage in the cell. Eventually, Na+ VGC become deactivated.
4) K+ VGC begin to open, which causes intracellular K+ to leave the cell.
5) The cell becomes hyperpolarized and and overshoots the resting membrane potential. K+ VGC’s close and the cell’s membrane potentail re-equilibrates.
What is the absolute and relative refractory period? What is the physiological basis for these refractory periods?
Absolute refractory period = impossible to trigger second action potential. It is due to the inactivation of Na+ VGCs
Relative refractory period = second AP is possible but requires more stimulus to accomplish. It is due to membrane hyperpolarization (from overshoot), residual K+ channel openings, and incomplete Na+ VGC recovery
How do action potentials differ in cardiac muscle?
Morphology of action potential is different. The elongated plateau allows for the heart to fully contract and empty of their blood. Initial increase of potential is caused by Na+ VGC. Ca VGC then open which allow Ca to flow into the cells, allowing for prolonged plateua phase of AP. Eventually, more K+ VGC open up to fully depolarize the cardiac cell.
ECG lines up with events of opening of certain VGC. I.e. QT interval = length of cardiac AP, T portion lines up with opening of K+ VGC etc.
What does penicillin do? What are its effects on GABA receptors?
Penicillin is an antibiotic. It also can bind to an OPEN GABA channel, thus preventing the flow of Cl- ions. This ultimately leads to seizures in some patients. It is an open channel inhibitor therefore it is an UNCOMPETITIVE inhibitor.
What is the difference between glutamate AMPA an dglutamate NMDA receptors?
NMDA = glutamate gated Calcium channel -> learning and memory but also can be cytotoxic
AMPA = glutamate gated Na+ channel
What is the role of the RAS/MAP Kinase pathway? What about the PI-3-kinase/AKT/mTOR pathway?
What are Katp (sulfonylurea) receptors? Why are there important in pancreatic beta cells?
During period of low glucose, the concentration of ATP in the beta pacreatic cells is low. As a result, the sulfonylurea K+ channel is open, allowing K+ to exit cell, thus hyperpolarizing cells. During high periods of ATP, ATP closes the sulfonylurea K+ channel, thus hyperpolarizing the membrane which raises the membrane potential enough to open voltage gated Ca2+ channels.
The influx of Ca2+ into the cell promotes the release of insulin from secretory vesicles.
Sulfonylurea BLOCKs Katp channels on beta pancreatic cells, thus promoting insulin release similar to ATP.
What is one way that a voltage gated channel can be sensitive to the membrane voltage?
Some voltage gated channels have transmembrane domains which are contain a significant amount of charged amino acids. As the voltage changes, thie domain (voltage sensing domain) wilil change conformation due to electrostatic forces. The conformation change in teh voltage sensing domain will cause a change in the structure of the channel, allowing it to be closed/open
What is N-Type inactivation?
It is a type of voltage gated K+ channel inactivation. N terminal amino acids block the channel, inactivating the K+ channel
What are local anesthetics used for? What is their mechanism of action? (-caine suffix) What is use dependent block?
Local anesthetics stop the propagation of AP in neurons by preventing the influx of sodium through the VGC. (block Na+ VGC) Local anesthetics preferentially interact with inactivated state of Na+ VGC. (post activation state) This is why dentist need to poke the gums during administration of lidocaine to gums. This phenomenon is called “use dependent block”
Other drugs that have similar mechanism : anticonvulstants/antiarrhythmic agent
What are the effects of Na+ channel blockers on cardiac action potential? What about K+? Ca2+?
Na+ blocker -> reduces amount of depolarization during intial AP spike
K+ blocker -> slows repolarization -> elongates caridac action potential
Ca2+ blocker -> decreases length of AP by reducing the “sustatining” effect of Ca2+ on cardiac AP
What is HERG? What does blocking it do?
HERG = Human ether-a-go-go reated gene potassium channel found on cardiac muscles
Blocking of HERG = prolongation cardiac action potential -> cause cardiac arrythmia
What are inverse agonists?
Agonists which bind to constituitively active receptors and inhibit them.
How do you tell if a receptor operates via cooperativity?
If the dose response curve on a regular arithmetic axis is S-shaped
What are quantal dose response curves?
For responses that are binary (sleep/nonsleep), we use dose response curve. Y axis = percent individuals responding to the drug and having the response. ED50 = concentration needed to elicit response from 50% of people.
What is the therapeutic index? What is it used for? Is it better to have a high or low TI?
Better to have a high TI.
TI = ratio of toxic ED50 to beneficial ED50
