final exam Flashcards
What is Pharmacokinetics?
What the body does to the drug
Ex) Half life after metabolizing
What is Phamacodynamics?
What a drug does to the body
Ex) Increases heart rate
What is a poison?
a nonbiological substance that has negative effects on the body.
Ex) lead
What is a toxin?
biological substance that has negative effects on the body (created from living substances)
Ex) poison mushrooms
What is a Stereoisomerism?
Isomers that differ in spatial arrangement of atoms, rather than order of atomic connectivity
(Optical Isomers or mirror images)
Where does orthosteric bonding take place?
Binding at the primary active site on the receptor
Where does allosteric bonding take place?
Drug binds to something other than the primary active site (Non-competitive)
What is the relationship between strength and bond specificity?
It is inversely proportional.
The stronger the bond, the less specific the bond. The weaker the bond, the more specific the bond.
What is the pharmacokinetics acronym?
ADME
Absorption
Distribution
Metabolism
Excretion
What is EC(50) and E(max) in the Drug Concentration Response Curve?
EC(50) is a point on the horizontal axis (Drug Concentration) where you see 50% of drug effects.
E(max) is a point on the curve where you max out the drug effects right before the curve plateaus.
What is K(d) and B(max) on the Drug Concentration Response Curve?
K(d) is a point on the horizontal axis (Drug Concentration) where 50% of the receptors are bound.
B(max) = max receptors bound
What is the difference between K(d) and EC(50)?
K(d) is referring to 50% of receptors bound vs EC(50) refers to 50% max effect of drug.
Describe the relationship between an agonist and an allosteric antagonist?
You cannot outcompete an allosteric antagonist (non-competitive antagonist) because it’s not competing for the same receptor site.
If you keep increasing dose of agonist, you will only see a toxic effect - insurmountable
Describe the relationship between an agonist and an allosteric activator?
An agonist and and allosteric activator (allosteric agonist) work together to get an increased result. An allosteric activator binds outside out of the active site.
What is an inverse agonist?
Acts as an antagonist; has a greater affinity to R(i) and stabilizes R(i) form.
Can shut down the downstream response.
Drops BELOW the constitutive activity
In practice, we will refer to as antagonist.
What is the relationship between K(d) and receptor affinity?
The relationship is inverse.
Low K(d) = high drug/receptor affinity; the drug binds well to the receptor.
High K(d) = low drug/receptor affinity; the drug doesn’t bind well to the receptor.
What is physiological antagonism?
Acts at a different receptor but produces an opposite physiological effect to that of the agonist
Effect: Does not compete with the agonist at the same receptor, but rather opposes its action through a different mechanism.
Example: Epinephrine (which increases heart rate) can act as a physiological antagonist to histamine (which decreases heart rate), even though they act on different receptors.
Describe a graph in which an agonist is alone, an agonist + competitive antagonist, agonist + allosteric agonist, and an agonist + allosteric inhibitor
Describe a graph showing constitutive activity, full agonist, partial agonist, antagonist, and an inverse agonist
How does therapeutic index correlate with drug safety?
The larger the therapeutic index the safer the drug is; est. margin of safety
If pH>pKa
favors unprotonated form
If pH<pKa
favors protonated form
If a weak acid is protonated it is…
Not charged
If a weak base is protonated it is…
charged
In order to cross barriers, a compound will want to be ____
uncharged; more lipid soluble
If aspirin (weak acid) has pKa = 3.5, what form does it take in the stomach (pH = 1.5)?
Protonated, uncharged
If aspirin (weak acid) has pKa = 3.5, what form does it take in the intestine (pH = 6.5)?
Unprotonated, charged
What medication for morning sickness was rejected by the FDA due to it causing Phocomelia?
Thalidomide
What are the 4 mechanisms of transmembrane signaling?
- Direct crossing to intercellular receptor (lipid soluble)
- Enzymatic action mediated by ligand binding
a. Tyrosine kinase activated receptors - Ligand gated ion channel
- G protein receptor
What receptors are intracellular?
Lipid soluble - uncharged
Gasses - easily diffuses through membrane
What are the steps to the GPCR cascade?
- Drug binds to receptor - activates alpha subunit of G protein (conformation change)
- G protein releases GDP and binds GTP
- G protein activates effector protein
- Secondary messenger cascade or ion conductance
Differentiate between desensitization and resensitization
- When first give agonist, response jumps up, peaks, then declines (muted response with same amount of agonist) - desensitization
- Stop giving agonist, then wait, then give agonist again → see same response - resensitization
Describe the steps to the desensitization process
- Drug binds to receptor → promotes receptor interaction with G proteins in cytoplasm (closed → open conformation)
- Agonist-activated receptors phosphorylated by G protein-coupled receptor kinase (GPK), preventing receptor interaction with G protein → attracts beta-arestin (B-Arr)
- B-Arr receptor complex binds to coated pits, promoting receptor internalization
- 2 possibilities:
Possibility 1 - resensitization (Drug falls off receptor→ phosphatase dephosphorylates receptor and receptor recyles back to cell membrane)
Possibility 2 → degradation (Can’t get drug off of receptor → lysosome merges with drug/receptor complex → enzymes from lysosome degrade receptor)
What are the 2 signal types for ion channels?
Ligand and voltage gated
Differentiate ionotropic from metabotropic ligand-gated ion channels
Ionotropic - Ligand binding site and channel on same protein
Metabotropic - Ligand activates GPCR, second messenger activity opens channel
First-order elimination
Rate of elimination varies with concentration - clearance constant
Zero-order elimination
Rate of elimination is constant, clearance varies with concentration
What is meant by a high Vd?
The higher the Vd, the less amount of drug is in the blood; drug distributed in other areas
What is the difference between elimination and clearance?
Elimination changes based on clearance (doesn’t change)
What is clearance?
Ability of body to eliminate drug in relation to drug concentration in body
What is volume of distribution?
Apparent volume in blood
- How much did we give them vs how much stayed in blood (how much stayed in blood vs how much went to other areas)
What are the main two components of standard drug dosing?
Volume of distribution and clearance
What is rational dosing?
Goal – to achieve desired beneficial effect with minimal adverse effects
Describe what occurs in zero-order elimination
Occurs when the body’s ability to eliminate a drug has reached its maximum capability (i.e., all transporters are being used). As the dose and drug concentration increase, the amount of drug eliminated per hour does not increase, and the fraction of drug removed declines.
What order of elimination do most drugs follow?
First-order
What are the 4 parameters affective passive diffusion?
Molecular weight
pKa
lipid solubility
plasma protein binding
How many half-lives are usually required for drug to achieve full effects?
4
What are the 4 phase I reactions?
Oxidation, reduction, dehydrogenation, and hydrolysis
Cytochrome 450 enzymes are _________
oxidases
Cytochrome p450 oxidation occurs in the ________ of the hepatocyte
Sarcoplasmic endoplasmic reticulum
Drugs that increase cytochrome P450 activity
induction
Drugs that decrease or irreversibly inhibit cytochrome P450 activity
inhibition
Cytochrome P450 induction causes a decreased drug effect – IF metabolism ________ drug
deactivates
Cytochrome P450 induction causes an increased drug effect – IF metabolism ________ drug
activates
Cytochrome P450 inhibition causes an increased drug effect – IF metabolism ________ drug
inactivates
Cytochrome P450 inhibition causes a decreased drug effect – IF metabolism ________ drug
activates
Define the role of drug efflux transporters.
Cell survival mechanism to pump unwanted substances out of the cell. Cell can increase the amount based on exposure over time.
1. Solute carrier (SLC) proteins - Passive transport via gradient
2. ABC gene family - ATP
Most drug efflux transporters are _______
ATP-binding cassette (ABC) transporters
3 major drug efflux transporters
B, C, G
List the components of the intact blood-brain barrier.
tight gap junctions
ABC transporters
Glial cells- astrocytes, podocytes
Where are neuron cell bodies of the autonomic system located?
outside the CNS (ganglia)
What are the subdivisions of the autonomic nervous system?
sympathetic, parasympathetic, and enteric
Chain ganglion are present in which NS? parasympathetic or sympathetic?
sympathetic
Where do sympathetic axons leave the CNS?
Thoracolumbar region
For sympathetic NS, preganglionic fibers are ________, while postganglionic fibers are _________.
preganglionic= short
postganglionic= long
For parasympathetic NS, preganglionic fibers are ________, while postganglionic fibers are __________
Preganglionic= long
postganglionic= short
Where do parasympathetic axons leave the CNS?
Craniosacral regions.
Most from brainstem, bladder and genitals from sacral
Which muscarinic receptors are excitatory?
M1, M3, M5
Which muscarinic receptors are inhibitory?
M2, M4
What neurotransmitter(s) acts on cholinergic receptors?
ACh
Which alpha receptors are stimulatory and what does it activate?
alpha 1, activates Gq protein, activates phospholipase C which activates secondary messengers IP3 and DAG
which alpha receptors are inhibitory and what does it inhibit?
alpha 2, inhibits adenylyl cyclase; leads to decreased cAMP
Where is the ganglia located in the sympathetic NS?
Close to the spinal cord
Where is the ganglia located in the parasympathetic NS?
In the visceral effector organs
What is the GPCR that alpha 1 activates? Effector?
Gq/G11 - activates phospholipase C
What is the GPCR that alpha 2 activates? Effector?
Gi - inhibits adenylate cyclase
What is the GPCR that beta activates? Effector?
Gs - stimulates adenylate cyclase
Where are alpha 1 receptors primarily found?
in the smooth muscle cell that surrounds the blood vasculature
What type of receptors are nicotinic receptors?
Ion channels
What type of receptors are muscarinic receptors?
GPCRs
Are Beta receptors inhibitory or stimulatory?
All beta receptors are stimulatory - stimulates adenylate cyclase, increasing cAMP
How does the activation of beta receptors work in the heart?
NE activates beta receptors - G stimulatory → stimulates adenylyl cyclase → increases cAMP → activates PK-A → more ICF Ca++ (from ECF and from sarcoplasmic reticulum) → contraction
How does the activation of beta 2 receptors work in the peripheral muscle?
NE binds to B2 in periphery → Increases cAMP → inhibit MLCK → no active myosin → relaxation - allows peripheral vessels to dilate
Compare the SNS vs PANS of the SA node and which receptors are present
SNS: accelerates SA node - B1 and B2
PANS: decelerates the SA node - M2
Compare the SNS vs PANS of the heart contractility and which receptors are present
SNS: increases heart contractility - B1 and B2
PANS: decreases heart contractility - M2
Compare the SNS vs PANS of bronchiolar smooth muscle and which receptors are present
SNS: relaxes bronchiolar smooth muscle - B2
PANS: contracts bronchiolar smooth muscle - M3
The ____ is the gap between the neuron and the cell
synapse
What is the role of the neuron?
Sends AP from neuron cell body to the telodendria (endpoints) capped with synaptic boutons (where neurotransmitters are stored)
info is coming into neuron through the _____
Dendrites
Action potentials are generated in the ________
axon hillock
What are the 6 Neurotransmitter Classes?
- Esters
- Monoamines
- Amino Acids
- Purines
- Peptides
- Inorganic gases
Give an example of an ester neurotransmitter
Acetylcholine (ACh)
Give an example of a monoamine neurotransmitter
NE, Serotonin, Dopamine
Give an example of an amino acid neurotransmitter
Glutamate, GABA, glycine
Give an example of a peptide neurotransmitter
Substance P, Endorphins - mediate pain and analgesia
Give an example of a purine neurotransmitter
Adenosine, ATP
Give an example of a inorganic gas neurotransmitter
Nitric oxide (NO)
NO is different than other neurotransmitters because it is not ______
stored - made as needed by nitric oxide synthase
Which drugs are esters of choline?
Ach, Methacholine, Succinylcholine (Sux), Carbachol, and Bethanechol
List Direct acting adrenergic agonists
albuterol
clonidine
dobutamine
dopamine
epinephrine
isoproterenol
norepinephrine
What drugs are indirect acting adrenergic agonists
amphetamine
What drug is both direct and indirect acting adrenergic agonist?
ephedrine
Which adrenergic receptor stimulates the heart?
B1
Which receptors does epinephrine act on
a1, a2, B1, B2
which receptors does norepinephrine act on?
a1, a2, B1
which receptors does isoproterenol act on?
B1, B2
which receptors does dopamine act on?
D1-5, higher doses: a1, B1
which receptors does dobutamine act on?
B1
Beta antagonists result in negative ________ & ________
inotropy, chronotropy
Differentiate between direct and indirect-acting cholinoceptor stimulants
Direct-acting - agonists of receptors (choline esters and alkaloids)
Indirect-acting - cholinesterase inhibitors, prolonging ACh in the synapse (reversible and irreversible)
Where are muscarinic receptors found?
Nerve, heart and smooth muscle, and glands and endothelium
Where are nicotinic receptors found?
Neuromuscular end plate, skeletal muscle, and autonomic ganglion cells
What are the indirect-acting cholinomimetics that we need to know?
Alcohols - edrophonium
Carbamates - neostigmine and pyridostigmine
Organophosphates - echothiophate
What is edrophonium used for and how long does it last?
Myasthenia gravis diagnosis, ileus, and arrhythmias; 5-15 min
What is the mechanism of indirect-acting cholinomimetics?
Targets ACh esterase (AChE), preventing the breakdown of ACh
How can an organophosphate covalent bond be broken?
Need a strong nucleophile - Pralidoxime
What are the 4 major therapeutic uses of indirect-acting cholinomimetics?
- Disease of the eye - glaucoma
- GI and urinary tracts - ileus
- Neuromuscular junction - MG and anesthesia
- Atropine overdose
What are the symptoms of overdose of direct-acting muscarinic stimulants?
SLUDGE-M: Need atropine
Salivation, lacrimation, urination, defecation, GI motility, emesis, myosis
What are the symptoms of overdose of cholinesterase inhibitors?
SLUDGE-M - need atropine and pralidoxime (organophosphate poisoning)
What are the indications for the use of atropine?
Blocks the parasympathetic response
- Bradycardia
- Poisonous mushrooms and organophosphate poisoning
What are the signs and symptoms of atropine overdose?
BRAND - blindness, redness, absent bowel sounds, nuts (CNS), dilated pupils
What is the treatment for atropine overdose?
Physostigmine - can produce dangerous CNS effects
Differentiate between direct acting and indirect-acting adrenergic agonists
Direct agonist - bind to receptors and illicit response
Indirect agonist - Increase amount of catecholamines in synapse; either facilitating removal or preventing reuptake
Alpha 1 vs alpha 2 effects
- α1: Gq → phospholipase C → increases IP3 and DAG
- contracts vascular smooth muscle, prostate contraction, heart - increases force of contraction
- α2: Gi → decreases cAMP
- inhibited transmitter release at adrenergic and cholinergic nerve terminals
Compare the effects of beta 1, 2, 3
Gs - all increase cAMP
- β1: increases force and rate of contraction (heart) and increases renin release (juxtaglomerular cells)
- β2: promotes smooth muscle relaxation at respiratory, uterine, and vascular smooth muscle
- β3: activates lipolysis in fat cells
Describe the mechanism of action for alpha 1 receptors
Describe what happens in the cardiovascular system after the administration of an alpha-agonist
- Increases vascular resistance/tone
- HR decreases (indirect effect)
- BP increases
Describe what happens in the cardiovascular system after the administration of a beta-agonist
- Decreases vasculature resistance/tone
- Increased contractility and HR
- BP decreases overall
Describe the effects of epinephrine
- Potent vasoconstrictor
- α receptors
- Cardiac stimulant (β1)
- Positive inotropic (force)
- Positive chronotropic (rate)
- β2 activation in some vessels
- Dilation of skeletal muscle vessels
- Dilation in bronchioles
Describe the effects of norepinephrine
- Effects on α and β1
- Little effect on β2
- Results
- Increase in systolic and diastolic
- Vagal reflexes overcome chronotropic effects
Describe the effects of isoproterenol
- Potent β agonist - vasodilator - heart
- Little effect on α receptors
- Results
- Increase cardiac output
- Fall in Mean arterial pressure
- Slight decrease or increase in systolic BP
Describe the effects of dopamine
Triphasic response:
- Low dose: Activates D1 receptors - vasodilation,
decrease in peripheral resistance
- Higher dose: mimics action of epinephrine; β1 receptors in the heart
- Highest dose: activates alpha, increases BP
Describe the effects of dobutamine
- β1 selective agonist
- Cardiac shock, acute heart failure
What is angina caused by
accumulation of metabolites due to myocardia ischemia
What drug is given for immediate relief of angina?
nitroglycerin
what type of angina is also known as Prinzmetal angina or vasospastic?
Variant angina
O2 delivery decreased due to coronary vasospasm
Which type of angina is classic angina
“angina of effort”
O2 requirement increases with activity, but coronary blood flow not enough, leads to O2 debt and ischemia with toxic metabolites
What drugs are good for angina prophylaxis?
calcium channel blockers and beta blockers
What type of angina is also known as “angina at rest”?
Unstable angina
microvascular disease s/t small patelet clots and atherosclerotic plaque
Which type of angina is an emergency?
unstable angina
Which type of angina is most rare?
variant
What is treatment of classic angina?
reduction of demand through beta blockers, calcium channel blockers
what is treatment of variant angina?
primarily calcium channel blockers to prevent , vasodilators/nitrates
How does NO lead to vasodilation?
NO activates guanylyl cyclase, which converts GTP to cGMP. cGMP dephosphorylates Myosin-LC leading to relaxation
What are the good effects from Nitrates and Nitrites?
Increased venous capacitance
decreased ventricular preload
decreased heart size
decreased cardiac output
What are the bad effects of nitrates and nitrites?
Headache (most common), orthostatic hypotension, syncope, reflex tachycardia, hemoglobin interactions (methehemoglobin = low affinity for oxygen)
Describe how Ca++ contributes to blood vessel contraction
- Ca++ binds to calmodulin (protein) → activates MLCK → MLC-P interacts with actin to contract
- cAMP inhibits MLCK
What are the different drugs that induce relaxation of vascular tone?
Ca++ channel blockers (prevent contraction)
K+ channel blockers (prevent depolarization)
B2 agonists (increase cAMP)
Nitrates (increase cGMP)
How are Beta Blockers used for angina treatment?
Not vasodilators - decrease oxygen demand
↓ HR
↓ BP
↓ Contractility
- more B2 receptors in micro-arteries → dilation
How do Ca++ channel blockers treat angina?
- L-type channel most dominant in cardiac and smooth muscle
- Drug binds to depolarized membranes
- Decreased opening frequency with drug binding
- relaxation and reduced BP in smooth muscle
- Heart: ↓ contractility, ↓ SA node pacemaker rate, ↓ AV node conduction velocity
What is an example of an irreversible alpha antagonist?
Phenoxybenzamine
What are the beneficial effects of beta blockers?
decrease oxygen demand,
decrease HR, BP and contractility
Calcium channel blockers target
L-type calcium channels of vascular smooth muscle and heart
Calcium channel blockers in smooth muscle cause
relaxation, reduce blood pressure
calcium channel blockers in heart cause
decrease contractility, decreased SA node pacemaker rate, decreased AV node conduction velocity
Which calcium channel blockers are more peripheral vascular selective?
Dihydropyridines (nifedipine, amlodipine, and nimodipine.)
which calcium channel blockers are more cardiac selective?
verapamil and diltiazem
What are toxicities of calcium channel blockers?
bradycardia, arrest
AV block
CHF
What are the 4 types of antihypertensive agents?
diuretics: deplete sodium
Sympathoplegics: decrease PVR, reduce CO
Direct vasodilators: relax VSM
Anti-angiotensins: block activity or production
What is the hydraulic equation?
BP= CO x PVR
Cardiac output is a function of
stroke volume, heart rate, venous capacitance (preload)
another word for preload is
venous capacitance
Which drugs are CNS sympathoplegics?
Methyldopa, clonidine
Which drugs are adrenoceptor antagonists
Propanolol, metoprolol, atenolol, prazosin, terazosin, doxazosin
Propanolol acts on which receptors?
B1 and B2
What are the effects of propanolol
Lowers BP, prevents reflex tachycardia
Decreases CO
Inhibits renin production
Which drugs are alpha 1 blockers?
Prazosin, Terazosin, Doxazosin
What are the effects of alpha 1 blockers?
block a1 receptors in arterioles and venules.
dilates both resistance and capacitance vessels
BP is reduced more in upright position
Which drugs are direct vasodilators
Minoxidil, hydralazine, sodium nitroprusside, fenoldopam
What is the mechanism of action of minoxidil
Opens K+ channels in smooth muscles, stabilizes
What are factors that affect blood pressure?
peripheral resistance
vessel elasticity
blood volume
cardiac output
Why is methyldopa better than clonidine for pregnant women?
Doesn’t cross the placental barrier like clonidine does
used for 2nd and 3rd trimester HTN
What are the 4 mechanisms of action of vasodilators? Give examples of drugs
What are the two main ways vasodilators lower BP?
- Relax smooth muscle of arterioles (all) and veins (nitroprusside and nitrates)
- Reduction of PVR and MAP - Elicits compensatory responses; Best when given in conjunction with other hypertensives that combat these mechanisms
Describe the effects of combination therapy of beta blockers and diuretics in lowering blood pressure
How does hydralazine lower BP?
Dilates arterioles – induces NO production in endothelium
What are the symptoms of hydralazine toxicity?
- HA, nausea, sweating, flushing
- Worse in slow acetylators (Symptoms resemble SLE)
How does Sodium Nitroprusside lower BP?
Relaxes vascular smooth muscle, dilating arterial and venous vessels
- Breaks down in blood to release NO
- Increases intracellular cGMP
What are the clinical indications for Sodium Nitroprusside?
HT emergencies and Cardiac failure
What is the upside and downside of Sodium Nitroprusside use?
Upside - Rapidly lowers BP; Effects disappear 1-10 min after d/c
Downside - CN accumulation, slowly eliminated by kidney
How does Fenoldopam lower BP?
Peripheral arteriolar dilator - Agonist of D1 receptors
- dilates renal vascular bed (lowers BP, diuresis)
What are the clinical indications for Fenoldopam use?
HTN emergencies, post-op HTN
What are the symptoms associated with Fenoldopam toxicity?
Reflex tachycardia, flushing, HA
How do Ca++ channel blockers lower BP?
Dilate peripheral arterioles by inhibiting Ca2+ influx in arterial smooth muscle
Which Ca++ channel blockers target the heart vs the periphery?
- Verapamil - more targeted to heart
- Diltiazem - both heart and periphery
- Dihydropyridine family - more targeted to periphery
What are the types of Inhibitors of Angiotensin?
ACE inhibitors (-pril)
Angiotensin competitive inhibitors (angiotensin receptor blockers, ARB) (-artan)
______ is the prototype drug of ACE inhibitors
Captopril
Renin release in kidney stimulated by what 4 mechanisms?
- Reduced arterial pressure
- Reduced sodium delivery
- Increased sodium concentration
- Sympathetic stimulation (beta receptors)
Why is a persistent, non-productive cough a symptom for ACE inhibitors but not ARBs?
ARBs have no effect on bradykinin - no cough
ACE inhibitors - inhibit breakdown of bradykinins, which stimulate PG synthesis - excess bradykinin causes non-productive cough
Which angiotensin inhibitors do we need to know?
ACE inhibitors - Captopril
Angiotensin receptor blockers – Losartan, Valsartan
What are the first line drugs for HTN?
- Low dose diuretic
- Beta blocker
- CCB
- Dual therapy
Define heart failure
Heart fails to meet the metabolic demands of tissues - CO inadequate
What is the most common cause of heart failure?
Coronary artery disease
Differentiate between systolic and diastolic heart failure
Systolic failure – reduced cardiac function
- Acute; heart walls thinned (less effective pumping)
↓ CO, ↓ Ejection fraction
Diastolic failure – reduced cardiac filling (can be peripheral)
- Chronic; heart more stiff/thicker walls (chronic HTN)
- ↓ CO, Normal Ejection fraction
- Does not respond well to positive inotropic drugs
Differentiate between symptoms of right vs left ventricular failure of CHF
Right ventricle – peripheral congestion
Left ventricle – pulmonary congestion
What are the 4 factors of cardiac performance?
CO = SV x HR
- Preload
- Afterload
- Contractility
- Heart Rate
Heart failure where the normal CO not sufficient for demands of body
“High-output” failure (rare)
- Hyperthyroidism
- Beriberi
- Anemia
- Arteriovenous shunts
Responds poorly to inotropic agents – treat underlying cause
In systolic heart failure, CO is ______ and ejection fraction is _______
decreased, decreased
In diastolic heart failure, CO is ______ and ejection fraction is _______
decreased, normal
Systolic heart failure responds ______ to positive inotropes
well
Diastolic heart failure responds _______ to positive inotropic drugs
poorly
Digoxin mechanism of action
Directly inhibits Na/K ATPase
maintains normal resting potential, positive inotrope
Digoxin has a ____ therapeutic index
narrow
What are ways to decrease preload?
salt restriction, diuretics, venodilation (Nitroglycerin)
Discuss the normal control of cardiac contractility
- Trigger Ca++ enters cell
- depends on number of L type channels, duration of channel opening, and sympathetic stimulation - Binds to channel is SR, release stored Ca++
- depends on amount stored and amount of trigger Ca++ - Frees actin to interact with myosin
- Removal of Ca++
- SR Calcium ATPase
- Na+/Ca2+ antiporter – sodium gradient
- Na+/K+ ATPase: removes sodium
What are the EKG changes that occur with digoxin toxicity?
tachycardia, fibrillation, arrest
What effect does hyperkalemia have on digoxin effects?
- Potassium competes with digoxin
- Excess K+, decreased effect
What effect does hypomagnesia have on digoxin effects?
Increased risk of digoxin induced arrhythmias
How do phosphodiesterase inhibitors help treat HF?
Enzymes that inactivate cAMP and cGMP - positive inotropic effects, vasodilation
Increase contractility w/o inhibiting Na+/K+ ATPase (increase/prolong Ca++)
PDE3 specific
The pacemaker of the heart is _______ and is located in the ________
SA node, right atrium
The SA node fires at a rate of
75bpm
Where is the AV node located
junction of the atria and ventricles
where is the atrioventricular bundle/bundle of His located
in the interventricular septum
Where are the purkinje fibers located
spread within the muscle of the ventricle walls
how fast does the AV node fire
40-50bpm
In phase 0 of the cardiac AP, which ions are moving, which direction, and through which channels
Na+, in, fast VG Na channels
In phase 1 of the cardiac AP, which ions are moving, which direction, and through which channels
K+ and Cl- moving out through leak channels
In phase 2 of the cardiac AP, which ions are moving, which direction, and through which channels
Ca++ moving in through L type Ca++ channels
K+ moving out through slow delayed rectifier channels
In phase 3 of the cardiac AP, which ions are moving, which direction, and through which channels
K+ moving out through slow delayed rectifier channels, rapid delayed rectifier channels and inward rectifier channels
Phase 4 of the cardiac AP is the
Vrm, resting membrane potential
What are the types of disturbances in impulse conduction that result in arrhythmias?
- Block
- Reentry
Describe the reentry block and “circus movement”
One impulse “circles around” and re-excites areas more than once
What must happen in order for reentry to occur?
- There must be an obstacle (scar tissue)
- Block must be unidirectional
- Conduction time must be long enough to reenter same areas after refractory period
What are the 4 classes of antiarrhythmic agents?
Vaughan-Williams classification:
- Class I – sodium channel blockade
- Class II – sympatholytic (beta blockers)
- Class III – prolong action potential duration (other mechanisms besides sodium channels – K+)
- Class IV – block cardiac calcium channel currents
What are the 3 subclasses of Class I antiarrhythmic agents?
IA, IB, IC
What meds are included in Class IA antiarrhythmic agents? What are the effects on APD and ERP? What are the cardiac effects?
Quinidine (Procainimide, Disopyramide)
- Prolong the action potential duration (APD)
- ↑ Effective Refractory Period (ERP)
- Cardiac effects: Depresses pacemaker rate, Lengthens QT interval, Depresses conduction and excitability
What meds are included in Class IB antiarrhythmic agents? What are the effects on APD and ERP?
Lidocaine
- Shorten the APD
- ↓ ERP
What meds are included in Class IC antiarrhythmic agents? What are the effects on APD and ERP?
Flecainide
- Minimal effects on APD
- Slow dissociation
- No effect on ERP (But Na+ channels are still blocked)
Which drug is the only antiarrhythmic with all 4 Vaughan-Williams’ class effects
Amiodarone
What is the drug of choice for VT
amiodarone
What meds are included in Class II antiarrhythmic agents? How do these agents work as antiarrhythmics?
Beta blockers - propanolol and esmolol (short acting)
- Antiarrhythmic properties associated with direct membrane effects - Exact antiarrhythmic action unknown
- Suppress ventricular ectopic depolarization
- Prevent infarction and sudden death in patients recovering from acute MI
What meds are included in Class III antiarrhythmic agents? How do these agents work as antiarrhythmics?
Amiodarone (VT) and dronedarone (A-fib)
Prolong AP usually by:
- Blocking cardiac K+ channels
- Enhancing inward current (Na+ or Ca2+ channels)
What meds are included in Class IV antiarrhythmic agents? How do these agents work as antiarrhythmics?
Calcium channel blockers - verapamil
- Prolongs AV node conduction
- Slows SA node
- Hypotensive action
- Useful for supraventricular arrhythmias
- Can reduce ventricular rate in atrial fibrillation and flutter
What is the treatment for symptomatic bradycardia?
1st - atropine
2nd - epi, dopamine
What is the treatment for chronic bradycardia?
pacemaker
What is the treatment for symptomatic heart block?
atropine and transcutaneous pacing
What is the treatment for chronic heart block?
pacemaker
What is the treatment for symptomatic SVT?
adenosine
What is the treatment for chronic SVT?
CCBs, beta blockers
What is the treatment for symptomatic sinus tachycardia?
Adenosine, CCBs, cardioversion
What is the treatment for chronic sinus tachycardia?
catheter ablation
What is the treatment for symptomatic Vtach?
amiodarone
What is the treatment for chronic Vtach?
amiodarone, satolol
(jesus)
What is the treatment for symptomatic Afib?
diltiazem, verapamil
What is the treatment for chronic Afib?
beta-blockers, amiodarone
What is the treatment for symptomatic Vfib?
CPR, defirillation
What is the treatment for chronic Vfib?
amiodarone, lidocaine, magnesium
What are the Proximal Tubule Targets?
NaCl and NaHCO3
Which drugs target Proximal Tubule Targets?
Carbonic anhydrase inhibitors (block NaHCO3 reabsorption)
Caffeine (weakly blocks adenosine receptors in PCT (Na+))
The _______ loop of henle is responsible for water reaborption
descending
The ______ loop of henle is impermeable to water
ascending
What is the pump that transports NaCl and K in the ascending loop of henle?
NKCC2 - sodium, potassium, 2 chloride
- all pumped from urine to thick ascending limb
The excess ____ in the urine of the ascending loop of henle drives ____ out of the urine and into the blood
K+ (charge gradient)
Mg++ and Ca++
What is the MOA of loop diuretics? What is an example?
Selectively inhibit NaCl reabsorption in the thick ascending limb (TAL)
- Reduction in NaCl absorption
- Diminish lumen positive potential - Increase secretion (loss) of Mg2+ and Ca2+ in urine
Lasix
Carbonic anhydrase inhibitors ___ pH, while loop diuretics and thiazides ___ pH
Decrease, increase
What diruertics should be avoided in patients with sulfa alergies?
Loop diuretics (lasix) and thiazides (HCT)
What is the MOA of thiazides?
- Inhibit NaCl transport in DCT
- Some inhibition of CA activity
- HCT
What is reabsorbed in the distal convoluted tubule? By what?
Ca++, by PTH
What is the role of the principal cells in the collecting tubule?
Builds up (-) charge in lumen
- more Na+ in than K+ out
- drives Cl- out through paracellular route
Diuretics upstream result in excess ___ in CT
Na+
What is the effect of aldosterone at the collecting tubule?
Increase Na+ and water reuptake (ENaC) - increasing BP and vol
K+ sparing diuretics work by what MOA?
- Antagonize the effects of aldosterone - spironolactone
- Inhibition of sodium flux through ion channels in luminal membrane - amiloride
What parts of the nephron are freely permeable to water?
PCT and descending loop
ADH agonist vs antagonist
- Agonist: Vasopressin
- Antagonist: Conivaptan
ADH (vasopressin) effects at the collecting duct
- Increases water reabsorption
- Adds preformed AQP2 to apical membrane
- Increases blood volume
- Makes more concentrated urine
What are the classes of diuretics?
- Carbonic Anhydrase Inhibitors
- Loop Diuretics
- Thiazides
- Potassium Sparing Diuretics
- Osmotic diuretics
Mannitol is an example of what type of diuretic
osmotic diuretic
Osmotic diuretics are mainly used to
reduce ICP
promote removal of renal toxins
Toxicity of mannitol includes
extracellular volume expansion and dehydration
What are the meds given for asthma progression?
Mild - SABA
Moderate - ICS or LTRA
- ICS for relief
Severe - oral corticosteroids, anti-IgE antibody
What are the 3 classes of short-term relievers in obstructive airway diseases?
- B2 agonists
- Methylxanthines
- M3 antagonists
Short term relief drugs for Asthma are
Bronchodilators:
beta agonists
Antimuscarinics
Methylxanthines
Long term controllers for asthma include
Anti-inflamatory agents:
steroids
antibodies
slow anti-inflammatory drugs
Leukotriene antagonists:
lipoxygenase inhibitors
Receptor inhibitors
What are the mediators in the autocoid group?
Histamine, serotonin, prostaglandins, leukotrienes
_____ is the mediator of allergic and inflammatory response
histamine
Where are histamine H2 receptors located?
GI, cardiac muscle, mast cells, brain
Where are histamine H4 receptors located?
eosinophils, neutrophils, CD4 T cells
What is the physiologic antagonist of histamine?
Epinephrine
Differentiate between H1 antagonists, 1st vs 2nd gen
1st generation
- Sedative effects
- ANS blocking
- motion sickness, nausea
2nd generation
- Less sedation (↓ CNS distribution, doesn’t cross BBB)
What are the 3 components of the triple response of allergy testing?
1- Wheal/welt development
2- flare/redness
3- Sensory nerve ending activation/itching
Histamine is released in response to what?
- Allergen binding to IgE on mast cells
- Displacement – morphine, tubucurarine
- Rupture of mast cells (mechanical)
Which histamine receptor causes bronchoconstriction and vasodilation
H1
Antihistamines are ____ selective inverse agonists
H1
diphenhydramine (Benadryl)
most useful for type 1 hypersensitivities
1st generation H1 receptor antagonists are used also used for
Sedation: resembles antimuscarinic drugs, sleep aids, children may have reverse effects
Antinausea/antiemetic: motion sickness
Antiparkinsonism: suppress extrapyramidal symptoms
Local anesthesia: block sodium channels in excitable membranes
Other: inhibition of mast cell release, negative feedback?
H2 receptor antagonists are used for
stomach ulcers, acid reflux/GERD. Not as effective as PPIs
What is the slow reacting substance of anaphylaxis?
leukotrienes
Where are leukotrienes liberated from?
lung during inflammation
Leukotrienes produce (GPCR)
Bronchospasm, mucous secretion, microvascular permeability, airway edema
Which drugs are leukotriene pathway inhibitors
interupt synthesis pathway:
inhibit 5-lipoxygenase = Zileuton
inhibit binding to receptor= Zafirlukast, Montelukast (Singulair)
What are the 3 drugs that are 2nd gen H1 antagonists?
Claritin, Allegra, Zyrtec
Histamine effect on on respiratory system
Bronchoconstriction
Where is serotonin produced?
Raphe nuclei
Serotonin effect on CV
- Contraction of vascular SM
- Exception: skeletal muscle, heart
- Platelet aggregation
Serotonin effect on GI
- Increases tone
- Facilitates peristalsis
- Overproduction - diarrhea
Serotonin effect on respiratory
- Facilitate ACh release - constriction
- Hyperventilation
Serotonin effect on nervous system
- Melatonin precursor
- Vomiting reflex
- Pain and itch (similar to histamine)
- Chemoreceptor reflex
- Bradycardia
- Hypotension
Which serotonin receptor is an ion channel?
5-HT3
- the other 6 are GPCRs
Which serotonin receptors are agonist targets?
1A, 1B, 1D
Which serotonin receptors are antagonist targets?
2A and 3
What are the 2 serotonin agonist drugs? Which receptors do they target? What do they treat?
- Buspirone
- 5-HT1A agonist (partial)
- Non-benzodiazapine anxiolytic - no drowsiness
- GAD, OCD - Sumatriptan
- 5-HT1D/1B agonist
- Migraine HA
How do triptans treat migraines?
- Bind 5-HT1D/1B in cranial blood vessels
- Prevent dilation and stretching of pain endings
- Not prophylactic
What are the 3 hyperthermic syndromes? and their treatments?
- Serotonin syndrome = Sedation (benzo), paralysis, intubation/ventilation
- Neuroleptic malignant syndrome= benadryl, cooling, sedation
- Malignant hyperthermia= dantrolene, cooling
What drugs can cause serotonin syndrome?
Antidepressants (SSRIs, SNRIs, MAOIs), opioids, illicit drugs, St. John’s wort, ginseng
What drugs can cause neuroleptic malignant syndrome?
D2-blocking antipsychotics
What drugs can cause malignant hyperthermia?
Volatile anesthetics, sux
What are the 3 drugs classified as serotonin antagonists? What receptors do they act at? What is their clinical use?
Phenoxybenzamine, Cyproheptadine
- 5-HT2
- Carcinoid tumors
- Cold induced urticaria
Ondansetron
- 5-HT3
- Prevent N/V for Surgery and CA chemotherapy
What are the 4 major classes of antidepressants?
- Selective serotonin reuptake inhibitors (SSRIs)
- Selective serotonin-NE reuptake inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs)
- Monoamine oxidase inhibitors (MAOIs)
Focal seizure treatment is
Lamotrigine, phenytoin, phenobarb, carbamazepine
Absence seizure treatment is
Ethosuxamide, valproic acid, benzo
Treatment for infantile spasms
carbamazepine, Vigabatrin
treatment for generalized seizures
phenytoin, phenobarb, carbamazepine, benzo
Which drug can displace phenytoin from albumin binding sites?
valporic acid
Which drugs compete with phenytoin for albumin binding sites?
Carbamazepine, sulfonamides, valporic acid
Differentiate between therapeutic, free, toxic, and lethal levels of phenytoin
- Therapeutic: 10-20 mcg/ml
- Free phenytoin: 1-2.5 mcg/ml
- Toxic: 30-50 mcg/ml
- Lethal: >100 mcg/ml
What are the toxic effects of phenytoin?
- Nystagmus
- Loss of extraocular pursuit of movement
- Diplopia
- Ataxia
- Sedation
What are the toxic effects of phenytoin with chronic use?
- Gingival hyperplasia
- Hirsuitism
- Coarsening of facial features
What is the #1 toxic effect of phenobarbital?
SEDATION
What are the 4 phases of thrombogenesis?
- Adhesion
- Aggregation
- Secretion
- Cross-linking of adjacent platelets
What is the blood vessel involvement in thrombogenesis
vasoconstriction, formation of platelet plugs, regulation of coagulation and fibrinolysis
What are the 2 parts to platelet adhesion?
- vWF binds to GP 1b receptor
- collagen binds to GP 1a receptor
Describe the coagulation pathway Dr. T wants us to know for final
____ is the over stimulation of the blood clotting mechanism
DIC - Disseminated coagulation
What are the 3 results of DIC?
- Generalized blood coagulation
- Excessive consumption of factors and platelets
- Leads to spontaneous bleeding
What are the 4 causes of DIC?
- Massive tissue injury
- Malignancy
- Bacterial sepsis
- Abruptio placentae
How is DIC treated?
Plasma transfusions and treat the underlying cause
10-50% mortality
What are the 2 major systems of coagulation regulation?
- Fibrin inhibition
- Fibrinolysis
What are the 4 classes of coagulation modifier drugs?
- anticoagulants
- anti-platelets
- thrombolytic drugs (fibrinolytic)
- hemostatic or antifibrinolytic drugs
Indirect thrombin inhibitors
Enhances antithrombin activity
-unfractionated heparin (HMW)
dec. thrombin, Xa
HIT, bleeding-treat with protamine
-LMW heparin
dec. Xa
-Fondaparinux
dec. Xa
Direct thrombin inhibitors
Bind to both active and substrate recognition sites of thrombin:
-Hirudin (from leeches) and lepirudin (recombinant)
-Bivalirudin (angiomax)
Bind only to thrombin active sites:
-argatroban
-melagatran
Warfarin MOA, onset, and therapeutic range
inhibits Vit K cycling
8-12hr delay in onset
therapeutic range defined by INR
Normal=0.8-1.2
Warfarin target= 2-3
How do fibrinolytics work?
Catalyze the formation of serine protease plasmin and rapidly lyse thrombi
What are the 3 fibrinolytics?
Streptokinase
Urokinase
Tissue plasminogen activators (t-PA)
What is the recombinant form of Tissue plasminogen activators (t-PA)?
Alteplase
What do fibrinolytic drugs treat?
MI and PE
What are the 3 antiplatelet aggregation drugs?
aspirin
clopidogrel
abciximab
MOA of aspirin
Inhibition of TXA2 synthesis, COX-1 Selective
platelet changes shape, granule release, aggregation
MOA of clopidogrel
Irreversibly inhibit ADP receptor on platelets
MOA of Abciximab
IIb/IIIa Receptor Blocker - Activation of this receptor complex in the final common pathway
What are the 5 drugs used to treat bleeding disorders?
- Vitamin K
- Plasma Fractions
- Desmopressin Acetate
- Aminocaproic acid
- Tranexamic Acid (TXA)
Vitamin K confers activity on what?
- Prothrombin
- Factors VII, IX, and X
What is the fibrinolytic inhibitors?
Aminocaproic acid
- inhibit plasminogen → plasmin
What are the 2 major types of secretory tissues of the pancreas?
Exocrine gland (digestive enzymes)
Endocrine gland (Islets of Langerhans)
What are the 2 main pancreatic cell types
Alpha and Beta
What do the alpha Islets of Langerhans cells secrete?
glucagon and proglucagon
What do the beta Islets of Langerhans cells secrete?
insulin, C-peptide, proinsulin, amylin
Insulin receptors are _____
RTKs - receptor tyrosine kinases
What are the 4 types of diabetes mellitus?
Type I - Insulin dependent
Type II - Non-insulin dependent
Type III - Other causes elevated blood glucose (pancreatitis, drug therapy, etc.)
Type IV - Gestational
The proform of insulin contains ______ which is _____ before entering the bloodstream
C-peptide
cleaved off
C-peptide is a measure of how much _____ function a patient has
beta cell
Describe the effects of inward movement of glucose into pancreatic beta cells via GLUT2 transporters
excess glucose converted into ATP via metabolism → higher level of ATP binds to potassium channel - closing the channel → more positive Vrm → calcium channels open up → calcium enters beta cell → calcium triggers vesicle fusion and insulin exocytosis
When insulin binds to insulin receptors, what occurs inside the cell?
Glucose transporters migrate to cell surface
Increased glycogen formation
Activation of multiple transcription factors
What are the 4 types of insulin preparations?
- Rapid acting
- Short acting (regular)
- Intermediate acting
- Long acting
What is the MOA of Biguanides?
Reduction in hepatic glucose production
- gluconeogenesis: making glucose from other things
What is the MOA of insulin secretagogues?
Bind to K+ channel
- Rectifier current
- Binding causes depolarization and additional release of insulin
What are the 3 classes of Insulin Secretagogues?
- Sulfonylureas
- Meglitinide
- Phenylalanine derivatives
What is the MOA Thiazolidinediones (TZDs)?
- Decrease insulin resistance (PPAR mediated)
- Increase insulin signal transduction
What is the MOA of α-glucosidase Inhibitors? What is the medication called?
Block digestion of complex carbohydrates - more beneficial for people have primary carbohydrate diet
Acarbose
What is the MOA of Bile Acid Sequestrant?
Surrounds food, preventing absorption
- Large cation exchange resins – not absorbed
- Bind bile acids – prevent reabsorption
What is the MOA of Amylin Analogs?
Suppresses glucagon release, decreases circulating glucose
What is the MOA of Incretin-based Therapies?
Mimicking a substance normally produces by intestines
What are the 2 types of Incretin-based Therapies?
- Glucagon-Like Polypeptide-1 (GLP-1) Agonists - Semaglutide
- Dipeptidyl Peptidase-4 (DPP-4) Antagonists - Sitagliptin
What is the MOA of SGLT2 Inhibitors (Gliflozins)?
Prevents glucose reabsorption in PCT
- specifically inhibits SGLT2
- increased glucosuria
Describe the cycle of atherosclerosis in LDLs
LDL entry and enlargement → foam cell formation → cholesterol crystallization in foam cells → apoptosis of foam cells and extracellular lipid deposit → plaque with lipid-rich necrotic core
What is the 3 part synthesis of cholesterol in cells
- Mevalonate from Acetyl-CoA
- Conversion of mevalonate to squalene
- Cyclication of squalene to cholesterol
What are the 4 types of lipoproteins?
chylomicrons, VLDLs, LDLs, and HDLs
Which type of lipoproteins are formed in the intestine and end up in the liver?
Chylomicrons
Which type of lipoproteins are secreted by the liver and travel to peripheral tissues?
VLDLs
Which type of lipoproteins transport cholesterol from the liver to the cells, resulting in deposition in arteries in excess?
LDLs
Which type of lipoproteins scavenge cholesterol from cells, resulting in decreased levels of atherosclerosis?
HDLs
Desirable lipoprotein levels
What are the 6 classes of hyperlipidemia drugs?
- Statins
- Niacin
- Fibrates
- Binding Resins
- Absorption Inhibitors
- Monoclonal Antibodies
What is the MOA of statins?
Structural analogs of HMG-CoA- decrease cellular cholesterol synthesis by inhibiting HMG-CoA reductase
What are the effects of statins?
- Mostly reduce LDL
- Increase LDLR
- Modest decrease of triglycerides
- Small increase in HDL
What is the toxicity of statins?
- Elevated liver enzymes - Increased with liver damage, patients of Asian descent
- CK elevations - Muscle pain or weakness
What are the effects of niacin?
- Decreases VLDL, LDL - Reduces VLDL secretion from liver
- Increases HDL
What is the toxicity of niacin?
1 - Cutaneous vasodilation (flushing)
- Pruritis, dry skin, rash
- N, abdominal discomfort (rare)
- Elevation of liver enzymes
What is the name of the medication that is a fibrate?
Gemfibrozil (Lopid)
What are the effects of fibrates?
- Decrease VLDL
- Modest decrease in LDL
- Increase lipolysis in liver - PPAR
What are toxicities of fibrates
Rare, include:
GI upset
arrhythmias
elevated liver enzymes
potentiation of comadin
myopathy
What are the 2 drugs that are bile acid binding resins?
Colestipol, cholestyramine
What are the side effects of bile acid binding resins?
- Constipation, bloating
- Steatorrhea (lipid in stool)
What is the medication considered an intestinal sterol absorption inhibitor?
Ezetimibe (Zetia)
What is the MOA of Ezetimibe?
Blocks the NPC1L1 transporter that transports cholesterol transport from the lumen into the enterocyte
Monoclonal antibodies used to treat hyperlipidemia are called ___________
PCSK9 Inhibitors
Monoclonal antibodies used to treat hyperlipidemia are called ___________
PCSK9 Inhibitors
How do PCSK9 inhibitors combined with statins lower LDLs? By how much?
Statin therapy upregulates PCSK9
PCSK9 inhibitors allow receptor recycling
65%
List the antibiotics that work by inhibiting cell wall synthesis. Describe their MOA
- Penicillin, ampicillin, and amoxicillin
- Cephalosporins
- Carbapenems
- Vancomycin
ß-lactam ring attaches to the enzymes that cross-link peptidoglycans and prevent cell wall synthesis (Gram +)
Which antibiotic is considered the “drug of last resort”? What is it used for?
Vancomycin
- Alternative to PCN resistant bacteria (MRSA)
Adverse reactions of vancomycin
Tissue irritation
Ototoxicity
Nephrotoxicity
“Red neck” syndrome
What are the 2 antibiotics that work by disrupting the cell membrane? What is their MOA?
- Polymyxin and Daptomycin
- Polypeptide antibiotics
- Act as detergents – bind to phospholipids
- Best action – Gram (-)
List the antibiotics that inhibit protein synthesis. What is their MOA?
Tetracycline
Macrolides (Erythromycin, Azithromycin)
Neomycin
- Attack bacterial cells without significantly damaging animal cells - wide spectrum
_______ have the widest spectrum of activity of any antibiotics
Tetracyclines
What is the main side effect of antibiotics that inhibit protein synthesis?
GI
What are the antibiotics that work by inhibiting nucleic acid synthesis? What is their MOA?
Rifamycin family - binds to bacterial RNA polymerase
Fluoroquinolones (Ciprofloxacin) - Inhibit DNA gyrase (bacterial)
What are fluoroquinolones used to treat?
- UTI, RTI
- Bone and joint infections
- ADR
- Excellent Gram (-) activity
What are the 2 antibiotics that work by inhibiting folic acid synthesis?
Sulfonamides, trimethoprim
What are the 2 ways antibiotics can function to inhibit folic acid synthesis?
- Competitive inhibition
- Incorporated into important molecules
What do folic acid synthesis inhibitors treat?
Pneumocystis, toxoplasmosis
Viruses are considered ______ instead of organisms
infectious particles
Define how viruses are considered obligate intracellular parasites
- Cannot multiply unless they invade a specific host cell
- Must instruct the genetic and metabolic machinery of the host cell to make and release new viruses
Instead of being alive or dead, viruses are what?
Active or inactive
What 2 parts do viruses have that are required to invade and control a host cell?
- External coating (capsid)
- Core containing nucleic acids
A naked virus only consists of a ______
nucleocapsid
The _______ is usually a modified piece of the host cell membrane
Envelope
A _______ is the protein shell that surrounds the nucleic acid
Capsid
Which drug is considered the prototype for antiviral drugs that inhibit viral DNA synthesis?
Acyclovir
When viruses mistakes acyclovir for dGTP, _______ is irreversible
chain termination
What does acyclovir look similar to? What is the difference?
the normal nucleotide bases - missing hydroxyl group
Acyclovir is _______ for pregnant women
safe
What are the 3 indications for acyclovir therapy?
HSV1, HSV2, and VZV infections
What is the main drug used to treat HIV?
Zidovudine (Azidothymidine, AZT)
What is the MOA of Zidovudine (Azidothymidine, AZT)?
Inhibitor of reverse transcriptase
What is the drug combination therapy called to treat HIV?
Highly Active Antiretroviral Therapy (HAART)
What is the MOA of lamivudine?
Inhibits HBV DNA polymerase and HIV reverse transcriptase
HIV targets which cells? and with which spike?
T-cells - CD4+
gp120 spike
The cell surface antigen that has a role in virus attachment to cells is ________
hemagglutinin (H1, H2, H3)
The cell surface antigen that has a role in virus penetration to cells is ________
neuraminidases (N1, N2)
Influenza subtypes are determined by what?
cell surface antigens hemagglutinin and neuraminidase
Differentiate between Influenza Type A and Type B
A - Causes moderate to severe illness; Affects all age groups
B - Milder illness; Primarily has had an impact on adolescents and schoolchildren
What are the 3 antivirals used to treat influenza?
Oseltamivir phosphate (Tamiflu)
Zanamivir (Relenza)
Baloxivir marboxil (Xofluza)
Which antiviral for the treatment of the flu must be taken when exposed?
Relenza
The hallmark of Parkinsonism is ______
Tremor at rest
______ is rhythmic movement around a joint
tremor
______ is muscle jerks in various areas that impair movement and coordination
Chorea
______ is a type of chorea that includes violent abnormal movements
Ballismus
______ - slow, writhing/twisting
Athetosis
______ – abnormal posture
Dystonia
____ – Single repetitive movements, especially of face
Tics
Choreathetosis combines which 3 involuntary movements?
Chorea, athetosis, and dystonia
Which neurotransmitter does the Substantia nigra release to control the thalamus?
Dopamine
What are the symptoms of Parkinsons?
TRAP
- Tremor
- Rigidity
- Akinesia
- Postural instability
- Cognitive decline
What is the pathogenesis of Parkinsons?
Dopaminergic neuron degradation
- Nigro-striatal pathway
- Decreased dopamine levels
What is the main gene associated with Parkinsons?
SNCA - α-Synuclein (neurotransmitter release)
What are the 3 main methods of treating Parkinsons?
- Exercise – physical therapy
- Restore dopamine levels – Levodopa
- CNS Antimuscarinics – control dopaminergic release
-Dopamine receptor agonists- Pramipexole, Ropinirole, Rotigotine
-MAOIs- Selegiline, Rasagiline
-COMT inhibitors- Tolcapone, Entacapone
-Apomorphine (for “off” periods, akinesia)
What should be avoided in Parkinsons treatment?
- Dopamine receptor antagonists (antipsychotic agents)
- MPTP – destroys dopaminergic neurons - Impurity in some illicit drugs (synthetic opioids)
What is the main adverse effect of L-DOPA? What is the treatment?
Hallucinations and delusions
Pimavanserin (Nuplazid) – antipsychotic
What is the MOA of Pimavanserin (Nuplazid)?
Antipsychotic - Inverse agonist at 5-HT2A – Visual cortex
What is the onset and symptoms of Huntington’s disease?
- Onset – age 30-40
- Progressive loss of muscle control, Chorea, Dementia, Death – 15-20 years after onset of symptoms
What is the cause of Huntington’s disease?
- GABA reduced in basal ganglia
- Reduction in Choline acetyltransferase (ChAT)
What are the treatments for Huntington’s disease?
- Tetrabenazine - Depletes dopamine
- Dopamine Receptor Blockers - Haloperidol
- Genetic counseling, speech therapy, PT/OT
What are the 2 pathways of arachidonic acid?
- Cyclooxygenase pathway - Arachidonic acid (AA) converted to prostaglandin by COX
- Lipoxygenase pathway - AA converted to leukotrienes by lipoxygenase
Differentiate between COX1 and COX2
COX1 - constitutive, wide distribution, homeostatic functions (platelets, GI, renal)
COX2 - expression is stimulus-dependent, facilitates inflammatory response
What is the original NSAID?
Aspirin
Which NSAIDs inhibit COX and lipoxygenase?
Indomethacin and Diclofenac
Which 2 NSAIDs inhibit COX1 < COX2?
Celecoxib and Meloxicam
Acetaminophen is used when ___________ effect of NSAIDs isn’t required
anti-inflammatory
What are the 5 mediators released during chronic inflammation?
- Interleukins
- GM-CSF
- TNF
- Interferons
- PDGF
All increase WBCs
What are the indications for indomethacin?
- Rheumatism
- Gout
Patent ductus arteriosus
Differentiate between acute and chronic effects of glucocorticoid use
acute - suppresses inflammation, salt and water retention, improved cognitive function, mobilizes energy stores
chronic - immunosuppression, diabetes, depression, HTN
glucocorticoid transcription
what is a DMARD
Disease modifying anti-rheumatic drug
Measures:
-reduced inflammation
-Decreased damage to bones and joints
Often given in conjuction with NSAIDs
Biologic DMARDs
Abatacept, Rituximab, Adalimumab
Non-biologic DMARDs
Methotrexate, Cyclophosphamide, Cyclosporine
Transmission of sensation
- interpret pain in the somatosensory cortex
- 3 main types of afferent neuron fibers:
- A beta - all cutaneous mechanoreceptors, highly myelinated
- A delta - sharp pain, initial reflex, highly myelinated
- C - slow, burning pain, unmyelinated
Gate Control Theory of Pain
- “Gates” in spinal cord allow pain signal through
- Gates can be adjusted - A and C can suppress each other depending on strength of stimulus
- Increase or decrease pain sensation
Noxious chemicals
- Tissue damage – bradykinin
- Receptors – B1 (inflammatory) and B2 (constitutive)
- Activate PLA and PLC
- AA Cascade – COX and LOX
- Prostaglandins
What are the different pain pathways and gate theory?
- spinothalamic - primary pain pathway
- spinoreticular - emotional pain sensation
- spinomesencephalic - terminates in periaquaductal grey matter → mu opioid receptors
Gate Control Theory of Pain
- “Gates” in spinal cord allow pain signal through
- Gates can be adjusted - A and C can suppress each other depending on strength of stimulus
- Increase or decrease pain sensation
What are the 3 opioid receptor subtypes?
μ (mu), δ (delta), and Κ (kappa)
What is the medication that is a μ (mu) receptor antagonist?
naloxone (Narcan)
What are the 2 medications that are μ (mu) receptor partial agonists?
codeine, oxycodone
What are the 2 medications that are μ (mu) receptor full agonists?
morphine, fentanyl
Pharmacokinetics of opioids: absorption
Well absorbed (IM, SQ, Oral)
- Nasal, patch – avoid first pass effect
- Codeine: low 1st pass metabolism
Pharmacokinetics of opioids: distribution
Highly perfused tissues – accumulation
- Brain, heart, kidney, liver
- Skeletal muscle – reservoir
Pharmacokinetics of opioids: metabolism
Varied:
- Morphine – Phase II to active forms (M3G, M6G)
- Esters (heroin) – tissue esterases to morphine
- Other – Phase I (CYP3A4, CYP2D6)
Pharmacokinetics of opioids: excretion
Mainly in urine
What is the MOA of opioids?
- Bind to receptors in brain and spinal cord
- Modulation of pain
- Receptor effects
- Reduce neurotransmitter release (Glutamate, ACh, NE, serotonin, substance P)
- Hyperpolarize postsynaptic neurons
What are the 6 CNS effects of opioids?
- Analgesia – sensory and emotional aspects
- Euphoria (dysphoria)
- Sedation
- Respiratory depression - brainstem
- Cough suppression
- Miosis (always – marker)
What are the CV effects of opioids?
- Most have no direct effects
- Bradycardia (CNS)
- Meperidine (Demerol) - tachycardia
What are the GI effects of opioids?
Constipation (ENS) – marked, no tolerance
List the 7 applications of opioids
- Analgesia
- ACS -MONA
- Acute pulmonary edema
- Cough
- Diarrhea
- Shivering
- Anesthesia
_____ is given for alcohol withdrawal
Naltrexone
______ is given for opioid drug overdose
Naloxone (Narcan)
Why should opioids be given sparingly in head injuries?
Opioids may enhance respiratory depression (lethal)
What are the 3 structural classes of opioids?
- Phenanthrenes
- Phenylheptylamines
- Phenylpiperidines
What are the 3 Phenanthrenes that are strong opioid agonists?
- Morphine, hydromorphone (Dilaudid)
- Heroin (diacetylmorphine)
What is the Phenylheptylamine that is a strong opioid agonist?
Methadone
Which opioid is the only opioid that causes tachycardia? How?
Meperidine (Demerol) - Antimuscarinic effects (tachycardia)
What is the main use for Meperidine (Demerol)?
Post-op shivering: k-opioid receptor
What are the 3 Phenanthrenes that are moderate opioid agonists?
- Codeine, oxycodone
- More effective as combinations
- Oxycodone + acetaminophen = Percocet
- Oxycodone + Aspirin = Percodan
What are the 3 opioid antagonists?
Naloxone, naltrexone, naloxegol
What are the 5 classes of sedative-hypnotics?
- Benzodiazepines - Diazepam, Midazolam
- Barbituates - Phenobarbital
- Sleep aids - Zolpidem (non-benzodiazepine)
- Anxiolytics - Buspirone
- Ethanol
What are the 2 major pathways of metabolism to acetaldehyde?
Alcohol dehydrogenase pathway
Microsomal ethanol-oxidizing system (MEOS)
What drug inhibits alcohol dehydrogenase
Fomepizole
What drug inhibits aldehyde dehydrogenase
Disulfiram
What enzyme breaks down ethanol to acetaldehyde?
Alcohol dehydrogenase
What enzyme breaks down acetaldehyde to acetate?
aldehye dehydrogenase
Differentiate alcohol dehydrogenase pathway from Microsomal ethanol-oxidizing system (MEOS)
During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH. A result of continuous alcohol oxidation, it creates an excess of NADH. Excess NADH production contributes to the metabolic disorders that occur with chronic alcoholism (i.e. lactic acidosis and hypoglycemia, both of which are present in acute alcohol poisoning).
Which sedative-hypnotics are useful anesthesia adjuncts?
Barbituates – thiopental and methohexital
- very lipid-soluble, penetrating brain tissue rapidly
-short duration of action
Benzodiazepines - diazepam, lorazepam, and midazolam
-In combination with other agents
-May contribute to a persistent postanesthetic respiratory depression
-reversible with flumazenil
What are the 3 phases of Drug development
In vitro -> animal study -> 3-4 human trials
Which supplement is claimed to improve memory, immune function, and analgesia?
Ginseng
What effects does the supplement St. John’s Wort have?
antidepressant
Which supplement reduces hepatotoxicity?
Milk Thistle
What effects does the supplement echinacea have?
Stimulation of immune system, Anti-inflammatory
What effects does the supplement garlic have?
HMG CoA Reductase inhibitor
What effects does the supplement ginkgo have?
improved blood flow, free radical scavenger
Which supplement is used for benign prostatic hyperplasia?
Saw Palmetto
3 tradition treatments for cancer
surgery, radiation, CHEMOTHERAPY
Differentiate chemotherapy modalities
Primary Chemotherapy:
- Primary treatment is chemotherapy
- Advanced disease – goal is to limit spread, improve QOL
Neoadjuvant Chemotherapy:
- Chemotherapy induced to reduce tumor size prior to and after surgery
- Surgery is primary treatment, chemotherapy secondary
- Useful in many GI cancers, breast, lung
Adjuvant Chemotherapy:
- After surgery – reduce incidence and resurgence of tumor
- Both surgery and chemotherapy equally important, possibly radiation
- Goal is disease-free survival (DFS) and overall survival (OS)
What are the 4 types of Alkylating Agents
Nitrogen Mustards (most common used)= cyclophosphamide, chlorambucil
Nitrosureas= cross BBB
Alkyl Sulfonate
Platinum analogs= cisplatin (testicular cancer), carboplatin
What is the primary use of Cisplatin
Testicular cancer
What is the MOA of methotrexate
Inhibits dihydrofolate reductase (DHFR)- interferes with DNA/RNA synthesis
Cytotoxic actions:
-predominant on bone marrow
-ulceration of intestinal mucosa
-Crosses placenta interferes with embryogenesis = fetal malformations and death
Immunosuppressive action
- prevents clonal expansion of B & T lymphocytes
Anti-inflammatory actions:
-interferes with release of inflammatory cytokines
Be able to match the name and drug class of the antineoplastic drugs
Antimetabolites- 6MP, 5-FU
Plant based- Vincristine, Paclitaxel (Taxol)
Antibiotics- Dactinomycin, Doxorubicin, Bleomycin
Hormonal Agents- Croticosteroids, Tamoxifen, Fulvestrant
Miscellaneous- Imatinib, Trastuzumab, Rituximab
Differentiate between the 2 types of host defenses
Innate - first and second line of defense
Acquired - third line of defense, B and T cells
What 3 components are involved in the first line of defense?
Physical barriers, chemical barriers, and genetic components
What 4 components are involved in the second line of defense?
Phagocytosis, inflammation, fever, antimicrobial proteins
What are the components involved in the third line of defense?
- B and T cells
active - infection
passive - maternal antibodies
What are the 5 immune system cytokines?
- Interleukins (ILs)
- signal among leukocytes - Interferons (IFNs)
-Antiviral proteins that may act as cytokines - Growth factors
-Proteins that stimulate stem cells to divide - Tumor necrosis factor (TNF)
-Secreted by macrophages and T cells to kill tumor cells and regulate immune responses and inflammation - Chemokines
-Chemotactic cytokines that signal leukocytes to move
What are the 4 types of hypersensitivity?
Types I-IV - ACID
- A – Anaphylaxis, allergies
- C - Cytotoxic
- I – Immune complex
- D - Delayed
_________ is the primary immunodeficiency disease lacking a thymus
DiGeorge Syndrome: No Thymus (no T cells)
_________ is the primary immunodeficiency disease lacking B cells and T cells
Severe combined immunodeficiency disorder (SCID)
What is an example of a secondary immunodeficiency disease?
Acquired Immune Deficiency Syndrome
_______ is the immune response against normal, healthy tissue
Autoimmune
Females are _____ affected than males in autoimmune diseases
more
_________ are self-antigens that induce immune response
Autoantigens
_______ are antibodies against autoantigens
Autoantibodies
Which neuromuscular autoimmunity involves autoantibodies and T-cells against neurons, myelin?
MS
Which neuromuscular autoimmunity involves destruction of ACh receptors?
MG
_____ is the autoimmune disease with autoantibodies against DNA
SLE - lupus
______ is the autoimmune disease of pancreas endocrine cells
- Insulin-dependent Diabetes mellitus
- Cytotoxic T cells attack beta cells (Insulin)
Which category of immunosuppressive agents suppress immune response and mimic naturally occurring adrenal corticosteroids?
Glucocorticoids (corticosteroids)
Which category of immunosuppressive agents involves inhibiting the activation of the T-cell pathway?
Calcineurin Inhibitors
Which category of immunosuppressive agents kill rapidly proliferating cells?
Cytotoxic Agents
Which category of immunosuppressive agents are antibodies directed against cell-surface antigens/receptors?
Immunosuppressive Antibodies
What are 3 examples of glucocorticoids?
Prednisone, hydrocortisone, Dexamethasone
What are 2 examples of Calcineurin inhibitors?
Calcineurin- necessary for T-cell receptor signaling, activation
Cyclosporine:
-Peptide antibiotic- transplantation, GVHD, other autoimmune disorders
-multiple toxicities: kidney, BP, hyperglycemia, liver, seizures
Tacrolimus:
-macrolide antibiotic
-similar uses, similar toxicities to cyclosporin
-topical-atopic dermatitis and psoriasis
What are 3 examples of Cytotoxic Agents?
Azothioprine, Cyclophosphamide, Hydroxychloroquine
What are the 5 categories of immunosuppressive agents?
- Glucocorticoids (corticosteroids)
-suppress immune response, mimic naturally occuring adrenal corticosteroids
-prednisone, hydrocortisone, dexamethasone - Calcineurin Inhibitors
-T cell activation pathway
-cyclosporine, tacrolimus - Cytotoxic Agents
-kill rapidly proliferating cells
-Azothioprine, cyclophosphamide, hydroxychloroquine - Immunosuppressive Antibodies
-antibodies created in lab, directed against cell-surface antigens/receptors
-Muromonab(CD3), RhoGAM, Adalimumab(TNF-a) - Additional Agents
-Sirolimus, mycophenylate mofetil, thalidomide derivatives
