The Final Flashcards
The study of chemical interaction with living systems.
Pharmacology
The outside substance that has an effect on our body.
Exogenous
The substance that’s already in your body that causes an effect at a particular receptor.
Endogenous
Inorganic substances from non living material
Poison (bleach)
Organic substances from animals
Toxins (Snake bite)
The effect of the drug on the body
Pharmacodynamic
The effect of the body on the drug
Pharmacokinetics
How a particular individual is going to react to a drug
Pharmacogenomic
Elicits the same effect at a receptor as the endogenous ligand
Agonist
Blocks activity of the agonist
Antagonist
What is a physiologic antagonist?
Drug that acts at different receptors to cancel out the effect of other drugs.
Example: Epi binds to beta receptor to increase HR. Other drug binds to muscarinic receptor to decrease HR.
Binds to same receptor but won’t have full effect of the agonist
Partial agonist
Suppresses agonist response even further than antagonist would do. Great affinity for inactive receptor.
Inverse agonist
Mirror images of itself; two molecules have the same bonds between the same atoms but different spatial arrangements.
Steroisomerism
What are the 4 types of permeation?
- Aqueous diffusion
- Lipid diffusion
- Special Carriers
- Endocytosis and exocytosis
if pH < pKa; favors ________ form
If pH > pKa; favors ___________ form
protonated form
nonprotonated form
ASA (weak acid) pKa= 3.5
In the intestine pH= 6.5
pH > pKa
nonprotonated and charged
ASA (weak acid) pKa= 3.5
In the stomach pH= 1.5
pH < pKa
protonated and uncharged
Morphine (weak base) pKa = 7.9
In the stomach pH =1.5
pH <pKa
protonated and charged
What is potency?
Concentration where we see 50% of the drugs maximal effect. EC50 (pharmacist) an ED50 (clinicians)
What is efficacy?
Maximal effect a drug can deliver regardless of dose.
The clinical effectiveness of a drug depends not on its __________, but on its maximal ___________.
Potency; Efficacy
Where we start to see warranted effect in 50% of the population.
Median Effect Dose (ED50)
Start to see negative side effects in 50% of the population
Median Toxic Dose (TD50)
Start to see 50% of the population die.
Median Lethal Dose (LD 50)
How do you calculate the Therapeutic index?
TD50 / ED50
What is the goal of rational dosing?
To achieve desired beneficial effect with minimal adverse effects
Bond strength is ____________ proportional to specificity.
indirectly
Flux is ______________ proportional to concentration.
directly
(Flux is a measure of transport by simple diffusion)
Kd is _______________ proportional to drug binding affinity.
indirectly
Drug safety is ___________ proportional to the TI.
directly
The volume of distribution is _____________ proportional to the concentration of the drug outside the systemic circulation.
directly
What are the 4 parameters affecting passive diffusion?
- Molecular Weight
- pKa
- Lipid Solubility
- Plasma Protein Binding
What are 4 basic mechanisms to transmembrane signaling.
- Directly crossing to intercellular receptor (lipid soluble)
- Enzymatic action mediated by ligand binding (Tyrosine kinase activated receptors)
- Ligand gated ion channels
- GPCR
What is an ionotropic channel?
Ligand gated ion channel
What receptor has a 7-transmembrane alpha helices structure?
GPCR
What does it mean when a GPCR has a pleiotropy effect?
Pleiotropy means several downstream effects.
What are the trimeric subunits of G-proteins?
alpha
beta
gamma
What protein drags the GPCR receptor to the Clathrin coated pit?
Beta-arrestin
Most drug efflux transporters are ___________transporters. They consist of 7 families and over 50 genes.
ATP-binding cassette (ABC)
What are the 3 major drug efflux transporters?
ABC-B- broadest substrate specificity
ABC-C- largest class, mainly antineoplastics
ABC-G - Breast CA resistance protein (BCRG), folate transport
In the BBB, what is the primary site of exclusion?
Vascular epithelium d/t it’s tight junction and multiple transporters
What are the two research targets for the BBB?
- Block transporters
- Increase Delivery to the brain
What is biotransformation?
Termination of activity (mechanism beside renal clearance).
Some metabolites become active AFTER biotransformation.
What are the 4 steps of Phase 1 metabolism?
- Oxidation (Cytochrome P450: 3A4, 2D6, 2B6)
- Reduction
- Dehydrogenation
- Hydrolysis
Cruciferous veggies are an inducer of CYP1A2.
Warfarin inactivated by CYP1A2.
If at patient is on warfarin therapy but they go to town on brussel sprouts for breakfast, lunch, and dinner. What effects will this have on the medication?
Warfarin will become less effective because the sprouts are inducing CYP1A2, thus inactivating the warfarin.
What is a perikaryon?
Cell body of neuron containing a nucleus
What part of the cell produces energy?
Mitochondria
What part of the cell produces NT?
RER and ribosomes
What part of the neuron perform many fine processes and receives information. This makes up 80-90% of neuron surface area.
Dendritic spines
What carries electrical signal (action potential) to target.
Axon
Here are 6 NT classes. Name examples in each one.
1. Esters -
2. Monoamines -
3. Amino Acids -
4. Purines -
5. Peptides -
6. Inorganic Gases -
- Esters - ACh, cholinergic
- Monoamines - NE, 5HT, Dopamine
- Amino Acids - Glutamine, GABA
- Purines - Adenosine, ATP
- Peptides - Substance P, Endorphins
- Inorganic Gases - NO (*not stored, made as needed)
During ACh production what does the CHT do?
What does the VAT do?
CHT - Choline transporter into the neuron
VAT - Transport ACh into vesicles
What anchors the NT vesicles?
Snare complex
Syntaxin
SNAP-25
VAMP
Calcium sensor in the neuron that will trigger ACh vesicle release.
Synaptotagmin
Tyrosine can be converted to these catecholamines:
Dopamine
Epinephrine
NE
Anatomy of the Autonomic NS
Division: Sympathetic NS
Origin of Fibers:
Length of Fibers:
Location of Ganglia:
Anatomy of the Autonomic NS
Division: Sympathetic NS
Origin of Fibers: Thoracolumbar
Length of Fibers: Short preganglionic, long postganglionic
Location of Ganglia: Close to spinal cord
Anatomy of the Autonomic NS
Division: Parasympathetic NS
Origin of Fibers:
Length of Fibers:
Location of Ganglia:
Anatomy of the Autonomic NS
Division: Parasympathetic NS
Origin of Fibers: Brain and Sacral Spinal cord
Length of Fibers: long preganglionic, short post ganglionic
Location of Ganglia: in the visceral effector organs
What adrenergic receptors are Gq GPCR and activates Phospholipase C?
What cholinergic receptors are Gq GPCR and activates Phospholipase C?
Alpha 1
M1, M3, and M5
What adrenergic receptors are Gi GPCR and inhibits Adenyl Cyclase?
What cholinergic receptors are Gi GPCR and inhibits Adenyl Cyclase?
Alpha 2
M2 and M4
What adrenergic receptors are Gs GPCR and activates Adenyl Cyclase?
Beta 1, 2, and 3
What secondary messengers come from Phospholipase C?
DAG and IP3
What secondary messenger come from Adenyl Cyclase?
cAMP
Sympathetic/Parasympathetic Activity on the Heart (SA Node and Contractility):
What are the actions?
What are the receptors?
Sympathetic
SA Node: Increase, Beta 1
Contractility Increase, Beta 1
Parasympathetic
SA Node: Decrease, M2
Contractility: Decrease, M2
Sympathetic/Parasympathetic Activity on Blood Vessels (Skeletal and SM)
Whats are the actions?
Whats are the receptors?
Sympathetic
Skeletal: Relax, Beta 2
SM: Contract, Alpha 1
Parasympathetic
Skeletal: Not indicated
SM: Relax, M3
Sympathetic/Parasympathetic Activity on Bronchiolar SM
Whats are the actions?
Whats are the receptors?
Bronchiolar SM
Sympathetic: Relaxation, B2
Parasympathetic: Contract, M3
Sympathetic/Parasympathetic Activity on GI Tract (Wall SM and Sphincter SM)
Whats are the actions?
Whats are the receptors?
Sympathetic
Wall SM: Relax, Beta2, Alpha2
Sphincter SM: Contract, Alpha1
Parasympathetic
Wall SM: Contract, M3
Sphincter SM: Relax, M3
**Bonus Secretions: Increase, M3
Sympathetic Activity on the Kidney and Renal Vasculature
Action and Receptors?
Sympathetic
Kidney: Renin release, Beta 1
Renal Vasculature: Vasodilation, D1
Sympathetic/Parasympathetic Activity on Bladder and Sphincter. Action and Receptors
Sympathetic
Bladder: Relax, Beta 2
Sphincter: Contract, Alpha1
Parasympathetic
Bladder: Contract, M3
Sphincter: Relax, M3
Describe the response in the autonomic feedback loop if there is a drop in MAP.
- Baroreceptors in the aorta arch, carotid arteries will sense decrease in MAP.
- The baroreceptors will activate the vasomotor center that will activate the sympathetic autonomic nervous system.
- NE is released resulting in increase HR (beta1) which will increase CO. Contractile Force increase, increasing SV. Increase venous tone (alpha1), increasing venous return.
- End result, increase MAP.
Describe the response in the hormonal feedback loop if there is a drop in MAP.
- If there is a sustained drop in MAP. Kidneys will sense a decrease in flow/pressure/oxygen to the glomerulus.
- Kidneys will release renin activating the RAAS, which will activate angiotensinogen to angiotensin.
- Angiotensin will release aldosterone. Aldosterone will go to kidney to retain more water. This will increase venous return, SV, and CO.
- End result, increase MAP.
Describe the response in the autonomic feedback loop if there is an increase in MAP.
- Baroreceptors will sense the increase MAP.
- Vasomotor Center will activate the Parasympathetic autonomic nervous system that will release ACh to the muscarinic receptors of the Heart to slow down HR and dilate blood vessels in peripheral vasculature to bring down MAP to normal.
What is the classification of the following drug groups?
Clonidine
Albuterol
Dobutamine
Dopamine
Isoproterenol
EPI
NE
Direct Acting Adrenergic Agonist Drugs
What kind of adrenergic agonist is amphetamine?
Indirect Acting
What kind of adrenergic agonist is ephedrine?
Direct and Indirect Acting
Direct effects of the heart are determined by _______ receptors.
Beta
Stimulation of beta receptors on the heart will result in increase _________ and decrease ___________.
Increase CO
Decrease Peripheral Resistance
Formula for CO
CO = SV x HR
What are the receptors for Epinephrine?
Alpha 1
Alpha 2
Beta 1
Beta 2
What are the receptors for NE?
Alpha 1
Alpha 2
Beta 1
What are the receptors for Isoproterenol?
Beta 1
Beta 2
What are the receptors for Dopamine?
D1 to D5
Higher doses: Alpha 1 and Beta 1
What are the receptors for Dobutamine?
Beta 1
What are adrenoreceptor antagonist drugs like Phentolamine (reversible) and Phenoxybenzamine (irreversible) used to treat?
Hypertension related to pheochromocytoma
What are the effects of beta antagonist on the Heart?
Negative Inotropic
Negative Chronotropic
What are the effects of beta antagonist on the Blood Vessels?
-Opposes Beta-2 mediated vasodilation
-Acute increase in peripheral resistance
-Chronic decrease in peripheral resistance mechanism unclear
What receptors does propranolol (inderal) work on?
Beta 1
Beta 2
What receptors does Metoprolol (Lopressor) and Atenolol (Tenormin) work on?
These drugs are safer in which patient population?
Beta 1
Safer in COPD and DM patients
What is an ultra short acting beta blocker (usually used in the OR or ICU).
Esmolol
What is the MOA for direct acting cholinomimetics?
Bind to and activate muscarinic or nicotinic receptors (esters of choline and alkaloids)
What is the MOA for indirect acting cholinomimetics?
Inhibit the hydrolysis of ACh
Inhibits action of Acetylcholinesterase
Prolongs effects of ACh release at junction
What are the muscarinic agonist effects on the eye?
-Miosis (Pupil constriction)
-Increase intraocular drainage
What are the effects of cholinomimetics to the cardiovascular system?
-Reduction of peripheral vascular resistance
-Vasodilation and reduction of BP with reflexive increase in HR
-Large doses = bradycardia
What are the three types of indirect acting cholinomimetics?
Simple Alcohols - Edrophonium
Carbamic acids of esters of alcohol- Carbamates and Neostigmine
Organic derivatives of phosphoric acid - Organophosphate
What are major therapeutic uses of indirect acting cholinomimetics?
-Glaucoma
-GI and Urinary Tracts
-NMJ- Myasthenia Gravis (Autoimmune against ACh receptors)
-Atropine OD
What are symptoms and treatment of Muscarinic Excess (poisonous mushrooms, pilocarpine, choline esters)?
SLUDGE-M (Salivation, Lacrimation, Urination, Defecation, GI Motility, Emesis, Miosis Constriction of Pupil)
Treatment: Atropine
What are symptoms and treatment of Organophosphate Exposure?
SLUDGE-M (Salivation, Lacrimation, Urination, Defecation, GI Motility, Emesis, Miosis Constriction of Pupil)
Treatment:
Pralidoxime (2-24 hours to prevent aging)
Atropine
What are symptoms and treatment of Atropine/ Belladona OD?
BRAND (Blind, Red, Absent Bowel Sounds, Nuts, Dry)
TX: Physostigmine
AHA Angina Classification: Stable Angina
Also Known As:
Cause:
Precipitating Factors:
Other:
AHA Angina Classification: Stable Angina
Also Known As: Angina of effort, Classic
Cause: Plaque
Precipitating Factors: Exercise, Stress
Other: Brief, May be relieved with rest
AHA Angina Classification: Unstable Angina
Also Known As:
Cause:
Precipitating Factors:
Other:
AHA Angina Classification: Unstable Angina
Also Known As: Acute Coronary Syndrome
Cause: Plaque
Precipitating Factors: Resting
Other: Emergency
AHA Angina Classification: Variant Angina
Also Known As:
Cause:
Precipitating Factors:
Other:
AHA Angina Classification: Variant Angina
Also Known As: Prinzmetal, Angina Inversa
Cause: Hyperreactive Vessels
Precipitating Factors: Resting
Other: Rare (2% of Angina)
What are the actions of NO, Nitrates, and Nitrites on vascular smooth muscles?
Activate Guanyl Cyclase
Increase cGMP
Resulting in relaxation.
What are the actions of Beta-2 agonist on vascular smooth muscles?
Activate GPCR
Increase cAMP
Relaxation (mainly respiratory)
What are the actions of Beta Blockers on vascular smooth muscles?
Decrease demand (Decrease HR)
What are the actions of Calcium Channel Blockers on vascular smooth muscles?
Less Calcium Influx
Results in Relaxation
What are the actions of Sildenafil on vascular smooth muscles?
Blocks PDE5
Increase cGMP
Results in Relaxation
What are the good effects of nitrates and nitrites?
Increase Venous Capacitance
Decrease Ventricular Preload
Decrease CO
What are the bad effects of nitrates and nitrites?
Orthostatic Hypotension
Syncope
Headache
Reflexive Tachycardia
What is the pathway of blood vessel contraction?
How does it contract?
- Ca2+ enters smooth muscle cell
- Ca2+ is released from SR and binds to Calmoudulin.
- Ca2+ Calmouldulin complex activates MLCK
- MLCK adds phosphate group to myosin causing an interaction with actin resulting in contraction.
cAMP will inhibit MLCK, relaxing SM
What are the targets to relax vascular tone?
Blocking Ca2+ Channels
Increasing cGMP (removes the phosphate group from MLC causing relaxation)
Target Beta-2 agonist (increase in cAMP to phosphorylate MLCK, inactivating the enzyme), but can have systemic effects.
Describe the pathway of Nitric Oxide
- Nitrates will activate guanylyl cyclase in the vascular smooth muscle
- Cyclates GTP to cGMP
- cGMP directly dephosphorylates myosin light chain.
- When myosin loses its phosphate group, it can no longer interact with actin, causing relaxation.
How do PDE inhibitors like Milrinone work?
PDE3 inhibitors like Milrinone prevent the break down of cAMP and cGMP.
cAMP in the cardiac muscle will cause contraction (inotropic).
cGMP in the smooth muscle will cause relaxation (vasodilation).
How to CCB work?
Blocks L-type Ca2+ channels and produce long lasting smooth muscle relaxation and decrease BP.
Heart: decrease contractility, decrease SA node pacemaker rate, decrease AV node conduction velocity
How to CCBs work?
What effect does CCBs have smooth muscle?
What effect does CCBs have on the heart?
Blocks L-type Ca2+ channels and produce long lasting smooth muscle relaxation and decrease BP.
Smooth Muscle:
Relaxation (mainly vascular), Reduce BP
Some effects on GI, GU, Bronchi, Uterine
Heart:
Decrease contractility
Decrease SA node pacemaker rate
Decrease AV node conduction velocity
Which CCB is more of a peripheral vasculature effect?
Dihydropyridines
Which CCB is more of a a cardiac effect?
Verapamil and Diltiazem
What are toxicities of CCBs?
Serious cardiac suppression (rare)
Bradycardia
AV Block
CHF
Are beta blockers vasodilators?
Not Vasodilators
Beta blockers are used for angina of effort and silent (ambulatory) ischemia.
What are the beneficial effects of beta blockers?
Decrease oxygen demand
Decrease HR
Decrease BP
Decrease Contractility
Antihypertensive agents act one or more of the four anatomical control sites.
What are the four sites?
- Resistance Arterioles (use alpha1 blockers)
- Capacitance Venules (use NO)
- Heart (Beta blockers)
- Kidneys (Aldosterone or RAAS system can affect kidney volume)
What electrolyte do diuretics deplete?
Depletes sodium
What are the actions of sympathoplegics on the blood vessels and CO?
Decrease PVR and reduce CO
What are the actions of direct vasodilators?
Relax vascular smooth muscles.
What are the actions of anti-angiotensins?
Blocks activity or production.
What is the Hydraulic Equation?
BP = CO x PVR
What are methyldopa and clonidine categorized as?
CNS Sympathoplegics
What category do all these drugs belong in?
Propanolol
Metoprolol
Atenolol
Prazosin
Terazosin
Doxazosin
Adrenergic receptor antagonist (beta and alpha receptor blockers)
How does methyldopa and clonidine work as a centrally acting sympathoplegic drug?
Predominantly Alpha-2 agonist activity in brainstem, decreasing sympathetic stimulation.
The effects of propanolol:
-Lowers BP, prevents ____________
-Antagonizes _______ and ______ receptors
-_________ Cardiac Output
-Inhibits __________ production
The effects of propanolol:
-Lowers BP, prevents reflex tachycardia
-Antagonizes Beta 1 and Beta 2 receptors
-Decreases Cardiac Output
-Inhibits renin production
What are three examples of alpha-1 blockers?
What do they do?
Prazosin, Terazosin, and Doxazosin
Block alpha 1 receptors in arterioles and venules
Dilate both resistance and capacitance vessels
BP is reduced more in upright position.
What is the MOA of Minoxidil?
Opens K+ Channels in smooth muscles.
Stabilizes potential, less likely to contract.
Dilates arteries and arterioles
What is the MOA of Hydralazine?
What are the toxicities of Hydralazine?
Dilates arterioles through NO production.
Toxicities: HA, Nausea, Sweating, Flushing
What is used in hypertensive emergencies, cardiac failure.
Sodium Nitroprusside
What is the MOA of Sodium Nitroprusside?
Medication is broken down in the blood to release NO and increase intracellular cGMP.
Dilates arterial and venous vessels.
What is fenoldopam and what is it used for?
It is a peripheral arteriolar dilator.
Used for HTN emergencies and post op HTNN.
What is the MOA for fenoldopam?
Agonist of D1 receptors
Where does ANGI get converted to ANGII ?
What enzyme is responsible for the conversion that can be a target hypertension?
Lungs
Angiotensin Converting Enzyme (ACE)
ACE Inhibitors (Captopril)
What sites does ANG II bind to?
What does it do?
How can we block this?
ANG II binds to Adrenal Cortex will secrete aldosterone, increase sodium and water retention, increasing BP.
ANG II binds to the arterioles and cause vasoconstriction increase peripheral resistance, increasing BP.
ANG II also binds to the PCT to promote reabsorption or Na+.
ARB (Losartan and Valsartan) can block this.
What is Heart Failure?
What is the most common cause of Heart Failure?
Heart failure: Heart fails to meet metabolic demands of the tissue.
Most common cause: Coronary Artery Disease
What are the types of Heart Failure?
Systolic Failure - reduce cardiac function, heart not pumping adequately
Diastolic Failure - reduced cardiac filling, usually do the the heart walls being too thick.
What is Congestive Heart Failure?
Increased left ventricle pressure at the end of diastole that results in increase pulmonary pressure (pulmonary edema). Blood backs up into the lungs
Steps to Normal Cardiac Contractility.
- Trigger Ca2+ enters the cell
- Binds to channel in SR, release stored Ca2+
- Frees actin to interact with myosin
What is the difference between systolic ventricular dysfunction and diastolic ventricular dysfunction?
Systolic: Typical of acute failures (MI), decrease CO and decrease EF
Diastolic: results from hypertrophy of myocardium. Decrease CO, Normal EF. Does not respond well to positive inotropic drugs.
What are the 4 factors of cardiac performance?
Preload
Afterload
Contractility
HR
What are the direct therapeutics of digoxin?
Inhibits Na+/K+ ATP-ase pump
Maintains normal resting potential
Positive Inotrope
Digoxin Toxicity:
What is the EC50
What is the TC50
EC50 - 1ng/ mL
TC50 - 2 ng/ mL
How does PDE3 inhibitors work?
Drugs?
PDE3 prevents the breakdown of cGMP in the smooth muscle, increasing relaxation.
PDE3 inhibitors also have a positive inotropic effect
by preventing breakdown of cAMP in the cardiac muscle, increasing contraction.
Drug Class Bipyridines: Milrinone and Inamrinone
What is the crescent shaped node in the RA that enforces a contraction rate of 75 bpm?
SA node/pacemaker
What is the junction of the atria and ventricles?
Atrioventricular Node (slow)
What is in the interventricular septum?
Atrioventricular bundle/ Bundle of His
What spreads within the muscles of the ventricle walls.
Purkinje Fibers
Describe the action potential of the atria, ventricular, and purkinje fiber cells.
- Vrm is -100 mV, once threshold potential is met there is an action potential upstroke (phase 0) dependent on sodium current. Massive influx of Na+ (m-gate open).
- Phase 1, H-gate inactivates sodium channel, providing the overshoot. K+ channels open and will provide the phase1 slope.
- Phase 2, plateau period d/t K+ being up and Ca2+ channels opening. Ca2+ and K+ balanced.
- Phase 3, Ca2+ channels have shut off. K+ is still leaving the cell.
- Before phase 4, N/K Pump is re-establishing the gradient.
- Phase 4 slow depolarization for the next action potential
What are the three states of sodium channels?
Resting - m-gate closed/ h-gate open
Activated - m-gate open/ h-gate open, massive Na+ influx
Inactivated- m-gate open/ h-gate closed
If some sodium channels reset too early what kind of disturbance in impulse formation can occur?
Afterdepolarizations which are abnormal depolarization occurring during phase 2, 3, or 4.
When does EAD occur?
What causes this?
Depolarization in phase 2 or 3
Caused by sodium or calcium channels, increases in the QT interval
When does DAD occur?
What causes this?
Depolarization occurs before a normal action potential (phase 4)
Caused by elevated intercellular Calcium, digitalis toxicity
What is Reentry/Circus Movement
Block allowing one way “circus” conduction, where the conduction is slow enough where it can re-excite tissue that have been excited once.
What are the requirements for a Reentry Block to occur?
- There must be an obstacle (usually scar tissue)
- Block must be unidirectional
- Conduction time must be long enough to reenter same areas AFTER refractory period
How are Type II and Type III blocks treated?
Transcutaneous Pacing/ Pacemaker
What are the four classes of Anti-arrhythmic Agents?
Class I - Sodium channel blockers
Class II - Sympatholytic
Class III - Prolong action potential duration (K+)
Class IV - Block cardiac calcium channel currents.
Sodium Channel Blockers Type IA
Examples:
APD/ERP:
Dissociation:
State Affinity:
Sodium Channel Blockers Type IA
Examples: Procainimide, Disopyramide
APD/ERP: Lengthens
Dissociation: Intermediate
State Affinity: Activated
Sodium Channel Blockers Type IB
Examples:
APD/ERP:
Dissociation:
State Affinity:
Sodium Channel Blockers Type IB
Examples: Lidocaine, Mexillitine
APD/ERP: Shortens
Dissociation: Fast
State Affinity: Inactivated, some activated
Sodium Channel Blockers Type IC
Examples:
APD/ERP:
Dissociation:
State Affinity:
Sodium Channel Blockers Type IC
Examples: Flecainide, Propafenone
APD/ERP: No effect
Dissociation: Slow
State Affinity: Activated
What is the only anti-arrhythmic with all four Vaughn-William’s Class effects?
Amiodarone - Drug of choice for V-tach
Bradycardia
Initial Treatment
Symptomatic Treatment
Chronic Treatment
Bradycardia
Initial Treatment: Underlying cause, d/c drugs
Symptomatic Treatment: 1st Atropine/ 2nd: Epi/Dopamine
Chronic Treatment: Pacemaker
Heart Block
Initial Treatment
Symptomatic Treatment
Chronic Treatment
Heart Block
Initial Treatment: 1st degree (not treated)
Symptomatic Treatment: Atropine, transcutaneous pace
Chronic Treatment: Pacemaker
SVT
Initial Treatment
Symptomatic Treatment
Chronic Treatment
SVT
Initial Treatment: Assess Cause
Symptomatic Treatment: Adenosine
Chronic Treatment: CCB, Beta Blockers
Sinus Tach
Initial Treatment
Symptomatic Treatment
Chronic Treatment
Sinus Tach
Initial Treatment: Assess Cause
Symptomatic Treatment: Adenosine, CCB, Cardiovert
Chronic Treatment: Catheter ablation
V-tach (wide complex)
Symptomatic Treatment
Chronic Treatment
V-tach (wide complex)
Symptomatic Treatment: Amio
Chronic Treatment: Amio, Satolol
A-fib
Symptomatic Treatment
Chronic Treatment
A-fib
Symptomatic Treatment: Diltiazem, Verapamil
Chronic Treatment: Beta Blockers, Amiodarone
V-fib
Symptomatic Treatment
Chronic Treatment
V-fib
Symptomatic Treatment: CPR, Defibrillation
Chronic Treatment: Amio, Lidocaine
Describe the process of how bicarb is reabsorbed into our body through the proximal convoluted tubule?
- NHE3 starts the cycle in the PCT cell. Na+ in for a H+ out into the lumen urine.
- The H+ in the lumen/urine will bind to HCO3- and form H2CO3 (carbonic acid)
- On the luminal surface there is an enzyme called carbonic anhydrase (CA) which will get rid of an H2O
- CA will break down H2CO3 to H2O and CO2
- CO2 is a gas and will freely diffuse into the cell.
- Once inside the cell, it also has H2O. The CA works in both directions and convert H2O and CO2 to carbonic acid.
- Carbonic acid can exist in an equilibrium as H+ and HCO3-
- HCO3- can now be reabsorbed into blood, maintaining bicarb buffering system
Where is H2O reabsorbed in the Loop of Henle?
Thin Descending Limb of the Loop of Henle
-Hypertonic medullary interstitium
What transporter will a loop diuretic target?
What are two examples of loop diuretics?
NKCC2 transporter
Furosemide (sulfanamide) and Ethancrynic acid
What area of the nephron has very little water movement. Low amount of sodium reabsorption and active calcium reabsorption by BTH.
Distal Convoluted Tubule
What transporter will Thiazides block?
Thiazides have some inhibition of this enzyme.
Give a thiazide drug example.
NCC transporter in the DCT
Thiazides have some inhibition on carbonic anhydrase.
Hydrochlorothiazide
Where are principal cells located?
What are the functions of principal cells?
Collecting tubules.
Site for Na+ and K+ transport.
Na+ reabsorption/ K+ secretion
Diuretics upstream result in excess sodium in the _________.
Collecting tubules.
Excess bicarb can be in the collecting duct from upstream diuretics (thiazides/acetazolamide).
If Acetazolamide is given how does it affect potassium level?
HCO3- won’t be able to leave the nephron, increase amount of HCO3- in the lumen.
In order to balance negative charge of the bicarb, greater amount of K+ will enter the collecting tubule.
Further driving K+ depletion.
Acetazolamide is greater wasting K+ diuretic than furosemide and thiazides.
How does Aldosterone work in the collecting duct
What does this do to Blood Pressure?
Aldosterone will increase activity of the ENaC and the Sodium potassium ATPase pump. Increasing the reabsorption of sodium.
Water follows Na+, increases BP.
What does ADH do in the collecting tubules?
-Increases water reabsorption by adding AQP2 to apical membrane.
-Increases blood volume
-Makes more concentrated urine
What can block ADH?
Conivaptan
How does Aldosterone work in the collecting duct
What does this do to Blood Pressure?
Aldosterone will increase activity of the ENaC and the Sodium potassium ATPase pump. Increasing the reabsorption of sodium.
Water follows Na+, increases BP.
What will antagonize the effects of aldosterone?
Spironolactone blocks the aldosterone receptors.
What is the primary use of mannitol?
To decrease ICP
Other uses: promote removal of renal toxins, great to use after radio contrast agents, acute hemolysis
What are the primary uses of mannitol?
To decrease ICP and promote removal of renal toxins.
Mannitol Toxicity:
Extracellular volume expansion
Rapidly distributed to extracellular compartments
Excessive use can lead to dehydration
What are the two components to an asthmatic response?
Early Response
Late Response
What is Early Response?
You breathe in whatever is going to cause this reaction that will trigger mast cell degranulation.
Histamine, Leukotrienes, PG, and Pro-inflammatory cytokines Released
Airway starts to close within 30 minutes to an hour.
Rescue inhaler used, FEV1 goes back to normal.
What is Late Response?
What is the cause of this?
This will usually occurs several hours later after an early response
Caused by WBC infiltration and inflammation.
What does PGD2 and Pro-inflammatory Cytokines drawn in?
WBC to trigger Late Response/ Late Reaction
What cells are responsible for the late reaction/ late response?
What do they do?
T-lymphocytes, Eosinophils, Neutrophils
These white blood cells will bring in a number of mediators that make the blood vessels more leaky and infiltrate the cells and overall increase the inflammatory response.
How are early response and late response treated?
Early Response use Beta 2 agonist
Late Response use anti-inflammatory medication (corticosteroids)
How many histamine receptors are there?
Four
(H1, H2, H3, and H4)
What does H1 histamine receptors do?
What does an antihistamine do?
Selective Inverse Agonist that cause bronchoconstriction and vasodilation
Antihistamine are H1 selective inverse agonist like Benadryl are useful in Type 1 hypersensitivity.
What are the effects of histamine on the nervous system?
Stimulates pain and itching
What are the cardiovascular effects of histamine?
Decrease BP (Vasodilation)
Increase HR (Reflex Tachcardia)
What is the Wheal (Welt) and Flare “Triple Response”?***
A patient has been inoculated with different compounds for allergy testing.
Three components involved
1. Microcirculation smooth muscle (becomes leaky)
2. Capillary endothelium (leaky)
3. Sensory nerve endings (flare)
Histamine can produce secretory effects in the stomach which can lead to ______.
Diarrhea
What effects does histamine produce in the lungs?**
What does histamine do to Gi smooth muscles?
Bronchoconstriction
Contraction (movement of food)
What are 3 uses of 1st generation H1 receptor antagonist?
- Sedation - resembles anti-muscarinic drugs, sleep aid, children may have reverse effects.
- Anti-emetic - motion sickness
- Anti-Parkinsonism - suppress extrapyramidal sx
What are H2 receptor antagonist used for?
H2 blockers to block stomach acid production, not as effective as PPI, heavy OTC use.
PPI are more expensive
What are leukotrienes?
What are the effect of leukotrienes?
Slow reacting substance of anaphylaxis, liberated from the lungs during inflammation.
Bronchospasm
Mucous secretions
Microvascular permeability
Airway edema
What are the 3 categories of drugs used in Asthma?
Bronchodilators (Beta-2 agonist, Anti-muscarinic-block vagus response, Methylxanthines-PDE Inhibitors)
Anti-inflammatory Agents (Steroids, Antibodies-usually for unrelieved cases)
Leukotriene Antagonist (Lipoxygenase Inhibitors and Receptor Inhibitors)
What are the toxic effects of sympathomimetics?
Name some sympathomimetic B-2 selective drugs used for asthma.
Skeletal tremors (Nebulizer Epinephrine)
Drugs Beta-2 Selective: Terbutaline, Formoterol, Salmeterol (no cardiac effect)
What drugs are in the Methylxanthine group?
What is the primary action of Methylxanthine?
Caffeine, Theophylline (most effective, found in tea), Theobromie
Primary Action is to inhibit PDE, thus keeping cAMP activate and contributing to smooth muscle relaxation in the lungs.
Pharmacodynamics of Methylxanthines
Mild Bronchodilation (Dr. T with his hot tea)
CNS-stimulation (trouble falling asleep)
How does muscarinic antagonist work as a short term reliever?
They are effective bronchodilators that block the contraction of smooth muscles and prevent mucous secretions.
Parenteral: Atropine
What muscarinic antagonist drug is used for COPD patients?
Ipratropium Bromide
Tiotropium (24 hours)
Leukotriene Pathway Inhibitor drug that works by inhibiting 5-lipoxygenase.
Zileuton
Leukotriene Pathway Inhibitor drugs that works by blocking receptor binding.
Zafirlukast
Montelukast
If you are loaded and have severe allergies what can you get? How does it work?
Anti-IgE monoclonal antibody (Omalizumab/Xolair)
They work by targeting portions of IgE that binds to mast cells and prevent them from degranulating.
Lessens asthma severity, decrease corticosteroid requirements, reduce hospitalization, $500-2000/shot (multiple shots/maintenance shots).
What are serotonin’s effect on the NS?
Nervous system:
Melatonin precursor
Vomiting reflex
Pain/itch (similar to histamine)
Chemoreceptor reflex (bradycardia, hypotension)
What are serotonin’s effect on the Respiratory System?
What are serotonin’s effect on the CV?
What are serotonin’s effect on the GI?
Respiratory: Facilitates ACh release (constriction), hyperventilation
CV: Contraction of vascular smooth muscles (exceptions: skeletal muscle and heart)
Platelet aggregation.
GI: Increase peristalsis, overproduction leads to diarrhea
How many receptor families does serotonin have?
Serotonin receptors are called 5-HT receptors.
There are 7 receptor families.
All are GPCRs except 5-HT3
What are the three primary serotonin agonist targets?
5-HT1A Agonist Buspirone non-benzo anxiolytic for GAD/OCD
5-HT1B and 5-HT1D Agonist Triptans for Migraines/HA
What are two examples of a 5HT2 receptor antagonist drug? What do they treat?
Phenoxybenzamine - carcinoid tumors
Cyproheptadine - cold induced urticaria
What is an example of a 5HT3 receptor antagonist drug? What does it drug.
Odansetron/Zofran - Anti-emetic
What is serotonin syndrome?***
What is the precipitating drug?
Clinical presentation?
Treatment?
Excess amount of serotonin that will lead to a hyperthermic response in the body.
Precipitating drugs: Anything that will increase 5HT, SSRI, St. John’t Wort, Ginseng
Clinical presentation: HTN, Hyperreflexia, hyperthermia, onset w/i hours.
Treatment: Sedation and use paralysis to slow down muscle movements. Intubation/Ventilation. Use of cyproheptadine (antihistamine 5HT blocker) or chlorpromazine, cooling.
What is the cause of Neuroleptic Malignant Syndrome? ***
What are the clinical presentation?
Treatment?
D-2 blocking antipsychotics (chlorpromazine, haloperidol)
Clinical presentation: hyperthermia, acute severe Parkinsonism
Treatment: Diphenhydramine and cooling
What is the caused of Malignant Hyperthermia? ***
Clinical presentation?
Treatment?
Genetic condition affected by volatile anesthetics and SCh, targets the RYR to release Ca2+ leading to more contraction.
Clinical presentation: Hyperthermia, muscle rigidity
Treatment: Muscle relaxant, dantrolene, and cooling.
What are 4 major classes of antidepressants that all carry black box warning for suicidal tendencies.
- MAOI
- TCA - Inhibit SERT, NET, and Anticholinergic (Elavil)
- SSRI- Inhibit SERT (Prozac, Zoloft)
- SNRI - Inhibit SERT and NET (Pristique and Cymbalta)
What are the three sub-categories of focal onset seizures?
- Focal Aware (simple partial)
- Focal Impaired Awareness (complex partial)
- Focal to bilateral tonic-clonic seizure (partial seizure secondarily generalized)– looks like generalized tonic-clonic
What are the five sub-categories of generalized onset seizures?
- Generalized tonic-clonic (grand mal)
- Generalized absence (petite mal)- very similar to focal impaired awareness
- Myoclonic (one particular muscle group)
- Atonic/tonic (drop attack) - muscle tone or lack muscle tone
- Infantile Spasms (West’s Syndrome)- developmental disorder
What drug can be used to treat all types of seizures?
Benzodiazapines
Lamotrigine is used to treat ___________ seizures.
partial
What are drugs used in Focal Seizures and Generalized Tonic Clonic Seizures?
Phenytoin, Phenobarbital, and Carbamazepine
What is the drug of choice of absence seizure?
Ethosuxamide
What drug can be used to treat infantile spasms?
Vigabatrin
What type of seizures can be treated with Valproic acid?
Absence seizure
Tonic seizures
Atonic seizures
Clonic/Myoclonic Seizures
What are toxicities with Phenytoin (Dilantin)?
- Nystagmus (rapid movement of eyes back and forth)
- Loss of extraocular pursuit of movement - can you follow my finger?
- Diplopia- double vision
- Ataxia- disordered movement, stumbling
- Sedation
- Rash/Lesions
(All these are dose related)
Toxicity of Carbamazepine (Tegretol)
Toxicity: Diplopia, Ataxia, GI, drowsiness
Toxicity of Phenobarbital?
Toxicity: SEDATION, hepatic enzyme inducer
Toxicity of Ethosuximide?
Toxicity: GI, Lethargy, Hiccup, Euphoria, Only available as syrup
Toxicity of Valproic Acid (Depakene)?
Toxicity: Hepato, GI, Sedation, Fine Tremors .
This drug will dislodge/displace phenytoin from albumin
What is the MOA of Benzodiazepines and indication of use?
MOA: Increase GABA
Used in Status epilepticus
What is the therapeutic level for total phenytoin?
What is the therapeutic level for free phenytoin?
What are toxic doses of phenytoin?
What are lethal doses of phenytoin?
Total: 10-20 mcg/ml
Total: 1-2.5 mcg/ml (10% of total)
Toxic: 30-50 mcg/ml (total)
Lethal: >100 mcg/ml (total)
Where does thrombogenesis usually occur and what will this lead to?
Thrombogenesis occurs in the blood vessels.
This will lead to:
Vasoconstriction
Formation of Platelet Plugs
Regulation of Coagulation and Fibrinolysis
What are the four phases of platelets?
- Adhesion to wounded area
- Aggregation- binding
- Secretion- pro-coagulation proteins to stablize clot
- Cross-linking of adjacent platelets
When there is a wall defect what two proteins are exposed in the vascular layer?
When these proteins bind to platelets, what receptors will they specifically bind to?
What will happen after the proteins are bound to the platelet?
How are platelets cross-linked?
Collagen and von Willebrand Factor
Collagen will bind to GP1a and vWF GP1b of the platelets.
Platelet will become activated and release ADP, TXA2, and 5-HT which will aid in clotting process and activate additional platelets and cause degranulation.
Platelets are cross-linked with Fibrin binding to the GP IIb/IIIa receptors.
How is fibrin produced?
The clotting cascade activates thrombin which causes fibrinogen to be converted to fibrin.
What does Tissue Factor Peptide Inhibitor do?
What does antithrombin do?
TFPI will inhibit Factor VII.
Antithrombin will inhibit Factor X and Thrombin.
What does protein C do?
Protein C will inhibit Factor VIII .
What is DIC?
What is the result of DIC?
Overstimulation of the blood clotting mechanism.
DIC will use up all the clotting factors which will lead to spontaneous bleeding.
What is the cause of DIC?
What is the treatment for DIC?
Cause:
Massive Tissue Injury (crush injury)
Malignancy
Bacterial Sepsis
Abruptio Placentae
Treatment:
Plasma transfusions
Treat underlying cause
10-50% mortality
What are ways to activate plasminogen (thrombotic disease therapy)?
Tissue Plasminogen Activator (tPA)
Urokinase from the kidneys
Streptokinase
In cases that we want a clot to stabilize what will protect clots from Lysis?
Aminocaproic Acid will block plasminogen from turning into plasmin
Usually used after surgery to prevent clot breakdown.
What are indirect thrombin inhibitors?
Examples.
These drugs will activate and enhance antithrombin activity which will inactivate Factor X.
Unfractionated Heparin (High Molecular Weight) - decrease Thrombin and Xa
LMW heparin (Decrease Xa)
Fondaparinux (Decrease Xa)
Adverse effect of HMW Heparin?
HIT, bleeding (treat with protamine sulfate)
How do direct thrombin inhibitors work?
Example?
Bind to both active and substrate recognition sites of thrombin.
Hirudin - from leeches (lepiruidin - recombinant)
Bivaliruidin (Angiomax)
What are direct thrombin inhibitors that bind only to thrombin active sites?
Agatroban and Melagatran
MOA of Warfarin.
How long of a delay is the onset of action for Warfarin?
What determines therapeutic range of warfarin?
MOA: Targets and inhibits Vitamin K reductase, decreasing synthesis of clotting factors
8-12 hours Start low, go slow
INR
What a normal INR?
What the target INR for Warfarin Therapy.
Normal: 0.8-1.2
Warfarin Target: 2-3
What preferentially activates plasminogen that is bound to fibrin?
t-PA
What fibrinolytic is synthesized by streptococci?
Streptokinase
What fibrinolytic is synthesized by the kidney and lyse thrombus from within?
Urokinase
How does aspirin work?
Aspirin is a COX inhibitor and prevent TXA2 from being produce.
Inhibition of TXA2 synthesis increase Bleeding Time
How does Clopidogrel (Plavix) and Ticlopidine (Ticlid) work?
Irreversibly inhibit ADP receptors on platelets and reduce platelet aggregation
What are the IIb/IIIa Receptor Blockers?
Abciximab- monoclonal antibody
Where do you find Vitamin K?
What does it confer activity on?
They are fat soluble vitamins found in leafy green vegetables and gut bacteria.
Confers activity on Prothrombin, Factor VII, IX, and X
How does aminocaproic acid work?
What are Fibrinolytic Inhibitors used for?
Aminocaproic acid competitively inhibits plasminogen activation.
Aminocaproic acid can be used for:
Adjunctive hemophilia therapy
Bleeding from Fibrinolytic therapy
Intracranial Aneurysms
Post surgical bleeding
What are the two main functions of the pancreas?
Endocrine Function- Islet of Langerhans
Exocrine Function - majority of the pancreas, produce digestive enzymes for proteins, lipids, and carbohydrates
What are the Four Types of Diabetes Mellitus?
Type I - Insulin Dependent (IDDM), destruction of beta cells, no insulin, greater than 80% loss of beta cells
Type II - Non-insulin Dependent (NIDDM)
Type III - Other causes elevate blood glucose (pancreatitis, drug therapy)
Type IV- Gestational
Describe how insulin is released from the beta cells.
- The pancreas has GLUT-2 (low affinity for glucose)
- After a meal, there will be a high amount of glucose circulation that will enter GLUT-2.
- Glucose goes through metabolism in the pancreas and generates a lot more ATP
- ATP in the pancreatic beta cell closes K+ channel (Rectifier current), causing depolarization.
- Depolarization causes VG Ca2+ to open
- Ca2+ floods into the cell and causes exocytosis of insulin
Describe the insulin receptor?
What are the effects of the receptor?
Tyrosine Kinase Receptor
Multiple effects:
Membrane Translocation of GLUT
Increase glycogen formation
Activation of multiple transcription factors
What are the 4 different types of insulin preparations?
- Rapid Acting - Lispro, aspart, glulisine
- Short Acting (Regular)- Novolin, Humulin
- Intermediate Acting- Neutral protamine Hagedorn (NPH)
- Long Acting- Glargine, detemir
These are oral antidiabetic agents, give an example of each. Possible matching question.
1. Biguanides
2. Insulin Secretagogues
3. Thiazolidinediones (TZDs)
4. Alpha-glucosidase Inhibitors
5. Bile Acid Sequestrant
6. Amylin Analogs
7. Incretin-base Therapies
8. SGLT2 Inhibitors
- Biguanides- metformin (500mg)
- Insulin Secretagogues- K+ Channels- sulfonylureas
- Thiazolidinediones (TZDs)- PPAR mediated increase in insulin signal
- Alpha-glucosidase Inhibitors- Acarbose (GI upset)
- Bile Acid Sequestrant- BABR
- Amylin Analogs - Suppress Glucagon Release
- Incretin-base Therapies- GLP-1 agonist, DPP-4 antagonist
- SGLT2 Inhibitors - Gliflozins, prevent glucose reabsorption in the PCT
What are the three parts to cholesterol synthesis?
- Mevalonate from Acetyl-CoA
- Conversion of mealonate to squalene
- Cyclication of squalene to cholesterol
Where do excess LDL go?
What happens over time with these LDL?
It will be deposited in the space between endothelial cells of the blood vessels and the smooth muscles.
They become oxidized and become more pro-inflammatory. This will cause WBC to migrate into the area and try swallowing the oxidized forms of cholesterol = foam cells.
What are foam cells?
Macrophages that engulfs a cholesterol molecule that ends up stuck in the macrophage.
Since cholesterol can not be broken down, over time they precipitate and become crystalized. This will rupture the foam cell which will increase inflammation even further.
What are Chylomicrons (exogenous pathway)?
They are lipoproteins formed in the intestines (dietary) that carry triglycerides and cholesterol.
Chylomicron is like Santa disposing cholesterol to all the good cells in the body.
The chylomicron remnant is degraded in the liver.
What are VLDL?
Very Low Density Lipoprotein are made in the liver and first ones secreted. Travel to peripheral tissues.
Enzymes will convert VLDL to IDL and LDL (endogenous pathway)
What are LDLs?
Low density lipoprotein - not made, converted from VLDL
Transport to cells
Cells have LDL receptors - LDL bind and drop off fat
Excess-deposit in arteries
What are HDLs?
High density lipoprotein- reverse cholesterol transport
Scavenger of cholesterol from cells, other lipoproteins
Decrease levels associated with atherosclerosis
What are desirable levels of:
Total Cholesterol
LDL
HDL Men
HDL Women
Triglycerides
Total cholesterol: < 200 ( greater than 200, statin candidate)
LDL < 130
HDL Men: > 40
HDL Women: > 50
Triglycerides: < 120
Here are 6 Hyperlipidemia Drug Classes: describe MOA for each. Possible matching.
1. Statins
2. Niacin
3. Fibrates
4. Binding Resins
5. Absorption Inhibitors
6. Monoclonal Antibodies
- Statins - HMG-CoA Reductase Inhibitors
- Niacin- Block transport to VLDL
- Fibrates - PPAR mediated lipolysis
- Binding Resins - Cationic bile acid binding (adjunct for diabetes and dyslipidemia)
- Absorption Inhibitors - (Ezetimibe) Inhibit cholesterol absorption
- Monoclonal Antibodies - PCSK9 Inhibitors
What is the MOA of Statins?
- Blocks the HMG-CoA reductase. Decrease overall cellular cholesterol synthesis.
- Cells will increase LDL receptors and scavenge LDL from blood.
- Major effect in the Liver
- Small increase in HDL
What time of day would a patients take their statins?
What increases the absorption of statins?
Who is restricted from using statins?
At night
Enhance absorption with food
Restricted use in children, pregnant, lactating
What are toxicities of statins?
Elevated liver enzymes- increase liver damage, patients of asian descent
CK Elevations will cause muscle pain and weakness
What does Niacin (Vitamin B3) do?
Decreases VLDL, LDL.
Reduces VLDL secretions from the liver.
Increase HDL
Incorporated into NAD, precursor for ATP
Toxicity of Niacin?
Toxicity: Flushing d/t cutaneous vasodilation
How do Fibrates work?
Decrease VLDL and modest decrease in LDL, they work by increasing breaking of cholesterol in the liver through the PPAR pathway.
Main toxicity with fibrate
Toxicity is rare (GI upset)
Arrhythmias
Elevated Liver enzymes
How does Ezetimibe work?
Inhibitor of Intestinal Sterol Absorption.
Ezetimibe is a NPC1L1 Transporter (cholesterol transporter) Antagonist and blocks the uptake of cholesterol.
How does PCSK9 work?
What is the problem with statin therapy with PCSK9?
What is an option to treat this?
- PCSK9 is a protein that occurs in the blood.
- PCSK9 binds to the LDLR, LDLR is internalized and is unable to get out onto the surface.
- End Result, LDLR bound to PCSK9 is digested in the lysosome.
- When this happens there will be fewer and fewer LDLR, resulting in higher blood cholesterol.
When we take statins, the promotes an upregulation of plasma PCSK9 level.
PCSK9 Inhibitors with the combination of statin therapy to bring down cholesterol levels.
What are PCSK9 inhibitors?
Monoclonal antibodies that bind to PCSK9 and inhibit the protein.
What are general properties of antimicrobial agent (5)?
- Selective Toxicity - bactericidal (kills) or bacteriostatic (slow growth)
- Spectrum of Activity - what types of organism (gram positive, gram negative, wide, narrow)
- Modes of Action
- Side Effects
- Resistance of Microorganisms
Here are the 5 main modes of action with ABX. Give med example, most likely matching.
- Inhibition of cell wall synthesis (gram +):
- Disruption of cell membrane function (gram -):
- Inhibition of protein synthesis (broadest group):
- Inhibition of Nucleic Acid synthesis:
- Block folic acid synthesis and inhibit metabolism:
- Inhibition of cell wall synthesis (gram +): PCN, bacitracin, cephalosporin, vancomycin)
- Disruption of cell membrane function (gram -): polymyxin
- Inhibition of protein synthesis (broadest group): Tetracycline, erythromycin, streptomycin, chloramphenicol
- Inhibition of Nucleic Acid synthesis: Rifamycin (transcription), Quinolones (DNA replication), Flagyl
- Block folic acid synthesis and inhibit metabolism: sulfanilamide, trimethoprim, Bactrim
Name two beta-lactamase inhibitors?
Why are beta-lactamase inhibitors sometimes given with PCN?
Clavulanic Acid
Sulbactam
Some bacterias can produce an enzyme call beta-lactamase which breaks the beta lactam ring of PCN.
By giving drugs like Sulbactam and Clavulanic Acid, the drug combo will result in bacteria’s sensitivity to penicillin.
What structure is highlighted in red below?
What two antibiotic have this structure?
What type bacteria will these drugs act on?
β-lactam ring
Penicillin and Cephalosporin
Gram (+) cocci and Anaerobes
What are allergic reactions to PCN/Cephalosporins (5)?
- Anaphylactic shock (0.05%)
- Skin Rash (<1%)
- Oral Lesions
- Hemolytic Anemia
- Interstitial nephritis
What is the most common drug allergy that exists?
- Penicillin allergy (urticaria, redness, etc.)
- Can cross react with similar abx
What is an alternative to PCN?
Why?
Does it have better activity on gram positive bacteria?
Cephalosporins
Cephalosporins are more resistant to b-lactamase.
Cephalosporins have a broader spectrum.
Cephalosporins have less allergies than PCN.
First Gen Cephalosporins have better gram (+) activity.
Used for UTI and Staph
What drug is good alternative for penicillin resistant gram + bacteria (MRSA)? This is also the drug of last resort.
- Vancomycin (resistant to beta-lactamase)
What adverse reactions can occur from vancomycin (10% adverse reaction)?
- “Red-neck” Syndrome - neck flushing from histamine release
- Ototoxicity
- Nephrotoxicity
- Chills/fever
How do cell membrane disruptors work?
What are polymyxins effective against?
- Act as detergents essentially. Bind to phospholipids in membrane & create pores.
Very effective against gram (-) bacteria
How do tetracyclines work?
Pharmacokinetics of tetracyclines?
They inhibit protein synthesis (bacteriostatic)
Readily absorbed and widely distributed.
What drug class/antibiotic has the widest spectrum of activity?
What is the downside of this?
Why are tetracyclines not given to children?
Inhibition of Protein Synthesis (Tetracycline)
Tetracycline will destroy the normal intestinal microbiota and often produce severe GI disorders- bone deposition disorder.
Abnormal bone development
What is the macrolide prototype drug?
What macrolides are semi-synthetic derivative
Spectrum covered with Macrolides?
Prototype: Erythromycin (Streptomyces erythreus)
Semi-synthetic derivatives:
-Azithromycin (Zithromax)
-Clarithromycin (Biaxin)
Spectrum: (+), (-), Atypicals
What drug, discussed in lecture, binds to bacterial RNA polymerase?
- Rifamycin
How do Fluoroquinolones work?
What characteristics do these drugs have?
Types and Uses of Quinolones?
Inhibition of DNA gyrase (enzyme that unwinds the DNA)
Excellent gram - activity
Good gram + activity
Types: Cipro, Levaquin, Floxin
Uses: UTI, Resp tract infections, bone, joint infections
What compound is needed to make folic acid?
What drug looks like this compound?
PABA
Sulfonamides
Sulfonamides are often used to treat these two conditions.
Sulfonamides are often paired with this medication.
- Pneumocystitis & toxoplasmosis
- Often paired with Trimethoprim (Bactrim and Septra)
Sulfonamide Toxicity.
Allergenic
May precipitate in urine
Hematopoetic disturbances
What are the unique properties of viruses?
- They are infectious particles (not organisms)
- They are active or inactive (rather than dead or alive)
- They can not replicate outside a host cell (obligate intracellular parasite). They must instruct the genetic and metabolic machinery of the host cell to make and release new viruses.
What are the components to a virus (3)
What is a naked virus?
- Capsid: shell surrounds the nucleic acid
-Nucleocapsid: capsid and nucleic acid together All viruses will have these two things - Envelope- usually a modified piece of the host cell membrane. some virus will have this
- Spikes - Project from either the nucleocapsid or envelope to allow viruses to dock with their host cells
Naked virus consist only of a nucleocapsid
Which viruses have targeted antiviral therapy?
Herpes simplex virus (HSV)
Cytomegalovirus (CMV)
Varicella Zoster Virus (VSV)
Hep C Virus (HCV)
Hep B Virus (HCB)
Influenza
Human Immunodeficiency Virus (HIV)
Respiratory Syncytial Virus (RSV)
Coronavirus (COVID-19)
What is acyclovir’s mechanism of action?
- Impersonates the deoxyribose sugar of a DNA chain. Missing a hydroxyl group so the chain ends up terminating.
When is acyclovir indicated?
Does this change for pregnancy?
- HSV 1 & 2, and Varicella Zoster Virus infections.
- Beneficial in pregnant women, ↓ viral shedding and ↓ c-section rate.
Which antiviral is a inhibitor of reverse transcriptase, treatment for HIV?
What is the therapy called when this drug is combined with others to treat HIV?
- Azidothymidine (AZT) Zidovudine, reverses transcriptase.
- Highly Active Antiretroviral Therapy (HAART), cocktail with a combination of 6 different drugs
What is the MOA of Lamivudine?
What is the MOA of Tebivudine?
When would you use Tenofivir?
Lamivudine:
Inhibits HBV DNA polymerase and HIV reverse transcriptase.
Tebivudine:
Inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5’-triphosphate.
Tenofivir:
- Activity against HIV & HBV
- Effective in treating Lamivudine-resistant HBV
What are the antiviral drugs recommended by the CDC for the flu?
- Oseltamivir (Tamiflu) - take within first 48hrs
- Zanamivir (Relenza) - target neuramindase protein
- Baloxivir Marboxil (Xofluza)- one time dose
Between Flu A & Flu B, which is generally more severe?
- Influenza A.
Which Influenza subtype has less antigenic shift and is generally more mild?
Who is generally more affected?
Does this flu infect anything other than humans?
- Influenza B
- Children
- Seals
What viral component allows HIV to bind to CD4⁺ T-lymphocytes?
-gp120 spike protein
Proto-oncogenes vs Tumor Suppressors. Differences?
Proto-oncogenes usually has a function in the cell cycle, when it gets mutated that function gets changed. A single mutation known as gain of function mutation.
Tumor Suppressor Genes (p53 and p16) cause cell to commit suicide if it has an error. If both p53 and p16 are knocked out (two-hit hypothesis), you will most likely develop cancer. Loss of function mutation.
Cancer cell types?
Carcinoma- epithelial origins (basal cell carcinoma, breast carcinoma)
Sarcoma- connective tissues or muscles (osteosarcoma, Kaposi’s sarcoma)
Leukemias/Lymphomas- immune cells (Hodgkin’s lymphoma, AML)
What are three traditional treatments for cancer.
Surgery
Radiation
Chemotherapy
What is Primary Chemotherapy?
What is Neoadjuntive Chemotherapy?
What is Adjunctive Chemotherapy?
Primary: Treatment is chemo, associated with advanced diseased and the goal is to limit spread and improve quality of life. (one treatment)
Neoadjuntive: Chemotherapy induced to reduced tumor size prior to and after surgery. Surgery would be primary treatment and chemo would be secondary. (GI, Breast, Lung CA) (two treatments)
Adjunctive: After surgery reduce incidence and resurgence of tumor. Both surgery and chemotherapy equally important, possible radiation. Goal: Disease free survival and overall survival. (three treatments)
Toxicity of Chemotherapy (7)?
Attacks rapidly dividing cells will result in:
Abortion/Fetal death
Teratogenicity
Carcinogencity
Alopecia
Bone marrow suppression
Immunosuppression
N/V
AT CABIN
Alkylating Agents are the largest and most diverse CCNS chemo class. How do these work?
What are 4 groups of Alkylating Agents?
Either alkylate DNA or interferes by cross linking (platinum compounds)
- Nitrogen Mustards
-Cyclophosphamide- cancer and immunosupressive
-Chlorambucil - least toxic - Nitrosureas- cross BBB
- Alkyl Sulfonate
- Platinum Analogs- cisplatin, carboplatin
MOA of Alkylating Agents (ABCD)?
- Abnormal base pairing
- Break DNA strand (decrease cell proliferation)
- Cross linkage
- Damages RNA and proteins.
What is the MOA of Cisplatin?
Where does Cisplatin concentrate?
Does Cisplatin cross the BBB?
Cisplatin enters the cell and forms highly reactive platinum complexes. Strands cross link resulting in DNA damage and inhibit cell proliferation.
Concentrate in the kidney, intestines, and testes.
Cisplatin does not cross the BBB.
What are the uses of Cisplatin?
How is Cisplatin excreted?
If a patient can’t tolerate Cisplatin, what is an alternative?
Testicular Cancer (85-95% curative)
Ovarian Cancer
Treat tumors in the lungs, esophagus, gastric
Cisplatin is slowly excreted through the urine.
Carboplatin can be an alternative because Cisplatin is very toxic (emesis, nephrotoxicity, peripheral neuropathy, ototoxicity).
What antimetabolite drug is a folate antagonist?
Methotrexate
What is the MOA of Methotrexate?
What are the cytotoxic actions of methotrexate (3)?
Inhibits dihydrofolate reductase (DHFR) and interferes with DNR/RNA synthesis.
Cytotoxic actions:
1. Predominant in the bone marrow (leukemia)
2. Ulceration of intestinal mucosa
3. Crosses placenta and interferes with embryogenesis (fetal malformation and death)
What are the immunosuppressive actions of methotrexate?
What are the anti-inflammatory action of methotrexate?
Immunosuppression: Prevent clonal expansion of B/T lymphocytes
Anti-inflammatory Action: Interferes with release of inflammatory cytokines
Antimetabolites (2).
5-FU
6-MP
Plant Based (2)
Vincristine
Paclitaxel (Taxol)
Antibiotics (3)
Bleomycin
Dactinomycin
Doxorubicin
Hormonal Agents (3)
Corticosteroids
Tamoxifen
Fulvestrant
Miscellaneous (3)
Rituximab
Trastuzumab
Imatinib
What do glucocorticoids do?
Examples?
Suppress immune response, mimic naturally occurring adrenal corticosteroids.
Prednisone, Hydrocortison, Dexamethasone
What are Calcineurin Inhibitors?
Examples?
Block T-cell receptor signaling, activation of the T-cell pathway
Cyclosporine, Tacrolimus
What are Cytotoxic Agents?
Examples?
They kill rapidly proliferating cells (many are antineoplastics)
Azothioprine, Cyclophosphamide, Hydroxychloroquine
What are immunosuppressive antibodies?
Examples?
Antibodies created in a lab, directed against cell surface antigens/receptors
Muromonab (CD3), RhoGAM, Adalimumanb (TNF-a inhibitor)
What symptom is the hallmark of Parkinson’s disease?
What are the TRAP symptoms with Parkinson’s disease? essay question
Tremor at rest (rhythmic movement around a joint)
Tremor
Rigidity
Akinesia - loss of ability to move muscle voluntarily
Postural instability.
What is Chorea?
What is Ballismus?
- Muscle jerking in various areas
- Violent abnormal movements (extreme version of chorea)
What is Athetosis?
Is this indicative of Parkinson’s disease?
- Slow, writhing movement
- Not typical of Parkinson’s
What is Dystonia?
What are Tics?
- Abnormal posture w/ no movement, jointed locked, usually seen with cerebral palsy.
- Single, repetitive movements (especially facial)
Communication from the motor cortex to the thalamus goes through the _____ ______.
Basal Ganglia
What is the pathogenesis of Parkinsonism?
Decrease in Dopamine Levels in the Nigro-striatal pathway
What genetic component is often present in Parkinson’s patients?
What is the result of this mutation?
- SNCA - α-Synuclein (NT release)
Misfolding produces Lewey Bodies
What are the treatments for Parkinson’s? Essay Question
- Exercise/ Physical Therapy
- Levo-Dopa- restore dopamine levels
-Improve uptake with carbidopa- inhibits dopa decarboxylase
-Improve uptake with COMT inhibitors (tolcapone)
-Decrease toxicity (hallucinations) with pimavanserin (Nuplazid) - CNS antimuscarinics- to reduce tremors
- Dopamine receptor agonist : Pramipexole, Ropinirole, Rotigotine
- MAO-B Inhibitors (Selegeline)
What should be avoided when one has Parkinson’s Disease?
Dopamine receptor antagonist (antipsychotics, D2 antagonist, Haldol)
MPTP-destroys dopaminergic neurons
What is the On-Off Phenomenon with Levo-dopa?
What can you take to decrease these symptoms?
Are drug holidays recommended?
Associated with long-term use (10 years+). Increased mobility followed by marked akinesia, very frustrating for patients.
Apomorphine
Drug holidays for 3 to 21 are not recommended, but patient’s will still self demedicate.
What characterizes the pathophysiology of Huntington’s disease?
- GABA reduced in the basal ganglia
- Reduction in ChAT (Choline Acetyltranferase)
- Excess Dopamine
What treatments are there for Huntington’s disease?
- Tetrabenazine = ↓ excess dopamine
- Dopamine Receptor blockers (ex. Haldol)
- Genetic Counseling, Speech Therapy, PT/OT
What is the cause of chronic inflammation?
What additional mediators are released?
WBC infiltration of the tissue in response to acute inflammation.
Interleukins
GM-CSF
TNF
Interferons
PDGF
What can block arachidonic acid production?
Corticosteroids
What is the most important autocoid involved in acute inflammation?
What are the other autocoid involved with acute inflammatory response?
Prostaglandin (most important)
Histamine
Serotonin
Bradykinin
Leukotrienes
What is the main pathway target when using NSAIDs?
What is the secondary pathway?
- COX pathway
- LOX pathway
Which NSAID irreversibly blocks COX-1, thus preventing platelet aggregation?
How long will this platelet inhibition last?
- Aspirin
- 8-10 days (the lifespan of the platelet)
What are clinical uses of aspirin?
What are adverse effects of aspirin?
How was aspirin extracted prior to modern medicine?
Widely used to treat mild/moderate pain (12-1500 mg TID)
Rheumatoid Arthritis, Fever
Clot Prevention (81-325 mg/day)
GI upset d/t inhibition of GI protective PG
Increase gastric ulcers d/t decrease buffering
- Willow Bark extraction
Celecoxib (Celebrex)
Use:
Adverse:
Other:
Celecoxib (Celebrex) - Selective COX-2 Inhibitor
Use: Arthritis
Adverse: CV Black Box Warning
Other: Sulfonamide, Very $$$
Ibuprofen
Use:
Adverse:
Other:
Ibuprofen: Inhibits COX1 and COX2
Use: Pain, Inflammation
Adverse: NSAIDs, agranulocytosis, aplastic anemia
Other: Less GI upset than ASA
Indomethacin
Use:
Adverse:
Indomethacin: Inhibits COX and LOX
Use: Patent Ductus Arteriosus , Arthritis, Gout,
Adverse: GI issues (1 in 3 patients)
Acetaminophen
Use:
Other:
Acetaminophen: NOT A NSAID
Use: Pain and Fever
Other: COX-2 inhibitor (primary effect is in the CNS, no significant anti-inflammatory effect)
What is the primary short-term use of glucocorticoid?
Suppression of Inflammation
Mobilize energy stores
Improve Cognitive Function - cortisol release
Salt and Water Retention
Crave carbohydrates for energy utilization.
What are the adverse effects of chronic glucocorticoid usage?
- Immunosuppression
- DM, obesity, muscle wasting
- Depression
- HTN
When glucocorticoids bind to glucocorticoid receptors in the cell what will increase in transcription (3 molecules)?
What will decrease in transcription?
Increase transcription in substances involved in immune suppression:
1. Annexin-1 (lipocortin-1): suppresses PLA2, inhibit leukocyte response
2. Secretory Leukoprotease Inhibitor (SLPI)
3. IL-10: immunosuppressive enzyme
Decrease transcription in pro-inflammatory cytokines:
-Inhibition of NFkappaB
What is Rheumatoid Arthritis?
What drug class will reverse the effects of rheumatoid arthritis?
What is also given in conjunction with this drug?
RA is a progressively worsening joint disorder involving rheumatic factors.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) will reverse the effects of RA and decrease inflammation.
NSAIDs
Name 3 Non-biologic DMARDs.
- Methotrexate
- Cyclophosphamide
- Cyclosporine
Name 3 biological DMARDs.
- Abatacept (Orencia)
- Rituximab (Rituxan)
- Adalimumab (Humira)
What are Aβ fibers associated with?
What are Aδ fibers associated with?
What are C fibers associated with?
Aβ fibers are myelinated fibers involved with touch and non-noxious mechanical stimuli.
Aδ fibers are fast myelinated fibers involved with noxious heat, mechanical stimuli, sharp pain, produces initial reflex response.
C fibers are slow thin non-myelinated fibers involved with noxious chemical, heat, mechanical stimuli. Slow burning pain. Also has a prolonged response.
What is the Gate Control Theory of Pain?
What can be used to suppress pain?
There are “gates” in the spinal cord that allow pain signals through. These gates can be adjusted to increase/decrease pain sensation.
Opioids (blocks signaling) and anti-inflammatory agents (suppress nociceptor signaling)
What will activate bradykinin release?
What two receptors does bradykinin bind to?
What do these receptors do?
Tissue damage
B1 receptors (inflammatory)
B2 receptors (constitutive)
Both receptors will activate PKA and PKC, which will send an action potential in the free nerve ending to release glutamate and substance P.
What three tracts are involved with pain transmission in the CNS?
Spinothalmic Tract (Affective Sensation)
Spinoreticular Tracts (Affective Sensation)
Spinomesencephalic Tract
Where is the signal sent in the spinomesencephalic tract?
What kind of receptors are at this location?
Periaqueductal gray matter (PAG).
Lots of opioid (mu) receptors that will suppress the spinothalmic and spinoreticular signaling.
The spinothalmic and spinoreticular tract will also send signals to the PAG to release more endogenous opioids.
Differentiate full agonist, partial agonists, & antagonists of the opioid receptors. Give examples for each.
- Full Agonists (strong to moderate effect) morphine, fentanyl
- Partial Agonists (moderate to mild effect) codeine, oxycodone, etc.
- Antagonists (Reversal) Naloxone
Name the 3 opioid receptors, which one is the the primary receptor?
Mu Receptor (Primary Opioid Receptor) - most responsive to endorphins/endogenous ligand
Delta Receptor- Analgesia
Kappa Receptor- Analgesia (May have negative analgesia effects mediated by dynorphins)
Pharmacokinetics of Opioids:
Absorption:
Distribution:
Metabolism: Morphine, Heroin, Other.
Elimination:
Pharmacokinetics of Opioids:
A: Well absorbed (IM, SQ, Oral- only with demerol or codeine)
D: Opioids can accumulate in the tissues
M: Morphine - metabolized by Phase II
M: Heroin - metabolized by tissue esterases to morphine
M: Other: Phase 1 (CYP3A4, CYP2D6)
E: Urine
Opioids will bind to the receptors in the brain and spinal cord. What type of receptor are opioid receptors?
How do μ(mu) opioid receptors suppress pain?
Gᵢ GPCRs
Gᵢ = ↓AC → ↓cAMP = ↑pK⁺, ↓pCa⁺⁺ = Hyperpolarized neuron. This will reduce NT release: glutamate, ACh, NE, serotonin, Substance P.
What are the CNS effects of opioids (9 items).
- Cough Suppression
- Hyperthermia (mu receptors)/ Hypothermia (kappa receptors)
- Analgesia- sensory/emotional
- Increase muscle tone (trunk)
- Respiratory Depression (brainstem)
- Miosis (always a marker, pinpoint)
- Euphoria (Dysphoria sometimes)
- N/V
- Sedation
CHAIRMENS
What are other uses of opioid besides pain relief?
Pulmonary Edema
Cough
Diarrhea
Shivering
Anesthesia
Name Opioid Toxicities (8 items)
Increase ICP
Constipation
Urinary Retention
Postural hypotension (worsens with hypovolemia)
Itchy nose, urticaria
Dysphoric Reactions: Restlessness, hyperactivity
Respiratory Depression
N/V
I CUPID RN
How quickly does opioid tolerance build?
What is the probable mechanism for this?
- Rapidly
- β-arrestin pathway
People who take opioids will develop a tolerance to what factors (8)?
Cough Suppression
Analgesia
Mental clouding
Euphoria/Dysphoria
Respiratory Depression
Antidiuresis
Sedation
N/V
CAMERAS N
People who take opioids do not develop a tolerance to what factors (4)?
- Miosis
- Constipation
- Convulsions
- Antagonist actions
What mild symptoms might be seen from opioid withdrawal (6)?
Piloerection (goosebumps)
Rhinorrhea
Lacrimation (tears)
Yawning
Chills
Hyperventilation
PR LYCH
What symptoms would be seen in severe opioid withdrawal (6)?
Hyperthermia
Mydriasis
Muscle aches
N/V/D
Anxiety
Hostility
HMM NAH
What is given to reverse opioid overdose?
Why are opioids partially contraindicated in head injuries?
What can occur when opioids are given to a pregnant mother?
Narcan (short half-life)
↑ Resp depression
Fetal dependence
Name 3 main structures of strong opioid agonist and examples for each.
- Phenanthrenes (Morphine, Dilaudid, Heroin) basket of morphine, 3 rings
- Phenylheptylamines (Methadone) 7 carbon chain with an amine group at the end
- Phenylpiperadine (Fentanyl, Demerol) Has a N inside the ring
What is heroin used for in the UK?
Palliative Care/ Terminal Care
What is methadone’s usefulness?
Why is this?
- Suppression of opioid withdrawal symptoms (and chronic pain)
- Long Half-Life = 25-50 hours
What is the primary use of Meperidine?
What cardiac effects are seen with it?
People who are prone to _________ should not receive demerol.
Post-op shivering
neg inotrope, + chronotrope (antimuscarinic effect)
Seizures
Give examples of moderate agonist in each structural class
Phenanthrenes:
Phenylheptylamines:
Phenylpiperadine:
Moderate agonist
Phenanthrenes: Codeine, Oxycodone
Phenylheptylamines: Propoxyphene (Darvon) decreasing
Phenylpiperadine: Loperamide (Imodium) diarrhea
What combination makes Percocet?
What combination makes Percodan?
Percocet = Oxycodone + Acetaminophen
Percodan =Oxycodone + ASA
What opioid antagonists are a derivative of morphine (2)?
- Naloxone (Narcan) - Overdose antidote (short duration, supportive therapy still needed)
- Naltrexone (longer acting)- EtOH abuse.
How long does it take Narcan to take effect?
What do you need to take into consideration with Narcan’s short duration?
1 to 3 minutes.
Short duration means that the effects may return there is a longer acting opioid in the system.
These are your classifications of sedative-hypnotics, give examples for each. Possible matching.
- Benzodiazepines
- Barbiturates
- Sleep Aids
- Anxiolytics
- Ethanol
- Benzodiazepines - Diazepam, Midazolam
- Barbiturates - Phenobarbital
- Sleep Aids - Zolpidem (non-benzo)
- Anxiolytics - Buspirone (non-hypnotic)
- Ethanol - Booze
How are sedative hypnotics used in anesthesia?
SH are useful as anesthesia adjuncts.
Barbiturates : Thiopental and Methohexital
Very lipid soluble, penetrate brain tissue rapidly
Short action of duration
Benzodiazepines: Diazepam, Lorazepam, Midazolam
Combined with other agents
Can cause post-anesthetic resp depression
What are Benzodiazepines reversed with?
Flumazenil, GABA antagonist
What are the two major pathways of metabolism of EtOH to Acetaldehyde?
- Alcohol Dehydrogenase Pathway (Liver)
- Microsomal Ethanol- Oxidizing System (MEOS)
What compound is a contributing factor to hangovers and headaches form EtOH?
Acetaldehyde
What enzyme is used to break down EtOH to acetaldehyde?
What coenzyme is used in this pathway and what does it get reduced to?
Alcohol Dehydrogenase
NAD+ is used and is reduced to NADH
What does NADH do to fatty acids?
When does this become a problem?
NADH blocks the breakdown of fatty acids.
Increasing NADH from increasing EtOH consumption will lead to increase fatty acids in the liver leading to alcohol steatohepatitis, cirrhosis, failure of the liver.
What enzyme breaks down acetaldehyde?
What is the end result?
Aldehyde dehydrogenase
Acetate (gas that is freely blown out through the lungs)
What are treatments for alcohol withdrawals?
Naltrexone- long lasting opioid antagonist
Acamprosate- requires adjunctive therapy
Disulfiram (Atabuse) (decline)- alcohol dehydrogenase
What are the phases of clinical testing?
Investigation New Drug (IND) is filed with the FDA.
Phase 1 (20-100 healthy volunteers)
-Dosing, Safety, ADME
Phase 2 (100-200 patients)
-Double-blind, efficacy
Phase 3 (1000s patient)
-Market formulation, route
New Drug Application (NDA) 1-2 year for approval
What are the effects of Echinacea
Issues?
Echinacea stimulate immune system, anti-inflammatory
Issues: GI Upset
What herbal supplements will you take for memory, immune, analgesia?
Ginseng
What herbal supplement will you take for reduction in hepatotoxicity?
Milk Thistle
What herbal supplement will you take for BPH?
Saw Palmetto
What are the effects of Garlic?
Garlic- HMG CoA Reductase Inhibitor- reduce cholesterol, reduce cancer rate, anti-bacterial
What are the effects of Ginkgo?
Ginkgo- improved blood flow, free radical scavenger, helps with memory and dementia.
What are the effects of St. Johns wort?
St. John’s Wort- antidepressant, increase serotonin
What do you take Coenzyme Q10 (CoQ10) for?
Blood pressure and prevent MI
This supplement will help improve your joint health.
Glucosamine
Take this supplement to improve mood and prevent jet lag.
Melatonin
