Final Review Flashcards
Somatic Nervous System vs Autonomic Nervous System
What do the control? Subdivisions?
Somatic: Consciously controlled functions that deal with movement, respiration, and posture
ANS: Largely independent system. Concerned with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion.
1. Sympathetic
2. Parasympathetic
3. Enteric- “gut feeling”
SNS
Anatomy, Primary Neurotransmitter
-Arise from the CNS at the level of the T-Spine (T1-L2) or Thoracolumbar spine
-The sympathetic chain is a collection of cells called ganglia that receive information and deliver it to their target organ
-Short preganglionic fibers originate in the chain ganglia at the level of the spine
-Long post-ganglionic fibers that innervate and terminate at their target organ
-Primary neurotransmitter is norepinephrine (adrenergic)
-Adrenal glands will also release epinephrine
ALL PREGANGLIONIC NEURONS RELEASE ACh
PNS
Anatomy, Primary neurotransmitter
-Nerves located in the craniosacral area (Cranial nerves except II)
-Long preganglionic fibers. Leave the CNS through the cranial nerves and sacral spinal roots
-Short postganglionic fibers, terminate on the target organ
-Ganglia are located in visceral organs
-Most important cranial nerve here is X (Vagus)
-> 75% of the PNS output goes through the vagus nerve
-Primary neurotransmitter is ACh (cholinergic)
ALL PREGANGLIONIC NEURONS RELEASE ACh
Autonomic Receptors
Adrenergic Receptors
Receptors and Locations
A1: Usually vascular smooth muscle
A2: Presynaptic adrenergic nerve terminals, smooth
B1: Heart, brain
B2: Smooth muscle in lungs, cardiac muscle
D1-D5: Brain
D4: Brain and CV systems
Cholinergic Receptors
Muscarinic vs Nicotinic
Locations. Excitatory or inhibitory?
Muscarinic:
M1- (E) CNS neurons, SNS postganglionic neurons
M2-(I) Myocardium, smooth muscle, CNS
M3- (E) Exocrine glands, vessels, CNS
M4- (I) CNS, vagal nerve endings
M5- (E) Vascular endotheliam (esp. cerebral vessels), CNS
M2, M4: Inhibitory
M1, M3, M5: Excitatory
Nicotinic:
Nn: Neuronal; postganglionic neurons
Nm: Muscular; skeletal muscle
Adrenoreceptors
A1
Receptor pathway, effects on CV system
-Gq Receptor Pathway
Activates phospholipase C–> cleaves PIP2 into IP3 & DAG–> IP3 stimulates release of Ca++ into cytosol–> increased levels of myosin light chain kinase
DAG + Ca++ –> activate protein kinase C–> inhibits myosin light chain phosphatase
-SNS activation: results in muscle contraction of vascular smooth muscle; however, decreases CO due to increased PVR. Can have reflex bradycardia initially
Adrenoreceptors
A2
GI pathway: Inhibits adenlyl cyclase –> less cAMP is formed–> usually means less Ca++ influx into the cell, less K+ out of the cell
Adrenoreceptors
B1 & B2
Receptor Pathway, Effects on CV & Respiratory System
GS Pathway: Stimulates adenylate cyclase–> causing an increase in cAMP (major second messenger in B receptor activation)–> increase in Ca++ influx
-SNS activation in heart: Increases contractility and chronotropy
-SNS activation in skeletal blood vessels (B2): Relax
-In bronchiolar smooth muscle (B2): Relax
Autonomic Feedback Loop, Increase & Decrease in BP
Cardiovascular Feedback Loops
Mean arterial pressure is sensed by the baroreceptors (carotid and aortic arch)
Increase in BP: Brainstem activates PNS –> ACh released to slow down HR and decrease cardiac output
Decrease in BP: Brainstem activates SNS –> NE binds to B1 in the heart –> increasing HR & CO
NE binds to A1 receptors in peripheral vascular system –> constriction, increasing blood return to the heart
Hormonal Feedback Loop
Cardiovascular Feedback Loop
-Renal BP decreases–> renin released–> angiotensinogen converted to angiotensin 2–> causes constriction
Aldosterone released–> Decrease UOP, Increase H20 retention –> increased blood volume, increased venous return, increased CO
Six Types of Neurotransmitters
- Esters; ACh
- Monoamines; NE, serotonin, dopamine
- Amino Acids; GABA, glutamate
- Purines; Adenosine, ATP
- Peptides; Substance P, Endorphins
- Inorganic gases; Nitric Oxide (released by presynaptic cell)
Examples of them
Directing acting cholinomimetic agents; alkaloids
-Act directly on the nACh-r or mACh-r.
-Considered stimulants
Alkaloids: Plant based
-Muscarine: Activates PNS system
-Nicotine: Stimulates nACh-r
-Pilocarpine, lobelin
Examples of them
Directing acting cholinomimetic agents; Esters of choline
-Act directly on nACh-r or mACh-r
-Not lipid soluble, permanently charged
-ACh: Used primarily for pupil dilation, but we have better drugs
-Methacholine: Dx of asthma
-Succinylcholine: Paralytic
-Carbachol: Decrease intraocular pressure
-Bethanecol: Bladder dysfunction
Examples of them, uses for them, 3 classes of them
Indirect acting cholinomimetic (Cholinesterase Inhibitors)
-Carbamates:
Neostigmine- Post Op ileus, MG
Pyridostigmine- MG
-Alcohols:
Edrophonium: Dx for MG
-Organophosphates:
Echothiopate: Glaucoma, lasts over 100 hours
Effects of Cholinomimetics in Major Organ Systems
Eye, CV, GI, Resp, CNS, NMJ
Eye:
-Muscarinic agonists cause contraction of the pupil
-increase intraocular drainage
CV:
-Reduction in PVR
-Vasodilation, reflex tachycardia. Large doses: bradycardia
Respiratory:
-Bronchiole smooth muscle contracts
-Tracheobronchial secretions increased
GI:
-Increased motility
-Salivary & gastric glands stimulated
-Sphincters relax
CNS:
-Primarily have muscarinic receptors in brain with few nicotinic receptors
-Nicotine crosses the BBB (unlike muscarine) and stimulates release of serotonin, dopamine, GABA, NE
NMJ:
-Immediate depolarization of the end plate
-Increased permeability to Na+ and K+
-Muscle contraction, and if not hydrolyzed immediately, depolariation blockade
How does atropine effect this?
Open-Angle & Narrow-Angle Glaucoma
In general, the iris of the eye is flat in comparison to the cornea. This allows aqueuos drainage to pass through the Canal of Schlemm.
In open-angle glaucoma, we can use cholinomimetics to contrict the pupil, widening the angle, allowing for more drainage to pass, and decrease intraocular pressure. Open-angle glaucoma makes up for about 90% of glaucoma cases
In narrow-angle glaucoma, the iris is being pushed forward towards the pupil. The Canal of Schlemm is very narrow because of this. Giving atropine to dilate the pupil, in this situation, would occlude the canal of schlemm and could result in blindness. This is a medical emergency
S/S, Tx
Organophosphate pesticide poisoning & Poisonous mushrooms
-SLUDGE-M
Organophosphates:
-Tx: Vital sign maintenance, decontamination, atropine or pralidoxime (must be given withint the first couple of hours)
Mushrooms:
Atropine
S/S, Tx
Nicotine Poisoning
-40mg is fatal dose. Usually happens if children eat cigarettes
-Tremor, vomitting, convulsions, fatal coma, and death
-Need to induce vomitting
Cholinesterase Inhibitors
Organophosphates MOA & Aging
Organophosphates target AChE. The organophosphate binds to the enzyme by hydrolysis and phosphorylation of the active site. A covalent bond is formed with the phosphorylated active site.
After the intial covalent bond is formed, the aging process begins; meaning, the phosphorous-active site bond continues to become stronger and irreversible
Pralidoxime needs to be given immediately, before aging progresses
Antimuscarinic Effects on Major Organ Systems
Eye:
-Dilation, decreased watering (via paralysis of the cilliary muscle)
Heart:
Increased HR
Misc: Decreases salivation, decreases rate at which urine is produced
Atropine Toxicity & Treatment
Belladona plant or deadly nightshade
-Tachycardia, agitation, increased body temperature, dilated pupils, decreased salivation and sweat, dry skin
-These symptoms can be overcome by increasing the amount of ACh in the synapse.
-Physostigmine (dangerous CNS side effects), Neostigmine
Indications & Contraindications for Atropine
Indications: Overproduction of PNS response, parkison’s, poisonous mushroom toxicity
Used to block toxic effects of muscarinic stimulants; use atropine if SLUDGE-M
Contraindicated in narrow-angle glaucoma, BPH
Basic Structure of Catecholamines
-Benzene ring with adjacent hydroxyl groups (cathechol) and an amine group
-Substitution greatly reduces potency
-Cannot be taken PO, inactivated immediately by cOMT in gut
-Catecholamines are degraded by catechol-O-methyltransferase (COMT)
Epinephrine
-Mixed Adrenergic Agonist
-Binds to A1, A2 (some), B1, B2
-Increases PVR, CO (HR, SV), BP
-B2 vasodilates blood vessels in skeletal muscles, dilation of bronchioles
Phenylephrine/Midodrine
-Pure A1 agonist
-Increases PVR
-Can cause decrease in CO
-Reflex bradycardia immediately after given
-Decongestant if given PO
Midodrine- pure A1 agonist
-Decreases orthostatic HTN, can cause HTN in supine patient
Isoproterenol
-Beta 1 & 2 agonist
-Increases HR, contraction, CO, SV
-Decreases PVR, can cause decrease in BP
Dopamine
-Dose dependent
-Low dose (0.3mcg/ml or less): D1 receptors in kidneys; Induces diuresis
-Intermediate Dose (0.3mcg-0.7mcg): Beta 1
-High dose (>1mg/ml): A1 agonist. Increases the work of the heart, can induce arrythmias
Norepinephrine
-A1, A2, B1 agonist
-Increases both SBP and DBP
-Hardly any B2 activity
Dobutamine
-B1 Selecive Agonist
-Cardiogenic shock, CHF exacerbation
Ephedrine
-Indirect acting; releases stored catecholamines
-Direc acting; acts as epinephrine, crosses BBB
-PO pseudoephedrine
Phentolamine
Reversible or not?
Competitive antagonist of A1 & A2
-Reduces PVR
-Causes some cardiac stimulation
-Minor agonist of muscarinic and histamine receptors
Adverse Effects:
Cardiac stimulation (M-r in heart, can increase HR)
Abdominal pain, N/V/D
Used for treatment of HTN linked to pheochromocytoma
ED- direct injections
Phenoxybenzamine
Reversible or not?
-Mostly selective for A1
-Forms covalent bonds, non-competitive, insurmountable
-Inhibits NE reuptake, blocks H1, ACh, and Serotonin receptors
-
Antimuscarinic Drugs
4 of them we need to know for class
-Atropine (bradycardia)
-Scopalamine (Motion Sickness)
-Tropicamide (eye)
-Ipratropium (COPD)
-MOA: Blocks mACh-r
-Block PNS effects
-Eye indications: Miosis (contraction of pupil), mydriasis (dilation of the pupil), paralysis of cilliary muscle (cycloplegia), accomodation (focus)
Beta Blockers
Propranolol, Metoprolol, Atenolol, Esmo, Labeta, and indications
-Propranolol is the prototype:
-Extensive first pass
-Non Selective, B1 and B2
Metoprolol, Atenolol:
Mainly B1 selectivity
Safer in COPD and diabetics
Esmolol:
Ultra short acting
Selective for B1
Safer in critically ill, fast on fast off
Labetalol:
Racemic mixture
S,R isomer is a1 blocker
R,R isomer is a B blocker
Four anatomic control sites for BP
- Arterioles: Provide resistance
- Venules: Increase return to the heart, contributes to preload
- Heart: CO
- Kidneys: Volume regulation via RAAS
Categories of Anti-HTN Agents
Act on one or more of the anatomic control sites
- Diuretics (Lasix, Bumex, HCTZ): Deplete Na+
- Sympathoplegics (Alpha & Beta blockers): Decrease PVR, reduce CO
- Direct vasodilators: Relax vascular smooth muscle
- Anti- Angiotensins: Block activity or production of
Clonidine & Precedex
Targets, Effects, Indications for use, major side effects
-Targets vasomotor center in CNS
-A2 agonist
-Primary activity is due to inhibition of sympathetic outflow and increased parasympathetic outflow in brainstem
-Crosses BBB, enters rapidly
-Side effect is sedation, used as anesthesia adjunct as well as
Clonidine is primarily used for ADHD, tourettes, w/d symptoms
Methyldopa
Targets, effects, indications, side effects
-Target is vasomotor center in the CNS
-Analog of L-dopa
-Prodrug; works by replacing NE and decreasing NE release
-Does not cross placental barrier
-Does cross BBB
-Primary use for pregnancy- induced HTN
-S/E sedation
Vasodilators
MOA
-Relax smooth muscle of arterioles (all vasodilators) and veins (nitroprusside & nitrates)
-Reduces MAP and PVR
-Elicits compensatory responses- RAAS system, so best when given in conjuction with anti-HTN that combat these responses
Vasodilators
Minoxidil
MOA
-Opens K+ channels in smooth muscle, hyperpolarizing membrane potential, less likely to contract
-Dilates arteries and arterioles
-Rogaine
Vasodilators
Hydralazine
MOA, toxicity
Dilates arterioles–> possibly NO production?
-Toxicity includes: HA, N, sweating, flushed. Symptoms are similary to lupus
Vasodilators
Sodium Nitroprusside
MOA, indictions, toxicity
-Relaxes venous and arterial smooth muscle by releasing NO
-Rapidly lowers BP
-Protect from light
-HTN emergencies and heart failure
-Breaks down into cyanide, begins to accumulate >48hours.
Can cause metabolic acidosis, arrythmias, death
Need to give sodium thiosulfate to metabolize CN
Three Classes of CCB & their targets
-Verapamil: Targets the heart
-Diltiazem: Targets heart and peripheral vasc
-Dihydropyridine blockers: end in -dipine, target the peripheral vasc
ACE Inhibitors & ARBS
MOA, drug name ending
Ace Inhibitors: By blocking ACE, we stop the conversion from Angiotensin I to Angiotensin II
This also inhibits the breakdown of bradykinins, leading to increased inflammation in the lungs –> dry hacking cough as side effect
Ace inhibitors end in -pril
ARBs block the angiotensin II receptors in the blood vessels and adrenal cortex
Arbs end in -sartan
Pathophysiology of stable angina, vasospastic angina, unstable angina
-Stable/Angina of Effort: Accumulation of metabolites. O2 requirement increases due to exercise or symapthetic stimulation, and those increased O2 demands are not met because blood flow does not increase proportionally
-Vasospastic/Prinzmetal: O2 delivery decreased due to coronary vasospams
-Unstable angina: Angina at rest; usually due to atherosclerotic plaque
CCB Vascular tone reduction pathway
-Blocks Ca++ channel–> Ca++ cannot flux into the cell–> this leads to a direct decrease in calmodulin activity –> inhibiting myosin light chain kinase –> preventing contraction
Nitrates/ Nitrites
-NO occurs naturally in the body, produced by vascular endothelial cells
-Blood flow against the vascular endothelium cause the release of Ca+ which activates NO synthase
-NO synthase converts L-Arginine into NO
-NO activates the enzyme guanylyl cyclase, found in vascular smooth muscle
-Guanylyl cyclase catalyzes the dephosphorylation of GTP to cGMP–> causes smooth muscle relaxation
1. Inhibits Ca+ entry into cell
2. Increases uptake of Ca+ into endoplasmic reticulum
Increase venous capacitance, decrease ventricular preload, decrease CO output
Can cause reflex tachycardiac, orthostatic hypotension
Methhemoglobin
Drug classes that reduce vascular tone
NO, Nitrates, Nitrites- MOA on other flashcard
Beta-2 Agonists- Increases cAMP in pulmonary vessels –> relaxation here
CCB: Block Ca++ channel, leading to decreased contraction
Sildenafil: PDE inhibitor–> leads to increase in cGMP –> relaxation of vascular smooth muscle
Heart Failure:
Systolic vs Diastolic
Systolic: Thin, floppy ventricles. Causes decreased cardiac output, decreased EJ
Diastolic: Thick, muscular ventricles. Unable to relax to allow to diastolic filling. Decreased CO, normal EJ
Congestive Heart Failure; L vs R
Left heart: Increased left ventricular pressure at the end of diastole. This causes pulmonary congestion.
Right heart: Blood can backup into R IJ, hepatic vein
Normal Cardiac Function; how does Ca++ interact with myocites to allow contraction?
-Ca++ enters the cell through a Ca++ channel. That Ca++ (referred to as the ‘“trigger” Ca++) interacts with the Ca++ release channel on the wall of the sarcoplasmic reticulum –> stored Ca++ is released into the cytoplasm, allowing for actin to interact with myosin –> one heart bear
Four Factors of Cardiac Performance; and how they are altered in heart failure
- Preload: This is our EDP; however, often synonymous with EDV. Decreased in diastolic HF, increased in systolic HF
- Afterload: Resistance in which the heart must pump against. Increases as CO decreases (compensatory)
- Contractility: The force with which the heart contracts. Very poor in systolic HF. Too forceful in diastolic HF
- Heart Rate: Main determinant of CO. First compensatory mechanism to respond to decreased CO. Lowering HR in diastolic HF will allow for more filling time
Strategies and drugs to tx HF-
Correcting Failure of Cardiac Contractility
-Positive Inotropes: Cardiac glycosides; digoxin
-Phospodiesterase Inhibitors: indirectly increase inotropy by inactivating cAMP and cGMP (milrinone)
-Beta adreneric stimulants: Dopamine & Dobutamine
-Ca++ sensitizers: Positive Inotropy & vasodilations
ADME
Digoxin
MOA & Toxicity, electrolytes, what do we see on EKG?
Inhibits the Na+, K+, ATPase pump on the heart and is a positive inotrope. Increases PR interval, decreases QT interval
Has a narrow therapeutic index. Toxic doses can cause tachycardia, a fib, v fib, and cardiac arrest.
Toxic doses also produce oscillatory after-depolarizations, increasing risk for v-fib and v-tach.
Hyperkalemia: K+ competes with dig
Hypercalcemia & hypomagnesium: Increased risk of arrhythmias
EKG- downward schwoop after QRS
Well absorbed, distributed widely in tissues and CNS
T1/2 36-40hrs
2/3 excreted unchanged in the kidneys
Cardiac Action Potential, Phases & Ion Movement
Phase 0: Depolarization of cardiac cells; action potential upstroke. AP is “over-shot” just a litte. Na+ moves in
Phase 1: K+ begins to leave the cell, membrane potential decreases slightly
Phase 2: K+ still leaving; however, Ca++ enters the cell, prolonging the action potential to allow the heart to pump
Phase 3: K+ leaving the cell, repolarization
Phase 4: Vrm
Main Classifications of Arrhythmias; Disturbances in impulse conduction
Disturbances in impulse conduction:
-1st degree, 2nd degree (Type I & II), 3rd degree block
-Re-entry:
-Block is unidirectional, there must be an obstacle (scar tissue), and conduction time must be long enough to reenter same areas after refractory period
Antiarrhythmic Agents-Four Classes
Class I: Sodium channel blockade
Class II: Sympatholytic (beta blockers)
Class III: Prolong action potential duration, K+ channels
Class IV: CCB
Antiarrhythmic Agents- Class IA, IB, IC
IA: Sodium channel blocker
-Procainimide, Quinidine
-Prolongs action potential duration and increases effective refractory period
IB: Sodium channel blocker
-Lidocaine, Mexiltine
-Shortens APD, decreases ERP
IC
-Flecainide, Propafenone
-Minimal effects on APD, no effect on ERP
Antiarrhythmic Agents- Class III
Amiodarone- prolongs cardiac action potential, dilation in peripheral vasculature
Toxicity: Bradycardia or heart block, precipitate heart failure, fatal pulmonary fibrosis, concentration in tissues
Antiarrhythmic Agents- Class IV
Verapamil; CCB
-Blocks inactivated and activated Ca++ channels
-Prolongs AV node conduction
-Slows SA node
-Can cause hypotension
Differentiate the following: Pharmacodynamics, Pharmacokinetics, Pharmacogenomics, & Toxicology
-Pharmacodynamics: Describes what the drug does to the body.
-Pharmacokinetics: Describes what the body does to the drug; absorption, distribution, metabolism, excretion
-Pharmacogenomics: Looking at a genetic profile to determine how effective a drug will be
-Toxicology: Specifically relates to poison, toxins, and how they relate to the body
Agonistic vs Antagonist
Agonistic: Elicits a response from a receptor when it binds to the receptor
-Effect may be lesser or greater than the native ligand (endogenous hormone or catecholymine)
Antagonistic: Blocks the endogenous/native ligand from binding to the receptor
-Does not activate a response
Allosteric vs Orthosteric
Specific Binding vs Non Specific Binding
Allosteric: Binds anywhere but the active site on the receptor
-Is a non competitive inhibitor because it does compete for the active site
Orthosteric: Binds directly to active site on the receptor
Specific Binding: Binds specifically to the receptor. There is a max dose because receptors are not infinite
Non-specific Binding: The more drug that is given, the more non-specific the binding becomes. The drug saturates the receptors and must bind somewhere else.
Ex: Albumin
Describe the difference between toxins and poisons
Poison: A nonbiological substance such as arsenic, cadmium, lead
Toxins: A biological substance such as toxic mushrooms, a puffer fish
Describe the Relative Bond Strengths
Covalent Bond: Share electrons. Strongest bond, but least specificity. Irreversible
Electrostatic: Ionic Bonds;
-Charged molecules
- Hydrogen bonds
- Van der waals forces
Hydrophobic, lipid soluble drugs: Weakest bond, highest specificity
Bond strength and specificity are inversely related
Racemic Mixtures, Stereoisomerism, Isomers
-Isomers of a drug have the same chemical equation, but different shape.
-Stereoisomerism (Optical Isomers) is when isomers are mirror images of each other, but do not behave the same way. This applies to more than half of all drugs
-Racemic Mixtures are optical isomers
Ex: (R) Ketamine- More toxic than (S) Ketamine, increased unwanted side effects
(S) Ketamine: 4x more potent, less unwanted side effects
Competitive & Allosteric Inhibitors
Competitive Inhibitor: Binds to the active site in place of agonist. If a high enough dose of the agonist is given, it can “out-compete” the competitive inhibitor
Allosteric Inhibitors: Bind somewhere other than the active site on the receptor, so they are not competitive. Agonist response is always muted when given with an Allosteric inhibitor
Active Receptors vs Inactive Receptors
Receptors live in equilibrium between the active and inactive state. These configurations can switch back and forth between active and inactive without a drug/endogenous ligand present. When a drug favors the active form of a receptor, a downstream response will be elicited
Other Mechanisms of Antagonism: Physiologic Antagonism
Two or more physiologic processes that have an opposite effect
Ex: SNS vs PNS; epinephrine secreted acts on the B1 receptors, increases heart rate. Acetylcholine acting on the muscarinic receptors decreases heart rate
Pharmacodynamics: What happens when an Agonist is given with a single dose of 1) Allosteric Agonist, 2) Competitive Inhibitor, or 3) Allosteric Inhibitor?
-Agonist + Allosteric Agonist/Activator: We will see an increased/maximal drug response here compared to giving an agonist alone
-Agonist + Competitive Inhibitor: We can initially have a muted response; however, giving more of the agonist will allow it to out-compete the competitive inhibitor and we will have an increased response
-Agonist + Allosteric Inhibitor: We will have a muted response here. There is no way to out-compete the Allosteric inhibitor because they do not bind to the same area on the receptor
Agonist Mimic, Indirect Agonist
Agonist mimics or Indirect Agonists are downstream inhibitors. You have a receptor activated that causes a cascade of effects: A—> B—>C. Let’s say there is an enzyme that is supposed to break down “C”. You give the agonist mimic and it breaks down that enzyme, increasing your amounts of “C”
Receptor- Antagonist Interactions; Competitive Inhibitors & Non-Competitive Inhibitors, insurmountable vs surmountable
Competitive inhibitors/antagonists: They are SURMOUNTABLE because you can continue to give increasing doses of the antagonist to overcome the competitive inhibitor as long as they do not form covalent bonds
Competitive Orthosteric inhibitors/antagonists: Compete for the active site, but if they form covalent, irreversible bonds, it makes make them INSURMOUNTABLE
Non-competitive Allosteric inhibitors/antagonists: They are INSURMOUNTABLE because they are not directly competing for the same site. These are irreversible
Partial Agonist, Inverse Agonist vs. Full Agonist
- A partial agonist, when given alone, will always have a muted/lessened response
-When given with full agonist; acts as antagonist
-Inverse Agonist: Favors the receptor in its inactive form. It lowers the receptors’ activity below its constituitive activity, causing it to be less active with the drug present than without. Clinically, these act as antagonists but stronger
-A full agonist elicits a full downstream response once given
Other Mechanisms of Antagonism: Administration of opposite charge
Ex: Protamine (+) binds to and inhibits the effect of Heparin (-)
Which axis is this reflected on?
Potency; Dose-Response Curve
-Potency is reflected on the dose axis (horizontal)
-Potency refers to the EC50 or ED50. Concentration or dose required to produce 50% of the drugs maximal effect
-Inversely related to the EC50/ED50 on the response curve
-As potency decreases, the EC50 increases and shifts to the RIGHT
-As potency increases, the EC50 decreases and shifts to the LEFT
-If graph is shifting horizontally, we are seeing a change in POTENCY
-Drugs can have different potency, but efficacy can be the same
Which axis is this reflected on?
Efficacy: Dose-Response Curve
-This parameter is reflected on the response axis (vertical)
-Also depends on intrinsic activity, are these drugs agonists, antagonists, partial agonists, etc..
-If curve is shifting vertically, there is a change in efficacy
-Drugs can have different potency, but efficacy can be the same
Efficacy is more important than potency
Therapeutic Index
The larger the therapeutic index, the safe the drug is.
TD50= Median toxic dose
ED50= Median effective dose
Calculate therapeutic index: TD50/ED50
(LD50 for animals, not used in humans)
Drug pH & pKa
-Most drugs are weak acids or weak bases. pKa is the pH at which ionized & unionized concentrations are equal.
-Drugs need to be uncharged in order to cross the cell membrane; pKa affects the charge
-pH < pKa; favors protonated form
-pH > pKa; favors unprotonated form
Weak acids: protonated form is uncharged, unprotonated is charged
Weak bases: protonated form is charged, unprotonated form is uncharged
Drug Variations in response
- Can be idiosyncratic
- Patient is hyporeactive, hyperreactive
- Hypersensitivity
- Tolerance or tachyphylaxis
Causes of Drug Variations in Individuals
- Alteration in drug concentration that reachese the receptor
- Variation in concentration of the endogenous ligand; not everyone has the same amount of receptor sites
- Functionality of receptors
- Changes in the downstream cascade (most likely) due to proteins altering the response
-Body has a natural ability to compensate for this
Receptor Type- Based on Molecular Structure (7 of them)
-GPCRs; Seven transmembrane receptors
-Ligand-Gated Channels; Chanel opens when something binds to them
-Ion Chanels; Do not need a ligand
-Catalytic Receptors: Catalyze an enymatic response (RTK)
-Nuclear Receptors; Located in the nucleus
-Transporters; Transport from one side of cell to another
-Enzymatic; The enzyme w/in the cell is the target
Lag period vs Persistence
-Lag Period: Response takes 30+ minutes to several hours. This typically requires transcription/translation (so mrna drug)
Persistence: Response hangs around for hours to days. Protein degradation pathways vary in each person
Mechanism of GPCR Signaling
Drug or endogenous ligand binds to receptor
–>receptor undergoes conformational change which activates the alpha subunit & binds GDP (inactive) –>GTP (Active) –> GTP activates the effector/signaling protein
–>activates the second messenger –>downstream process
Structure of GPCRs
-Binding to the receptor actives the G-protein (guanine nucleotide binding protein).
GDP –>GTP
-Receptor has seven transmembrane alpha-helices
-Binds to the active site on the cell wall, interacts with the G-protein inside the cell
-Trimeric, have three subunits; alpha (binds to GDP, activates GTP) beta, gamma
Structure of RTKs
-Ligands are growth factors or adhesion factors
-Ligand binding stimulates
-Dimerization (two monomers forming one dimer)
-This then causes phosphorylation of tyrosine molecules on dimer (uses 6 ATP) –> downstream cascade of effects
Describe the role of second messengers. List a few examples of common ones
-Second messengers play an important role in activating an effector protein or starting the downstream cascade of effects once a receptor is bound by a ligand or drug
-cAMP: Exerts most of it’s effects by phosphorylation (this uses ATP); mobilizes stored energy, increases rate & force of contraction
DAG
IP3
cGMP
Desensitization, and how it works in the GPCR
Desensitization is the process of stopping the signaling cascade after a ligand has bound to a receptor.
Ex in a GPCR: Ligand binds to receptor–>undergoes a conformational change (now in the open confirmation) –>The carboxyl end of the receptor has OH groups hanging off it within the cell –>Alpha subunit on the g-protein floats away, activating GDP –>GTP. GTP activates adenylyl cyclase–> cAMP (second messenger) is activated –>downstream cascade of effects.
If the ligand forms a covalent bond, there are two options:
1. Beta-arestin binds to the OH groups on the carboxyl end of the receptor, drags it along the cell membrane to a clarithen coated pit. The pit engulfs the receptor, separates the receptor and ligand, and the receptor is recycled
2. If the bond cannot be broken, lysosomes will use their acidic, digestive enzymes to break up the receptor into it’s smaller AA counterparts and release those to be reused in the cell.
Voltage Gated Ion Channel
-Ion specific channels (Na+, K+, Ca++, Cl-)
-Can be fast or slow, depends on the ion and the gradient
-Found in excitable cells; neurons, muscle, endocrine
-Closed at resting membrane potential
- Na + Channel has two gates- Gate 1 opens when threshold is reached –> Gate two immediately inactivates (regulates how much of each ion can pass through) –> deactivates (both gates closed), then circles back to closed
Ligand Gated Ion Channels: Inotropic vs Metabotropic
Inotropic:
-Most common
-Ligand binding site & channel are on the same protein
-Ligand binds, channel opens
Ex: Nicotinic aCH receptor
Metabotropic:
GPCR in close proximity to the ion channel
-Ligand binds to the site –> activates GPCR –> second messenger activity opens ion channel
Ex: Olfactory nerve, scents/smell
Receptors Inside the Cell
(2 of them)
-Must be a gas or lipid soluble
Ex: Blood vessels lined with endothelial cells–> strong shearing force/turbulent blood flow against the endothelial cells–> activates nitric oxide synthase –> nitric oxide is produced–> diffuses out to smooth muscle (can freely diffuse across the cell membrane)–> relaxes smooth muscle, opens blood vessel
Steroid Hormones: Can freely diffuse across membrane because they are lipid soluble and uncharged
Steroid hormone binds to steroid receptor-> migrates to nucleus–> binds to steroid regulatory elements in the nucleus and increase transcription and translation of genes
Four methods of Permeation
Different forms of permeation:
- Aqueous Diffusion; If water soluble, water diffuses down it’s concentration gradients typically through aquaporins. Cannot cross this way if the molecule is highly charged or bound to a large protein
- Lipid Diffusion: Lipid soluble drugs such as steroids. The ability to move between aqueous & lipid phases is important for good drug
- Special carriers: Drug binds to the carrier, the carrier will internalize the drug and spit them out into the cell. This is not the target cell. Active transport & Facilitated diffusion
- Endocytosis: Cell surface surrounds the drug, engulfs it, spits it out on the other side
-Exocytosis: Secretion of a substance from the cell. Ex: Neurotransmitters are stored in membrane bound vesicles until ready to use
Volume of Distribution (Vd)
-The space available in the body to contain the drug (theoretical number)
-Relates the amount of drug in the body to the amount of drug in the blood stream
Clearance (Cl)
-Ability of the body to eliminate the drug. Predicts the rate of elimination in relation to drug concentration. Multiple organs play a role here
Concentration (C), Target Concentration (TC), Rate of Elimination (ROE)
-C: The amount of drug given in a volume
-TC: The desired concentration at the effector site
-ROE: Predicted by clearance
Vd & Cl in relation to drugs in the system
-The higher the Vd, the lower the amount of drug in the bloodstream
-The lower the Vd, the higher the amount of drug in the bloodstream
Vd along with clearance will determine the T1/2 of drugs
First Order, Zero Order, Capacity Limited Elimination
1) First order elimination; how most drugs are eliminated from the body. Clearance remains constant, ROE varies
2) Zero order elimination; ROE remains constant. Clearance varies with concentration. Occurs when the body’s ability to eliminate a drug has reached its maximum capacity. (EtOH, ASA, phenytoin)
Capacity limited elimination happens when we have zero order elimination. This can start as first order, but because of the drug amount in the body can become zero-order/ capacity limited
Half Life ( T1/2)
-The time required for the body to eliminate half of the drug. Half life is dependent upon the extraction ratio, organ health, Vd, and clearance
-In “steady state” dosing (meaning no boluses of the drug have been given), it is generally assumed that it will take 4x half-lives in order to achieve target concentration. Conversely, it should take approximately 4x half lives for the drug to be eliminated from the body
Accumulation
The drug continues to accumulate in the body until dosing stops. Can reach toxic levels of the drug if our dosing intervals are shorter than 4x half-lives
Bioavailability (F)
The fraction of unchanged drug reaching systemic circulation
Drug Biotransformation
The drug is metabolically converted, either into an inactive metabolite or a metabolite that is more active.
Primarily occurs in the liver
First Pass Effect
When an oral drug is absorbed, intact, from the small intestine and transported through the hepatic portal system through the liver, where it undergoes extensive metabolism before reaching systemic circulation
Phase I Metabolic Reaction
(Oxidation, Reduction, Dehydrogenation, Hydrolysis)
Phase I Reactions:
-Converts a drug into a more polar metabolite.
-Adds or unmasks a functional group (-OH, -NH)
-Usually makes the drug more readily excretable; a lipophilic drug becomes more hydrophilic
Oxidation: Loss of an e-
Reduction: Gain of an e-
Dehydrogenation: Remove an OH group
Hydrolysis: Breaks down water
Oxidation and reduction always happen together
Cytochrome P450
Generic Cyp450 Pathway
Cytochrome P450: A protein with a heme. Function is to introduce an oxygen to xenobiotic compound
Cyp450 Oxidation-Reduction requires P450, P450 Reductase (flavoprotein), NADPH, and molecular oxygen
P450 (Fe3+) combines with RH group (drug)
P450(Fe3+)-RH
–> NADPH donates e- to P450 reductase –> P450 (Fe2+)-RH
–> NADPH donates another e- to P450 reductase, reduces molecular oxygen–> O2-P450(Fe2+)-RH
–> Activated oxygen is transferred to the drug substrate group to form P450(Fe3+)-ROH = making the drug more water soluble
Phase II Reactions: Conjugation
-Adding molecules to something typically resulting in the compound being more polar, readily excretable, and inactivated
Types of Conjugation:
-Glucuronidation: UDP glucuronic acid carries a glucose-like substance to the drug compound & attaches it.
-Glutathione: Glutathione-S-Transferase attaches glutathione molecule. Important for detoxification
-Acetylation
-Sulfation
-Glycine
-Methylation
-Water conjugation
Cytochrome P450 Isoforms (Including wildtype)
CYP3A4- Responsible for metabolization of 50% of all drugs undergoing Phase I
CYP2B6, CYP2D6 also important
CYP3A4 *1 is the “wild type,” meaning, most commonly seen
Hepatic Enzyme Induction
Induction of P450: Increases the presence of P450
DECREASED drug effect if P450 deactivates drug
INCREASED drug effect if P450 activates drug
Ex: Drug 1 given (metabolized by P450)
Drug 2 given (inducer of P450) –> Drug 1 becomes inactivated much more quickly
Prodrug given –> activated by P450–> Drug 3
Drug 2 also given –> can reach toxic levels of drug 3 quickly because Drug 2 is an inducer of P450
Hepatic Enzyme Inhibition
P450 Inhibition: Decrease activity or irreversibly inhibit
Ex:
Drug 1 given (inactivated by p450)
Drug 4 is given (inhibits P450) –> Drug 1 can reach toxic levels
Role of drug transporters & drug efflux transporters
And factors that affect drug transport
-Drug transporters are located in the endothelial cells of many tissues (intestinal, renal, hepatic) and mediate selective uptake of endogenous compounds and xenobiotics
-Molecular weight, pKa, lipid solubility, and plasma protein
-Drug efflux transporters are membrane proteins that specialize in expelling foreign molecules
Important ABC transporters & their drug affinity
-These transporters bind ATP. ATP binding cassette (ABC)
-ABCB: Broadest substrate specificity; Antineoplastics, HIV protease inhibitors, abx, antidepressants, antiepileptics, opioids
-Drug interactions w/ ABCB: Cyclosporine, quinidine, ritonavir & dig.
When loperamide & quinidine are given together, causes CNS effects
-ABCC: Antineoplastics
-ABCG: Breast cancer resistance protein; antineoplastic, toxins, food-borne carcinogens, folate transport
Drug transporters in different organs & their overall effects
GI, Liver, BBB
GI tract: Transporters are localized in microvilli, transport drugs from the intestine into the bloodstream
Liver: Transporters typically bring drug into the liver.Metabolize xenobiotics and excrete metabolites into bile
BBB: Allows certain drugs to cross into the BBB (highly hydrophobic), but overall most things are going to be pushed back out
Components of the intact BBB
-Functional separation of the circulating blood from the extracellular fluid in the CNS
1. Specific transporters
2. Endothelial cells & tight junctions
3. The cells that surround it; astrocytes and pericytes (podocytes)
Mediators released in early & late stages of asthma and their effects
Early stages: Histamine & Prostaglandins. Cause immediate bronchoconstriction from muscular contraction and vascular leakage
Later Stages: Leukotrienes. Liberated from the lungs during inflammation. Cause bronchospasm, mucus secretion, microvascular permeability, and airway edema
MOA, SABA & LABA, Toxicity
Beta 2 Agonists
Short Term Relievers- Asthma & COPD
-Bronchodilators
-Nebulized Epi & Isoproterenol: Non-specific for beta cells. Can cause tachycardia and arryhthmias
-Albuterol (SABA): B2 selective. Aerosol. Takes effect in 30 mins, lasts 3-4 hours
-Salmeterol/Formotorol (LABA): B2 Selective. Aerosol. Lipid soluble, lasts 12 hours. Only 10-20% delivered due to droplet size
Toxicity: Skeletal muscle tremors
MOA? Toxicity?
Methylxanthines
Short term relievers- Asthma & COPD
-Inhibits PDE & adenosine receptors resulting in mild bronchodilation
-Theophylline: Most effective methylxanthine, found in natural tea.
-Toxicity: CNS stimulation, (+) chronotropy and ionotropy in heart, tremors
Muscarinic (M3) Antagonists
Short Term Relievers- COPD
-Bronchodilators
-Atropine: Given IV
-Ipratropium Bromide: Inhaled, can combine with B2 agonists
-Titroprium: Inhaled, long acting
-No CNS effects
Corticosteroids & Glucocorticoids
Long Term Controllers- Asthma
-Glucocoritcoids: Inhibit immune response by blocking DNA transcription/translation
-Cortico: Reduce bronchial activity, increase airway caliber, reduce frequency of exacerbations
-S/E: Increased risk of osteoporosis, slow growth rate in children, oropharyngeal candida & other opportunistic infections
Leukotriene Pathway Inhibitors
Long Term Controllers- Asthma
-Inhibit 5-Lipoxygenase: Zileuton
-Inhibit synthesis of leukotriene: -ukast
-Both improve aspirin induced asthma
How many types of histamine receptors?
Organ System Effects of Histamine
CNS, CV, GI/stomach, Lungs
CNS: Stimulates pain & itching
CV: Vasodilation (H1), increased HR
GI/Stomach: Release of HCl, contraction
Lungs: Bronchoconstriction (H1)
4 types- GPCR
Organ Effects of Serotonin
CV, Respiratory, GI, Brain
CV: Vasocontriction, platelet aggregation
Respiratory: ACh release –> bronchoconstriction, hyperventilation
GI: Overproduction causes diarrhea
Brain: Melatonin precursor. Mood, appetite, temperature regulation, pain perception, migraines, vomitting reflex, BP
Triple Response of Histamine Reaction
-Used for allergy testing
-Increased blood flow to capillary endothelium (redness)
-Flare: Widespread dilation of surrounding arterioles
-Wheal: Local swelling due to increased permeability in the walls of surrounding vessels
1st & 2nd Generation Histamines
Drugs, Uses, Toxicity
1st: Benadryl, Phenergan, Dramamine
-Used for motion sickness, nausea, anesthesia
-Cause sedation
2nd: Zyrtec, Claritin, Allegra
-Used for allergic response, seasonal allergies, urticaria
-No CNS effects. Near equal efficacy to first gen
Toxicity: Sedation, urinary retention, blurred vision, convulsions, postural hypotension
H2 Antagonists
Use, drug names
-Reduce the amount of HCl produced in the stomach
-Not as effective as PPI
-Zantac, Pepcid
Serotonin is made where?
How many 5-HT families?
90% of body’s serotonin is created in the enterochromaffin cells. 10% from the Raphne Nuclei in the pons
-Seven Families of 5-HT. 6 are GPCR, 5-HT3 is an ion channel
5-HT Agonists
Buspar, Triptans
-Buspirone; 5-HT1a. Non-benzo anxiolytic, GAD, OCD
-Sumatriptan; 5-HT1D/1B agonist. Tx for migraines. Non-prophylactic. Bind 5-HT in cranial blood vessels, preventing dilation and stretching of pain nerve endings.
-Toxicity: Recurrence of migraine, coronary vasospasm (rare), serotonin syndrome if taking triptans + SSRI, MAOI
5-HT Antagonists
Cyproheptadine, Phenoxybenzamine, Zofran
-Cyproheptadine & Phenoxybenzamine: 5-HT2.
Carcinoid tumors and cold induced urticaria
-Zofran: 5-HT3
N/V
Hyperthermia Disorders
Serotonin, Neuroleptic, Malignant. S/S, causes, Tx
- Serotonin Syndrome: HTN, hyperreflexia, clonus
-Contributing Factors: SSRIs, MAOIs, Triptans, MDMA, St. John’s Wort
-Tx: Sedation with benzos, 5-HT block with cyproheptadine or chlorpromazine - Neuroleptic Malignant Syndrome: HT, Hyperthermia, acute, sever parkinsonism
-D2 blocking antipsychotics
-Tx: IV diphenhydramine, cooling, sedation w/ benzos - Malignant Hyperthermia: HTN, hyperthermia, muscle rigidity
-Volatile anesthetics & succinylcholine
-Dantrolene, cooling
Four Categories of anti-depressants, drugs in them, and side effects
- SSRIs- Most common, first line
-Inhibition of SERT
-Fluoxetine, Citalopram, Paroxetine, Sertraline, Escitalopram - SNRIs- Used for major depression & pain disorders
-Inhibition of SERT and NET
-Desvenlafaxine, Duloxetine - TCAs- Supplanted by SSRIs
-Amitrypyline - MAOIs- Rarely used, lethal drug interactions. For refractory depression
-Irreversible: Phenelzine
-Selegiline - All work by increasing monoamine neurotransmitter levels within the synapse
- Adverse effects: Suicidal ideation, drug interactions, N/V/D, sexual dysfunction
Partial/Focal Seizures
3 types
-Start in small area of the brain
1. Simple: Not aware of occurence
2. Complex: LOC, automatisms
3. Secondarily generalzed: Just like general
General Seizures
5 subtypes
- Start all over the brain
1. Tonic Clonic: Grand Mal
i. Aura- Seizure- Post-ictal
ii. Tonic - clonic (usually <5 mins)
2. Absence: Petite mal
3. Drop Attacks: Tonic, Atonic
4. Clonic: Jerking & myoclonus (twitching)
5. Infatile spasms: Indicative of underlying pathology
MOA? Toxicity?
Phenytoin
Focal & Tonic Clonic
-Oldest non-sedative AED
-Alters Na+, K+, and Ca++ conductance
-Enhances gaba, inhibits glutamate
-Highly protein bound: competes with carbamazepine, valproic acid, sulfonamides
-Fosphenytoin- More soluble prodrug of phenytoin; can be given IV
-Accumulates in brain, liver, muscle, and fat
-Approaches zero order kinetics
-Highly Toxic; dose related- nystagmus, loss of extraocular movement, diplopia, ataxia, sedation, gingival hyperplasia, hirsuitism
MOA? Toxicity?
Carbamazepine
What does it do specifially to metabolism?
MOA is similar to Phenytoin, but blocks Na+ channels at therapeutic levels
-TCA
-DOC for focal seizures, can also be used in bipolar disorder, effective in trigeminal neuralgia
-Can be used with Phenytoin
-Induces CYP450, increasing it’s own metabolic rate with prolonged use
-Enhances metabolic rate of other AEDS
A/E: Diplopia, ataxia
Phenobarbital
-MOA Unknown. We think enhancing GABA
-Sedative
-Can worsen absence, drop, or infantile seizures
-DOC in infants
-Toxicity: Sedation, increase in hepatic enzymes
Lacosamine, Lamotrigine, Vigabatrin
Lacosamide: Focal Seizures
Lamotrigine: Partial & Absence Seizures.
-MOA; Ion channel
Vigabatrin: GABA analog
Ethosuximide
MOA?
-DOC for absence seizures
-Syrup
-Ca++ channel inhibition
-A/E: GI upset, sedation, tremor, hepatotoxicity
Works for two types of seizures and what othr 2 conditions?
Valproic Acid
-MOA: Blocks sustained high frequency firing. Effects Na+ channels, increases GABA, increases K+ conductance
-Absence seizures
-Generalized tonic-clonic
-Bipolar
-Migraine
Displaces phenytoin from proteins
-Inhibits metabolism of phenobarb, phenytoin, carbamazepine
-Toxicity: GI upset, n/v, abdominal pain, heartburn.
Endocrine vs Exocrine in the Pancreas
- Endocrine: Islets of Langerhans
-Alpha Cells produce Glucagon
-Beta Cells produce insulin, C-peptide, proinsulin - Exocrine: Produces digestive enzymes
Four Types of DM
- DM I: Insulin Dependent (IDDM)
- Destruction of beta cells, severe or absolute insulin deficiency. Immune or idiopathic
- DM II: Non-insulin dependent (NIDDM)
-Metabolic syndrome. Combination of relative deficiency of insulin secretion with tissue insulin resistance - DM III: Other causes: drugs, pancreatitis
- DM IV: Gestational
-Hormones block insulin. Higher birth weight. Infant 30% more likely to develop DMII
How the ATP-Gated K+ Channels work in the Beta Cells
Insulin is released from the beta cell and by sulfonylurea drugs. In a resting cell, ATP levels are low, and K+ diffuses down its concentration gradient through ATP-gated K+ channels maintaining Vrm.
If glucose concentration increases, ATP production increases –> K+ channels close, causing the cell to depolarize. Ca++ channels open in response to depolarization, and the increase in intracellular Ca++ results in an increase in insulin secretion.
What happens after glucose is brought into the cell?
Insulin Receptor Pathway
- After insulin has entered circulation, it diffuses into tissues and binds to specialized receptors.
- Insulin receptors consist of two covalently linked heterodimers each containing an extracellular Alpha subunit (recognition site) and a Beta subunit, a tyrosine kinase, that spans the membrane. Insulin binds to the alpha subunit–>receptor undergoes conformational change bringing the catalytic loops of the B subunits closer together –>facilitating mutual phosphorylation of tyrosine residues-»ultimately resulting in translocation of GLUT transporters (2, 4) to the cell membrane to increase intake of glucose, increase in glycogen formation, and multiple effects on protein synthesis, lipolysis, and lipogenesis, as well as the activation of DNA transcription factors.
i. GLUT 2- Located in beta cells, liver, kidney, gut
ii. GLUT 4- Muscle, adipose
Four Insulin Types and Examples
- Rapid Acting: Lispro, Aspart, Glulisine
i. Given w/ meals - Short Acting (Regular): Novolin, Humalin
i. Given BID; not tightly controlled - Intermediate Acting: NPH (Neutral protamine Hagedorn)
i. Given BID; not tightly controlled - Long Acting: Glargine, Detemir
i. Given once daily - Basal + Bolus is the best way to control, or use of an insulin-pump
Biguanides
i. First line therapy in NIDDM
ii. Reduction in hepatic glucose production
iii. GI toxicities
iv. Metformin
Black box warning
Insulin Secretagogue-Drug form
i. Bind to K+ channel in beta cell causing depolarization
ii. Sulfonylureas (-ide), Meglitinide, Phenylalanine derivatives
iii. Black box warning: Increased risk of cardiovascular mortality
- Thiazolidinediones (TZD)
Risk of??
i. Decrease Insulin Resistance, Increase insulin signal transduction
ii. Risk of MI: If using insulin w/ nitrates, or Avandia
- A-Glucosidase Inhibitors
i. Block digestion of complex carbohydrates
ii. Flatulence, diarrhea, abdominal pain
- Bile Acid Sequestrant
i. Bind bile acids and prevent reabsorption
ii. GI upset
- Amylin Analogs
i. Suppresses glucagon release
ii. Decrease circulating glucose
iii. Use w/ insulin
Risk of what?
- Incretin-based therapies
i. GLP-1 -> stimulates insulin release
ii. Risk of pancreatic cancer
- SGLT2 Inhibitors
i. Prevents glucose reabsorption in PC
ii. Causes glucosuria, osmotic diuretic, weight loss, dehydration, genital necrosis
iii. -liflozin
Platelet Phases During Thrombogenesis
Platelets go through four phases:
a. Adhesion
b. Aggregation
c. Secretion of vasocontrictive factors (5-HT, ADP, TXA2)
d. Cross-linking of adjacent platelets
Thrombogenesis Pathway
Injury–> reactive proteins collagen & vWF exposed –> results in platelet adherence, activation, and secretion of 5-HT, TXA2, and ADP from platelet granules
–> vasoconstriction and platelet aggregation due to increased 5-HT –> fibrinogen cross-links platelets –> resulting in the formation of platelet plugs
DIC- Causes, Tx
Disseminated Intravascular Coagulopathy
i. Excessive consumption of clotting factors and platelets
ii. Spontaneous bleeding
iii. Causes: Massive tissue injury, malignancy, bacterial sepsis, abruptio placentae
iv. Tx: Plasma transfusions, treat underlying cause, up to 50% mortality
Fibrinolysis
Fibrinolysis refers to the process of fibrin digestion
Precursor- Plasminogen circulates in its inactive form. Tissue factor plasminogen activator is released by endothelial cells in response to injury, converting plasminogen into plasmin –> plasmin releases fibrin degradation products and begin to digest the fibrin clot
-udins belong to which?
Indirect vs Direct Thrombin Inhibitors
Drugs in each class
Indirect Thrombin Inhibitors:
Enhances antithrombin activity
i. Inactivation of factor Xa
iii. Ex: Heparin, LMW heparin, fondaparinux
Direct Thrombin Inhibitors:
i. Bind to both active and substrate recognition sites of thrombin
ii. Hirudin
iii. Bivalrudin
iv. Bind only to thrombin active sites: Argatroban, Melagatran, Dabigatran
Heparin vs LMW Heparin vs Fondaparinoux
MOA
Heparin
i. Binds and activates antithrombin III (enhances the activity 1000x)
ii. High molecular weight/unfractionated
iii. Extracted from porcine intestinal mucosa & bovine lung
LMW Heparin- (Enoxaparin, Dalteparin, Tinzaparin)
i. More specific for factor Xa, less effective on antithrombin
ii. Less effective coagulation
Fondaparinux
i. Not as effective; selective for factor X
ii. Less bleeding risks
iii. Can give with HIT
MOA, Therapeutic range, Drug Interactions
Warfarin
Reversal, Toxicity
Warfarin:
An anticoagulant that inhibits vitamin K epoxide reductase. blocking the formation of clotting factors II, VII, IX, X
ii. 8-12 hour delay in onset of action; bridge with Heparin
iii. Therapeutic range defined by INR. Normal : 0.8-1.2, Warfarin: 2-3
Drug Interactions:
1. Pharmacokinetic:
Enzyme induction, inhibition, and reduced plasma protein binding
2. Pharmacodynamic: Synergism, Competitive Antagonism, Altered vitamin K
Reverse w/ large dose vitamin K, FFP, factor IX
Toxicity: Hemorrhagic disorder in the fetus, birth defects, cutaneous necrosis
Factor Xa Inhibitors
MOA, reversal?
Eliquis, Xarelto, Bevyxxa, Pradaxa (Factor Xa inhibitors)
i. No reversal agent
ii. Inhibits factor Xa and thrombin
Three of them
Fibrinolytic Drugs
Streptokinase
i. Synthesized by streptococci
Urokinase
i. Lyses thrombus from within
Tissue plasminogen activator (TPA)
i. Preferentially activates plasminogen that is bound to fibrin
ii. Physiologic TPA confines fibrinolysis to the formed thrombus & avoids systematic activation. Pharmacologic TPA loses clot specificity
How are they different?
Anti-platelet Drugs
ASA, Plavix, Abciximab
ASA
i. Cox-1 selective
ii. Inhibits TXA2 formation inhibiting platelet aggregation
Plavix, Ticlid
i. Irreversibly inhibit ADP receptors on platelets reducing platelet aggregation
ii. Reduction in ischemic events by 8.7% compared to ASA
Abciximab- Monoclonal antibodies
i. Antiplatelet
ii. Targets IIb/IIIa receptor complex leading to inhibition of platelet aggregation
Aminocaprioc/TXA, Vitamin K, Plasma Fractions, Desmopressin
Tx of Bleeding Disorders
Aminocaprioc Acid/ Tranexamic Acid
i. Inhibitor of the fibronolytic system; competitively inhibits plasminogen activation
Vitamin K:
i. Precursor prothrombin and factors VII, IX, X
Plasma Fractions:
i. Used for deficiencies in plasma coagulation factors; diseases such as hemophilia and antithrombin III deficiency
ii. Concentrated plasma & plasma recombinant can be given to reduce bleeding
e. Desmopressin:
i. Tx for mild hemophelia A and von Willebrand disease
ii. Increases factor VIII activity
Tremor, Chorea, Ballismus, Athetosis, Dystonia
a. Tremor: Rhymic movement around a joint, repetitive
b. Chorea: Muscle jerks in various areas, quick
i. Ballismus: Violent abnormal movements
c. Athetosis: Slow, writhing, rotational
d. Dystonia: Abnormal posture
Explain the relationship between the basal ganglia, motor cortex, and thalamus; and describe the pathology in Parkinson’s & Huntington’s Disease
The basal ganglia, motor cortex, and thalamus work together to control movement. The basal ganglia help plan and coordinate movements, while the motor cortex sends signals to the muscles. The thalamus acts as a relay station, passing information between these areas.
The substantia nigra is a key player in movement control. It’s part of the basal ganglia and produces dopamine, a chemical that helps regulate movement.
In movement disorders this communication is disrupted. For example, in Parkinson’s, there’s less dopamine in the basal ganglia due to degradation of the substantia nigra, leading to tremors, stiffness
Huntingtons- Destruction of GABAnergic neurons; need to decrease dopamine
Occupations at risk
S/S of Parkinson’s, Cause, Risk Factors
And things that reduce risk
Idiopathic, progressive
Caused from dopaminergic neuron degradation and decreased dopamine levels
Rigidity, bradykinesia, tremor, postural instability, cognitive decline
Decreased risk: Cigarette smoke, coffee, anti-inflammatories, uric acid
Increased risk:
i. lead, manganese, vit D deficiency
ii. 60 or older
iii. Hereditary
iv. Men: Women 2:1
v. Occupation; teaching, healthcare, farming
vi. Toxin Exposure
Role of Alpha Synuclein in Parkinson’s
Alpha-synuclein is a protein involved in regulating neurotransmitter release in the brain.
In Parkinson’s disease, it clumps together to form Lewy bodies. These clumps disrupt brain cells, leading to cell death, particularly in the substantia nigra
Non-pharmacologic interventions for Parkinson’s
-Exercise
-Physical Therapy
-Speech Therapy
-Deep brain stimulation
-Lesional Ablation
-Stem cell therapy
i. Implantation of fetal substantia nigra
ii. Controversial
Levodopa, MOA, Role of Carbidopa
Also on-off phenomenom
a. Levodopa: L-Isomer of Dopa
i. Crosses BBB. Prodrug that is converted into dopamine as it crosses the BBB (1-3% of the drug makes it across). A lot of it is deactivated in the gut before reaching the bloodstream
b. Carbidopa prevents the breakdown of L-dopa by cOMT
c. Decreased effectiveness overtime
On-Off Phenomenon with long term use
i. Periods of increased mobility followed by marked akinesia
ii. Drug holiday- D/C drugs for a period of time
Which A/E does Carbidopa help? Which does it make worse?
Side Effects, Contraindications, Drug Interactions for Levodopa
a. N/V- decreased with carbidopa
b. Depression, anxiety, hallucinations and delusions worsen with carbidopa
-Can treat with Pimavanserin; antipsychotic
c. Tachycardia/ afib
d. Dyskinesias
Contraindications:
Psycosis, Glaucoma, Melanoma
Drug Interactions:
Vit. B6, MAOIS
MAO-B Antagonists, cOMT inhibitors, and dopamine receptor agonists
For tx of Parkinsons- MOA, drug examples
a. MAO-B antagonists:
i. Specifically target dopamine. Increase dopamine in the substantia nigra
ii. Selegeline
iii. Rasagiline
b. cOMT Inhibitors
i. Inhibit cOMT, increasing circulating dopamine
ii. Tolcapone, Entacapone
c. Dopamine Receptor Agonists:
i. Pramipexole
ii. Ropinirole
iii. Rotigotine
iv. All less effective than levodopa, early disease tx
v. Reduced side effects
Huntington’s Disease
What causes it? Symptoms? Onset? Tx to reduce symptoms?
i. Autosomal dominant, chromosome 4
ii. Gene produces huntington protein- function unkown
iii. Losing GABAnergic neurons, overproduction of dopamine, reduction in choline acetyltransferase
iv. Tx: Tetrabenazine (reduces dopamine activity), speech therapy, PT/OT; Need to do genetic counseling
v. Onset in 30-40’s
i. Progressive loss of muscle control
ii. Chorea
iii. Dementia
iv. Death 15-20yrs after onset
Inflammatory Response Pathway & where drugs work
Stimulus–> leads to disruption of cell membrane and the release of phospholipids (Phospholipase inhibitors and corticosteroids work here)
This activates arachadonic acid which is then converted into Lipoxygenase and COX 1/2 –> (lipoxygenase inhibitors, nsaids work here)
-Signaling molecules such as prostaglandins, TXA2, and leukotrienes are released which results in inflammation
Leukotrienes also promote bronchoconstriction and vascular permeability
Cox 1 & Cox 2
Cox 1 is always active- helps maintain kidney function, protect the lining of the stomach, and produce thromboxane. Also plays a role in prostaglandin synthesis
Cox 2 is activated during inflammation and is responsible for the production of prostaglandins
Cox 1 Inhibitors- ASA
1200mg -1500mg TID for pain
Clot prevention dose 81mg-325mg
Anti-platelet effect takes 8-10 days
Gi upset, bleeding, increased incidence of gastric ulcers due to inhibition of GI protective prostaglandin
Allergies & BB warning for Celebrex
COX 2 Selective Inhibitors
Celebrex, Meloxicam
Celecoxib- Analgesic, antipyretic, anti-inflammatory
Sulfanomide (allergies), expensive, BB warning- serious risk of thrombotic events
Meloxicam- Less effective than celebrex
Other NSAIDS
Ibuprofen, Ketorolac, APAP, Diclofenac, Indomethacin
Ibuprofen: Pain, inflammation. Less GI upset than ASA
Ketorolac: Used for severe pain in conjunction w/ opioids, good for sports medicine
APAP: Pain, fever, not anti-inflammatory, 15gm fatal dose
Diclofenac: Pain, inflammation, fever (GI upset 20%, decrease w/ misoprostol)
Indomethacin: Arthritis, gout, patent ductus arteriosus (GI upset 1/3rd of patients)
Glucocorticoids- Inflammation
Acute vs Chronic Use
Acute use:
Supresses inflammation
Mobilize energy stores
Improve cognitive function
Salt and water retention
Chronic use of them affects:
Immunosuppresion
Diabetes, obesity, muscle wasting
Depression
HTN
Glucocorticoid Transcription
How do they work? Annexin? IL-10? SLPI? NFkB?
Glucocorticoids bind to receptors inside the cell, forming a complex that enters the nucleus. This complex binds to DNA, influencing the transcription of specific genes.
This decreases the synthesis of Annexin-1; which decreases phospholipase A2 and inhibits leukocyte response
Inhibits nuclear factor kappa pathway
Increases synthesis of IL-10, an immunosuppresive enzyme, but also helps to reduce inflammation
Increases levels of SLPI- protects tissue from damage by inhibiting enzymes that break down proteins during inflammation
Inh-NFkB
reduce inflammation rate by decreasing..
DMARDs
General MOA & drugs
Disease Modifying Anti-Rheumatic Drugs
-Initially targeted to join disorders
-Reduce inflammation rate, by decreasing sedimentation rate, c-reactive protein, and rheumatoid factor
-Decreases damage to bones and joints
Often given w/ NSAIDS
Drugs: MTX, Cyclophosphamide, Cyclopsorine
Biologic: Orencia, Rituximab, Humira
Fibers for Transmission of Sensation
a. A-beta fibers; Non-noxious mechanical stimuli
b. A-delta fibers: Noxious heat, mechanical stimuli (sharp pain, produces reflex response)
c. C-fibers: Un-myelinated, slower. Noxious, chemical, heat, slow/burning pain
d. A-fibers can suppress pain from C-fibers
Noxious Stimuli
Harmful substances that cause pain-
Histamine
Tissue Damage- Bradykinin, PKA, PKC
Arachadonic Acid Pathway: Cox & Lox Pathway –> prostaglandins
Spinothalamic, Spinoreticular, Spinomesencephalic Pathways
PAG - “Gate Control Theory of pain”
a. Spinothalamic (Primary): Spinal Cord –> Pons –>Thalamus
–>Somatosensory cortex
b. Spinoreticular (Limbic System): Spinal Cord–>Reticular formation of medulla –> reticular formation of pons –> Thalamus –> Somatosensory cortex
c. Spinomesencephalic: Spinal cord –>Pons –>Periaqueductal grey of the midbrain. PAG initiates the descending inhibitory pathway
MOA: Bind to receptors where? Modulate release of which NT?
Pharmacokinetics/dynamics- Opioids
ADME
A: Well absorbed (IM, SQ, ORAL)
i. Nasal, patch can avoid first pass
ii. Codeine has a low first pass
D: Highly perfused tissues- accumulation i. Brain, heart, kidney, liver ii. Skeletal muscle; reservoir
M: Varies
i. Morphine- phase II to active forms (M3G, M6G)
ii. Esters (heroin) – converts to morphine
E: Mainly in urine
MOA: Bind to receptors in brain and spinal cord: modulate pain, reduce neurotransmitter release (glutamate, ACh, NE, 5-HT, substance-P), hyperpolarize post-synaptic neurons
Effects on organ systems- opioids
CNS, CV, GI
i. CNS: Analgesia, euphoria, sedation, respiratory depression (brainstem), cough suppression, miosis (always), hyperthermia (mu), hypothermia (kappa)
ii. CV: Most have no direct effects. Bradycardia from brainstem stimulation, Demerol causes tachycardia
iii. GI: Constipation
Uses for Opioids
Analgesia: Severe, constant (chronic), terminal illness, OB, renal or biliary colic in infants. Not as effective for sharp, intermittent pain
Acute Coronary Syndrome: MONA
Acute Pulmonary Edema: Reduce preload, afterload, and anxiety; Lasix is a better option
Cough
Diarrhea
Post-op shivering
Anesthesia adjunct
Tolerance builds quickly due to? 3 things
Opioid Tolerance vs Dependence
Degrees of tolerance, withdrawal symptoms
a. Tolerance develops quickly through multiple mechanisms (receptor phosphorylation, cAMP, uncoupling w/ G-Proteins)
b. Dependence
i. Physically dependent –>withdrawal symptoms if discontinuation –>can lead to addiction
W/D symptoms: Rhinorhhea, lacrimation, yawning, chills, N/V/D, hyperthermia, muscle aches
Degrees of tolerance:
-High Degree of Tolerance: Analgesia, euphoria, dysphoria, mental clouding, sedation
-Moderate degree of tolerance: bradycardia
-Minimal or no degree of tolerance: Miosis, constipation, convulsions
Opioids- Strong Agonists
Phenanthrenes, Phenylheptylamines, Phenylpiperidines
i. Phenanthrenes: Morphine, dilaudid, heroin (UK)
ii. Phenylheptylamines: Methadone (morphine tolerance, chronic opioid use)
iii. Phenylpiperidines: Fentanyl, meperidine
Opioids- Moderate Agonists
Phenanthrenes, Phenylpiperidines
i. Phenanthrenes: Codeine, Oxycodone (more effective in combination with APAP or ASA)
iii. Phenylpiperidines: Tramadol, Loperamide
Opioid Antagonists
i. Naloxone, naltrexone, naloxegol
ii. Reverse opioid effects in 1-3 minutes
Gram + or -
- Inhibition of Cell Wall Synthesis
MOA- Beta Lactam ring does what?, Drugs?
MOA- Beta-lactam antibiotics attach to the enzymes that cross-link peptidoglycans and prevent cell wall synthesis
i. Penicillin, cephalosporins, carbapenems, vancomycin
ii. Selectively damage gram (+) cocci
iii. Contain B-Lactam Ring
Broad or narrow spectrum? More resistant to what?
Cephalosporins
alternative to which abx?
-More resistant to beta-lactamase
-Broad spectrum, better gram (+)
-First Generation, alternative to PCN if allergy
Hypersensitivty to PCN & Cephalosporins
Hypersensitivity
i. Most common drug allergy
ii. Anaphylactic shock, hemolytic anemia, interstitial nephritis, rash
Vancomycin
a. Gram (+), supposed to be “last resort:
b. Resistant to beta-lactamase
c. 10% have adverse reactions
d. Irritating to tissues
e. Chills, fever, red man syndrome
f. Ototoxicity, nephrotoxicity
Gram + or -
2)Disruption of Cell Membrane Function
i. Act as detergents, bind to phospholipids
ii. Especially effective against Gram (-) that have an outer membrane
iii. Polymixin, Daptomycin
Bind to what? And that inhibits…?
3) Inhibition of Protein Synthesis
i. Widest spectrum of activity
ii. Bind to bacterial ribosomes and inhibit protein synthesis. Attack bacterial cells without significantly damaging animal cells;however, destroy normal microbiota, bone deposition disorder
iii. Tetracyclines, macrolides, aminoglycosides
Macrolides
Prototype- Erythromycin
Clarithromycin
Azithromycin
Mostly Gram (+)
MOA: Inhibit protein synthesis
4) Inhibition of Nucleic Acids
Rifamycin, Quinolones
Differentiate between the enzymes used by bacterial cells and animal cells
Rifamycin disrupts mRNA synthesis
Quinolones (Cipro, Levaquin, Floxin)- Inhibit DNA gyrase in bacteria
Excellent gram (-)
Good gram (+)
UTI, RTI, bone and joint infections
5) Inhibition of Folic Acid Synthesis
Sulfas, use, toxicity
-Sulfonamides
-Treat pneumocystitis, toxoplasmosis
Use w/ trimethoprim (Bactrim Septra)
-Toxicity: Allergic rxns, may precipitate urine, hematopoetic disturbances
Unique Properties of Viruses
Particles, Active or Alive, Do they need a host? Lyso/lytic
-Infectious particles that are active or inactive
Not an organism that is alive or dead
Obligate intracellular parasites:
Cannot multiply unless they invade a specific host
Must instruct the machinery of the host to make and release new viruses
i. If host cell is kept alive- lysogenic cycle (prolonged/chronic)
ii. If host cell is killed; “bursts”: Lytic cycle (acute)
Capsid/Naked Viruses, Envelope, Spikes
i. Naked: Capsid (protein shell) with a viral spike (targets cell proteins)
ii. Enveloped: Additional lipid membrane- Takes part of the host cell’s cell membrane, and creates an envelope around itself
Chain Termination of Acyclovir
How is Acyclovir makeup similar to HSV?
Mimics a DNA building block (dGTP) and gets incorporated into viral DNA during replication.
Virus mistakes acyclovir for dGTP and it prevents further DNA elongation, causing irreversible chain termination
Acyclovir- similar to HSV virus makeup, missing an OH group
HIV viral spike protein targets what?
Antiretrovirals
HIV/HBV
Viral spike protein (gp120) specifically targets our CD4+ cells (T-Cells)
-AZT- Zidovudine, Azidothymidine
i. Reverse transcriptase inhibitor
ii. HIV Cocktail- HAART; Highly Active Antiretroviral Therapy
c. Lamivudine
i. Inhibits HBV polymerase and HIV reverse transcriptase
Antivirals- Flu tx
a. Oseltamivir
i. FDA approved for early tx (first 48hrs)
ii. BID x 5 days
iii. Targets N1, N2
b. Zanamivir (Relenza)
i. Targets N1, N2
ii. Must be taken when exposed to flu, not when symptoms appear
c. Baloxivir Marboxil (Xofluza)
i. Targets polymerase
ii. Not for pregnant women, breast feeding mothers, may shorten flu by about a day
Chemical makeup of triglycerides? Form what if there’s excess?
Triglycerides vs Cholesterol
Cholesterol is a precursor to what? Mevalolate pathway?
Triglycerides:
i. Consist of glycerol esters (3) combined with free fatty acids
ii. Form adipose tissue and are the main storage form of fats in the human body
iii. Stored triglycerides can be catabolized into free fatty acids and used for energy during fasting or between meals
Cholesterol:
i. Important precursors to steroid hormones, cell membranes, Vit D, bile salts
ii. Produced via dietary intake (20%), or De Novo Synthesis (made in liver)
iii. Acetyl-Coa is converted by HMG-CoA into Mevalolate –> Cholesterol
Chylomicrons, VLDL, LDL, HDL
Lipoproteins
Transported to?
Chylomicrons:
i. Formed in intestine
ii. Carry triglycerides and cholesterol through the lymphatic system, then the blood stream, to the liver
VLDL
i. Secreted by the liver, transported to peripheral tissues
ii. Converted into IDL, LDL
LDL
i. “Bad” cholesterol. Transported to cells from liver
ii. In excess, deposited into arteries
HDL
i. “Good” cholesterol
ii. Scavenges cholesterol from other cells and lipoproteins
iii. Low HDL associated with atherosclerosis
Target levels of cholesterol- Total, LDL, HDL, Triglycerides.
LDL/HDL Cholesterol Risk Ratio
a. Total: <200
b. LDL: < 130
c. HDL: >40 Men, >50 Women
d. Triglycerides <120
1.00- One half the average
3.5- Average
6- Twice the average
8- Three times the average
Decreases LDL how much?
Statins
MOA, A/E
a. Statins- HMG-CoA Reductase Inhibitors. Decrease cellular cholesterol synthesis (LDL) significantly, increases HDL. Decreases LDL 65% when combine with Mab
i. Muscle Pain
Works by reducing the transport of….
Niacin
b. Niacin- Reduces transport of VLDL from liver; Decrease LDL, decrese triglycerides, increases HDL
i. Flushing
Fibrates
c. Fibrate: PPAR mediated lipolysis in liver (increases the breakdown of fatty acids and reduces triglyceride levels in the blood); decrease VLDL, LDL, increase HDL
i. GI Upset- Rare
Two possible A/E?
Cholesterol Absorption Inhibitors
e. Absorption Inhibitors- Inhibit intestinal cholesterol absorption (LDL)
i. Ezetimbe
ii. Possible hepatotoxicity
iii. Promoting arterial wall thickening?
Mabs- PCSK9 Inhibitors
PCSK9 inhibitors are drugs that help lower cholesterol levels. They block the PCSK9 protein, which normally tags LDL receptors for destruction. By inhibiting PCSK9, more LDL receptors remain on liver cells to remove LDL cholesterol from the blood.
PCSK9 increase in circulation after long-term statin use
Atherogenesis
-process of forming atherosclerotic plaques in arteries. It begins with damage to the artery wall, leading to the accumulation of lipids and inflammatory cells.
Macrophages begin to engulf LDL that is stored in the arterial wall, and that causes the formation of foam cells. These begin to accumulate and contribute to plaquestion formation
Major Subgroups of Sedative-Hypnotics
Which receptor do they work on? Classes and drug names
- Benzodiazepines
-Diazepam, midazolam - Barbituates
-Phenobarbitol, Thiopental (replaced by propofol), methohexital - Sleep Aids
-Zolpidem - Anxiolytics
-Buspar - Ethanol
These are all GABAa Receptor agonists. Potentiate inhibition at all levels of the CNS
-Increase flow through GABA receptor
-Increase channel opening time
Treatment of Alcoholism
-Rehab
-Naltrexone; Approved by FDA to tx ETOH dependance. Opioid- antagonists
-Can cause acute opioid w/d in a patient physically dependent on opioids
-Acamprosate: Reduces urge to drink. Adjunct therapy, used in Europe
-Disulfiram
ETOH Pathway & where Disulfiram acts
- Ethanol goes through a redox reaction where alcohol dehydrogenase converts ethanol into acetaldehyde
-This pathway creates calories from ETOH, causing weight gain - With chronic ETOH use, overtime the body begins to metabolize ETOH via the microsomal ethanol-oxidizing system. This system does not produce calories, chronic alcoholics will be thinner
-Acetaldehyde is converted into acetate via aldehyde dehydrogenase
-Disulfiram inhibits aldehyde dehydrogenase, causing acetaldehyde accumulation (hang over symptoms)
Echinacea
St. John’s Wort
-Stimulation of immune system, anti-inflammatory
-Anti-depressant (cyp450)
Garlic
Ginkgo
-HMG CoA Reductase inhibitor- reduces cholesterol
-Improved blood flow, free radical scavenger
Ginseng
Milk thistle
-Memory, immune, analgesia
-Reduction in hepatotoxicity
Saw Palmetto
Kava Kava
Kombucha
- BPH
- Anxiety, muscle relaxant, sedative
- Yeast and bacteria
Alkylating Agents
Four groups
● Largest and most diverse class (CCNS)
● Either alkylate DNA or interfere by crosslinking (platinum compounds)
● Groups:
○ Nitrogen Mustards
■ Cyclophosphamide, chlorambucil
○ Nitrosoureas- cross BBB
■ Carmustine, lomustine, streptozocin
○ Alkyl Sulfonate
■ Busulfan
○ Platinum Analogs
■ Cisplatin, Carboplatin
Cisplatin
MOA, Excretion, BBB? Uses, A/E
MOA: Enters cells, forms highly reactive platinum complexes, damages DNA with intrastand and interstrand crosslinks, inhibits cell proliferation
Highly bound to plasma proteins
Concentrates in kidney, intestine, testes
● Poorly penetrates BBB
● Slowly excreted in urine
● Uses
○ Testicular cancer (85% - 95% curative)
○ Ovarian cancer
○ Other solid tumors: lung, esophagus, gastric
● Adverse effects
○ Emesis
○ Nephrotoxicity
○ Peripheral neuropathy
○ Ototoxicity
Alternative:
● (Carboplatin – better tolerated)
MTX
MOA, Cytotoxic & immunosuppresive actions
-inhibits the enzyme dihydrofolate reductase (DHFR). This blocks the synthesis of DNA, RNA, and proteins, affecting rapidly dividing cells.
-Cytoxic actions:
Predominant on bone marrow
Ulceration of intestinal mucosa
Cross placenta, fetal malformations & death
Immunosuppressive action:
Prevents clonal expansion of B & T lymphocytes
Anti-inflammatory
Cancer drugs
Antimetabolites
Plant-based
Antibiotics
Drugs
-6-MP, 5-FU
Vincristine, Paclitaxel
Dantinomycin, Doxorubicin, Bleomycin
Cancer drugs
Hormonal Agents
Misc.
Corticosteroids, Tamoxifen, Fulvestrant
-Imatinib, Trastuzumab, Rituximab
Cell types and general tx
Neoplasia
Cell types: Carcinoma, sarcoma, leukemia, lymphoma
Treatments: Primary, neoadjuvant, adjuvant
