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
