Pharm I Final Review Flashcards by Brashe Webster

Comparison of the amount of drug that causes intended therapeutic effect to the amount that will cause toxicity or death

Therapeutic index

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TD50/ED50

Therapeutic Index

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Narrow Therapeutic Index drugs have TI of

Less than 2

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toxic dose in 50% of patients

TD50

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minimum effective dose in 50% of patients

ED50

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Time to achieve a 50% reduction in drug concentration after a prolonged infusion at steady state

Context-Sensitive Half-time

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Relationship between drug dose administered and the resulting concentration in the plasma or at the effective site (target site

Pharmacokinetics

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The fraction of the dose administered of drug that reaches the systemic circulation unchanged. Notated by f or as a percent F. Intravenous considered 1.0 or 100%

Bioavailability

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Pharmacokinetic concept, not an actual volume, that describes the concentration of drug in plasma based on how much you gave

Volume of Distribution

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removal of a drug from the body without any chemical change

Elimination

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chemical change of a drug to a new compound. May be to either an active form or inactive form

Metabolism and Biotransformation

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3 Steps to metabolize a drug

Modification (Phase 1)
Conjugation (Phase 2)
Excretion

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biosynthesis of an enzyme is upregulated by exposure to a drug. Will increase rate of metabolism of drugs processed by the enzyme. In drug-drug interactions, will decrease the drug level below it’s effective concentration

Enzyme induction

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drug can directly inhibit the activity of the enzyme. Will decrease rate of metabolism of drugs processed by the enzyme. Does not have to be the drug that metabolizes that enzyme, cross reactivity is more common

Enzyme inhibition

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Warfarin and grapefruit juice interact with

EVERYTHING

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Intentionally delivered in a form that becomes pharmacologically active when metabolized by the body. May help absorption, protect compound from gastric pH, prevent side effects of administration

Prodrug

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GI absorption of drugs get passed through the liver prior to entering systemic circulation. Liver is a major source of drug metabolism

First-Pass effect

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the process of removing drug from a volume in the body. Elimination or transformation to metabolites

Clearance

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volume that is cleared of drug/unit time

Clearance

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Ratio of the amount of blood flow to the liver, and the clearance of drug from that flow. How much does the liver take out per cycle

Extraction Ratio

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Drug is moved from access to its active site

Distribution Clearance

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Length of time it takes drug concentration to drop to ½ its starting dose. Regulated by Bioavailability, Vd, Clearance t1/2 = Vd/Cl

Half-Life

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What a drug does to the body- Transduction of body signals, molecular pharm, clinical evaluation of drug effects

Pharmacodynamics

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A receptor is a component of a cell that interacts with an outside compound to exert a biochemical effect that results in an observed effect

Receptor Theory

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Drugs that induce an effect that mimics endogenous compounds when bound to a receptor

Agonist

Drugs that inhibit or prevent receptor-mediated agonist effects by occupying the receptor. * Have affinity, but no efficacy at receptors

Antagonist

Can be displaced from the receptor by a larger dose of agonist

Competitive Antagonist

Binds irreversibly to the receptor complex and cannot be overcome by a larger dose of the agonist. Reduces max effect , but does not eliminate it.

Noncompetitive Antagonist

In the presence of a full agonist- acts as an antagonist (Buprenorphine)

Partial Agonist

Effects of genetic variation on drug action based on polymorphisms (Pseudocholinesterase deficiency, MH RyR1)

Pharmacogenetics

Waning of physical response to a drug over time. Continuous stimulation of receptor provides negative feedback loop to further effects

Desensitization

- Measurement of the attractiveness of a specific drug to a receptor. “How sticky the drug is”

Affinity

binds to receptor, even at low doses

High Affinity

little binding

Low Affinity

Relationship between receptor occupancy and ability to produce an effect

Efficacy

max response from receptor occupation

Emax

* Concentration at which 50% of maximal effect is obtained

EC50

Barbiturates are contraindicated in

Porphyria

Endogenous ligand inhibitory neurotransmitter found diffusely in the CNS. Agonists alter conformation of the ion channel proteins so that GABA binding is enhanced

GABA

GABA-A

Chloride Channel

Sedation, amnesia, anti-convulsant

Alpha 1

Alpha 2

anxiolysis and muscle relaxation

NMDA Receptor blockade, analgesia mediated by mu-opioid receptor, CO-Dependent. Catecholamine-depleted patients may show adverse hemodynamic consequences

Ketamine

Liver metabolism by ester hydrolysis- GABA-mediated, Reduces CBF and CMRO2, Does not alter MAP, CPP is maintained. Adrenocortical suppression after single dose

Etomidate

Sedation at Locus Caeruleus and analgesia in spinal cord, Decr. HR, Decr. SVR, indirect reduction in myocardial contractility, CO, and Systemic BP

Dexmedetomidine

More lipid soluble means more able to cross BBB and dissolve into the lipid membrane of neurons

Brain: Blood Partition Coefficient

MAC is inversely proportional to

Potency

the alveolar partial pressure of an inhalational anesthetic at which 50% of a population of non-relaxed patients remain immobile at the time of skin incision

MAC- Mean Alveolar Concentration 1.0

concentration required to block autonomic reflexes to nociceptive stimuli

MAC BAR 1.7-2.0

– concentration required to block voluntary reflexes and perceptive awareness

MAC Awake .3-.5

The MAC of a volatile substance is inversely proportional to its lipid solubility (oil:gas partition coefficient)

Meyer-Overton Hypothesis

denoted by the partition coefficient

Solubility of volatile anesthetics

a distribution ratio describing how the inhaled anesthetic distributes itself between two phases at equilibrium (partial pressures equal at both phases).

Partition Coefficient

Ratio of the alveolar (or end- tidal) anesthetic concentration (FA) to inspired anesthetic concentration (FI)

Uptake Fa/ Fi

Reflects the ability of high-volume uptake of one gas (first gas) to accelerate the rate of increase of the PA of a concurrently administered “companion gas” (second gas)

Second Gas effect

The PA and ultimately the Pbr of inhaled anesthetics are determined by input (delivery) into alveoli minus uptake (loss) of the drug into arterial blood.

Determinant of Alveolar Partial pressure

* Increased solubility in blood (slows/ speeds) inhalational induction

Slows

* Decreased solubility in blood (slows/speeds) inhalational induction

Speeds

* What is the effect of cardiac output on induction (rate of rise of FA/FI)

High CO slows induction Low CO speeds induction

Stage I of CNS Depression

Analgesia

Stage II of CNS Depression

Excitement

Stage III CNS Depression

Surgical Anesthesia

Stage IV CNS Depression

Medullary depression

Concerns with Halothane

Hepatotoxicity

Nm receptor

Neuromuscular junction of skeletal muscle

Peripheral ganglia and central nervous system

GPCR- Widely distributed within both peripheral and central nervous systems

Muscarinic Receptor

* Potency determined by dose needed to produce 95% suppression of single-twitch response (ED 95)

NMBA

Fine muscles, fingers, Eye muscles, swallowing, grip strength/arms, Legs, neck (Head lift), Intercostals, Diaphragm,

Resistance to NMBAs

Diaphragm, intercostals, neck (Head lift), Legs, grip strength, swallowing, eye muscles, fingers/fine muscles

Recovery of NMBA

Surmountable with increased levels of ACH

Competitive Antagonist

Concern with Atracurium

Histamine release

Concerns with atracurium and Vecuronium

Bradycardia

Moderate inc. in HR/CO, no change in SVR- Due to vagolytic action in both direct and indirect sympathetic stimulation

Pancuronium

* Ratio = ED50 undesired effect /ED95 desired effect

Margin of Safety

Non-competitive blockade (insurmountable with increasing amounts of ACH)

Sux

Stimulation of cardiac muscarinic receptors in the SA Node

Bradycardia in PEDS w/ sux

Phase I blockade w Sux

* Decreased contraction in response to single-twitch stimulation * Decreased amplitude but sustained response to stimulation

Phase II Blockade w Sux

Large doses * Resembles response seen w NDMBAs * May be antagonized with anticholinesterase drug * Differentiate with Edrophonium test * Fade is present W/ TOF stimulation

inhibits normal enzyme- #80

Dibucaine

Dibucaine heterozygous #

50-60

Dibucaine homozygous atypical

20-30

What can potentiate NM Blockade

Magnesium

What can decrease sensitivity to NMDRs

Calcium Local Anesthetics

How do anti-epileptic drugs affect NMBA

resistance to NMDRs hypersensitivity to Sux

Works at effector cells (in the smooth muscle, heart, exocrine glands, but not on ganglia

Muscarinic

Works at autonomic ganglia and skeletal muscle NMJ, but not on effector cells

Nicotinic

muscarine and nicotine- Hydrolysis of ACH is accomplished by acetylcholinesterase. Acts to increase endogenous ACH by inhibiting its breakdown

Alkaloids

Autoantibodies to NM Receptor, highly sensitive to NMDRs- resistant to Sux

Myasthenia Gravis

Edrophonium used to diagnose , short half-life, improves symptoms

Tensilon Test

- μ – mu, δ – delta, Κ – kappa, σ – Sigma, ε - Epsilon

Opioid receptors

Enkephalins-  δ > μ receptor activity– Met-enkephalins and leu-enkephalins

Endogenous Opioids

Endorphins, Dynorphins, Endomorphins, Nocioception/Orphanin FQ

Endogenous opioids

How is CO2 curve affected by opioid administration

Right-Shift

CYP 2D6 converts to morphine

Codeine

synthetic analog of codeine- Mu, K, S, blocks norepi and serotonin uptake

Tramadol

Black-box warning for codeine

Ultra-metabolizers, contraindicated in children

Smooth muscle constriction

Alpha 1

inhibition- prevent depolarization of neurons by preventing norepi release-> Sedation, decr. HR and BP

Alpha 2

increased APs, -> SA, AV, HIS, Myocardium, kidneys

Beta 1

dilation of smooth muscle/ glucose production in liver

Beta 2

glycogenolysis- adipose tissue

Beta 3

CNS, gastric glands --> secretion of gastric secretions for digestion

M1 (+)

Heart (SA, AV) --> inhibit action potentials --> decrease HR

M2 (-)

Glands (lacrimal, salivary, sweat), pancreas, smooth muscle (bronchi, GI tract, bladder, sphincters, eye) --> increase secretions, increase Insulin, bronchoconstriction, GI peristalsis, vasoconstriction, pupil constriction

M3 (+)

CNS --> memory, arousal, analgesia

M4 (-)

memory, arousal, analgesia

M5 (+)

* Cardiac- Inc HR- M2 antagonism * Pulmonary- Bronchodilation- M3 antagonism * Secretions- Decr. All secretions , but salivary decrease is pronounced

Atropine

No parasympathetic tone * Can be seen with any muscarinic antagonist * CNS-Hallucination, delirium * Secretions- decr. Sweat, saliva

Atropine Overdose

Pesticides, sarin gas, profound inhibition of acetylcholinesterase-> Ach overload

Organophosphate poisoning

Cure for organophosphate poisoning

* Pralidoxime (2-pram)

* Cleaves organophosphate-acetylcholinesterase bond, allowing resumption of normal function

Pralidoxime (2-pram)

Phenylalanine->Tyrosine->Dihydroxyphenylalanine “Dopa”->Dopamine->Norepinephrine-> Epinephrine

Catecholamine synthesis Pathway

Describe the synthesis pathway of catecholamines

Phenylalanine->Tyrosine->Dihydroxyphenylalanine “Dopa”->Dopamine->Norepinephrine-> Epinephrine

Caution when patient is on MAOIs

Don't give Norepi

Can dopamine cross the BBB?

D1 dopamine dosing

* 1-5mcg/kg/min

B1, B2>D1 Dopamine dosing

* 5-15mcg/kg/min

A1>B>D1 Dopamine dosing

* 15+mcg/kg/min

prevent cAMP breakdown and allow for further propagation of the downstream effects

Phosphodiesterase inhibitors

- Increase activation of cAMP and subsequent increase in intracellular Ca++ release in myocardium

PDE 3 inhibitor- Milrinone

cAMP -> cGMP activation -> smooth muscle dilation

PDE 5 Inhibitor Sildenafil Tadalafil

Works on the V1 receptors to cause vasoconstriction and works on the V2 receptors in the collecting duct of the kidney to increase aquaporin expression and therefore water retention. Also causes a release of Factor VIII and vWF from endothelial cells that will play a role in clotting cascade

Vasopressin/ ADH

treatment for diabetes insipidus will also cause these factors to be released without the V1 effects on BP

DDAVP- Desmopressin

CO x PVR

Arterial BP

HR x SV) x PVR

inhibit Na+ cl- uptake in DCT, can incr. Ca2+ reabsorption as 2ndary effect. Side effects- Decreased K+, hypokalemic metabolic aklalosis

Thiazides

Selectively inhibit Na+, Cl-, and K+ transporter, preventing reabsorption in LOH. Side effects- decreased K+, hypokalemic metabolic alkalosis, ototoxicity

Loop Diuretics

antagonize aldosterone in the collecting duct- Side effects- incr. urine output, ED, gynecomastia

* K+-Sparing – Spirinolactone

decr. Intracellular calcium, decr. Muscle contraction

* Vasodilators- * Ca2+ Channel Blockers-Amlodipine, Nicardipine, Clevidipine, Verapamil, Diltiazem

Selectively work on arterial smooth muscle -Side effects: reflex tachycardia

* Dihydropyridines- Amlodipine, nifedipine, clevidipine, nicardipine

Primarily work on cardiac myocytes, very minor vasodilator. Powerful myocardial depressant, mostly used as an anti-arrhythmic

Alternative CCBs Verapamil Diltiazem

binds to guanylyl cyclase converting GTP to cyclic-GMP which then activates Protein Kinase G which decreases Ca++ release from the sarcoplasmic reticulum. Side effects- Reflex tachycardia , orthostatic hypotension, can cause drug-mediated lupus w chronic use

Direct-Acting Vasodilators

activates guanylyl cyclase which will convert GTP to cGMP therefore decreasing intracellular Ca++. Side effects- Reflex tachycardia, Monday Morning headaches, Cyanide toxicity (Metabolic lactic acidosis), coronary steal

Nitric Oxide

What can have a synergistic effect w/ PDE inhibitors and Alpha blockers

Nitric Oxide

Low-Dose Nitroglycerin

venous dilation -> decrease pre-load

High-Dose Nitroglycerin

arterial dilation -> decrease SVR

* Nitroprusside works on both arterial and venous systems, so the vasodilation will

decrease both SVR and pre-load

Selectively inhibit B1 receptors, causing decr. HR and SV, and therefore CO. Decr. In HR will also increase myocardial perfusion and decrease myocardial O2 consumption, making it a good choice for CAD, AS, HOCM, HF- Side effects- inability to increase CO during exercise or decompensated HF, Bradycardia

Beta Blockers

Selectively inhibit A1 adrenergic receptor causing vasodilation. Can be used in prostate hyperplasia, pheochromocytoma. Side effects- Reflex Tachycardia

Alpha Blockers Prazosin, Terazosin, Doxazosin

Mixed A/B Agonists

Labetalol- B:a 3:1: Carvedilol 10:1

- inhibit norepinephrine via a2 receptors within the central nervous system to indirectly inhibit peripheral adrenergic receptors. Side effects- Sedation, Bradycardia

Centrally-Acting

inhibits norepinephrine synthesis in the CNS. Prodrug, metabolized in the brain into active form. Really only used in pregnancy

Alpha-Methyldopa

Inhibit ACE, therefore preventing AT I to AT II. Increase aldosterone production in response to Na+ loss. Side effects- angioedema leading to cough,

ACE Inhibitors

Antagonist to angiotensin receptor, therefore completely inhibiting AT II causing vasodilation and decreased aldosterone synthesis

ARBS

inhibits Na/K+ ATP-ase and increase intracellular Ca2+ in cardiac myocytes, resulting in increased contractility and SV. *Can cause ANY Arrhythmia Toxicity- Lethargy, AMS, Hallucinations, N/V, SOB, Syncope, Bradycardia, DIgibind is the treatment

Digoxin

MONA

Morphine-Decr. sympathetic response O2-max myocardial o2 delivery Nitrates-Venodilation Aspirin-prevent clots

Mediators of acute inflammation (complement, C-Reactive protein, and Antibodies leak out. Mast cell degranulation

Histamine Reaction

Drugs that cause histamine/ mast cell degranulation

Morphine, atracurium, curare

Epi, cromolyn, nedocromil, Histamine receptor antagonists

Physiologic Antagonists

Direct Vasodilation- Decreased systolic and diastolic BP, Reflex tachycardia, Bronconstriction, uterine smooth muscle contraction-> Spontaneous abx

Pain and Itching

H1, H3

Presynaptic modulation of release of neurotransmitters in the CNS

Blockade of H2 receptors on acid-producing parietal cells of the stomach. ECL stimulate to release gastric acid

H2 Receptor antagonists

Tests for airway hyper-responsiveness

Methacholine challenge

synthesized from tryptophan, Precursor for melatonin- Enterochromaffin cells of the GI Tract. , platelets- aggregation, Brain- neurotransmitter. Released primarily at night

Serotonin

5HT2

Platelet Aggregation

Stimulates ganglion cells of enteric system-causes increased ACH release- increased tone and peristalsis, severe diarrhea in carcinoid syndrome

5HT4

Work by inhibiting the release of vasodilating peptides. Effective during prodrome, less so once symptomatic. Can precipitate coronary vasospasm – contraindicated in pts with CAD

* 5-HT1B/1D agonists – “triptans”, eg. Sumatriptan

* 5HT1A-agonist- Buspirone-

Anxiolytic

* Cisapride – 5-HT4 agonist

GERD and GI motility disorders-Compassionate use only, causes arrhythmias

* Tegaserod – 5-HT4 partial agonist

Irritable bowel syndrome-Selective serotonin reuptake inhibitors (SSRIs)-Block reuptake of the neurotransmitter-Major depression and other psychiatric disorders

Antihypertensive used to treat pheochromocytoma

Phenoxybenzamine – 5-HT2 antagonist & alpha blocker

Also antimuscarinic & potent H1 blocker (antihistamine)- Causes sedation-Blocks smooth muscle effects of 5-HT and histamine- Uses: Carcinoid, cold-induced urticaria, serotonin syndrome

* Cyproheptadine – 5-HT2 antagonist

- Strong platelet aggregation inhibitor- Also, strong α1 blocker – hypotensive effect- Only approved in Europe to treat HTN & vasospasm

* Ketanserin – 5-HT2 antagonist-

Use in prevention of N/V assoc with chemotherapy and general anesthesia

* Ondansetron (“-setrons”) – 5-HT3 antagonists

reduced by 5HT2A agonists in animal models of glaucoma

Intra-Ocular Pressure (IOP)

Rare- Iatrogenic, Extreme serotogenic activity in the CNS. May see agitation, tachycardia, skeletal muscle contractions, hyperactive reflexes, hyperthermia

Serotonin Syndrome

under trials, may have antinocioceptive action while reversing opioid-induced respiratory depression

* Repinotan-5HT1A

a region in the brainstem that plays a crucial role in triggering the vomiting reflex. Located on the floor of the fourth ventricle, outside the blood-brain barrier, it detects blood-borne chemicals and hormones, including those associated with nausea and vomiting.

* Chemotactic Trigger Zone (CTZ)-

5-HT3-sensitive vagal nerve endings in the coronary vasculature, stimulation causes bradycardia (vagal) and hypotension (decreased CO due to low HR

* Chemoreceptor Reflex- (Bezold-Jarisch reflex)- 5-HT3

Most common- diarrhea, n/v, More serious- prolonged vasospasm, refractory to most vasodilators

Ergot Alkaloid Toxicity

Dopa receptor agonist-prolactinoma-excess prolactin w galactorrhea-excess breast milk, cabergoline, pergolide (highly selective

Bromocriptine

most selective for uterine smooth muscle (Uterine muscle stimulant)

* Ergonovine (methylergonovine, methergine)

Contraindicated in CAD and HTN disorders- especially pre-eclampsia

Methergine

Ergotamine is highly specific for _____ pain, not analgesic for any other condition

Migraine

Increased prolactin secretion is associated with tumors of the pituitary gland and use of the centrally acting dopamine antagonists (esp. D2 antagonists used as antipsychotics)-Bromocriptine - agent of choice

Hyperprolactinemia

Rate-limiting step for Dopamine synthesis

catalysis by tyrosine hydroxylase to L-Dopa, which crosses the BBB, whereas Dopamine does not

the primary mechanism of termination of DA action- MAO and catechol-O-methyltransferase (COMT) metabolize DA to DOPAC then HVA, which is excreted in urine

Reuptake

receptors modulate release of NE and epinephrine.

D1 and D2

tonic inhibition(tone, regularity of excretion) of epinephrine release from chromaffin cells of adrenal medulla

high frequency DA release promotes release of catecholamines from adrenal medulla

Low concentrations: vasodilation, reduced afterload (D1) under 5-Moderate concentrations: increased cardiac contractility (B2) 5-15, tachycardia-High concentrations: vasoconstriction, increased BP (A1) over 15

* D1>beta>alpha-

* Primary inhibitory regulator of prolactin secretion

Dopamine

Which medication is relatively contraindicated in a patient taking the non-selective MAOI phenelzine? A. Morphine B. Ephedrine C. Phenylephrine D. Haldol E. None of the above

Ephedrine

Tricyclic antidepressant side effects include all of the following EXCEPT: A. Weight gain B. Fatal arrhythmias C. Sexual dysfunction D. Cholinergic effects (SLUDGE) E. Decreased seizure threshold

Cholinergic effects (SLUDGE)

SNRIs may precipitate manic episodes if given to bipolar patients. A. True B. False

TRUE

Which of the following symptoms is consistent with serotonin syndrome but NOT malignant hyperthermia? A. Hypertension B. Hyperreflexia C. Diarrhea D. Hyperthermia E. Same-day onset when given offending agent

C- Diarrhea

Why do atypical antipsychotics have a lower incidence of extrapyramidal symptoms (EPS) at clinical doses than typical antipsychotics? A. Lower affinity for 5-HT2A receptor B. Lower affinity for D2 receptor, more likely not to worsen negative symptoms C. Wider therapeutic index D. Greater 1st pass metabolism E. All of the above

B. Lower affinity for D2 receptor, more likely not to worsen negative symptoms

Adverse effects of antipsychotics include all of the following EXCEPT: A. Hyperglycemia B. Ventricular arrhythmias C. Orthostatic hypotension D. Tardive dyskinesia E. Weight loss

E. Weight loss-typically weight gain occurs

Which of the following is a physiologic action of histamine? a. Mediator of allergic reactions b. Gastric acid secretion c. Neurotransmitter in the CNS d. All of the above

D-All of the above

Which of the following is a precursor of melatonin? a. Histamine b. Histidine c. Serotonin (from tryptophan) d. 5-HIAA

Serotonin (from tryptophan)

Match the histamine receptor subtype with the action it is most known for: a. H1 receptor A. Presynaptic receptor for neurotransmitter release b. H2 receptor B. Gastric acid secretion c. H3 receptor C. Chemotaxis of eosinophils and mast cells d. H4 receptor D. Allergic reaction response

H1- Allergic reaction response H2-Gastric Acid Secretion H3-Presynaptic receptor for neurotransmitter release H4- Chemotaxis of eosinophils and mast cells

Ergot alkaloid poisoning causes which of the following symptoms: a. Gangrene b. Involuntary muscle spasms c. Hallucinations d. All of the above

D- All of the above

Ergot alkaloids are useful in the treatment of which of the following conditions: a. Postpartum hemorrhage b. Coronary vasospasm (Contraindiction c. Preeclampsia (Contraindication) d. Diarrhea (Side Effect)

Postpartum hemorrhage

Dopamine is heavily involved with which of the following physiologic functions: a. Decreased cardiac contractility b. Increased prolactin secretion from the pituitary gland (Decrease) c. CNS control of reward, emotion, cognition and memory d. All of the above

CNS control of reward, emotion, cognition and memory

Minimum alveolar concentration (MAC) is a term used to describe the potency of inhaled anesthetics. The best definition of 1.0 MAC is: A. The partial pressure of an inhalational anesthetic in the alveoli of the lungs at which 50% of a population will have no hemodynamic change at the time of skin incision. B. Approximately 2% concentration for desflurane. C. The partial pressure of an inhalational anesthetic in the alveoli of the lungs at which 100% of a population of nonrelaxed patients remained immobile at the time of skin incision. D. The partial pressure of an inhalational anesthetic in the alveoli of the lungs at which 50% of a population of nonrelaxed patients remained immobile at the time of skin incision. E. None of the above

D-The partial pressure of an inhalational anesthetic in the alveoli of the lungs at which 50% of a population of nonrelaxed patients remained immobile at the time of skin incision.

What is the primary driving force for uptake of an inhaled anesthetic? A. The alveolar concentration of the inhaled anesthetic B. The alveolar concentration of oxygen C. The cardiac output D. The pulmonary venous concentration of the inhaled anesthetic E. None of the above

Cardiac output

. Increased alveolar ventilation will _______ the rate of induction

SPEED

The speed of induction is fastest for the _______ blood-soluble inhaled anesthetics.

Least

Which of the following agents will decrease normal cardiac contractility? A. Halothane B. Isoflurane C. Sevoflurane D. Desflurane E. All of the above

E. All of the above

Which of the following is NOT a cerebral effect of inhaled anesthetics? A. Decreased cerebral metabolic rate B. Cerebral vasoconstriction C. Unconsciousness D. Electroencephalogram (EEG) changes

B. Cerebral vasoconstriction

Modern inhaled anesthetics are primarily eliminated from the body by: A. Hepatic metabolism B. Renal metabolism C. Ventilation D. Excretion via the skin E. None of the above

C. Ventilation

Which of the following incorrectly pairs the classical stage of CNS depression with its descriptor? A. Stage I – Analgesia B. Stage II – Excitement C. Stage III – Surgical anesthesia D. Stage IV – Medullary depression E. None of the above

E-None of the above

What is the principle neurotransmitter found in the neuromuscular junction? A. Muscarine B. Nicotine C. Acetylcholine D. Norepinephrine E. Serotonin

C. Acetylcholine

Vecuronium is: A. An intermediate acting neuromuscular blocker B. A depolarizing neuromuscular blocker C. A benzylisoquinoline D. An agent that produces a phase I blockade E. Is broken down by spontaneous degradation in the plasma (Hofmann elimination)

An intermediate acting neuromuscular blocker

Neuromuscular blocking agents are most specific for blocking what type of receptor? A. Muscarinic receptor B. Neuronal-type nicotinic receptor C. Ganglionic receptor D. 5HT3 (serotonin) receptor E. Muscle-type nicotinic receptor

E. Muscle-type nicotinic receptor

Pancuronium: A. Is primarily eliminated by the liver B. Is the shortest acting neuromuscular blocking agent C. Causes a transient bradycardia with common induction doses D. Is several times more potent than tubocurarine E. Has a rapid onset and recovery

Is several times more potent than tubocurarine

Potential side effects of nondepolarizing muscle relaxants include: A. Tachycardia B. Bradycardia C. Hypotension D. Histamine release E. All of the above

E. All of the above

Which of the following is NOT an indication for use of neuromuscular blocking agents? A. Control of ventilation in an intubated ICU patient B. Keeping an poorly anesthetized patient from moving during surgery C. Treatment of epileptic convulsions D. Facilitation exposure during abdominal surgery E. Endotracheal intubation

C. Treatment of epileptic convulsions

Post-tetanic potentiation (facilitation) is seen with: A. Phase I blockade during succinylcholine use B. Phase II blockade during succinylcholine use C. Use of nondepolarizing muscle relaxants D. B and C are correct E. All of the above

D. B and C are correct

Potential side effects of succinylcholine use include all of the following EXCEPT: A. Cardiac arrest B. Increased intragastric pressure C. Hypokalemia D. Increased intraocular pressure E. Myalgias

C. Hypokalemia

Muscarinic receptors can be found in the following, EXCEPT: a. The neuromuscular junction b. The myocardium c. Smooth muscle cells d. The central nervous system e. Secretory glands

a. The neuromuscular junction

The prototypical antimuscarinic drug is a. Nicotine b. Epinephrine c. Clonidine d. Atropine e. Nifedipine

Atropine

Antimuscarinic effects in the body include the following, EXCEPT: a. Mydriasis b. Cycloplegia c. Tachycardia d. Bronchodilation e. Sweating

e. Sweating

Antimuscarinic drugs are used in the treatment of the following disorders, EXCEPT: a. Motion sickness b. Prostatic hypertrophy c. COPD d. Parkinson’s disease e. Diarrhea

b. Prostatic hypertrophy

Severe overdose or poisoning with cholinergic agonists can be due to exposure to the following, EXCEPT: a. Insecticides on farms b. Nerve gas in warfare c. Eating wild mushrooms d. Atropine overdose in the hospital e. All of the following are correct

d. Atropine overdose in the hospital

Which of the following is “cholinesterase regenerator” used to treat organophosphate poisoning? a. Propranolol b. Physostigmine c. Pralidoxime d. Papaverine e. Properivine

c. Pralidoxime

Adverse effects of atropine overdose may include the following, EXCEPT: a. Hypothermia b. Tachycardia c. Dry mouth d. Delirium e. Agitation

a. Hypothermia

Which is the most common form of local anesthetic to pass through the neuron cell membrane to enter the cell? a. Cation b. Anion c. Uncharged base d. Uncharged acid

C- Uncharged base

Local anesthetics with which of the following will be more likely to exist in the cationic form at physiologic pH? a. Higher pKa b. Lower pKa

Higher pKA

Which of the following will prolong the duration of effect of local anesthetics? a. Injection into well perfused tissues b. Use of a local anesthetic with lower lipid solubility c. Use of a local anesthetic with lower protein binding d. Presence of vasoconstrictor

Presence of Vasoconstrictor

Which of the following is the desired physiologic target of local anesthetics? a. Voltage-gated potassium channels b. Muscarinic acetylcholine receptors c. Voltage-gated sodium channels d. Nicotinic acetylcholine receptors

c. Voltage-gated sodium channels

Which of the following is an ester-type local anesthetic? a. Lidocaine b. Procaine c. Etidocaine d. Bupivacaine

B-Procaine

Identify the correct order of loss of sensation by local anesthetic: a. Temperature > Pain > Touch > Deep pressure > Motor b. Pain > Temperature > Touch > Deep pressure > Motor c. Temperature > Touch > Pain > Motor > Deep pressure d. Pain > Touch > Temperature > Motor > Deep pressure

A) Temperature > Pain > Touch > Deep pressure > Motor

Which of the following symptoms could constitute local anesthetic systemic toxicity? a. Arrhythmia b. Confusion c. Seizure d. Metallic taste e. All of the above

D- All of the above

Allergic Response

Gastric Acid Secretion

Presynaptic receptor for neurotransmitter release

Chemotaxis of eosinophils and mast cells

Increase cAMP

D1 Receptor Family

Decrease cAMP Increase K+ Currents decrease voltage-gated ca2+ Currents

D2 Receptor Family

Synthesis of Dopamine

Precursors include AAs phenylalanine and tyrosine

Phase 4 Cardiac AP

K+ in

Phase 0 Cardiac AP

Na+ in

Phase 1 Cardiac AP

K+ out

Phase 2 Cardiac AP

Ca2+ in, K+ out

Phase 3 Cardiac AP

K+ out

Phase 0 Pacemaker AP

Calcium in Depolarization

Phase 3 Pacemaker AP

Potassium Out Repolarization

occurs when a signal comes retro-grade from the ventricles through the accessory pathway into the atria which stimulates the AV node, and sends another signal down through the ventricles and back up through the accessory pathway

WPW Re-entrant tachycardia

No accessory pathway, only an functional issue with the AV node, often created by scaring in that area Slow conduction through abnormal tissues can allow for a circular depolarization in the AV node, leading to SVT

AVNRT

Class I anti-arrhythmics

Na+ Channel Blockers

Class II anti-Arrhythmics

Beta Blockers

Class III Anti-Arrhythmics

K+ Channel Blockers

Class IV Anti-Arrhythmics

Ca2+ Channel Blockers

Class V Anti-Arrhythmics

Miscellaneous Adenosine (Class V) Digoxin (Class V)

suppression of non-pacemaker cells to restore a normal sinus rhythm

Rhythm control

blockade of the AV node and prevention of supra-ventricular tachycardias (AFib, AFlut, SVT)

Rate Control

Diltiazem Verapamil

Class IV Ca2+ Channel Blockers

Disopyramide Quinidine Procainamide

Class 1A Na+ channel blockers

Lidocaine Mexeletine Tocainide

1B Na+ Channel Blocker

Moricizine Flecanide Propefanone

1C Na+ channel Blocker

Proporanolol Atenolol Metoprolol

Beta Blocker

Solatol Amiodarone Dolfelitide

K+ Channel Blocker

prevent inappropriate depolarization of non-pacemaker cells by preventing opening of voltage gated Na+ channels, A.K.A. preventing 0-slope from occurring

Sodium Channel Blockers Class I Anti-Arrythmic

Potency for Class I anti-Arrhythmics

C>A>B for potency.

What drug can be used to cardiovert re-entrant tachycardia in WPW w/ A-Fib

Procainamide Class IA

What drug can be used to treat ventricular arrhythmias like V-Tach

Lidocaine Class 1B

Fast acting Na+ channel blockade Also causes some K+ blockade and can prolong action potential duration (APD), preventing repeat depolarization

Class 1B anti-arrhythmic Lidocaine

inhibit B1 receptor and preventing G-protein activation, therefore preventing the c-AMP cascade that opens Ca++ channels on the pacemaker cells within the SA and AV nodes, prolonging the Phase 4 Slope

Class II Beta Blockers

Are Class I or II anti-arrhythmics more effective in suppressing ventricular ectopy?

Beta blockers (class II) are less effective than Na+ blockers

Most common side effect of Beta Blockers

Bradycardia

Selective B1antagonist Short elimination, half-life of approximately 10 mins Rapidly metabolized in the blood by hydrolysis of an ester linkage

Esmolol

prevent the efflux of K+ ions in phases 1 and 2 of non-pacemaker cells, extending the Action Potential Duration (APD), and prolonging the time for the cells to repolarize and be ready to fire again

K+ channel blockers Class III anti-Arrhythmic

Amiodarone

Class III Anti-Arrhythmic

Primary use: atrial and ventricular tachycardias

Amiodarone

What drug is a structural analog of thyroid hormone

Amiodarone

Side effects of Amiodarone

Acute use: hypotension, myocardial depression Chronic use: pulmonary fibrosis (high doses), hepatic dysfunction, dysregulation of thyroid hormones, neuromuscular symptoms, blue discoloration of skin/eyes

direct blockade of Ca++ channels in the pacemaker cells of the SA and AV nodes, slowing the phase 0 depolarization and prolonging time that the cell is depolarized

Ca2+ channel blocker Class IV Anti-Arrhythmic

block re-entrant tachycardias OR ventricular rate control for supraventricular tachycardias

Ca2+ Channel blocker Class IV Anti-Arrhythmic

the preferred calcium-channel blocker for the acute rate control in clinical practice

Diltiazem

Major side effect is hypotension as it also blocks Ca++ channels in contractile myocardiocytes Avoid in patients with heart failure SA and AV nodal blocks can occur in patients receiving other rate controlling medications like beta-blockers

Verapamil Class IV Anti-Arrhythmic

Primary use: ventricular rate control in A-fib Can also cause hypotension and decreased cardiac output, but less so than verapamil Commonly used infusion for acute rate control

Diltiazem

binds to adenosine receptor (inhibitory protein) which opens K+ channels, further polarizing the pacemaker cells(more negative), and preventing depolarization. Fast acting, short duration of action, useful in breaking SVT

Adenosine

Sometimes used to induce asystole in certain neuro cases where they need a pause to intervene on an aneurysm

Adenosine

blocks adenosine receptors and can lead to tachyarrhythmias and palpitations at high doses

Caffeine

Adverse reactions to adenosine

Coronary steal syndrome, bronchospasm, transient hypotension

inhibits Na+/K+ ATPase pump, preventing the efflux of K+ and hyperpolarizing the SA and AV nodes Also inhibits the flow of Ca++ ions

Digoxin

Primary uses: treatment of A-fib in the setting of HFrEF

Digoxin

Increases intracellular Ca++, allowing for increased inotropy of cardiac myocytes, making it a good choice in HF Can improve symptoms but not shown to increase life expectancy

Digoxin

Treatment for Digoxin toxicity

supportive measures, correct electrolytes, Digibind

lethary, AMS, hallucinations, N/V, palpitations, syncope, SOB, bradycardia

Signs and symptoms of digoxin toxicity

Use when treating A-Fib who is also in heart failure

Digoxin

Treatment for Torsade's de Pointes

Magnesium Class V

Magnesium bolus

2g Bolus IV

Adverse effects of magnesium

hypotension and prolonged duration of non-depolarizing paralytics

Common medications that prolong the Q-T interval

high dose ondansetron (>16mg), methadone, haldol, droperidol, amiodarone, procainamide, SSRIs, fluoroquinolone antibiotics, etc

Contraindication to Disopyramide, flecanide

Heart failure

Contraindication to digoxin, verapamil, diltiazem, B agonist, amiodarone

Sinus or AV Node dysfunction

Contraindication to Digoxin, verapamil, diltiazem

WPW syndrome Risk of extremely rapid rate if a-fib develops

Contraindication to Na+ channel blockers, amiodarone

infranodal conduction disease

Contraindication to bretrylium

Aortic/subaortic stenosis

Contraindication to flecanide

Hx of MI

Contraindication to Quinidine, Procainamide, disopyramide, solatol, dofelitide, ibutilide, amiodarone

Prolonged QT interval

Contraindication to Adenosine

Cardiac transplant

Contraindication to Quinidine

Diarrhea

Contraindication to Disopyramide

Prostatism Glaucoma

Contraindication to chronic procainamide

Arthritis

Contraindication to Amiodarone

Lung disease

Contraindication to Mexelitine

Tremor

Contraindication to verapamil

Constipation

Contraindication to Beta blockers and Propafenone

Asthma, PVD, Hypoglycemia

"Ideosyncratic reaction to dopamine blockers (e.g. anti-psychotic) or due to abrupt cessation of dopamine agonists (e.g. Parkinson’s Tx)"

NEMS

Triggered by Dopamine Antagonists OR withdrawal of Parkinson's meds (Dopamine agonists)

NEMS

AMS w/wo Catatonia, Lead pipe rigidity

Symptoms of NEMS

Tx for NEMS

Restart DA agonist if it was held DA agonists (bromocriptine, amantadine) may also be useful In severe cases consider dantrolene

Tx for thyroid storm

Beta-Blockers, Propylthialuracil (PTU), Methimazole, Iodide, Steroids

Tachycardia, diarrhea, pain, jaundice, Gradual onset metabolic acidosis, Gradual hypercarbia, No muscle rigidity, Decreased CPK Levels, No myoglobinuria,

Symptoms of Thyroid storm

Longstanding untreated/undertreated hyperthyroidism (Grave's dz), TMG, Toxic Adenoma, Elevated FT3/T4

Trigger of Thyroid storm

Excessive release of 5H5, usually d/t combination of serotogenic meds, rarely with 1

Serotonin syndrome

Pharmacogenetic disease, mutation in ryr1/ryanodine receptor (Autosomal dominant)

Malignant hyperthermia

Onset of MH

30 min to 24 hrs

Onset of thyroid storm

<12 Hours

Onset of NEMS

1-3 days after starting med or after dose change

Triggered by Succinylcholine or Volatile anesthetics

MH Malignant HYperthermia

Triggered by Antidepressants: SSRI, MAOIs, SNRI, stimulants- cocaine, meth, MDMA, Triptans, Opioids, lithium, valproate, ondansetron, metoclopramide (Reglan)

Serotonin syndrome

Rigidity, Hypercarbia, Rapid increase in core temp 1c/10 min, Muscle rigidity persists despite NMBA

Symptoms of Malignant Hyperthermia

Slow continuous horizontal eye movements (OCULAR CLONUS) Diagnosis is based on either Hunter Criteria (Se84% Sp97%) or presence of Sternback criteria (Se75 Sp96%

Symptoms of Serotonin syndrome

Tx for MH

Stop triggering agent, Call for help, increase FiO2, increase MV, Dantrolene/Ryanodex

Tx for Serotonin syndrome

Cyproheptadine

Tx for Thyroid storm

Beta-Blockers, Propylthialuracil (PTU), Methimazole, Iodide, Steroids

Processing of endogenous opioids occurs where?

Pituitary gland

1st order synapse of spinothalamic tract neurons Multiple opioid receptors found both pre- and post-synaptically μ and κ receptor types

Substantia Gelatinosa

May increase dosing needs 35-fold Typically happens over weeks to months Develops to analgesia, sedation, and respiratory depression

Tolerance

Increasing doses of opioid will reduce MAC

By up to 80%

Opioids have potential to cause

neuroexcitatory phenomena Not often clinically seen Seizures have been reported

Complex interaction of spinal descending inhibitory pathways Not always related to temperature, but can be Can increase cardiac workload remarkably

Post-op Shivering

What percentage of patient's shivering can be treated by meperidine?

70-80%

Alternative med to meperidine for post-op shivering

Tramadol

Common side effect of all opioid analgesics Even produced by non-histamine releasing opioids Reversed with naloxone Mixed agonist/antagonist can be used to preserve some analgesic activity while temporizing itching (nalbuphine and butorphanol)

Pruritis

Depress mucocilliary flow of upper airways and blunted upper airway reflexes – Ideal for induction, not post-op

Opioids

In the presence of B-blockers or CCB, opioids can exacerbate

conduction delays

Peripherally restricted antagonist reverses GI side effects

Methylnaltrexone

Which approaches should you consider when anesthetizing a opioid-dependent patient? Multi-modal analgesia Regional anesthesia Rapid Sequence Induction Infection Precautions All of the Above

All of the above

Kidney plays key role in extrahepatic metabolism 10% to M6G which is more active μ agonist Renal dysfunction can lead to adverse effects

Morphine conjugated primarily to M3G in liver

Significant first pass uptake by lungs, ~75% Highly protein bound at 80% Large volume of distribution Metabolites appear ~ 1.5 minutes after injection

Fentanyl

Ester linkage with plasma hydrolysis Not affected by liver or hepatic function No active metabolites

Remifentanil

Body weight to use for opioid dosing

Lean body mass

Morphine and meperidine with large clinical implications Morphine active metabolites Meperidine with toxic metabolites - seizures

Renal failure

Effects rare in OR except with liver transplant Decreased P450 function, decreased blood flow, and decreased protein binding

Hepatic Failure

Half as potent as morphine High oral:parenteral ratio CYP 2D6 converts to morphine Ultra-rapid metabolizers Black Box warning Good anti-tussive effects

Codeine

Stigmatized, but clinical revival underway Equivalent potency to morphine Slow onset and long duration of action μ agonist with NMDA blocking properties Plasma half life is 13-100 hours

Methadone

Synthetic analog of codeine μ- receptor primarily, but also δ and κ opioid Also blocks serotonin and norepinephrine reuptake 0.1-0.2 the potency of morphine Less respiratory depression and GI effects Ex: Often seen in elderly patients with mild pain – Avoid side effects

Tramadol

κ – opioid and weak μ- agonist or antagonist 5-8 times potency of morphine Ceiling effect on respiratory depression Duration similar to morphine Plasma half life 2-3 hours Ex: Obstetrics

Butorphanol (Stadol)

Binds μ- as well as κ- and δ- opioid receptors Antagonist at the mu and agonist at kappa Limited analgesia, respiratory depression, and sedation Can be used in conscious sedation, analgesia, or chronic pain Ex: reverses epidural opioid pruritis without eliminating analgesia

Nalbuphine

Pure opioid receptor antagonist (all subtypes) Opioid reversal can produce pain, rapid awakening from opioid overdose, and sympathetic activation Reports of pulmonary edema, sympathetic surge with hypertension and cardiovascular stress

Naloxone

Pure opioid antagonist (mu, delta, kappa) Plasma half life 8-12 hours Narcotic dependent/abstinence desired Reverse pruritis, nausea, vomiting from neuraxial morphine

Naltrexone

Will remain in CSF longer Delayed onset, long duration of action Will spread in CSF, covering more dermatomes, and higher central sites More side effects, including respiratory depression May see early and later onset respiratory depression

Hydrophillic (Morphine, Hydromorphone)

Migration from CSF is rapid Epidural effects will be localized dermatomally Similar to systemic dosing Low doses produce fewer systemic side effects

Lipophillic (Fentanyl/Sufentanil)

Mediator of immediate allergic and inflammatory reactions 🞄 Urticaria 🞄 Only modest role in anaphylaxis Signal for gastric acid secretion Neurotransmitter and neuromodulator Role in immune functions and chemotaxis of white blood cells

Histamine

Local tissue vasodilation and leakage of plasma – Causes red flare & swollen wheal Mediators of acute inflammation (complement, C- reactive protein) and antibodies leak out Activates chemotactic attraction for inflammatory cells

Allergic rxn Histamine

Mast cell degranulation occurs when antigen binds to IgE on mast cell surface Mediates immediate (type I) allergic rxns

Histamine storage and release

Certain drugs can displace histamine from its bound form within cells –

morphine, curare, atracurium

Presynaptic modulation of release of neurotransmitters in CNS

Powerful stimulant of sensory nerve endings, esp. for pain and itching Modulation of appetite and satiety

H1, H3

Direct vasodilation 🞄 Decreased systolic and diastolic BP 🞄 Reflex tachycardia

Bronchoconstriction 🞄 Worsened response in asthmatics

Can cause contraction (e.g. if pregnant pt has anaphylaxis, spontaneous abortion may occur)

Histamine

Gastric acid stimulant

Receptor knockout mice show increased food intake, decreased energy expenditure, obesity and insulin resistance

Mast cell stabilizers – prevent degranulation

Cromolyn and nedocromil

May be useful in sleep disorders, narcolepsy, obesity, and cognitive and psychiatric disorders

H3 Selective agents

May have use in chronic inflammatory conditions, such as asthma

H4-Selective agents

Synthesized from tryptophan Precursor for melatonin Locations: Enterochromaffin cells of GI tract (90%) Platelets-aggregation Brain-Neurotransmitter

Serotonin

5-HT1A agonist drug in clinical trials, may have antinociceptive action while reversing opioid-induced respiratory depression. Variable efficacy

Reptinotan

Vomiting reflex

5-HT3 receptors in GI tract and vomiting center in the medulla (chemotactic trigger zone), especially that caused by chemical triggers such as chemotherapy drugs

Chemoreceptor reflex (Bezold-Jarisch reflex)

5-HT3-sensitive vagal nerve endings in the coronary vasculature, stimulation causes bradycardia (vagal) and hypotension (decreased CO due to low HR)

Selective MT1 and MT2 agonist 🞄 Approved for medical treatment of insomnia

Ramelteon,Tasimelteon-Uncommon

Selective MT1 and MT2 agonist and 5-HT2C antagonist 🞄 Approved for treatment of depression in Europe

Agomelatine

Direct vasoconstriction, esp in pulmonary & renal vessels Contraction of smooth muscle

5HT2

Long-Term serotonin exposure can lead to

subendocardial fibroplasia and electrical malfunction in the heart

Stimulates ganglion cells of enteric nervous system – causes increased ACh release 🞄 Increased tone and peristalsis 🞄 Severe diarrhea seen in carcinoid syndrome

5HT4

Intraocular pressure reduced by _____agonists in animal models of glaucoma

5HT2A agonists

Extreme serotonergic activity in the CNS May see agitation, tachycardia, skeletal muscle contractions, hyperactive reflexes, hyperthermia

Serotonin syndrome-Rare, iatrogenic

🞄 Work by inhibiting the release of vasodilating peptides 🞄 Effective during prodrome, less so once symptomatic 🞄 Can precipitate coronary vasospasm – contraindicated in pts with CAD

5-HT1B/1D agonists Tx for Migraines triptans”, eg. sumatriptan

5-HT1A agonist Non-benzodiazepine anxiolytic

Buspirone

Appetite suppressant, withdrawn due to cardiac valve toxicity

Dexfenfluramine (ingredient of fen-phen)

5-HT4 agonist GERD and GI motility disorders

Cisapride

5-HT4 partial agonist Irritable bowel syndrome

Tegaserod

Block reuptake of the neurotransmitter Major depression and other psychiatric disorders

SSRIs

5-HT2 antagonist & alpha blocker Antihypertensive used to treat pheochromocytoma

Phenoxybenzamine

– 5-HT2 antagonist Also antimuscarinic & potent H1 blocker (antihistamine) Causes sedation Blocks smooth muscle effects of 5-HT and histamine Uses: Carcinoid, cold-induced urticaria, serotonin syndrome

Cyproheptadine

5-HT2 antagonist Strong platelet aggregation inhibitor Also, strong α1 blocker – hypotensive effect Only approved in Europe to treat HTN & vasospasm

Ketanserin

5-HT3 antagonists Use in prevention of N/V assoc with chemotherapy and general anesthesia

Ondansetron -"Setrons"

Burning sensation in gangrenous limbs

St. Anthony's fire

Muscle spasms due to convulsive symptoms

St. Vistus' Dance

Dopamine receptor agonists in the pituitary suppress

prolactin release

-Dopa receptor agonist-prolactinoma-excess prolactin w galactorrhea-excess breast milk, cabergoline, pergolide (highly selective)

Bromocriptine

(abnormal involuntary movements) related to dopamine receptor

Extrapyramidal symptoms Bromocriptine

Strong vasoconstrictor at small doses 🞄 Partial agonist at alpha adrenergic & 5-HT2 receptors 🞄 Binds w high affinity and slow dissociation 🞄 Not easily reversed by alpha antagonists, serotonin antagonists or combinations of both Nitric oxide/nitro-prusside

Ergot Alkaloids

most selective for uterine smooth muscle

Ergonovine (methylergonovine, methergine

highly specific for migraine pain, not analgesic for any other condition 🞄 Must be given during prodromal period as an abortive agent 🞄 Often given along with caffeine to facilitate absorption 🞄 Strict maximum doses due to prolonged vasoconstriction

Ergotamine

Increased prolactin secretion is associated with tumors of the pituitary gland and use of the centrally acting dopamine antagonists (esp. D2 antagonists used as antipsychotics)

Hyperprolactinemia

Treatment for hyperprolactinemia

Bromocriptine - agent of choice

can be associated with the surge in prolactin seen a the end of pregnancy

Heart Failure Cabergoline has been used successfully to treat

Bromocriptine & pergolide can lead to cardiovascular toxicity if used for this purpose

Suppression of physiologic lactation

2nd line agent after oxytocin 🞄 Contraindicated in CAD and HTN disorders (especially preeclampsia)

Methylergonovine (methergine) 0.2mg IM

Most common Diarrhea, nausea, vomiting More serious Prolonged vasospasm 🞄 Refractory to most vasodilators

Ergot alkaloid toxicity

Increase cAMP

D1 Receptor family

Decrease cAMP Increase K+ Currents Decrease voltage-gated Ca2+ currents

D2 Receptor family

Major dopamine pathways in the brain

Mesocortical Mesolimbic Nigrostriatal Tuberoinfundibular

Precursors include amino acids phenylalanine and tyrosine

Dopamine

Rate-limiting step to dopamine synthesis

Rate limiting step is catalysis by tyrosine hydroxylase to L- DOPA

Does dopamine or L-Dopa cross the BBB

L-DOPA readily crosses the BBB, whereas dopamine does NOT

Primary mechanism of termination of DA Action

Reuptake

Increases natriuresis (excretion of Na+) Can increase renal blood flow and glomerular filtration Proven not to be renal protective

Dopamine

Primary inhibitory regulator of prolactin secretion

Dopamine

modulate release of NE and epinephrine

D1 and D2 Receptors

tonic inhibition(tone, regularity of excretion) of epinephrine release from chromaffin cells of adrenal medulla

D2 Receptor

high frequency DA release promotes release of catecholamines from adrenal medulla

D1 Receptor

Parkinsonism, Tourette’s, bipolar, depression, schizophrenia, ADHD, addiction/substance abuse

Dopamine disorders

DA receptor antagonists used to treat

Schizophrenia

Rapidly metabolized by liver by glucuronidation Inactive metabolites excreted through kidneys Plasma clearance exceeds hepatic blood flow. How? Metabolism must be happening outside of the liver! Lungs may account for up to 30% elimination of a bolus dose Inhibitor of CYP p450

Propofol

Clinical effects are shorter than elimination times

Redistribution effect

Hypnotic actions mediated via GABAA receptor increases in chloride current Also: NMDA and α-2 adrenoreceptors

Propofol

Hepatically metabolized Oxidation (and some by N-dealkylation, desulfuration)

Barbiturates

Increased duration of chloride channel opening

Barbiturates

Barbiturates are contraindicated in

Acute Intermittent Porphyria AIP

Genetic syndrome Impaired synthesis of heme Mutation in porphobilinogen deaminase  accumulation of porphobilinogen Porphobilinogen = toxic to neurons  CNS and PNS effects

Acute intermittent porphyria AIP

Barbiturates increase production of porphyrins via stimulation of

aminolevulinic synthase

Does not really act on GABAB (site for baclofen) GABAA receptor subtypes selective for actions α1 subtypes : sedation, amnesia, anti-convulsant α2 subtypes: anxiolysis and muscle relaxation Increased frequency of ion channel opening

Benzodiazepines

receptor is a chloride channel

GABA-A

an endogenous ligand inhibitory neurotransmitter found diffusely in the CNS

GABA

Agonists alter conformation of the ion channel proteins so that GABA binding is enhanced

Benzos

Caution with Flumazenil

Re-Sedation

Ketamine metabolism

Hepatic microsomal enzymes Active metabolites with 20-30% activity Whole body clearance = hepatic blood flow Cardiac output dependent

Ketamine neuro effects

CNS excitation effects Increases CMRO2, CBF, and ICP CBF in excess of CMRO2 CO2 responsiveness intact, hypocarbia reduces ICP

Catecholamine depleted patients may show adverse hemodynamic consequences with what drug

Ketamine

Contraindications to Ketamine

High ICP Eye injury or inc. IOP Ischemic HD Psych disorders-schizophrenia High-Risk post-op delirium

Is ketamine safe for intrathecal or epidural delivery?

Imidazole derivative Water insoluble, suspended in propylene glycol (or as emulsion in Europe) Not known to cause precipitation issues

Etomidate

Liver metabolism by ester hydrolysis Inactive metabolite

Etomidate metabolism

Produces EEG changes similar to barbituates

Etomidate

Reduces CBF and CMRO2 Does not alter MAP, CPP is maintained

Etomidate

Adrenocortical suppression after single dose Pathway to cortisol and aldosterone synthesis

Etomidate

Reversible inhibition of the enzyme 11β-hydroxylase Relatively minor effect on 17α-hydroxylase

Etomidate Steroid synthesis pathway

Sedation at locus caeruleus and analgesia in spinal cord Act via natural sleep pathways to cause sedation Hallmark is easy to arouse, but sedated when undisturbed Analgesia via α2 receptors Narcotic sparing, up to 50% reduced usage May be sedation-related more than anti-nociceptive

Dexmedetomidine

Hemodynamic effects of Precedex

decreased heart rate decreased systemic vascular resistance indirectly decreased myocardial contractility, cardiac output, and systemic blood pressure

(HR x SV) x PVR

CO x PVR

Arterial BP

Side effect of thiazide diuretic

Decrease K+ Hypokalemic metabolic alkalosis Gout flares

Side effect of Loop Diuretics

Decreased K+ Hypokalemic metabolic alkalosis Increased urine output Ototoxicity

Side effects of K+- SParing diuretics

Increased urine output Hyperkalemia Erectile dysfunction Gynecomastia

Most common side effects of diuretics

: increased urine output --> decreased intravascular volume and hypokalemia

Side effets of Ca2+ Channel blockers

Reflex tachycardia

Selectively work on arterial smooth muscle

Ca2+ channel blockers

Primarily work on cardiac myocytes, very minor vasodilator Powerful myocardial depressant, mostly used as an anti-arrhythmic

Alternative CCBs Verapamil Ditiazem

inhibit calcium channels and therefore decrease intra-cellular calcium, subsequently decreasing actin/myosin interaction therefore causing decreased muscle contraction

Calcium channel blockers

Amlodipine, nifedipine, clevidipine, nicardipine

Dihydropyridines

: binds to guanylyl cyclase converting GTP to cyclic-GMP which then activates Protein Kinase G, which decreases Ca++ release from the sarcoplasmic reticulum

Hydralazine

Side effects of hydralazine

Reflex tachycardia Orthostatic hypotension Can cause drug mediated lupus (chronic use)

Does hydralazine primarily work on arteries or veins

Arteries

Low dose --> venous dilation --> decrease pre-load High dose --> arterial dilation --> decrease SVR

Nitroglycerin

Activates guanylyl cyclase which will convert GTP to cGMP therefore decreasing intracellular Ca++

Nitric oxide Vasodilator

works on both arterial and venous systems, so the vasodilation will decrease both SVR and pre-load

Nitroprusside

Synergistic effect with PDE inhibitors and alpha blockers

Nitric oxide vasodilators

selectively inhibit a1 adrenergic receptor causing vasodilation Can also be used in prostate hyperplasia

Alpha blockers

Side effect of Alpha blockers

Reflex tachycardia

selectively inhibit B1 adrenergic receptors causing decreased HR and SV and therefore CO Decrease in HR will also increase myocardial perfusion and decrease myocardial O2 consumption making it a good choice in CAD, AS, HOCM, CHF

Beta Blockers

Side effects of Beta blockers

Inability to increase CO during exercise or decompensated heart failure Bradycardia

antagonizes B:a in a 3:1 ratio Primarily used in hypertensive emergency, pheo's, and anesthesia

Labetalol

antagonizes B:a in a 10:1 ratio Ratio of selectivity can vary patient to patient Reduces mortality in heart failure Excellent synergistic treatment for HF w/ HTN

Carvedilol

inhibit norepinephrine via a2 receptors within the central nervous system to indirectly inhibit peripheral adrenergic receptors Rarely used for outpatient HTN because of the sedative effects

Centrally-Acting Sympathiolytics

inhibits norepinephrine synthesis in the CNS Prodrug, metabolized in the brain into active form. Really only used in pregnancy

Alpha-Methyldopa

Side effects of centrally-acting sympathiolytics

Sedation Bradycardia

inhibit angiotensin converting enzyme therefore preventing the conversion of AT-1 to AT-2 Also inhibit increased aldosterone production in response to Na+ loss As a result, patients can have a minor increase in K+ which may become problematic in ESRD

ACE inhibitor

Particularly effective in patients with decreased glomerular blood flow The kidneys will increase renin production as a result of decrease renal blow Common in diabetic nephropathy

ACE inhibitor

Some patients can have profound angioedema that may compromise the airway and become life threatening Cough Significant hypotension when starting, usually start low and uptitrate Especially in patients with high renin levels or concurrent diuretic use and low circulating volumes

Side effects of Ace inhbitors

antagonist of angiotensin receptor therefore competitively inhibiting AT-2 causing vasodilation and decreased aldosterone synthesis Slow onset of action, full antihypertensive effects may take weeks Particularly effective in patients with decreased

Angiotensin Receptor Blockers-ARBs

Angioedema and cough, but less common than ACE-I Mild hyperkalemia Not as effective in African-Americans*

Side effects of ARBs

We should never use what drugs in decompensated heart failure

Beta Blockers

PDE inhibitor that increased myocardial contractility and can decrease SVR via vasodilation

Milrinone

Issues with milrinone

Long half-life can be potentially problematic

B2 agonist increasing myocardial contractility, can help with temporizing cardiac output while other conditions are addressed

Dobutamine

inhibits Na/K-ATPase and increases intracellular Ca++ in cardiac myocytes resulting in increased contractility and SV Parasympathetic effects on HR Often used in A-fib/A-flut

Digoxin

Alternative CCBs (verapamil, diltiazem) should be avoided in CHF because

their myocardial depressants effects will not be tolerated

Things that increase O2 Demand

Tachycardia Increased contractility Increased myocardial thickness (more tissue)

Things that influence O2 Delivery

Coronary blood flow Time to perfusion Oxygen availability

Imbalance between myocardial O2 consumption and O2 delivery

Ischemic Heart disease

venodilation to decrease pre-load and contractile work, dilation of coronary arteries Do not give in RV failure as they are pre-load dependent

Nitrates

Drug is moved from access to its active site

* Distribution Clearance-

Oxidation/Reduction/Hydrolysis. Forms an active site on the drug molecule

Modification (Phase 1 of metabolizing a drug)

the true detoxifying pathway that creates a polar conjugate for excretion

Conjugation Phase 2 of metabolizing a drug

Phase 3 of Metabolizing a drug

Excretion

Pharm I Final Review Flashcards

(485 cards)