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Pharmacology - Pharmacologie - Farmacologia - Farmacología

SIMPLE CONTENTS 
NEWS & UPDATES
MAPS
OVERVIEW
PRINCIPLES, PHARMACOKINETICS, PHARMACODYNAMICS
TOXICITIES, ADVERSE EFFECTS, ABUSE
PNS, AUTONOMIC, NEUROMUSCULAR, OCULAR
CNS,
RENAL
CARDIOVASCULAR
REFERENCES

TOC
DETAILED CONTENTS
NEWS & UPDATES
MAPS
OVERVIEW

PRINCIPLES
PHARMACOKINETICS_&_PHARMACODYNAMICS
TOXICOLOGY
ABUSE

PERIPHERAL NERVOUS
AUTONOMIC
CHOLINERGIC
CHOLINOMIMETIC AGENTS (DIRECT AGs,  INDIRECT AGs (ANTICHOLINESTERASES), ANTICHOLINESTERASE POISONING) & NICOTINIC AGs
MUSCARINIC ANTAGs (ATROPINE) & NICOTINIC ANTAGs
SKELETAL MUSCLE RELAXANTS, NEUROMUSCULAR BLOCKING DRUGS, MALIGNANT HYPERTHERMIA,
NORADRENERGIC
SYMPATHOMIMETICS (DIRECT, INDIRECT, PHYSIOLOGIC EFFECTS)
SYMPATHOLYTICS (α2-AGONISTS), α-BLOCKERS, β-BLOCKERS, PHOSPHODIESTERASE INHIBITORS

OCULAR, GLAUCOMA
EAR

AUTACOID_&_INFLAMMATION
SEROTONIN
PURINES
HISTAMINE
EICOSANOIDS
PEPTIDES & PROTEINS
CANNABINOIDS
NITRIC OXIDE

CENTRAL_NERVOUS
LOCAL ANESTHETICS
GENERAL ANESTHETICS
ANALGESIC
ANTIEPILEPTIC
NEURODEGENERATIVE PARKINSON
ANTIPSYCHOTIC
ANXIOLYTIC & HYPNOTIC/SEDATIVE
ANTIDEPRESSANT
PSYCHOACTIVE

CARDIOVASCULAR
ARRHYTHMIAS
VASODILATORS
ANGINA PECTORIS

RENAL

BLOOD
ATHEROSCLEROSIS & LIPOPROTEIN
HEMOSTASIS & THROMBOSIS
HEMOPOIETIC & ANEMIA

SKIN
MUSCULOSKELETAL
GENITO-URINARY
GASTROINTESTINAL
PULMONARY

ENDOCRINE
DIABETES MELLITUS
PITUITARY & ADRENAL CORTEX
THYROID
BONE
REPRODUCTIVE

ANTIMICROBIAL
ANTIBACTERIAL
ANTIFUNGAL
ANTIVIRAL
ANTIHELMINTH
ANTIPROTOZOAL

CANCER
IMMUNE

FLUID & ELECTROLYTE BALANCE
HERBALS
DISINFECTANTS & ANTISEPTICS

EMERGENCY

REFERENCES

TOC
MAPS

TOC
OVERVIEW
(Minimum Vital) V1 PDF
(Rosenfeld BRS 6e Contents) V1 PDF (Lerchenfeldt BRS 7e 2019 Contents) V2 PDFs
(Jacob NMS contents) V1 PDF
(Tellingen Phenomenology Contents) V1 JPG  Archive
(Rang 9e 2019 Contents) V1 PDF
(Whalen LIR 7e Contents) V1 PDF
(Page Crash Course 4e Contents) V1 PDF
(Wikipedia ATC) V1 PDF
(Neal Glance 9e 2020 Contents) V1 PDF
(Weiss HY 2009 Contents) V1 PDF

TOC
PRINCIPLES

TOC
PHARMACOKINETICS & PHARMACODYNAMICS

OVERVIEW
(Page Crash Course 4e 2012) V1 PDF
(Weiss HY 3e 2009, Le FA BS 3e 2017 & Le FA 1 32e 2022) V1 PDF
(Neal Glance 9e 2020) V1 JPG 1 2 ADE 3 M 4
(Jacob NMS Contents) V1 JPG
(Lerchenfeldt BRS 7e 2019 Contents) V1 PDF

Pharmacokinetics describes what the body does to the drug
Pharmacodynamics describes what the drug does to the body
ADMET - Absorption, Distribution, Metabolism, Excretion, Toxicity

TOC
PHARMACOKINETICS
(Jacob NMS Contents) V1 JPG

CONTENTS

METRICS
Loading dose - Volume of distribution (Initial) - Rate of infusion - Onset of action - Biological half-life - Plasma protein binding - Bioavailability
LADME
(L)ADME : (Liberation) - Absorption - Distribution - Metabolism - Excretion (Clearance)
Compartment - Bioequivalence
GENERAL
DRUG PERMEATION
ABSORPTION
BIOAVAILABILITY
DISTRIBUTION
BIOTRANSFORMATION : DRUG METABOLISM
EXCRETION
KINETIC PROCESSES

END OF CONTENTS

GENERAL
PHARMACOKINETICS IS THE FATE OF DRUGS WITHIN THE BODY
IT INVOLVES DRUG :
ADME - Absorption, Distribution, Metabolism, Excretion

DRUG PERMEATION
Passage of drug molecules across biological membranes
PROCESSES OF PERMEATION :
PASSIVE DIFFUSION
Characteristics
Passive diffusion driven by concentration gradient
Aqueous diffusion
Aqueous diffusion via pores in cell membranes
Lipid diffusion
High lipid-to-oil PC favors lipid diffusion
Most drugs are absorbed by passive diffusion
CARRIER-MEDIATED TRANSPORT
Transporters are being identified and characterized that function in movement of molecules into (influx) or out (efflux) of tissues
Carrier-mediated transport is mediated by influx and efflux transporters
Numerous transporters such as the ABC (ATP-binding cassette) family including P-glycoprotein or multidrug resistant-associated protein type 1 (MDR1) in the brain, testes, and other tissues play a role in excretion as well as in drug-resistant tumors
Characteristics of carrier-mediated transport
Drug competition at transporters is a site of drug-drug interactions
Active transport
Active transport requires energy to move molecules against concentration gradient
Facilitated diffusion
Sugars, amino acids, purines, pyrimidines and L-dopa by facilitated diffusion
PINOCYTOSIS/ENDOCYTOSIS/TRANSCYTOSIS

ABSORPTION
Absorption involves the process by which drugs enter into the body
FACTORS THAT AFFECT ABSORPTION :
SOLUBILITY IN FLUIDS BATHING ABSORPTIVE SITES
CONCENTRATION
BLOOD FLOW
Blood flow to site of absorption important for speed of absorption
Drugs given intramuscularly are absorbed much faster than those given subcutaneously
ABSORBING SURFACE
Absorbing surface of intestine is much greater than stomach
CONTACT TIME
pH
Weak organic acids are un-ionized (lipid soluble form) when protonated
Weak organic base are ionized (water soluble form) when protonated
Weak organic acids pass through membranes best in acidic environments
Weak organic bases pass through membranes best in basic environments

BIOAVAILABILITY (F)
Bioavailability depends on the extent of an orally administered drug getting into the systemic circulation
FIRST-PASS METABOLISM
Sublingual nitroglycerin avoids first-pass metabolism, promoting rapid absorption
DRUG FORMULATION
Slow release formulations are designed to extend the time it takes a drug to be absorbed so that the drug can be administered less frequently
BIOEQUIVALENCE
Bioequivalence depends on both rate and extent of absorption
ROUTE OF ADMINISTRATION
Both pharmacokinetics and pharmacodynamics depends on the drug’s route of administration
Transdermal (across the skin)
Across a mucous membrane
Sublingual
Rectal
Vaginal
Enteral (oral) administered drugs are subject to first-pass metabolism
Parenteral (by injection)
Subcutaneous
Intramuscular
Intravenous (IV) / intra-arterial - Drugs administered intravenously can reach the systemic circulation and target organ before modification
by the liver
Intrathecal (into the subarachnoid space)

DISTRIBUTION
Distribution is the delivery of a drug from systemic circulation to tissues - brain testes
Drugs may distribute into certain body compartments
APPARENT VOLUME OF DISTRIBUTION (Vd)
Large High when drug concentrated in tissue - All tissues including fat - Small lipophilic molecules, especially if bound to tissue protein
Medium - ECF - Small hydrophilic molecules
Low when drug remains in plasma - Intravascular - Large/charged molecules; plasma protein bound
FACTORS THAT AFFECT DISTRIBUTION
Plasma protein and tissue binding, gender, age, amount of body fat, relative blood flow, size, and lipid solubility
Plasma protein binding
Plasma protein binding favors smaller Vd
Sites of drug concentration
Redistribution
Thiopental’s anesthetic action is terminated by drug redistribution
Ion trapping
Weak organic acids are trapped in basic environments
Weak organic bases are trapped in acidic environments
Sites of drug exclusion (places where it is difficult for drugs to enter)
L-Dopa is converted dopamine after transport across BBB

BIOTRANSFORMATION : DRUG METABOLISM
primary site liver, primary goal drug inactivation - Diseases that affect the liver influence drug metabolism
Geriatric patients lose phase I first
Patients who are slow acetylators have ↑ adverse effects from certain drugs because of ↓ rate of metabolism (eg, isoniazid)
Drugs can be metabolized by either or both phase 1 and phase 2 reactions
These reactions serve to bioactivate or deactivate substances, and do not have to take place sequentially (eg, phase I can follow phase II, or take place as a single reaction)
PRODUCTS OF DRUG METABOLISM
Valacyclovir (good oral bioavailability) is a prodrug to acyclovir (treats herpes)
LIPOPHILIC DRUGS → PHASE I BIOTRANSFORMATION (OXIDATION, REDUCTION, HYDROLYSIS)
Many oxidations by microsomal cytochrome P-450 enzymes - (predominantly CYP450-dependent)
→ Slightly polar metabolite (active or inactive) Reactive oxygen metabolites
POLAR DRUGS (water-soluble) → PHASE II BIOTRANSFORMATION
General
Phase II are synthesis reactions; something is added to the molecule
Conjugation reactions (e.g., glucuronidation, sulfation) usually make drugs more water soluble & more excretable
Methylation & acetylation reactions often make drugs less water soluble
→ Very polar, hydrophilic metabolite (except acetylated metabolite)
→ Excretion Serum (urine, sweat), bile (stool)
Glucuronidation
Newborn babies have very low enzyme glucuronysyltransferase activity, cannot eliminate chloramphenicol -> "Gray baby" syndrome
Sulfation
Methylation & acetylation reactions
PHASE III DISPOSITION PROCESSES
Phase III of disposition; influx and efflux transporters
DRUG INTERACTIONS
Inducers of cytochrome P-450
Many anticonvulsants induce cytochrome P-450 enzymes but valproic acid inhibits these enzymes
Inducers of drug metabolism: chronic alcohol, phenobarbital, phenytoin, rifampin, carbamazepine, St. John’s wort
Inhibitors of cytochrome P-450
Inhibitors of drug metabolism: acute alcohol, cimetidine, ketoconazole, erythromycin
Inhibitors of intestinal P-glycoprotein transporters
GENETIC POLYMORPHISMS
Influence the metabolism of a drug, thereby altering its effects
Pharmacogenomics
Personalized medicine uses patient’s genotype or gene expression profile to tailor medical care to an individual’s needs
Personalized medicine means adjusting dose according to individual’s phenotype
Drugs recommended by the U.S. Food and Drug Administration (FDA) for pharmacogenomic tests
Codeine has to be converted by CYP2D6 to morphine in brain to be an active analgesic
FDA recommends phenotyping for: warfarin, isoniazid, mercaptopurine, irinotecan, codeine
REACTIVE METABOLITE INTERMEDIATES
Acetaminophen overdose common choice for suicide attempts

EXCRETION
Excretion is the amount of drug & drug metabolites excreted by any process per unit time
EXCRETION PROCESSES IN KIDNEY
Glomerular filtration rate
A drug with a larger Vd is eliminated more slowly than one with a smaller Vd
Tubular secretion
Probenecid inhibits the tubular secretion of most beta-lactam antimicrobials
Excretion by tubular secretion is rapid, but capacity limited
Passive tubular reabsorption
Weak organic acids are excreted more readily when urine is alkaline
Weak organic bases areexcreted more readily when urine is acidic
Urine pH and drug elimination
Ionized species are trapped in urine and cleared quickly - Neutral forms can be reabsorbed
pKa
EXCRETION PROCESSES IN THE LIVER - Biliary Excretion
Size of molecule determines if a compound is more likely to be actively secreted in kidney (small molecular weights) or liver (larger molecular weights)
Large polar compounds or their conjugates (molecular weight >325) may be actively secreted into bile
These large drugs often undergo enterohepatic recycling, in which drugs secreted in the bile are again reabsorbed in the small intestine
Antimicrobials can disrupt enterohepatic recycling
OTHER SITES OF EXCRETION

KINETIC PROCESSES
The therapeutic utility of a drug depends on the rate and extent of input, distribution, and loss
CLEARANCE KINETICS
Clearance (CL)
Clearance is the volume of plasma from which drug is removed per unit of time
Total body clearance
Cl = Rate of elimination of drug / Plasma drug concentration
Know formula Cl = Vd x Kel
Renal clearance
ELIMINATION KINETICS
Zero-order kinetics
Zero order clearance occurs when clearance mechanisms are saturated: high drug doses
Zero-order: dose- dependent pharmacokinetics
First-order kinetics
Constant half-life (t1/2) with first order kinetics
First-order: dose- independent pharmacokinetics
Know formula t1/2 = 0.693/Kel
Repetitive dosing kinetics; IV bolus or oral
Css occurs when input equals output
It takes 4 to 5 half-lives to reach steady state
Maintenance dose depends on clearance
Repetitive dosing kinetics; intravenous infusion
Amount of drug in body at any time:
Know formula Xb = Vd x Cp

Dosage Calculations
Loading Dose
Maintenance Dose

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PHARMACODYNAMICS
(Jacob NMS Contents) V1 JPG

LIGAND (BIOCHEMISTRY)
Excitatory
Agonist - Endogenous agonist - Irreversible agonist - Partial agonist - Superagonist - Physiological agonist
Inhibitory
Antagonist - Competitive antagonist - Irreversible antagonist - Physiological antagonist - Inverse agonist - Enzyme inhibitor
other
Drug - Neurotransmitter - Agonist-antagonist - Pharmacophore

CONTENTS

Activity at receptor
Mechanism of action - Mode of action - Binding - Receptor (biochemistry) - Desensitization (medicine)
Other effects of ligand
Selectivity (Binding, Functional) - Pleiotropy (drugs) - Non-specific effect of vaccines - Adverse effect - Toxicity (Neurotoxicity)
Analysis 
Dose–response relationship - Hill equation (biochemistry) - Schild plot - Del Castillo Katz model - Cheng-Prussoff Equation - Methods (Organ bath, Ligand binding assay, Patch clamp)
Metrics
Efficacy - Intrinsic activity - Potency (EC50, IC50, ED50, LD50, TD50) - Therapeutic index - Affinity
DEFINITIONS
DOSE-RESPONSE RELATIONSHIPS
DRUG RECEPTORS
PHARMACODYNAMICALLY ALTERED RESPONSES
ADVERSE EFFECTS
FEDERAL REGULATIONS

END OF CONTENTS

DEFINITIONS
Pharmacodynamics
A drug’s pharmacodynamics relates to its receptor interactions, efficacy, potency, and toxicity
Receptor
Receptor is site that drug binds to, producing its actions
Agonist
Pharmacological antagonist
Competitive antagonist
Irreversible antagonist
Be able to distinguish reversible from irreversible binding drugs by how they affect log dose-response curves of an agonist
Partial agonist
Be able to distinguish a full agonist from a partial agonists from log dose- response curves
Graded dose-response curve
Quantal dose-response curve
Understand the difference between a graded and quantal log dose-response curve

DOSE-RESPONSE RELATIONSHIPS
OVERVIEW
PROPERTIES OF LDR CURVES
Graded response is in an individual subject
Quantal (all-or-none) response is in a population of subjects
Graded response measures degree of change; quantal measures frequency of response
TI = LD50 / ED50
MS = LD1 / ED99

DRUG RECEPTORS
Drug receptors are biologic components on the surface of or within cells that bind with drugs, resulting in molecular changes that produce a certain response

TYPES OF RECEPTORS & THEIR SIGNALING MECHANISMS

MEMBRANE RECEPTORS ARE COUPLED WITH A G PROTEIN, AN ION CHANNEL, OR AN ENZYME
G PROTEIN-COUPLED RECEPTORS (GPCRS)
GPCRs; Gs stimulates cAMP; Gi inhibits cAMP; Gq stimulates phospholipase C
cAMP activates protein kinase A
IP3 releases calcium from endoplasmic reticulum
Calcium activates Ca2+/Calmodulin kinase
DAG activates protein kinase C
LIGAND-GATED CHANNELS
RECEPTOR-LINKED ENZYMES
Growth factors signal via ligand-regulated tyrosine kinases
Cytokines signal via ligand-regulated tyrosine kinases

INTRACELLULAR RECEPTORS; INSIDE CELLS
CYTOPLASMIC GUANYLYL CYCLASE IS ACTIVATED BY NITRIC OXIDE TO PRODUCE CGMP
cGMP activates protein kinase G
NUCLEAR & CYTOSOLIC RECEPTORS
Steroid hormones, thyroid hormone, vitamin D and retinoic acid affect gene transcription via nuclear receptors
OTHER INTRACELLULAR SITES CAN SERVE AS TARGETS FOR DRUG MOLECULES CROSSING CELL MEMBRANES (E.G., STRUCTURAL PROTEINS, DNA, RNA); DRUGS USING THESE MECHANISMS INCLUDE
Most antimicrobials, antivirals, and anticancer drugs act on intracellular sites: ribosomes; DNA pathways; RNA pathways; mitochondria; folate pathways

DEGREE OF RECEPTOR BINDING
Drug affinity for a receptor is inversely proportional to the dissociation constant (KD = k–1/k1)

TERMS USED TO DESCRIBE DRUG-RECEPTOR INTERACTIONS
Be able to compare affinities, potencies, and intrinsic activities of drugs from LDR curves 
DOSE RESPONSE
       
AFFINITY

EFFICACY VS POTENCY
POTENCY Amount of drug needed for a given effect
EFFICACY (INTRINSIC ACTIVITY) Maximal effect a drug can produce

SPARE RECEPTORS

THERAPEUTIC INDEX

RECEPTOR BINDING

AGONISTS

FULL AGONIST
PARTIAL AGONIST (alone) - Acts at same site as full agonist - partial antagonists or mixed agonist-antagonists
INVERSE AGONIST

ANTAGONISTS

NONRECEPTOR ANTAGONISTS
Do not bind to receptors but inhibit the ability of the agonist to initiate its action
CHEMICAL ANTAGONIST
PHYSIOLOGIC ANTAGONIST

RECEPTOR ANTAGONISTS
Bind to either the active site or an allosteric site

ALLOSTERIC BINDING
REVERSIBLE - IRREVERSIBLE - NONCOMPETITIVE ALLOSTERIC ANTAGONIST

ACTIVE SITE BINDING
REVERSIBLE
COMPETITIVE ANTAGONIST - Can be overcome by ↑ agonist concentration
Propranolol is a competitive antagonist of epinephrine at beta-adrenergic receptors
Phentolamine is a competitive antagonist of epinephrine at alpha-adrenergic receptors
IRREVERSIBLE
NONCOMPETITIVE active site ? ANTAGONIST - Cannot be overcome by ↑ agonist concentration
Phenoxybenzamine is a noncompetitive antagonist of epinephrine at alpha-adrenergic receptors

ENZYME KINETICS
Michaelis-Menten kinetics
Lineweaver-Burk plot

PHARMACODYNAMICALLY ALTERED RESPONSES - DRUG EFFECT MODIFICATIONS

DECREASED DRUG ACTIVITY
ANTAGONISM RESULTING FROM DRUG INTERACTIONS - Antagonistic Effect of substances A and B together is less than the sum of their individual effects
Physiologic (functional) antagonism
Anaphylactic reaction is produced by release of histamine; epinephrine is the drug of choice (DOC) for treatment
Competitive antagonism
Atropine is a competitive antagonist of ACh at muscarinic receptors
Hexamethonium is a competitive antagonist of ACh at ganglionic nicotinic receptors
Tubocurarine is a competitive antagonist of ACh at neuromuscular junction nicotinic receptors
TOLERANCE DEFINITION Diminished response to the same dose of a drug over time - MECHANISMS OF TOLERANCE
Desensitization
Down-regulation
Continuous use of a beta-adrenergic agonist involves both desensitization and down-regulation of receptors
Tachyphylaxis - Tachyphylactic Acute decrease in response to a drug after initial/repeated administration
Multiple injections of tyramine in short time intervals produce tachyphylaxis

INCREASED DRUG ACTIVITY
Supersensitivity or hyperactivity
Continuous use of a beta-adrenergic antagonist causes up-regulation of receptors
Potentiation Similar to synergism, but drug B with no therapeutic action enhances the therapeutic action of drug A
Be able to depict drug potentiation, competitive antagonism, and noncompetitive antagonism from LDR curves
Physostigmine potentiates the effects of ACh
Cocaine potentiates the effects of NE
Clavulanic acid potentiates the effects of amoxicillin
Synergism - Synergistic Effect of substances A and B together is greater than the sum of their individual effects
Trimethoprim plus sulfamethoxazole are synergistic

Additive Effect of substances A and B together is equal to the sum of their individual effects
Permissive Presence of substance A is required for the full effects of substance B

DEPENDENCE
Physical dependence
Psychological dependence
Substance dependence (addiction)
Drugs that may lead frequently to addiction: alcohol, barbiturates, benzodiazepines, opioid analgesics

ADVERSE EFFECTS

TOXICITY
REFERS TO DOSE RELATED ADVERSE EFFECTS OF DRUGS
BENEFIT-TO-RISK RATIO
It is important to understand the benefit-to- risk ratio of every drug prescribed; all drugs can be harmful -> some drugs can be beneficial if administered appropriately for the right situation
OVEREXTENSION OF THE PHARMACOLOGICAL RESPONSE
ORGAN-DIRECTED TOXICITIES
Aspirin can induce ulcers
Aminoglycosides can produce kidney damage
Acetaminophen can produce fatal hepatotoxicity
Doxorubicin can produce heart failure
FETAL TOXICITY
Some drugs are directly toxic whereas others are teratogenic
Drug use should be minimized during pregnancy; some drugs are absolutely contraindicated
Directly toxic effects include
Teratogenic effects
Human teratogens: thalidomide; antifolates; phenytoin; warfarin; isotretinoin; lithium; valproic acid; fetal alcohol syndrome, anticancer drugs

DRUG ALLERGIES (HYPERSENSITIVITY)
Abnormal response resulting from previous sensitizing exposure activating immunologic mechanism when given offending or structurally related drug
Drug allergies are prominent with beta-lactam antibiotics; drugs containing sulfonamide structure; ester-type local anesthetics

DRUG IDIOSYNCRASIES
Refers to abnormal response not immunologically mediated; often caused by genetic abnormalities in enzymes or receptors; referred to as pharmacogenetic disorders
Classical drug idiosyncrasies; primaquine-induced hemolytic anemia; isoniazid-induced peripheral neuropathy; succinylcholine-induced apnea; barbiturate- induced porphyria.

FEDERAL REGULATIONS
Safety and efficacy of drugs are regulated by the U.S. Food and Drug Administration (FDA)
NOTICE OF CLAIMED INVESTIGATIONAL EXEMPTION FOR A NEW DRUG (IND)
CLINICAL TRIAL PHASES
Phase 4 picks up rare adverse effects of a drug

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INTERACTIONS & THEIR MECHANISMS - PHARMACOKINETIC INTERACTIONS - PHARMACODYNAMIC INTERACTIONS
(Jacob NMS Contents) V1 JPG

TOC
TOXICOLOGY & DRUG OF ABUSE - TOXICITIES & ADVERSE EFFECTS
(Neal Glance 9e 2020) V1 JPG Poison 1 AE 2
(Jacob NMS Contents) V1 JPG
(Lerchenfeldt BRS 7e 2019 Contents) V1 PDF

CONTENTS

GENERAL PRINCIPLES OF TOXICOLOGY
SYMPTOMS & TREATMENT OF ACUTE POISONING
TERATOGENIC EFFECTS OF SPECIFIC DRUGS
DEPENDENCE & DRUGS OF ABUSE

END OF CONTENTS

GENERAL PRINCIPLES OF TOXICOLOGY

DEFINITIONS
Toxicology is the study of the hazardous effects of chemicals, including drugs, on biologic systems
Toxicity is a reflection of how much, how fast, and how long an individual is exposed to a poison
Paracelsus, the father of toxicology, wrote: “All things are poison and nothing is without poison, only the dose permits something not to be poisonous.”

PRIMARY DETERMINANTS OF TOXICITY
Dose and dose rate
Duration of exposure
Route of exposure

FACTORS THAT AFFECT TOXICITY
Large overdoses of chemicals often switch kinetics from first to zero-order because
BIOTRANSFORMATION
GENETIC FACTORS
Polymorphic metabolism (toxicokinetics)
Polymorphic targets (toxicodynamics)
IMMUNE STATUS (HYPERSENSITIVITY)
Hypersensitivity to beta-lactam antibiotics demonstrate cross- allergenicity including penicillins, cephalosporins, and carbapenems but not aztreonam
Drugs with sulfonamide structures include: sulfonamide antimicrobials; sulfonylurea drugs used to treat diabetes, most diuretics, and celecoxib
PHOTOSENSITIVITY
SPECIES DIFFERENCES
AGE
Elderly are often much more sensitive to drugs’ adverse effects than young adults
Toxicodynamics affected by age
Toxicokinetic parameters vary with age
GENDER
ENVIRONMENTAL FACTORS
NUTRITIONAL STATUS/PROTEIN BINDING
DRUG INTERACTIONS
An example is tyramine in foods and drinks can cause a hypertensive action in patients taking monoamine oxidase inhibitors (e.g., phenelzine)
Drug-drug or drug- environmental chemical interactions can lead to marked enhancement of adverse effects
ENVIRONMENTAL PATHOLOGY

SYMPTOMS & TREATMENT OF ACUTE POISONING - MANAGEMENT OF THE POISONED PATIENT
Most poisons do not have a specific antidote
SYMPTOMS AND TREATMENT OF POISONING
SPECIFIC ANTIDOTES FOR SELECTED DRUGS AND TOXINS
Drugs That Chelate Metals
Substances That Act Against Specific Drugs or Toxins

GENERAL APPROACH TO THE POISONED PATIENT
Systematic
Treatment and diagnostic actions are in parallel
Basic goals
Rapid stabilization of the patient
Categorization of poison class
Initiation of general treatment (supportive)
Specific treatment when available
Remember that poisonings are often mixed, with multiple drugs/chemicals
Treatment often nonspecific
Prevent further toxin exposure
Enhance toxin elimination

ABCDTs OF TREATMENT
Treatment requires ABCDTs: Airway, Breathing, Circulation; Drugs, Temperature
AIRWAY SHOULD BE :
Cleared of vomitus or any other obstruction
An airway or endotracheal tube inserted
BREATHING ASSESSED BY :
Observation
Measurements of arterial gases
Pulse-oximetry
Intubate and mechanically ventilate if needed
CIRCULATION
Monitor
Pulse rate
Blood pressure
Urine output
Start IV and draw blood for:
Glucose
Laboratory determination
DRUGS
Dextrose
Every patient with altered mental status
Administer 100 mg of thiamine to alcoholic and malnourished patients
Prevents Wernicke-Korsakoff syndrome
Naloxone
Remember multiple doses of naloxone may be required for opioid overdoses
Flumazenil
May cause seizures if used improperly
Stop seizures with diazepam or lorazepam
IV lorazepam or diazepam for seizure control
TEMPERATURE (COOLING)
Tepid sponge bath or fan

REMOVE STOMACH CONTENTS IF INDICATED

GASTRIC LAVAGE
Not recommended after 4 hours of poisoning
Usually not helpful after 1 hour
Contraindications
After 30 minutes of ingestion of corrosive material
Ingestion of hydrocarbon solvents (aspiration pneumonia)
Coma, stupor, delirium, or seizures (present or imminent)
Substances used to reduce absorption of poison
Charcoal
Cholestyramine (acidic compounds)
Activated charcoal adsorbs many toxins if given immediately before or after lavage

INDUCED EMESIS
Same contraindications as for gastric lavage
Makes use of syrup of ipecac (slow-acting oral emetic)
Contraindications of emesis & gastric lavage include : coma, seizures, corrosives, petroleum solvents

CURRENT CHANGES IN EMERGENCY TREATMENTS
Emergency treatment today uses less induction of emesis & expanded use of activated charcoal
Gastrointestinal (GI) decontamination
Ipecac now much less commonly used
Gastric lavage used much less
Whole bowel irrigation used more
Expanded use of activated charcoal
Toxin elimination
Hemodialysis used much more than hemoperfusion
Expanded use of multiple doses of activated charcoal

HISTORY & PHYSICAL EXAMINATION PROVIDE CLUES TO POTENTIAL EXPOSURE

ORAL STATEMENTS MAY BE UNRELIABLE
Oral statements are not always reliable especially when illicit substances are involved
ALWAYS TREAT SYMPTOMS
PHYSICAL EXAMINATION SHOULD FOCUS ON CLUES OF INTOXICATION
Rapid review of adverse effects of chemicals is high yield for Board examinations

VITAL SIGNS SHOULD BE CHECKED
May lead to clues of intoxication

HYPERTENSION WITH TACHYCARDIA
Sympathomimetics & parasympatholytics cause hypertension with tachycardia
Amphetamines
Cocaine
Antimuscarinics

HYPOTENSION & BRADYCARDIA
Beta blockers
Glucagon is the antidote for beta-blocker overdose
Calcium channel blockers
Clonidine
Sedative-hypnotics

HYPOTENSION WITH TACHYCARDIA
Drugs that produce vasodilation cause a reflex tachycardia
Tricyclic antidepressants
Sodium bicarbonate is the antidote for wide QRS caused by tricyclic antidepressants and quinidine overdoses
Phenothiazines
Theophylline (acute)
ß2-agonists

RAPID RESPIRATION
Rapid respiration from stimulation of central nervous system (CNS) respiratory centers
Salicylates
Carbon monoxide
Chemicals producing metabolic acidosis
Chemical producing cellular asphyxia (cyanide)

HYPERTHERMIA
Overdoses of sympathomimetics and parasympatholytics cause hyperthermia
Sympathomimetics
Anticholinergics
Salicylates
Uncouplers of oxidative phosphorylation (dinitrophenol)
Uncouplers of mitochondrial oxidative phosphorylation switch metabolism from aerobic to anaerobic speeding up metabolism with the generation of lactic acid and heat
Chemicals producing seizures or muscular rigidity

HYPOTHERMIA
Phenothiazines
Ethanol
Other CNS depressants

EYES
PUPIL CONSTRICTION (MIOSIS) - Sphincter muscle contraction M3 - Pinpoint pupils : opioids, parasympathomimetics, alpha blockers
Sympatholytics (eg, α2-agonists)
Opioids (except meperidine)
Parasympathomimetics (eg, pilocarpine), organophosphates
Phenothiazines (alpha-blockade)
Cholinesterase inhibitors
Alpha receptor blockers
PUPIL DILATION (MYDRIASIS) - Radial muscle contraction alpha 1 - Open pupils : cocaine, sympathomimetics, parasympatholytics
Anticholinergics (eg, atropine, TCAs, tropicamide, scopolamine, antihistamines)
Indirect sympathomimetics (eg, amphetamines, cocaine, Lysergic acid diethylamide LSD) meperidine
Phencyclidine (PCP)
Direct sympathomimetics

SKIN
Flushed, hot, and dry
Atropine High dose atropine flush; mechanism unknown
Antimuscarinics
Excessive sweating
Excessive sweating; ganglionic stimulants parasympathomimetics and sympathomimetics
Cholinesterase inhibitors
Sympathomimetics
Parasympathomimetics
Nicotine

CYANOSIS
Hypoxemia
Methemoglobinemia (nitrites)

DRUG REACTIONS GASTROINTESTINAL

LIVER

JAUNDICE (LIVER TOXICITY) - ACUTE CHOLESTATIC HEPATITIS, JAUNDICE
Macrolides (eg, erythromycin)
Liver toxins increase bilirubin accumulation leading to yellow color skin
Acetaminophen
Erythromycin estolate (cholestatic)
Carbon tetrachloride
Troglitazone
Valproic acid

FOCAL TO MASSIVE HEPATIC NECROSIS
Amanita phalloides (death cap mushroom), valproate, acetaminophen

HEPATITIS
Rifampin, isoniazid, pyrazinamide, statins, fibrates

ABDOMEN

CONSTIPATION
Ileus is typical of : Low bowel activity, parasympatholytics, opioids, sedatives
Antimuscarinics (eg, atropine), antipsychotics, opioids, non-dihydropyridine CCBs, ranolazine, amiodarone, aluminum hydroxide, loperamide, 5HT3 receptor antagonist (ondansetron), vincristine
Antimuscarinics
Opioids
Sedatives

DIARRHEA
Hyperactive bowel sounds, cramping, & diarrhea; common with: Hyperactive bowels; parasympathomimetics, iron, arsenic, mushrooms
Acamprosate, antidiabetic agents (acarbose, metformin, pramlintide), colchicine, cholinesterase inhibitors, lipid-lowering agents (eg, ezetimibe, orlistat), macrolides (eg, erythromycin), SSRIs, chemotherapy (eg, irinotecan)
Organophosphates
Iron
Arsenic
Theophylline
Mushrooms

NERVOUS SYSTEM - DRUG REACTIONS NEUROLOGIC
TWITCHING & MUSCULAR HYPERACTIVITY
Anticholinergics
Sympathomimetics
Cocaine
MUSCULAR RIGIDITY Muscular rigidity produced by neuroleptics and convulsants
Antipsychotics (especially haloperidol)
Strychnine
SEIZURES
Seizures (treat with intravenous diazepam or lorazepam)
Seizure producing agents
Isoniazid, bupropion, imipenem/cilastatin, tramadol - With seizures, I bit my tongue
Theophylline
Isoniazid - Pyridoxine best treats isoniazid-induced seizures
Cocaine
Amphetamines
Tricyclic antidepressants
Diphenhydramine
Lidocaine
Meperidine
FLACCID PARALYSIS & COMA - Flaccid paralysis and coma with marked CNS depression
Opioids
Sedative/hypnotics
Central nervous system depressants

TREATMENT FOR ALL POISONS
SYMPTOMATIC
SUPPORTIVE
For all poisons, always provide supportive treatment to minimize symptoms
ANTIDOTES WHEN APPROPRIATE
For a few poisons, antidotes are available

LABORATORY & PROCEDURES

ELECTROLYTE ANALYSIS
Anion gap = serum Na+ - (serum HCO3- + serum Cl-)
Normal = 12 +- 2 mEq/L
Elevated by :
Renal failure
Diabetic ketoacidosis
Shock-induced lactic acidosis
Drug-induced metabolic acidosis
Examples of toxins that elevate anion gap :
AT MUDPILES M ?pneumonic for acidosis. Alcohol (chronic ethanol ketoacidosis), Toluene (renal tubular acidosis), Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Iron, Isoniazid, Lactic acid, Ethylene glycol, Salicylates
Salicylates
Methanol transforms to formic acid; also osmolar gap
Ethylene glycol transoforms to oxalic acid; also osmolar gap
Isoniazid
Iron
Metformin (lactic acidosis)

RENAL & LIVER FUNCTIONAL TESTS
Increased creatinine levels indicate renal toxicity; increased liver functional transaminases (LFTs) indicate hepatotoxicity

OSMOLAR GAP (SOLVENTS)
Calculation of the osmolal gap is useful in evaluating causes of an increased anion gap metabolic acidosis
The plasma osmolality (POsm) is calculated - POsm = 2 (serum Na+) + serum glucose/18 + serum blood urea nitrogen/2.8 + serum ethanol (mg/dL)/ 4.6 (if the patient is drinking ethanol) and is then subtracted from the measured POsm
A difference of less than 10 mOsm/kg is normal
A difference more than 10 mOsm/kg is highly suspicious for methanol and/or ethylene glycol poisoning
Measured vs. calculated
285 mOSmol (normal)
Calc. OS = 2 Na+ + glucose/18 + BUN/2.8
Toxins that increase osmolar gap : Polyhydroxyl compounds produce an osmolar gap
Ethanol
Methanol (also anion gap)
Ethylene glycol (also anion gap)

TOXICOLOGY SCREENS
Results from toxicology screens are usually too late to help with treatment but are valuable in follow-up legal manifestations

COMPUTED TOMOGRAPHY (CT) STUDIES RECOMMENDED IF HEAD TRAUMA IS SUSPECTED
CT scans help rule out brain trauma

ELECTROCARDIOGRAM (ECG)

WIDENING OF QRS COMPLEX
Widening QRS caused by TCAs or quinidine is treated with sodium bicarbonate
Tricyclic antidepressants (TCAs)
Quinidine

TORSADES DE POINTES - DRUG REACTIONS CARDIOVASCULAR
Prolonged QT interval
Followed by ventricular tachycardia
A QRS that spirals around the isoelectric line
Caused by - Agents that prolong QT interval
antiArrhythmics (class IA, III), antiBiotics (eg, macrolides, fluoroquinolones), anti“C”ychotics (eg, ziprasidone), antiDepressants (eg, TCAs), antiEmetics (eg, ondansetron), antiFungals (eg, fluconazole) (ABCDEF)
Quinidine (Class IA and III antiarrhythmics)
Tricyclic antidepressants (TCAs)
Phenothiazines
“Non-sedating” antihistamines (astemizole, terfenadine)
Cisapride
Fluoroquinolones
Prolonged QT caused by Potassium channel blockers prolong QT interval
beta1 Stimulation
Intense sympathetic activation
Factors that contribute to torsades de pointes
Hypokalemia
Hypomagnesemia
Hypocalcemia
Bradycardia
Ischemia
Tissue hypoxia
Treatment
Magnesium sulfate

INCREASE THE RATE OF EXCRETION WHEN APPROPRIATE

ALTERATION OF URINE PH
Acidification of urine - Acidification of the urine can lead to rhabdomyolysis
Use ammonium chloride
Increases excretion of weak organic bases Phencyclidine Amphetamines
Not often used today but often tested on Boards
Alkalinization of urine - Either acetazolamide or sodium bicarbonate can be used to alkalinize the urine
Use sodium bicarbonate or acetazolamide
Increases excretion of weak organic acids Salicylates Phenobarbital

CATHARTICS
Magnesium sulfate
Osmotic diuretics
Mannitol
MgSO4
Polyethylene glycol

WHOLE BOWEL IRRIGATION
Body packers
Swallowed condoms filled with drugs of abuse
Used in drug trafficking
Oral overdose with sustained release compounds

HEMODIALYSIS
The smaller the volume of distribution (Vd), the more effective the hemodialysis

PERITONEAL DIALYSIS

HEMOPERFUSION

TERATOGENIC EFFECTS OF SPECIFIC DRUGS

DEPENDENCE & DRUGS OF ABUSE
Repeated drug use may lead to dependence
PHYSICAL DEPENDENCE
Disulfiram discourages ethanol use
Withdrawal symptoms occur when a physical dependent individual does not have substance in body
PSYCHOLOGICAL DEPENDENCE
Psychological dependence promotes drug-seeking behaviors
SUBSTANCE DEPENDENCE (ADDICTION)
An addicted individual will continue to seek and use substances despite medical, financial, and social problems

UNSORTED
Ingested seafood toxins
Age-related changes in pharmacokinetics
Beers criteria
Specific toxicity treatments

DRUG REACTIONS 
DRUG REACTIONS CARDIOVASCULAR
DRUG REACTIONS ENDOCRINE/REPRODUCTIVE
DRUG REACTIONS GASTROINTESTINAL
DRUG REACTIONS HEMATOLOGIC
DRUG REACTIONS MUSCULOSKELETAL/SKIN/CONNECTIVE TISSUE
DRUG REACTIONS NEUROLOGIC
DRUG REACTIONS RENAL/GENITOURINARY
DRUG REACTIONS RESPIRATORY
DRUG REACTIONS MULTIORGAN

DRUGS AFFECTING PUPIL SIZE
CYTOCHROME P-450 INTERACTIONS (SELECTED)
SULFA DRUGS

TOXIC CHEMICALS IN THE ENVIRONMENT
Pollutants
Air CO SO2 NO2 O3
Environmental PCBs, dioxins, asbestos, metals
Agricultural chemicals
Pesticides Chlorinated hydrocarbons, cholinesterase inhibitors, botanical
Herbicides Chlorophenoxy acids, glyphosate, bipyridyl
Solvents
Halogenated aliphatic hydrocarbons,
aromatic hydrocarbons

HEAVY METALS & CHELATORS
Heavy metals
Lead
Arsenic
Mercury
Iron
Chelators
Dimercaprol
Succimer
Penicillamine
Deferoxamine,
deferasirox
EDTA

TOC
MISCELLANEOUS
Drug names
Biologic agents

TOC
AUTONOMIC ANS & PERIPHERAL NEUROMUSCULAR NMJ
(Lerchenfeldt BRS 7e 2019 Contents) V1 PDF
(Page Crash 4e 2012, Weiss HY 3e 2009 & Le FA 1 32e 2022) V1 PDF
(Neal Glance 9e 2020) V1 JPG R 1 Micturition 2 GPLR 3

CONTENTS

DIVISIONS OF THE EFFERENT AUTONOMIC NERVOUS SYSTEM (ANS)
NEUROCHEMISTRY OF THE AUTONOMIC NERVOUS SYSTEM
PHYSIOLOGIC CONSIDERATIONS

END OF CONTENTS

DIVISIONS OF THE EFFERENT AUTONOMIC NERVOUS SYSTEM (ANS) - AUTONOMIC RECEPTORS
 
PARASYMPATHETIC (PSNS) : CRANIOSACRAL DIVISION - conservation of energy at rest - Pelvic splanchnic NN & CNs III, VII, IX & X
Ach - Nn → Ach - M1, M2, M3 SM, gland cells, nerve terminals, cardiac M
ACh stimulates both N & M

SYMPATHETIC (SNS) : THORACOLUMBAR
Ach - Nn → M3 sweat glands
ACh is NT at sympathetic thermoregulatory sweat glands
NE is NT at sympathetic apocrine (stress) sweat glands
Sweat glands are part of the sympathetic pathway but are innervated by cholinergic fibers (sympathetic nervous system results in a “chold” sweat)
Sympathetic M-cholinergic innervation of some sweat glands & some muscle blood vessels - These cells lack parasympathetic innervation
Ach - Nn → NE α1, α2, β1, β2 Smooth muscle, gland cells, nerve terminals, cardiac muscle
Ach - Nn → NE D α1, α2, β1, D1 Renal vasculature smooth muscle
Ach Adrenal Blood (catecholamine transmission) → NE E α1, α2, β1, β2 Cardiac muscle, vessels - Adrenal medulla is directly innervated by preganglionic sympathetic fibers

SOMATIC
Voluntary motor nerve Neuromuscular junction Ach - Nm Skeletal muscle

G-PROTEIN–LINKED SECOND MESSENGERS - GPCR

H1 α1 V1 M1 M3 - Cutie (q-tie), HAVe 1 M&M !
q → ↑ IP3 & DAG → ↑ Ca2+ → SM Cont & ↑ Ca2+ → ⊕PKC

β1 β2 β3 D1 H2 V2 
s → CA → ↑ cAMP → PKA → ↑ Ca2+ (heart)  & PKA → ⊝Myosin light-chain kinase (SM Cont)

M2 α2 D2 - People who are too (2) MAD inhibit themselves
i ⊝ inhibition of CA → ↓ cAMP

NICOTINIC R - LGIC allowing efflux of K+ & influx of Na+ & in some cases Ca2+
Nn Autonomic ganglia, adrenal medulla - Postganglionic cell body - Dendrites - Excitation of postganglionic neurons
Nm Skeletal neuromuscular junctions - Muscle contraction

MUSCARINIC R GPCR that usually act through 2nd messengers
M1–5 found in heart, smooth muscle, brain, exocrine glands, & on sweat glands (cholinergic sympathetic) 
M1
Autonomic ganglia - Presynaptic nerve terminal - CNS neurons
Modulation of neurotransmission
Mediates higher cognitive functions
Stimulates enteric nervous system
M2
Cardiac tissue (sinoatrial and atrioventricular nodes) - Nerves
Increased potassium efflux
Slowing of heart rate & conduction - ↓ heart rate & contractility of atria
M3
Smooth muscles & glands - Contraction & Stimulation secretion
Endothelium - Increased nitric oxide formation - Nitric oxide vasodilation
Vascular smooth Muscle - Increased cGMP (from nitric oxide)
↑ exocrine gland secretions, gut peristalsis, bladder contraction, bronchoconstriction, vasodilation
↑ pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation)

ADRENERGIC R
α Usually excitatory (contraction of smooth muscle)
α1
↑ vascular smooth muscle contraction
Visceral SM Cont
↑ pupillary dilator muscle contraction (mydriasis)
↑ intestinal & bladder sphincter muscle contraction
α2
↓ of insulin secretion
Presynaptic terminals - Inhibition of neurotransmitter release -  norepinephrine - ↓ sympathetic (adrenergic) outflow
↓ Lipolysis
Salivary glands - Inhibition of secretion
↓ aqueous humor secretion
(Mediation of) ↑ platelet aggregation
mediation of CNS effects
β1 - Located in the heart & are excitatory
↑ in heart rate, ↑ contractility (1 heart) & conduction
↑ in secretion of renin
↑ Lipolysis
β2 - Usually inhibitory Relaxation of SM - Uptake of potassium in SM
Vasodilation -  Arterial smooth muscle
Bronchodilation (2 lungs) Bronchi Bronchioles
↑ Lipolysis adipocytes
↑ insulin release
↑ in heart rate, contractility
Liver - ↑ Glycogenolysis, glucose release
↓ uterine tone (tocolysis)
↑ aqueous humor secretion
↑ cellular K+ uptake
β3
Adipose - ↑ Lipolysis
↑ thermogenesis in skeletal muscle
↑ bladder relaxation

DOPAMINE
D1
Relaxes renal vascular smooth muscle
activates direct pathway of striatum
D2
Modulates transmitter release, especially in brain,
inhibits indirect pathway of striatum

HISTAMINE
H1
↑ bronchoconstriction, airway mucus production
↑ vascular permeability/vasodilation, pruritus
H2
↑ gastric acid secretion

VASOPRESSIN
V1
↑ vascular smooth muscle contraction
V2
↑ H2O permeability and reabsorption via upregulating aquaporin-2 in collecting twobules (tubules) of kidney
↑ release of vWF

NEUROCHEMISTRY OF THE AUTONOMIC NERVOUS SYSTEM

MECHANISM - DRUGS THAT AFFECT CHOLINERGIC NEUROTRANSMISSION - DRUGS THAT AFFECT ADRENERGIC NEUROTRANSMISSION
Inhibit synthesis of neurotransmitter - Hemicholinium* - Metyrosine
Prevent vesicular storage of neurotransmitter - Vesamicol* - Reserpine
Inhibit release of neurotransmitter - Botulinum toxin - Bretylium Guanethidine
Stimulate release of neurotransmitter - Black widow spider venom* - Amphetamine Tyramine
Inhibit reuptake of neurotransmitter - - Tricyclic antidepressants Cocaine
Inhibit metabolism of neurotransmitter - Cholinesterase inhibitors (physostigmine, neostigmine) - Monoamine oxidase inhibitors (tranylcypromine)
Activate postsynaptic receptors - Acetylcholine (M, N) Bethanechol (M) Pilocarpine (M) - Albuterol (β2) Dobutamine (β1) Epinephrine (α, β)
Block postsynaptic receptors - Atropine (muscarinic receptors); hexamethonium (ganglia) & tubocurarine (NMJ) (nicotinic receptors) - Phentolamine (α-adrenergic receptors) & propranolol (β-adrenergic receptors)

CHOLINERGIC PATHWAYS ACH

CHOLINERGIC FIBERS
SYNTHESIS, STORAGE, & RELEASE
choline and acetyl coenzyme A by choline acetyltransferase
stored in vesicles
calcium-induced membrane-vesicle fusion leads to ACh release into the synapse
RECEPTOR ACTIVATION & SIGNAL TRANSDUCTION
INACTIVATION = BREAKDOWN
ACh action terminated by cholinesterases

DRUGS THAT AFFECT CHOLINERGIC PATHWAYS
BOTULINUM TOXIN
Botulinum toxin inhibits ACh release
CHOLINESTERASE INHIBITORS
Physostigmine reverses the CNS effects of atropine poisoning
Physostigmine crosses blood-brain barrier (BBB); neostigmine does not
CHOLINERGIC RECEPTOR ANTAGONISTS
Atropine blocks muscarinic receptors
Hexamethonium blocks ganglionic nicotinic receptors
Tubocurarine-like drugs block nicotinic receptors in NMJ

ADRENERGIC PATHWAYS NA

ADRENERGIC FIBERS
SYNTHESIS, STORAGE, & RELEASE
Tyrosine hydroxylase is the rate-limiting step - for negative feedback inhibition
Dopamine (DA) - metabolized to NE by the granular enzyme DA β-hydroxylase
RECEPTOR ACTIVATION & SIGNAL TRANSDUCTION
Epinephrine and norepinephrine both stimulate alpha- and beta-adrenergic receptors
INACTIVATION = BREAKDOWN
NE - taken back up into the nerve ending (reuptake) - metabolized; or it can diffuse away from the synapse
Reuptake  - Cocaine or tricyclic antidepressants block reuptake
Uptake 1 most important for termination of action
Uptake 1 also referred to as NET (NorEpinephrine Transporter)

Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) convert NE to methoxyhydroxymandelic acid (vanillylmandelic acid, VMA)

Cells that produce epinephrine (EPI) have a methyltransferase that converts NE to EPI

Release of norepinephrine from a sympathetic nerve ending is modulated by NE itself, acting on presynaptic α2-autoreceptors → negative feedback
Amphetamines use the NE transporter (NET) to enter the presynaptic terminal, where they utilize the vesicular monoamine transporter (VMAT) to enter neurosecretory vesicles
This displaces NE from the vesicles
Once NE reaches a concentration threshold within the presynaptic terminal, the action of NET is reversed, and NE is expelled into the synaptic cleft, contributing to the characteristics and effects of ↑ NE observed in patients taking amphetamines

DRUGS THAT AFFECT ADRENERGIC PATHWAYS
GUANETHIDINE
RESERPINE
Reserpine used to treat Huntington’s disease
Guanethidine and reserpine are adrenergic nerve blocking agent
ADRENERGIC RECEPTOR ANTAGONISTS

PHYSIOLOGIC CONSIDERATIONS

DUAL INNERVATION
Most organs are dually innervated
Parasympathetic and sympathetic responses are coordinated
Presynaptic receptors can modulate neurotransmitter release
Postsynaptic receptors can be up- or down-regulated

PHYSIOLOGIC EFFECTS OF AUTONOMIC NERVE ACTIVITY

α RESPONSES
Usually excitatory (contraction of smooth muscle)

β1 RESPONSES
Located in the heart & are excitatory
Cause renin secretion in the kidney

β2 RESPONSES
Usually inhibitory (relaxation of smooth muscle)
Cause vasodilation in vasculature
Cause bronchodilation in bronchi
Responsible for metabolic effects in liver & adipocytes

ADRENAL MEDULLA
EPI and NE secretion N-increases
Epinephrine is main adrenergic hormone secreted from adrenal medulla
This modified sympathetic ganglion releases epinephrine and norepinephrine
These circulating hormones can affect α and β responses throughout the body

EYE MM CONTRACTS predominant tone is PS
PUPIL (IRIS)
Radial
α1 ⊕ mydriasis
Circular
M3 ⊕ miosis
CILIARY
M3 ⊕ near vision accommodation & opens pores facilitating outflow of AH into canal of Schlemm
β2 Relax for far vision & facilitates the secretion of AH ??

LACRIMAL GLAND & respiratory secretions
M ⊕ tear sec

SALIVARY GLANDS
α1 secretion of thick saliva
M much secretion of watery saliva thin

HEART
β1 rate & force increased
M rate & force reduced
SA NODE
β1 > β2 Acc
M2 Dec
ECTOPIC PACEMAKERS
β1 > β2 Acc
CONTRACTILITY
β1 ↑ > β2 ↑
M2 ↓ (atria)

Sympathetic effects increase cardiac output
Positive chronotropic effect (increased heart rate)
Positive inotropic effect (increased force of contraction)
Positive dromotropic effect (increased speed of conduction of excitation)
Parasympathetic effects (M2) decrease heart rate & cardiac output - At rest, the predominant tone to the heart is parasympathetic
Negative chronotropic effect (decreased heart rate)
Negative inotropic effect (decreased force of contraction) - Exogenous ACh only (no vagal innervation of the ventricular muscle)
Negative dromotropic effect (decreased velocity of conduction of excitation)

BLOOD VESSELS (+) (-)
α VC
β2 VD
SKIN, SPLANCHNIC VESSELS
α-constricts
SKELETAL MUSCLE
α-constricts
β2-dilates
M-dilates
RENAL, MESENTERIC VESSELS
DA-dilates
ENDOTHELIUM
M-releases EDRF
Most blood vessels have uninnervated muscarinic cholinoceptors
Relaxation involves release of endothelium-derived relaxing factor (EDRF) from the endothelium in response to circulating muscarinic agonists

ARTERIOLES
Coronary
β2 Dil M3 Dil - Endot of most blood vessels releases endothelium-derived releasing factor (EDRF), which causes vasodilation in response to muscarinic stimuli
However, these muscarinic receptors are not innervated & respond only to circulating muscarinic agonists
α1 > α2 Cons
Skin & mucosa
α1 > α2 Cons
M3 Dil
Skeletal muscle
α1 > α2 Cons M3 Dil
β2 M Dil - Vascular smooth muscle has sympathetic cholinergic dilator fibers
Splanchnic
α1 > α2 Cons M3 Dil
Renal & mesenteric
D β2 Dil
α1 > α2 Cons

VEINS
Systemic
β2 Dil
α1 > α2 Cons

BP : THE OVERALL EFFECTS OF AUTONOMIC DRUGS ON BP ARE COMPLEX & ARE DETERMINED BY AT LEAST 4 PARAMETERS :
Direct effects on the heart
β1 stimulation leads to an increased heart rate & increased force : produces increased blood pressure & increased pulse pressure.
Muscarinic stimulation leads to a decreased heart rate & decreased force : produces decreased blood pressure
Vascular effects
Muscarinic stimulation results in dilation, which decreases blood pressure - Exogenous muscarinic drugs only (no PSNS innervation of the vascular system)
Alpha (α1) stimulation results in vascular constriction, which increases blood pressure; both venules & arterioles
Beta (β2) stimulation results in dilation, which decreases blood pressure; both venules and arterioles
Redistribution of blood
With increased sympathetic activity, the blood is shunted away from organs & tissues such as the skin, gastrointestinal tract, kidney, & glands and toward the heart & voluntary (e.g., skeletal) muscles
This process occurs as a result of a predominance of β2 vasodilation rather than α1 constriction at these sites
Reflex phenomena
A decrease in blood pressure, sensed by baroreceptors in the carotid sinus and aortic arch, causes reflex tachycardia
An increase in blood pressure causes reflex bradycardia

BRONCHIOLAR MUSCLE - LUNG AIRWAYS
SMOOTH M
β2 BD
M3 BC & secrecretion

GI TRACT SM
S decrease in motility & tone
P increase in motility & tone
GUT CONTRACTILITY WALLS
α2 β2 Relax
M3 Cont
SPHINCTERS
α1 Cont
M3 Relax
SECRETION
α2 Inhibits
M3 Increases

SPLEEN
α capsule contracts

PANCREAS
M increase in exocrine & endocrine secretion

GENITOURINARY SMOOTH MUSCLE - MICTURITION  M (+) bladder detrusor (–) sphincter
BLADDER MOTILITY
β2 Relax
M3 Cont
SPHINCTER
α1 Cont et β2 ?
M3 Relax

UTERUS, PREGNANT
β2 Relax (depends on hormonal state)
α1 Cont

PENIS, SEMINAL VESICLES Point & Shoot
α Ejac
M Erec (co-release of nitric oxide)

MICTURITION CONTROL
Micturition center in pons regulates involuntary bladder function via coordination of sympathetic and parasympathetic nervous systems
P Det M3 (1) ⊕ parasympathetic → ↑ urine voiding
S Det β3 (2)  IUS α1 (3) ⊕ sympathetic → ↑ urinary retention
Som EUS N
Some autonomic drugs act on smooth muscle receptors to treat bladder dysfunction
(1) Muscarinic antagonists (eg, oxybutynin) - ⊝ M3 receptor → relaxation of detrusor smooth → ↓ muscle detrusor overactivity - Urgency incontinence
(1) Muscarinic agonists (eg, bethanechol) - ⊕ M3 receptor  → contraction of detrusor smooth muscle → bladder emptying → ↑ bladder emptying - Urinary retention
(2) Sympathomimetics (eg, mirabegron) - ⊕ β3 receptor →  relaxation of detrusor smooth muscle → ↑ bladder capacity- Urgency incontinence
(3) α1-blockers (eg, tamsulosin) - ⊝ α1-receptor → relaxation of smooth muscle (bladder neck, prostate) → ↓  urinary obstruction - BPH

RECTUM
M Defecation

SKIN
PILOMOTOR SMOOTH MUSCLE
α1 Cont
SWEAT GLANDS
Thermoregulatory
M inc
Apocrine (stress)
α1 inc

MUSCLE
β2 Promotes K+ uptake

LIVER
α β2 inc Gluconeogenesis & Glycogenolysis

FAT CELLS
β3 inc Lipolysis

KIDNEY
Renin release
β1 inc
α1 inh
Sodium reabsorption

TOC
PHARMACOMODULATION

TYPES
Enzyme : Inducer - Inhibitor
Ion channel : Opener - Blocker
Receptor : Agonist - Partial agonist- Antagonist - Inverse agonist - Positive allosteric modulator (PAM)- Negative allosteric modulator (NAM)
Transporter [Reuptake vs Efflux] : Enhancer (RE) - Inhibitor (RI) - Releaser (RA)
Miscellaneous : Precursor - Cofactor

CLASSES   

ENZYME
Enzyme inhibition

ION CHANNEL
Ion channel modulators

RECEPTOR & TRANSPORTER

BA/M

ADRENERGIC
ADRENERGIC R AG-ONIST (α - β (1-2))
ADRENERGIC R ANTAG-ONIST (α (1-2) - β)
NOREPINEPHRINE REUPTAKE INHIBITOR (NRI)

DOPAMINERGIC
DOPAMINE R AG
DOPAMINE R ANTAG
DOPAMINE REUPTAKE INHIBITOR (DRI)

HISTAMINERGIC
HISTAMINE R AG
HISTAMINE R ANTAG (H1H2H3)

SEROTONERGIC
SEROTONIN R AG
SEROTONIN R ANTAG (5-HT3)
SEROTONIN REUPTAKE INHIBITOR (SRI)

AA

GABAERGIC
GABA RECEPTOR AGONIST
GABA RECEPTOR ANTAGONIST
GABA REUPTAKE INHIBITOR (GRI)

GLUTAMATERGIC
GLUTAMATE RECEPTOR AGONIST (AMPA)
GLUTAMATE RECEPTOR ANTAGONIST (NMDA)
GLUTAMATE REUPTAKE INHIBITOR

CHOLINERGIC
ACETYLCHOLINE R AG (MUSCARINIC - NICOTINIC) (CHOLINESTERASE INHIBITOR)
ACETYLCHOLINE R ANTAG (MUSCARINIC - NICOTINIC (GANGLIONIC - MUSCULAR))

CANNABINOIDERGIC
CANNABINOID RECEPTOR AGONIST
CANNABINOID RECEPTOR ANTAGONIST
ENDOCANNABINOID ENHANCER (ECBE)
ENDOCANNABINOID REUPTAKE INHIBITOR (ECBRI)

OPIOIDERGIC
OPIOID MODULATOR
OPIOID RECEPTOR AGONIST
OPIOID RECEPTOR ANTAGONIST
ENKEPHALINASE INHIBITOR

OTHER
ADENOSINE REUPTAKE INHIBITOR (ADORI)
ANGIOTENSIN II RECEPTOR ANTAGONIST
ENDOTHELIN RECEPTOR ANTAGONIST
NK1 RECEPTOR ANTAGONIST
VASOPRESSIN RECEPTOR ANTAGONIST

MISCELLANEOUS
Cofactor (Enzyme cofactors)- Precursor (Amino acids)

TOC
AUTONOMIC DRUGS

CHOLINERGIC
ACh R MODULATORS
PRECURSORS (& PRODRUGS)
Acetyl-coA - Adafenoxate - Choline (lecithin) - Citicoline - Cyprodenate - Dimethylethanolamine - Glycerophosphocholine - Meclofenoxate (centrophenoxine) - Phosphatidylcholine - Phosphatidylethanolamine - Phosphorylcholine - Pirisudanol
ACh METABOLISM & TRANSPORT MODULATORS
ENZYME (MODULATORS)
ChAT
Inhibitors
AChE
Inhibitors : Reversible : Carbamates : Stigmines : Irreversible : Organophosphates : Others : Unsorted :
Reactivators : pralidoxime
BChE
Inhibitors
Many of the other AChE inhibitors listed above
TRANSPORTER (MODULATORS)
CHT
Inhibitors :
Enhancers :
VAChT
Inhibitors :
RELEASE (MODULATORS)
Inhibitors
SNAP-25 inactivators :
VAMP inactivators :
Others :
Enhancers
LPHN  agonists :
Others :

NORADRENERGIC

TOC
CHOLINERGIC - mAChRs - nAChRs (Musc Nm, Gang Nn)
(Neal Glance 9e 2020) V1 JPG

TOC
CHOLINOMIMETIC AGENTS & DIRECT-ACTING NICOTINIC AGONISTS

CONTENTS
MUSCARINIC RECEPTOR AGONISTS
CHOLINESTERASE INHIBITORS
ANTICHOLINESTERASE POISONING
GANGLIONIC STIMULANTS
NEUROMUSCULAR JUNCTION
END OF CONTENTS

WATCH FOR EXACERBATION OF COPD, ASTHMA, & PEPTIC ULCERS IN SUSCEPTIBLE PATIENTS !!!!!

DIRECT ACTING AGONISTS

EFFECTS OF MUSCARINIC RECEPTOR AGONISTS
Also activate uninnervated cholinoceptors (e.g., M- cholinoceptors in blood vessels to lower blood pressure) & M-cholinoceptors at sympathetic cholinergic synapses
The dilating effect of parasympathomimetics on blood vessels is mediated by the release of endothelium-derived relaxing factor (EDRF),
which is probably nitric oxide, from the endothelium
An intact endothelium is required for these effects to occur.
CARDIOVASCULAR
Hypotension from direct vasodilation
Bradycardia at high doses
Slowed conduction and prolonged refractory period of atrioventricular node
GASTROINTESTINAL
Increased tone and increased contractile activity of gut
Increased acid secretion
Nausea, vomiting, cramps, and diarrhea
GENITOURINARY
Involuntary urination from increased bladder motility and relaxation of sphincter
Penile erection
EYE
Miosis: contraction of sphincter muscle, resulting in reduced intraocular pressure
Contraction of ciliary muscle; accommodated for near vision
RESPIRATORY SYSTEM
Bronchoconstriction
GLANDS
Increased secretory activity, resulting in increased salivation, lacrimation, and sweating

PHARMACOKINETICS & CLASSES - SPECIFIC DRUGS

INHIBITS ACH RELEASE
BOTULINUM TOXIN
Strabismus Blepharospasm Cervical dystonia Wrinkles Hyperhydrosis
AE : Arrhythmias Syncope Hepatotoxicity Anaphylaxis
CI : Hypersensitivity

ACh N M
two binding sites
quaternary nitrogen
carbonyl oxygen
disadvantages
activates all cholinoceptors in most internal organs -  many side effects
short duration of action
QUATERNARY AMMONIUM ANALOGS OF ACH - CHOLINE ESTERS -  do not cross BBB
Methacholine
Bethanechol M (Urecholine) & Carbachol M should not be used systemically because it also has unpredictable nicotinic activity
longer durations of action
(Succinylcholine N)
PROPERTIES OF ACh & ACh ANALOGUES
AChE / N / GI / CV
ACh +++ / + / ++ / +++
Methacholine + / - / + / +++
Carbachol - / +/ +++ / +
Bethanechol - / - / +++ / +
PLANT ALKALOIDS - (Nicotine N)
Muscarine M quaternary amine
Pilocarpine M  tertiary amine -> more readily absorbed & penetrates the blood–brain barrier
Pilocarpine & Nicotine cross BBB - Pilocarpine used to treat glaucoma & increase secretions
SYNTHETIC DRUGS
Cevimeline M

MECHANISM OF ACTION

USES AGs - DIRECT AGONISTS
AE Rhinitis, nausea, dizziness ↑ frequency of urination (oral formulations)
CI Hypersensitivity Asthma Epilepsy Peptic ulcer disease

BETHANE-CHOL M2-3 - Bethanechol used to get GI atony & GU going
Activates bladder smooth muscle ; resistant to AChE - no nicotinic activity -“Bethany, call me to activate your bladder”
Urinary retention <- bladder atony

CARBA-CHOL - topically Glaucoma
Carbon copy of acetylcholine (but resistant to AChE)
Constricts pupil - Used for intraoperative miosis induction

METHA-CHOLINE M1-2-3
Stimulates muscarinic receptors in airway when inhaled - Challenge test for diagnosis of asthma

PILOCARPINE M1-2-3 - Pilocarpine & Cevimeline used to increase secretions
Contracts ciliary muscle of eye (open-angle glaucoma), pupillary (constriction) sphincter (closed-angle glaucoma); resistant to AChE, can cross BBB
“You cry, drool, & sweat on your ‘pilow’ ”
Potent stimulator of sweat, tears, & saliva Open-angle & closed-angle glaucoma, xerostomia (Sjögren syndrome)

CEVEMILINE
Xerostomia (cevimeline and pilocarpine)

ADVERSE EFFECTS - OVERDOSE
DUE TO OVERSTIMULATION OF PARASYMPATHETIC EFFECTOR ORGANS
A marked fall in blood pressure
An increase in heart rate
reflexes
DUMBELS syndrome
Defecation, diarrhea
Urination
Miosis, muscle weakness
Bronchoconstriction
Emesis
Lacrimation
Salivation, seizures, sweating
TREATMENT OF OVERDOSE
Overdoses of muscarinic agonists can be treated with atropine and/or epinephrine

END OF DIRECT ACTING AGONISTS

CHOLINESTERASE INHIBITORS = INDIRECT AGONISTS (ANTICHOLINESTERASES) - used as drugs, insecticides & warfare agents
PHARMACOKINETICS
Alcohol Edrophonium (short acting)
Carbamates (intermediate to long acting) (Neo-stigmine) Pyro-
Organophosphates (very long acting) (Parathion insecticide) Echothiophate, Poisoning Cholinesterase regenerator Oximes (Pralidoxime)
Central Donepezil (Alzheimer dlaease)
MECHANISM OF ACTION
inhibit acetylcholinesterase - increasing ACh concentration
indirect parasympathomimetics -  do not bind to ACh receptors
Butyrylcholinesterases (pseudocholinesterases) are also inhibited by cholinesterase inhibitors
bind both the esteratic (E) & anionic (A) sites, and some bind only to one site
PROPERTIES OF VARIOUS CHOLINESTERASE INHIBITORS
Binding Sites / Chemical Properties
Physostigmine (Antilirium) / E & A / Tertiary carbamate
Neostigmine (Prostigmin) /  E & A / Quaternary carbamate
Pyridostigmine (Mestinon) / E & A / Quaternary carbamate
Edrophonium (Tensilon) / A / Quaternary (noncarbamate), short duration
Organophosphates / E / Irreversible
SUBSETS OF ACHE INHIBITORS
TRULY REVERSIBLE compete with ACh at the enzyme active site
Edrophonium (MG) competes with ACh at AChE
Tacrine (A)
Donepezil (A)
Galantamine (A)
CARBAMATES carbamylate the serine hydroxyl at active site of enzyme which is slowly hydrolyzed PSEUDO-REVERSIBLE - form a covalent bond at AchE
Anticholinergic poisoning can be diagnosed & treated with cholinesterase inhibitors
Neo-stigmine (C, MG)
Physo-stigmine (C)
Pyrido-stigmine (C, MG)
Riva-stigmine (A,C)
Physostigmine and rivastigmine cross BBB
Neostigmine and pyridostigmine do not cross BBB
IRREVERSIBLE ORGANOPHOSPHATES - form a covalent bond at AChE that does not readily hydrolyze, but AChE can be reactivated by pralidoxime prior to aging
very lipid soluble
Diisopropyl phosphorofluoridate (DFP, isofluorphate)  prototype - Isoflurophate (DFP; experimental)
Echothiophate (glaucoma)
Malathion (insecticide) & Parathion (insecticide) - They must be metabolized to their active forms, malaoxon and paraoxon
Sarin (war nerve agent)
(Soman (war nerve agent)
USES
Tacrine may cause hepatotoxicity
AChE inhibitors are beneficial in treating Alzheimer’s and other dementia
Drugs used in the management of myasthenia gravis : neostigmine, pyridostigmine, edrophonium (diagnosis)
Malathion and parathion have to be converted to malaoxon and paraoxon, respectively before they phosphorylate AchE

AChE INHIBITORS
AE DUMBELS plus Seizures Bronchospasm Cardiac arrest Respiratory depression
CI  Intestinal or urinary obstruction Cardiovascular disease

EDROPHONIUM
DX of MG or differentiate a myasthenic crisis from a cholinergic crisis
Paroxysmal supraventricular tachycardia (PSVT)

DON-EPEZIL, RIVA-STIGMINE, GALA-NTAMINE
↑ ACh
1st line for AD (DOn RIVA forgot the GALA) - tacrine ?

NEO-STIGMINE
↑ ACh - NEO CNS = NO CNS penetration due to positive charge
Postoperative & Neurogenic ileus & urinary retention  = Intestinal & bladder atony (or physo)
MG
reversal of NMJ blockade (postoperative) = Competitive NM blockade -  to reduce the parasympathetic side effects of the cholinesterase inhibitors, atropine should also be administered

PY-RID-O-STIGMINE
↑ ACh - ↑ muscle strength -  Does not penetrate CNS - PyRIDostiGMine gets RID of MG
MG (long acting) - Used with glycopyrrolate or hyoscyamine to control pyridostigmine adverse effects

PH-YSO-STIGMINE 
↑ ACh - PHreely (freely) crosses BBB as not charged  → CNS
Antidote for anticholinergic toxicity; physostigmine “phyxes” atropine overdose = Reversal of anticholinergic effects

AChE INHIBITORS PLUS OTHER MECHANISMS FOR TREATMENT OF AD
Donepezil Alzheimer’s disease Anorexia, nausea and vomiting
Galantamine Dementia  Cramps
Rivastigmine  Vivid dreams
Tacrine  Hepatotoxic  CI Liver disease

END OF INDIRECT AGONISTS (ANTICHOLINESTERASES)

ADVERSE EFFECTS
Overstimulation of muscarinic receptors leads to DUMBELS: Defecation, Urination, Miosis, Bronchoconstriction, Emesis, Lacrimation, Salivation

ANTICHOLINESTERASE POISONING
Often due to organophosphates (eg, parathion) that irreversibly inhibit AChE -  commonly used as insecticides; poisoning usually seen in farmers

MUSCARINIC EFFECTS = Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Sweating, Salivation - DUMBBELSS
Reversed by ATROPINE
a competitive inhibitor - can cross BBB to relieve CNS symptoms

NICOTINIC EFFECTS = NM  blockade (mechanism similar to succinylcholine)
Reversed by PRALIDOXIME
regenerates AChE via dephosphorylation if given early
Must be coadministered with atropine to prevent transient worsening of symptoms
does not readily cross BBB

CNS EFFECTS
Respiratory depression, lethargy, seizures, coma

EFFECTS
The effects of the cholinesterase inhibitors are primarily muscarinic in nature
DUMBELS syndrome is induced
Nicotinic effects occur only at high doses

OVERDOSE of cholinesterase inhibitors
death - respiratory insufficiency
Reduced respiratory function is due to
Increased bronchial secretions
Bronchoconstriction
Central respiratory depression
Depolarizing neuromuscular blockade
Specific antidotes
Atropine at high dosages
Pralidoxime (2-PAM) - reactivate the cholinesterases - must be administered within a few hours after the exposure - no effect on poisoning from the carbamates

CHRONIC EXPOSURE
delayed neurotoxicity
demyelinization of motor neurons

CONTRAINDICATIONS
Asthma
Peptic ulcers

END OF ANTICHOLINESTERASE POISONING

DIRECT-ACTING NICOTINIC
AG (& PAMs) = NICOTINIC AG
Nicotine (by definition), acetylcholine (the endogenous agonist of nAChRs), choline, epibatidine, lobeline, varenicline & cytisine

GANGLIONIC STIMULANTS   
EFFECTS DEPEND ON THE PREDOMINANT AUTONOMIC TONE AT THE ORGAN SYSTEM BEING ASSESSED
Must pretreat subject with atropine in order to give sufficient doses of ACh to stimulate nicotinic receptors
ACh
Very high doses of ACh or nicotine desensitize nicotinic receptors (“depolarizing blockade”)
NICOTINE
Uses
CHOLINESTERASE INHIBITORS

NEUROMUSCULAR JUNCTION
ACH, NICOTINE & SUCCINYLCHOLINE ALL ARE NICOTINIC AGONISTS AT THE NMJ
Overstimulation produces a desensitizing or “depolarizing” blockade
SUCCINYLCHOLINE IS USED AS DEPOLARIZING NEUROMUSCULAR BLOCKER FOR = NICOTINIC RECEPTOR AGONIST THAT PRODUCES A DEPOLARIZING BLOCKADE
CA
Adjunct to general anesthesia
Induction of neuromuscular blockade during surgery
Endotracheal intubation
Reduction of intensity of muscle contractions of pharmacologically- or electrically-induced convulsions
Electroconvulsive therapy
AE
Cardiac slowing and arrest
Malignant hyperthermia
Respiratory depression
↑ intraocular pressure,
Rhabdomyolysis
CI
History of malignant hyperthermia

END OF DIRECT-ACTING NICOTINIC

TOC
MUSCARINIC ANTAGONISTS & NICOTINIC ANTAGONISTS

CONTENTS
ANTIMUSCARINIC - MUSCARINIC ANTAGONISTS
ANTINICOTINIC - NICOTINIC RECEPTOR ANTAGONISTS
END OF CONTENTS

MUSCARINIC ANTAGONISTS

CLASSES
GI, Gastrointestinal tract; B, bladder; A, anesthesia; O, ophthalmic; MS, motion sickness; P, Parkinson’s; L, lung
Belladonna alkaloids
Atropine (Prototype)
Hyoscyamine (GI, B)
Scopolamine (A, O, MS)
Synthetic muscarinic antagonists
Benztropine (P)
Cyclopentolate (O)
Darifenacin (B)
Homatropine (O)
Ipratropium (L)
Oxybutynin (B; transdermal)
Solifenacin (B)
Tiotropium (L)
Trihexyphenidyl (P)
Tolterodine (B)
Tropicamide (O)
Other classes of drugs with atropine-like effects, such as
First generation antihistamine, many antipsychotics, tricyclic antidepressants, some antiparkinson drugs, & quinidine all have significant antimuscarinic effects

MECHANISM OF ACTION
block the effects of the parasympathetic nervous system
effects of ACh are reversed
muscarinic vasodilating actions - blocked
nicotinic (ganglion) vasoconstricting actions - unmasked
Atropine competitive, surmountable antagonist
Scopolamine
Both are tertiary amines

atropine will not increase blood pressure because there is no parasympathetic tone to the blood vessels
Both anticholinergics & phenylephrine, an α1-adrenoceptor agonist, induce mydriasis, but phenylephrine will not induce cycloplegia (loss of accommodation)

EFFECTS / USES / SIDE EFFECTS

M1-SELECTIVE (PIRENZEPINE)

IDecrease secretions / Preanesthetic medication / Dry mouth
Sedative / Preanesthetic medication

Antagonize poisoning from cholinesterase inhibitors & muscarine

ATROPINE (PROTOTYPE) NONSELECTIVE , HOMATROPINE, TROPICAMIDE

Blocks muscarinic effects (DUMBBELSS) of anticholinesterases, but not the nicotinic effects
CA AChEI overdose

CA Anesthesia premedication
CA Antidote for mushroom poisoning

Eye
↑ pupil dilation, cycloplegia
CA Eye exam - ophthalmic applications
AE Blurred vision Photophobia Angle closure glaucoma
Airway
Bronchodilation, ↓ secretions
Heart
↑ HR (may be an initial decrease due to vagally mediated (e.g., vagal nuclei activity)
CA severe (acute) Bradycardia that is vagally mediated (e.g.,digoxin therapy)
AE Tachycardia
Stomach
↓ acid secretion
Gut
↓ motility
Bladder
↓ urgency in cystitis
AE
Hot as a hare Fast as a fiddle Dry as a bone Red as a beet Blind as a bat Mad as a hatter Full as a flask
↑ Body temperature (due to ↓ sweating )
↑ HR
Dry mouth
Dry, flushed skin
Cycloplegia Blurred vision ↑ IOP
Constipation
Disorientation
Can cause
acute angle-closure glaucoma in older adults (due to mydriasis)
Urinary retention in men with prostatic hyperplasia
hyperthermia in infants
Jimson weed (Datura) → gardener’s pupil (mydriasis)
CI Narrow angle glaucoma

SCOPOLAMINE BENZTROPINE OXYBUTYNIN M1-2-3

BENZ-TROPINE, TRIHEXYPHENIDYL
CNS
Parkinson’s disease (“park my Benz”) some symptoms - Acute dystonia 

GLYCOPYRROLATE
GI, Respiratory
Parenteral : preoperative use to reduce airway secretions
Oral : reduces drooling, peptic ulcer

HYOSCYAMINE, DICYCLOMINE
GI
Antispasmodics for irritable bowel syndrome

IPRATROPIUM M3 , TIOTROPIUM
Respiratory Bronchodilation
CA COPD, asthma
Duration : tiotropium > ipratropium quaternary

S-OLIFENACIN, O-XYBUTYNIN, F-LAVOXATE, T-OLTERODINE   (SLIGHTLY) M3-SELECTIVE (DARIFENACIN)
Genitourinary
CA Reduce bladder (overactive) spasms & urge urinary incontinence (overactive bladder) Make bladder SOFT
Oxybutynin is available as a transdermal formulation; it has 1/5 the anticholinergic activity of atropine but has 4 to 10 times the antispasmodic activity; increases bladder capacity, decreases uninhibited contractions, and delays desire to void, therefore, decreases urgency & frequency

SCOPOLAMINE
CNS
CA Motion sickness - patch behind the ear - Nausea & vomiting
AE Like atropine, more sedation - Drowsiness
CI Like atropine

LARGE THERAPEUTIC INDEX
Side effects
Flushing (red as a beet)
Blurred vision, cycloplegia (blind as a bat)
Xerostomia, anhydrosis (dry as a bone)
Hyperthermia (hot as a hare)
Confusion, delirium, hallucinations (mad as a hatter)
Atropine toxicity: “mad as a hatter, dry as a bone, blind as a bat, red as a beet, hot as hell, heart goes on alone”
life-threatening toxicity only in children
Adult anticholinergic poisoning
cholinesterase inhibitor
Death follows coma and respiratory depression
Treatment of overdose

END OF MUSCARINIC ANTAGONISTS

ANTINICOTINIC - NICOTINIC RECEPTOR ANTAGONISTS
ANTAG (& NAMs) =  NICOTINIC ANTAG
Ganglionic blocking
Nondepolarizing neuromuscular blocking
Depolarizing neuromuscular blocking
Centrally acting nicotinic antagonists

GANGLIONIC BLOCKERS -  GANGLIONIC BLOCKING DRUGS
BLOCK NICOTINIC RECEPTOR AT GANGLION
competitively inhibit nicotinic cholinoceptors in the ganglion
PRIMARILY USED IN MECHANISTIC STUDIES
EXAMPLES - polar amines
Hexamethonium
is often tested on Board Exams; because it is an excellent experimental drug to attenuate reflex responses by blocking the ganglia
Trimethaphan
Used to control blood pressure during surgery
Discontinued in United States
Trimethaphan has a very short duration of action and is thus useful to treat hypertensive crises
Blockade of sympathetic ganglia by trimethaphan reduces peripheral vascular resistance and lowers blood pressure
THE MAJOR LIMITATION
inhibit both sympathetic and parasympathetic ganglia
many autonomic side effects
Less toxic drugs are available for the treatment of essential hypertension

There is no therapeutic use for nicotine except in smoking cessation products
Nicotine activates nicotinic receptors in the
Sensory nerve endings
Ganglia
Adrenal medulla
Neuromuscular junction, leading to depolarization block

NEUROMUSCULAR BLOCKERS
MECHANISM OF ACTION
Block nicotinic receptors at the neuromuscular junction - Nicotinic receptor antagonists
Examples
Cisatracurium
Tubocurarine Lethal injections
Pancuronium
Rocuronium
Vecuronium
USE
Relaxation of striated muscle
CA NMJ blockade during surgery & intubation
AE Apnea Bronchospasms Hypertension Arrhythmias Respiratory failure Histamine release (tubocurarine)
CI Hypersensitivity
Relaxation may be reversed by cholinesterase inhibitors
Neostigmine
Pyridostigmine

END OF ANTINICOTINIC

TOC
SKELETAL MUSCLE RELAXANTS - BLOCKING DRUGS
(Neal Glance 9e 2020) V1 JPG

CONTENTS

PERIPHERALLY ACTING (PRIMARILY ANTINICOTINIC, NMJ BLOCK)
block skeletal neuromuscular transmission, thereby inducing paralysis
NON-DEPOLARIZING - CURARE ALKALOIDS
Alcuronium - Dimethyltubocurarine - Tubocurarine Long action
NON-DEPOLARIZING - 4° AMMONIUM AGENTS
Ultra-short duration : Gantacurium
short duration : Rapacuronium - Mivacurium- Chandonium
Intermediate duration : Atracurium - Cisatracurium  - Fazadinium - Rocuronium- Vecuronium
Long duration :  Doxacurium - Dimethyltubocurarine - Pancuronium - Pipecuronium-  Laudexium - Gallamine
Unsorted : Hexafluronium (Hexafluorenium)
DEPOLARIZING
Choline derivatives : Suxamethonium (Succinylcholine)
Polyalkylene derivatives : Hexamethonium
ACH RELEASE INHIBITORS
Botulinum toxin

CENTRALLY ACTING - CNS ACTION
Carbamic acid esters
Carisoprodol - Cyclarbamate - Difebarbamate - Febarbamate - Meprobamate - Phenprobamate - Styramate - Tybamate
Benzodiazepines
Bromazepam - Diazepam  Chronic use - Clonazepam - Flunitrazepam - Lorazepam - Nitrazepam - Temazepam - Tetrazepam
Nonbenzodiazepines
Eszopiclone
Thienodiazepines
Etizolam
Quinazolines
Methaqualone
Anticholinergics (Antimuscarinics)
Cyclobenzaprine  Acute use - Orphenadrine
Other
Arbaclo -fenplacarbil - Baclofen Chronic use - Chlormezanone - Chlorphenesin- Chlorzoxazone - Eperisone - Fenyramidol - Flopropione- Gabapentin- GHB - Inaperisone-  Lanperisone - Mephenesin- Mephenoxalone -Metaxalone - Methocarbamol - Phenibut - Pregabalin- Pridinol - Promoxolane-- Quinine - Silperisone - Thiocolchicoside -Tizanidine Chronic use - Tolperisone - Zoxazolamine

DIRECTLY ACTING
Dantrolene Muscle action

END OF CONTENTS

SPASMOLYTICS - SKELETAL MUSCLE RELAXANTS
Certain chronic diseases (e.g., cerebral palsy, multiple sclerosis) and spinal cord injuries are associated with abnormally high reflex activity in neuronal pathways controlling skeletal muscles, resulting in painful spasms or spasticity
Maintenance intrathecal infusion can be administered via an implanted pump delivering the drug to a selective site of the spinal cord
GOALS OF SPASMOLYTIC THERAPY
Reduction of excessive muscle tone without reduction in strength
Reduction in spasm, which reduces pain and improves mobility

GAMMA-AMINOBUTYRIC ACID (GABA)-MIMETICS
Diazepam acts on GABAA; baclofen acts on GABAB receptors

BAC-LOFEN (GABAB AGONIST) Acts on the BACk (spinal cord)
MA
is a central muscle relaxant that activates GABAB receptors - thereby decreases spasticity
CU
Muscle spasticity, dystonia, multiple sclerosis
Spasticity associated with multiple sclerosis or spinal cord lesions
AE
May cause sedation
Slurred speech
Hypotension
Polyuria
CI
HS

DIAZEPAM
MA
GABAA agonist
CU
Skeletal muscle relaxant
AE
Amnesia
Sedation
Slurred speech
Paradoxical excitement
CI
Hypersensitivity
Narrow-angle glaucoma
Pregnancy

OTHER RELAXANTS

BOTULINUM TOXIN (BOTOX)
MA
Inhibits blocks acetylcholine (Ach) release , which induces muscle paralysis
CU
It is used to reduce motor unit activity in eye and facial muscles
Strabismus
Blepharospasm
Cervical dystonia
Wrinkles Botox
Hyperhydrosis
AE
Arrhythmias
Syncope
Hepatotoxicity
Anaphylaxis
CI
HS

C-YCLOBENZAPRINE - Structurally related to TCAs
MA
Acts within CNS, mainly at the brainstem - Centrally acting
CU
Muscle spasm associated with acute painful musculoskeletal conditions
AE
May cause anticholinergic adverse effects, sedation
Drowsiness
Xerostomia
Dyspepsia
Blurred vision
CI
Hypersensitivity
Hyperthyroidism
Don’t use with MAO inhibitors
Heart disease

D-ANTROLENE
not effective,in serotonin syndrome
MA
reduces calcium release from the sarcoplasmic reticulum in skeletal muscle
This reduces the spasticity from malignant hyperthermia (e.g., as induced by inhalation anesthetics & neuromuscular blocking drugs)
MA
Prevents release of Ca2+ from sarcoplasmic reticulum of skeletal muscle by inhibiting the ryanodine receptor - Acts Directly on muscle
CU
Malignant hyperthermia (toxicity of inhaled anesthetics & succinylcholine) & neuroleptic malignant syndrome (toxicity of antipsychotics)
Spasticity associated with: spinal cord injury, stroke, cerebral palsy, or multiple sclerosis
AE
Drowsiness
Headache
Blurred vision
Diarrhea (severe)
Respiratory depression
CI
Hepatic disease

TIZANIDINE - Tizanidine is similar to clonidine with fewer peripheral effects
MA
α2 agonist, acts centrally
CU
Muscle spasticity, multiple sclerosis, ALS, cerebral palsy
good for spasticity associated with spinal cord injuries
AE
Hypotension
Somnolence
Xerostomia
CI
Hypersensitivity
Concomitant therapy with ciprofloxacin or fluvoxamine (potent CYP1A2 inhibitors)

END OF SPASMOLYTICS

PHARMACOLOGY OF MOTOR END PLATE  - NEUROMUSCULAR BLOCKING DRUGS

GENERAL
CA Muscle paralysis in surgery or mechanical ventilation
Selective for Nm nicotinic receptors at neuromuscular junction but not autonomic Nn receptors
ACh acts on nicotinic receptors at motor end plate or NMJ

COMPARISON OF NONDEPOLARIZING & DEPOLARIZING NEUROMUSCULAR BLOCKERS
EFFECT / COMPETITIVE / DEPOLARIZING
Action at receptor / Antagonist / Agonist
Effect on motor end plate depolarization / None / Partial persistent depolarization
Initial effect on striated muscle / None / Fasciculation
Muscles affected first / Small muscles / Skeletal muscle
Muscles affected last / Respiratory / Respiratory
Effect of AChE inhibitors / Reversal / No effect or increased duration
Effect of ACh agonists / Reversal / No effect
Effect on previously administered D-tubocurarine / Additive / Antagonism
Effect on previously administered succinylcholine / No effect of antagonism / Tachyphylaxis or no effect
Effect of inhalational anesthetics / Increase potency / Decrease potency
Effect of antibiotics / Increase potency / Decrease potency
Effect of calcium channel blockers / Increase potency / Increase potency

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS - COMPETITIVE NICOTINIC ANTAGONISTS quaternary amines
Also known as curariform drugs, of which tubocurarine is the prototype

MA
Atracurium, Cisatracurium, Pancuronium, Rocuronium, Vecuronium -  competitive Nm nicotinic receptor antagonist
Tubocurarine ?
These drugs compete with ACh at nicotinic receptors at the neuromuscular junction, producing muscle relaxation and paralysis
MOA: compete with ACh at nicotinic receptors at NMJ
The end-plate potential (EPP) is reduced
The EPP must be reduced to 20% of the normal amplitude for muscle paralysis to occur
reduction of the safety factor : Myasthenia gravis General anesthetics Aminoglycoside antibiotics Calcium channel blockers
increase in the safety factor : cholinesterase inhibitors

CU
Lethal injections (tubocurarine)
All others are used for NMJ blockade during surgery and intubation

DRUG INTERACTIONS
Nondepolarizing neuromuscular blockers are reversed by AChE inhibitors

Reversal of blockade - sugammadex or cholinesterase inhibitors (eg, neostigmine).
Anticholinergics (eg, atropine, glycopyrrolate) are given with cholinesterase inhibitors to prevent muscarinic effects (eg, bradycardia)

AE
Respiratory paralysis failure
Blockade of autonomic ganglia Blocks ganglionic nicotinic receptors, which can also lower blood pressure
Histamine release (most profound with d tubocurarine) which can lead to bronchospasm and lower blood pressure
Apnea
Bronchospasms
Hypertension
Arrhythmias

CI
Hypersensitivity

Pancuronium (Pavulon) induces a vagal blockade, which can increase heart rate and increase blood pressure.
Atracurium (Tracrium) is very short acting
Vecuronium (Norcuron) has no cardiovascular side effects

END OF NONDEPOLARIZING

DEPOLARIZING NEUROMUSCULAR BLOCKERS
neuromuscular blocking drugs act like ACh but are not broken down as quickly
SUCCINYLCHOLINE
strong Nm nicotinic receptor agonist ; produces sustained depolarization & prevents muscle contraction
MECHANISM OF ACTION Reversal of blockade Nicotinic receptor agonist that produces a depolarizing blockade
Depolarizing neuromuscular blockers may be potentiated by AChE inhibitors
ACTIVATES THE NICOTINIC CHOLINOCEPTORS
Phase 1 depolarization block - Phase I (prolonged depolarization) - no antidote - Block potentiated by cholinesterase inhibitors.
opening of sodium channels, depolarization, and fasiculations - flaccid paralysis
Phase 2 block - Phase II (repolarized but blocked ; Nm nicotinic receptors are available, but desensitized) - may be reversed with cholinesterase inhibitors
receptor desensitization - Sodium channels close and are refractory to further stimulation
METABOLIZED BY BUTYRYLCHOLINESTERASES
Succinylcholine apnea - genetic - ↑  risk of prolonged muscle paralysis in patients with pseudocholinesterase deficiency
Excessive paralysis will be induced by a standard dose - Paralysis of the respiratory muscles
no antidote
ventilated
RAPID ONSET AND SHORT DURATION

CU
Intubation
Induction of neuromuscular blockade during surgery
Electroconvulsive therapy

ADVERSE EFFECTS
Complications include hypercalcemia, hyperkalemia, malignant hyperthermia
Muscle pain

CI
History of malignant hyperthermia

PRECAUTION

PRIMARY USES OF NEUROMUSCULAR BLOCKING DRUGS ARE AS AN ADJUNCT DURING INTUBATION & FOR MUSCLE RELAXATION DURING SURGERY

END OF DEPOLARIZING

MALIGNANT HYPERTHERMIA
Rare, life-threatening, hypermetabolic condition caused by the administration of potent inhaled anesthetics (sevoflurane, desflurane, isoflurane) or succinylcholine in susceptible individuals
Susceptibility to malignant hyperthermia is caused by de novo or inherited (autosomal dominant) mutations to ryanodine (RYR1) or dihydropyridine receptors (DHPR)
↑ ↑ Ca2+ release from sarcoplasmic reticulum → sustained muscle contraction → hypercapnia, tachycardia, masseter/generalized muscle rigidity, rhabdomyolysis, hyperthermia.
Treatment : dantrolene (ryanodine receptor antagonist)

OTHER DRUGS CAN AFFECT MUSCLE FUNCTION BY VARIOUS MECHANISMS
Hemicholinium blocks the uptake of choline and leads to depletion of ACh in the motor nerve terminal
α-Bungarotoxin binds irreversibly to the neuromuscular nicotinic cholinoceptor

TOC
NOR-ADRENERGIC R MODULATORS
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α1 Ag Antag
α2 Ag Antag
β Ag Antag

TOC
SYMPATHOMIMETICS

DIRECT SYMPATHOMIMETICS

α β AG NONSELECTIVE
NOREPINEPHRINE

α1 AG
MIDODRINE

α1 AGs
A Hypotension (phenylephrine) - Nasal congestion -  Eye hyperemia
AE Arrhythmias - Hypertension - Nervousness - Rebound nasal congestion
CI Severe hypertension - Narrow-angle glaucoma
PHENYLEPHRINE α1 > α2
(NAPHAZOLINE)
(OXYMETAZOLINE)

α2 AGs SYMPATHOLYTICS
A Hypotension (not tizanidine) - CNS effects (clonidine) - Muscle spasms (tizanidine)
AE Bradycardia - Dry mouth - Constipation - Sedation - Autoimmune hemolytic anemia (methyldopa)
CI Abrupt withdrawal
CLONIDINE α2
(GUANABENZ)
α METHYLDOPA (PRODRUG)
TIZANIDINE

β AG NONSELECTIVE
ISOPROTERENOL

β1 AG
DOBUTAMINE
A
Cardiac decompensation
AE
Tachycardia - Hypertension - Dyspnea
CI
Idiopathic hypertrophic subaortic stenosis - Hypersensitivity to dobutamine or sulfites

β2 AGs
ALBU-TEROL
(SALME-TEROL)
TERBUTALINE
(RITODRINE)
A
Asthma - COPD - Tocolytic (terbutaline and ritodrine)
AE
Tremors - Nervousness - Xerostomia - Tachycardia - Hypertension
CI
Hypersensitivity

D1 Ag
FENOLDOPAM
A
Emergency hypertension
AE
Arrhythmias - Angina - Facial flushing - Hypokalemia
CI
Hypersensitivity

INDIRECT SYMPATHOMIMETICS

RELEASERS (AMPHETAMINE)
REUPTAKE INHIBITORS (COCAINE)
EPHEDRINE

PHYSIOLOGIC EFFECTS OF SYMPATHOMIMETICS

TOC
ADRENERGIC RECEPTOR ANTAGs

α-BLOCKERS NONSELECTIVE
PHENTOLAMINE (REVERSIBLE)
PHENOXYBENZAMINE (IRREVERSIBLE)
A
Pheochromocytoma - Extravasation of alpha agonists - Sweating
AE
Postural hypotension - Tachycardia - Inhibition of ejaculation - Nasal congestion
CI
Shock - Coronary artery disease

α1 ANTAGs SELECTIVE
PRAZ-OSIN
TERAZ-OSIN
DOXAZ-OSIN
A
Hypertension
AE
First-dose postural hypotension - ↑ urinary frequency - Nasal congestion - Hepatotoxicity - Pancreatitis
CI
Concurrent use with phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil

α1 ANTAGs SELECTIVE
DOXAZ-OSIN
TAMSUL-OSIN (PROSTATE SPECIFIC)
ALFUZ-OSIN (PROSTATE SPECIFIC)
A
Benign prostatic hyperplasia (BPH)
AE
Same as doxazosin but tamsulosin and alfuzosin produce less hypotension
CI
Hypersensitivity

ALPHA2-SELECTIVE (YOHIMBINE) ANTAGs

β-BLOCKERS NONSELECTIVE
PROPRANOLOL β1-2
NADOLOL
TIMOLOL
A
Hypertension - Angina - Supraventricular arrhythmias - Migraine headache (propranolol) - Essential tremor (propranolol) - Glaucoma (timolol)
AE
AV block - Bronchospasm - Sedation - Wheezing - Mask hypoglycemia
CI
Lung disease - Cardiogenic shock - Heart block

β1-BLOCKERS SELECTIVE
METOPROLOL
ATENOLOL
ESMOLOL (SHORT ACTING)
A

AE

CI

A

AE

CI

Beta2-selective (Butoxamine)
Carvedilol α1 β

PHOSPHODIESTERASE INHIBITORS

TOC
LOCAL ANESTHETICS
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Esters
Long action (tetracaine)
Short action (procaine)
Surface action (benzocaine, cocaine)
Amides
Long action (bupivacaine, ropivacaine)
Medium action (lidocaine)

TOC
OCULAR
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Glaucoma therapy
Drugs affecting pupil size
Antiallergic agents
Anesthetics
Anti-infectives
Anti-inflammatories
Steroidal anti-inflammatories
Nonsteroidal anti-inflammatories
Lubricants
Miotics. Carbachol Pilocarpine.  Sphincter, Improve AH outflow
Mydriatics. Dipivefrin Epinephrine Hydroxyamphetamine Phenylephrine. Dilator, Lower IOP
Mydriatics & Cycloplegics. Atropine sulfate Cyclopentolate hydrochloride Homatropine hydrobromide Tropicamide. Ciliary Body Muscle ?, Preventing accommodation for near vision
Other drugs to lower IOP.
Adrenergic blockers (topical). May reduce aqueous humor formation & slightly increase AH outflow
Carbonic anhydrase inhibitors. Thus decreasing AH production
Osmotic agents. Reduce volume of vitreous humor, Decrease IOP
Prostaglandin analogues. Decrease IOP

TOC
OTIC

TOC
CENTRAL NERVOUS

TRANSMITTER
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(Lerchenfeldt BRS 7e 2019 Contents) V1 PDF
(Gould BRS Neuroanatomy 2019 Neurotransmitters and Pathways) V1 PDF

Monoaminergic
Dopamine : Controls arousal levels, vital for physical motivation
NE : Mental arousal and affects mood
E
Serotonin 5HT : Affects mood and anxiety
Cholinergic
Acetylcholine : Attention, memory, and learning
AA
Glutamate, GABA : Basis of learning and long-term memory
Peptide
Enkephalins : Sensation of calm
NO

Preferred medications for selected psychiatric conditions
Central nervous system stimulants

GENERAL ANESTHETICS
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General principles
Inhaled anesthetics
Gas (nitrous oxide)
Volatile liquids (haloth-ane)
Intravenous anesthetics
Barbiturates (thiopental)
Miscellaneous (etomidate, propofol)
Benzodiazepines (midazolam)
Dissociative (ketamine)
Opioids (fentanyl)

ANXIOLYTICS & HYPNOTICS/SEDATIVES Anxiety disorders : Increased NE; decreased GABA and serotonin

(Neal Glance 9e 2020) V1 JPG

Barbiturates Ultra-short action (thiopental) Short action (seco-barbital) Long action (pheno-barbital) Benzodiazepines Short action (tria-zolam) Intermediate action (alpra-zolam) Lora-zepam Long action (flura-zepam) Non BZ Miscellaneous agents Buspirone Chloral hydrate Eszopiclone Ramelteon Zaleplon Zolpidem Insomnia therapy Triptans

CLINICALLY IMPORTANT ALCOHOLS & THEIR ANTAGONISTS

EPILEPSY/SEIZURES

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Epilepsy therapy Tonic-clonic & partial seizures Absence seizures Myoclonic seizures Back-up & adjunctive drugs

Neurodegenerative disease therapy Alzheimer disease Amyotrophic lateral sclerosis Huntington disease PARKINSON Parkinson’s disease : Decreased dopamine

(Neal Glance 9e 2020) V1 JPG

Parkinsonism disease therapy Carbidopa/levodopa Other movement disorders

ALZHEIMER Alzheimer’s disease : Decreased acetylcholine Huntington’s disease : Decreased GABA & acetylcholine

Acetylcholinesterase inhibitors N-methyl-D-aspartate (NMDA)-receptor antagonist Memantine

PSYCHOSES & BIPOLAR LITHIUM Schizophrenia : Increased dopamine

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ANTIPSYCHOTICS Typical Classic drugs (D2 receptor affinity) Haloperidol Atypical Newer agents (5HT2 receptor affinity) Queti-apine -idone BIPOLAR Classic drug Lithium Newer agents carbamazepine clonazepam olanzapine valproic acid others

ANTIDEPRESSANTS Depression : Decreased NE & serotonin

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Antidepressants Selective Serotonin Reuptake Inhibitors (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Serotonin-Norepinephrine Reuptake Inhibitors (duloxetine, venlafaxine) Tricyclic Antidepressants (ami-triptyline, clom-ipramine, im-ipramine) Monoamine Oxidase Inhibitors (phenelzine, selegiline, tranylcypromine) Atypical Heterocyclic Tetracyclic (amoxapine, bupropion,mirtazapine (tetra)) 5HT2 R Antagonists (nefazodone, trazodone) DNRI Bupropion

OPIOID ANALGESICS & ANTAGONISTS

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Opioid analgesics Tramadol Mixed agonist and antagonist opioid analgesics Capsaicin Opioid detoxification and relapse prevention

DRUG ABUSE

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RENAL

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DIURETICS/DRUGS THAT MODIFY SALT EXCRETION Site of action PCT Carbonic anhydrase inhibitors (acetazolamide) TAL Loop diuretics (furosemide) DCT Thiazides (hydrochlorothiazide) CCT K+-sparing diuretics (spironolactone) Osmotic diuretics (mannitol) Electrolyte changes Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Aliskiren ANTIDIURETIC/DRUGS THAT MODIFY WATER EXCRETION Mannitol ADH agonists (desmopressin) ADH antagonists (conivaptan)

CARDIOVASCULAR

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HYPERTENSION

Hypertension treatment Cardiovascular agents & molecular targets Emergency Diuretics Sympathoplegics—blockers of CNS sympathetic outflow (Clonidine) Ganglia (Hexamethonium) Nerve terminals (Guanethidine, Reserpine) Alpha or beta receptors (Prazosin, Propranolol) Vasodilators Older oral vasodilators (Hydralazine) Calcium channel blockers (Nifedipine) Parenteral vasodilators (Nitroprusside) Angiotensin antagonists ACE inhibitors (Captopril) Receptor blockers (Losartan) Renin inhibitor (Aliskiren)

ANGINA PECTORIS

Antianginal therapy Ranolazine Sacubitril Vasodilators Nitrates Short duration (sublingual nitroglycerin) Intermediate (oral nitroglycerin) Long duration (transdermal nitroglycerin) Vasodilators Calcium blockers (verapamil) Cardiac depressants Calcium blockers (verapamil) Cardiac depressants Beta blockers (propranolol) Other drugs Metabolism modifiers; rate inhibitors

HEART FAILURE

Positive inotropic drugs Cardiac glycosides (digoxin) Beta agonists (dobutamine) PDE inhibitors (milrinone) Vasodilators Vasodilators Nitroprusside nitrates hydralazine Loop diuretics, angiotensin inhibitors, nesiritide, sacubitril, SGLT2 inhibitors Miscellaneous drugs for chronic failure Beta blockers, spironolactone

ARRHYTHMIAS

Group 1 Sodium channel blockers (procainamide) Group 2 β blockers (esmolol) Group 3 Potassium channel blockers (amiodarone,dofetilide) Group 4 Calcium channel blockers (verapamil) Group 5 Miscellaneous group (adenosine, K+, Mg2+) Ivabradine

VASCULAR

GASTROINTESTINAL

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ANTIEMETIC/NAUSEA & VERTIGO

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Benzodiazepine (Lorazepam) Selective 5-HT3 blockers (ondansetron) D2 blockers (prochlorperazine) H1 blockers (diphenhydramine) Antimuscarinics M1 (scopolamine) Corticosteroids (dexamethasone) Cannabinoids (dronabinol) Neurokinin receptor 1 antagonists (aprepitant)

OBESITY

GLP 1 R Ago Lipase I 5-HT agonist (lorcaserin) Amphetamine-mimetics (phentermine) Symp Miscellaneous

TO INCREASE APPETITE Megestrol Dronabinol

ACID-PEPTIC ULCER

Acid suppression therapy Antacids (Mg[OH]2), CaCO3 H2-blockers (cimetidine) Proton pump inhibitors (omeprazole) Mucosal protective agents (sucralfate, misoprostol, bismuth compounds) Antibiotics

OTHER

Constipation Bulk-forming laxatives Irritant (stimulant) laxatives (cathartics) Lubricating agent Osmotic laxatives Opoid R antago Stool softener Diarrhea Flatulence Motility promoters Prokinetic Metoclopramide, cholinomimetics Drugs for irritable bowel syndrome IBS Anticholinergics, serotonin antagonists Drugs for inflammatory bowel disease IBD 5-ASA drugs, corticosteroids immunosuppressants, anti-TNF drugs Other agents Pancreatic lipase, laxatives, antidiarrheals ursodiol Octreotide Sulfasalazine Loperamide Orlistat

PULMONARY

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ASTHMA & OTHER BRONCHIAL Bronchodilators COPD Beta2 agonists : SABAs LABAs Muscarinic antagonists Methylxanthines Anti-inflammatory agents Release inhibitors Steroids Ihn GC COPD Slow anti-inflammatory drugs Antibodies Leukotriene antagonists Is Lipoxygenase inhibitors Receptor inhibitors PDE4 Inh Anti-IgE Ab RHINITIS Anti H1 H1-blockers Alpha ago COUGH Antitussives Expectorants Mucolytics Chromones Dextromethorphan Pseudoephedrine, phenylephrine CHRONIC OBSTRUCTIVE PULMONARY DISEASE Antibiotics PULMONARY HYPERTENSION

ENDOCRINE (Lerchenfeldt BRS 7e 2019 Contents) V1 PDF

HYPOTHALAMIC/PITUITARY DRUGS

HYPOTHALAMUS GnRH Agonist action Gonadorelin Antagonist action GnRH receptor agonist (leuprolide) GnRH receptor antagonist (ganirelix) ANTERIOR PITUITARY Growth hormone Agonist action Somatropin Mecasermin Antagonist action Octreotide Pegvisomant Gonadotropins Agonist action Mixed LH & FSH Menotropins LH Lutropin hCG FSH Follitropin Prolactin Antagonist action D2 dopamine agonists (bromocriptine) POSTERIOR PITUITARY Oxytocin Agonist action Oxytocin Antagonist action Atosiban (not FDA approved) Vasopressin Agonist action Desmopressin Antagonist action Conivaptan

CORTICOSTEROIDS

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Agonists Glucocorticoids (prednisone) Mineralocorticoids (fludrocortisone) Antagonists Receptor antagonists Glucocorticoid antagonists (mifepristone) Mineralocorticoid antagonists (spironolactone) Synthesis inhibitors (ketoconazole) Cinacalcet Sevelamer Cation exchange resins

REPRODUCTIVE

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Estrogens (ethinyl estradiol) Antiestrogens Receptor antagonists Full antagonists (fulvestrant) SERMs (tamoxifen) Aromatase inhibitors (anastrozole) Other (GnRH agonists, danazol) Progestins (L-norgestrel)  R modulator ? Ulipristal acetate ? Antiprogestins (mifepristone) Androgens (testosterone) methyltestosterone Antiandrogens Receptor antagonists (flutamide) 5α-Reductase inhibitors (finasteride) Synthesis inhibitors (ketoconazole) Other (GnRH agonist, combined oral contraceptives) Control of reproductive hormones Degarelix Hormone replacement therapy Combined contraception Copper intrauterine device Tocolytics Danazol Tamsulosin Minoxidil

THYROID

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Hypothyroidism Levothyroxine (T4) Liothyronine (T3) Hyperthyroidism Thioamides (propythiouracil) Iodide (Lugol solution) Beta blockers (propranolol) 131I

DIABETES MELLITUS

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Diabetes mellitus therapy Insulins Ultra short Rapid, short-acting (lispro, regular) Intermediate-acting (NPH, lente) Slow, long-acting (glargine) Ultra long Noninsulin antidiabetic drugs Insulin secretagogues (glipizide) sulfonylureas            Meglitinides ? Biguanides (metformin) Alpha-glucosidase inhibitors (acarbose) Thiazolidinediones (pioglitazone) Amylin analogs (pramlintide) Incretin modulators GLP-1 analog (exenatide) DPP-4 inhibitor (sitagliptin) SGLT2 inhibitors (canagliflozin) Increase blood glucose Diazoxide Glucagon

BONE MINERAL HOMEOSTASIS

Hormonal PTH Vitamin D Calcitonin Estrogen Glucocorticoids Nonhormonal Bisphosphonates Fluoride Calcimimetics

RETINOIC ACID DERIVATIVES

AUTACOIDS, ERGOTS & ANTI-INFLAMMATORY (Lerchenfeldt BRS 7e 2019 Contents) V1 PDF

Kinins    Kininogen (HMWK, LMWK) Bradykinin Kallidin Tachykinins Urotensin-II Others    Angiotensin Eicosanoid Histamine Platelet-activating factor Serotonin Palmitoylethanolamide

HISTAMINE RECEPTOR BLOCKERS

H1 blockers -tadine First generation (diphenhydramine) Second generation (cetirizine) H2 blockers (cime-tidine)

SEROTONIN RECEPTOR AGONISTS AND ANTAGONISTS

Agonists, partial agonists 5-HT1 agonists (sumatriptan) 5-HT4 partial agonists (tegaserod) Antagonists 5-HT2 antagonists (ketanserin) 5-HT3 antagonists (ondansetron)

ERGOT ALKALOIDS

VASOACTIVE PEPTIDES Vasoconstrictors (angiotensin II, endothelins, neuropeptide Y) Mixed (substance P) Vasodilators (bradykinin, BNP, ANP,CGRP, VIP)

Antagonists of peptides Renin (aliskiren) ACE (captopril) Angiotensin (losartan) Vasopressin (conivaptan) Endothelin (bosentan) Vasopeptidase (omapatrilat) Substance P (aprepitant)

EICOSANOIDS

Arachidonic acid pathways Leukotrienes (LTB4, LTC4, LTD4) Prostaglandins (PGE1, PGE2, PGF2), Prostacyclin (PGI2), Thromboxane (TXA2) Eicosanoid antagonists Leukotriene antagonists (zileuton, montelukast, zafirlukast) Prostaglandin antagonists (corticosteroids, NSAIDs)

NITRIC OXIDE

NSAIDS, ACETAMINOPHEN, & RHEUMATOID ARTHRITIS & GOUT

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ANTI-INFLAMMATORY NSAIDs Aspirin Other nonselective NSAIDs COX-2 inhibitors (celecoxib) DMARDs Conventional synthetic (cs) DMARDS Biologic (b) DMARDS ACETAMINOPHEN GOUT Acute NSAIDs Glucocorticoids Chronic Colchicine Uricosurics (probenecid) Xanthine oxidase inhibitors (allopurinol, febuxostat) Leflunomide Bisphosphonates Teriparatide TNF-α inhibitors Imiquimod

ANEMIA & HEMOSTASIS & LIPIDS

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LIPIDS-LOWERING HMG-CoA reductase inhibitors (lovastatin) Resins Ezetimibe Niacin Fibrates (gemfibrozil) PCSK9 Inhibitors (alirocumab, evocumab)

HEMATOPOIETIC FACTORS

Erythrocyte factors Vitamins (B12, folate) Iron Erythropoiesis-stimulating agents (ESAs; erythropoietin) Platelet factor Oprelvekin (IL-11) Granulocyte factors Filgrastim (G-CSF) Sargramostim (GM-CSF)

COAGULATION/CLOTTING

ANTICLOTTING Anticoagulants Heparins Direct thrombin inhibitors Direct factor Xa inhibitors Warfarin Heparin vs warfarin Direct coagulation factor inhibitors Anticoagulation reversal Thrombolytics t-PA derivatives Streptokinase Antiplatelet drugs Aspirin Glycoprotein IIb/IIla inhibitors ADP inhibitors (clopidogrel) PDE/adenosine uptake inhibitors FACILITATE CLOTTING Replacement factors Vitamin K Antiplasmin drugs

ANTIMICROBIAL

ANTIBACTERIAL

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ANTIMICROBIAL THERAPY CELL WALL SYNTHESIS INHIBITORS Penicillins Narrow spectrum : Penicillinase-sensitive, Penicillinase-resistant Wider spectrum Prototype G V, G benzathine and G procaine Penicillinase-resistant Extended-spectrum Beta·Lactamase inhibitors Antipseudomonal Piperacillin -cillin Transpeptidase inhibitor Ampicillin Cephalosporins Narrow spectrum 1st generation Wider spectrum 2nd, 3rd, 4th generations 5th generation Combinations Carbapenems Monobactam Aztreonam Glycopeptides Vancomycin Lipopeptide Daptomycin Other PROTEIN SYNTHESIS INHIBITORS Broad spectrum Chloramphenicol Tetra-cycline-s Protein synthesis inhibitor Moderate spectrum Macrolides -thromycin Ketolide Narrow spectrum Lincosamides Clindamycin Streptogramins Quinupristin plus dalfopristin Oxazolidinones Linezolid AMINOGLYCOSIDES 30S & SPECTINO-MYCIN Glycylcline Tigecycline SULFONAMIDES, TRIMETHOPRIM, & FLUOROQUINOLONES Antimetabolites Antifolates Sulfonamides Trimethoprim Trimethoprim-sulfamethoxazole Pyrimethamine Fluoroquinolones Narrow spectrum 1st generation (eg, nor-floxacin) Wide spectrum 2nd generation (eg, ciprofloxacin) 3rd generation (eg, levofloxacin) Miscellaneous inhibitors of bacterial nucleic acid synthesis Metrodinazole Nitrofurantoin Miscellaneous Mupirocin  Polymixin B ANTIMYCOBACTERIAL Drugs used in tuberculosis First-line drugs (isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin) Alternative drugs (amikacin, ciprofloxacin, ethionamide, p-aminosalicylate) Drugs used in leprosy Acedapsone, dapsone, clofazimine, rifampin Drugs used for nontuberculous mycobacteria Azithromycin, clarithromycin, moxifloxacin Tigecycline Clindamycin Linezolid Daptomycin Rifamycins ANTIMICROBIAL PROPHYLAXIS PROPHYLAXIS IN HIV INFECTION/AIDS

ANTIFUNGAL

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ANTIFUNGAL THERAPY DRUGS ACTING ON FUNGI Alter cell membrane permeability Azoles Polyenes Terbinafine -conazole Ergosterol synthesis inhibitor Ketoconazole Block beta-glucan synthesis Echinocandins Block nucleic acid synthesis Flucytosine Disrupt microtubule functions Griseofulvin Amphotericin B Nystatin

ANTIVIRAL

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ANTIVIRAL THERAPY ANTIVIRAL AGENTS Drugs for herpes Acycl-ovir Viral DNA polymerase inhibitor Ganciclovir Foscarnet Drugs for HIV Fusion inhibitor Reverse transcriptase inhibitors Nucleosides Nonnucleosides Integrase strand transfer inhibitors Protease inhibitors Drugs for influenza Amantadine Zana-mivir Neuraminidase inhibitor Drugs for HBV and HCV INF-α Lamivudine Boceprevir Sofos-buvir NS5B inhibitor Ribavirin -asvir NS5A inhibitor Ledipasvir -navir Protease inhibitor Ritonavir -previr NS3/4A inhibitor Simeprevir -tegravir Integrase inhibitor Elvitegravir Oseltamivir, Baloxavir Remdesivir famciclovir, valacyclovir Cidofovir HIV therapy Pre-exposure prophylaxis Disinfection and sterilization Antimicrobials to avoid in pregnancy

MISCELLANEOUS ANTIMICROBIAL AGENTS & ANTISEPTICS Miscellaneous antimicrobials Metronidazole Mupirocin Polymyxins Fidaxomicin Rifaximin Urinary antiseptics Nitrofurantoin Nalidixic acid Methenamine Disinfectants & antiseptics Alcohols, Aldehydes Acids, Halogens, Oxidizing agents Heavy metals Chlorinated phenols Cation surfactants CLINICAL USE OF ANTIMICROBIAL AGENTS

ANTIHELMINTH

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Antihelminthic therapy ANTIHELMINTHIC DRUGS Drugs active against nematodes Albendazole Diethylcarbamazine Ivermectin Mebendazole Pyrantel pamoate Drugs active against trematodes Bithionol Metrifonate Oxamniquine Praziquantel Drugs active against cestodes Al-bendazole Mebendazole Niclosamide Praziquantel

ANTIPROTOZOAL

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Antiprotozoal therapy ANTIPROTOZOAL DRUGS Antimalarial agents Chloroquine Artemisinins Mefloquine Primaquine Quinine Antifolates Others Drugs for amebiasis Metronidazole Diloxanide Emetine Iodoquinol Drugs used for other parasites Pneumocystosis Toxoplasmosis Leishmaniasis Trypanosomiasis Anti-mite/louse therapy

CANCER

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Cancer therapy—cell cycle Cancer therapy—targets Alkylating agents Nitrogen mustards Cyclophosphamide Alkyl sulfonate Nitrosoureas car-mustine Platinum analogs compounds Cis-platin Proteasome inhibitors Borte-zom-ib carfilzomib Antimetabolites 5-Fluorouracil, methotrexate, gemcitabine, 6-mercaptopurine Natural products Etoposide Microtubule inhibitors damaging agents Taxanes Pacli-taxel, Microtubule inhibitors damaging agents Vinka alkaloids Vincristine Topoisomerase inhibitors I Irino-tecan II Eto-poside Antitumor antibiotics Bleomycin, Anthracycline Doxo-rubicin mitomycin Miscellaneous Hydroxyurea L-Asparaginase Bortezomib Tretinoin Hormonal Prednisone, tamoxifen Miscellaneous 2 Imatinib Cetuximab Antibody-drug conjugates Monoclonal antibodies Tyrosine kinase inhibitors Immumomodulators small molecule inhibitors Chemotoxicity amelioration Key chemotoxicities

IMMUNOLOGICAL

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Immunosuppressants Corticosteroids (prednisone) Immunophilin ligands (cyclosporine, tacrolimus, sirolimus) Mycophenolate mofetil Cytotoxic drugs (azathioprine) Immunoglobulin based agents (etanercept) Immune potentiators Aldesleukin Interferons

BONE

Bone (Rang)

Structure & Composition (Rang)

Remodelling (Rang)

Vitamin D (Moi)

Disorders (Rang)

Drugs (Rang)

TOC
REFERENCES

OVERVIEW, DIDACTIC, REVIEW, REFERENCE

Le. First Aid USMLE Step 1. Pharmacology. 34e. 2024. 30e. [ 27 pages ] [ Pharmacokinetics & Pharmacodynamics - Autonomic Drugs - Toxicities & Adverse Effects - Miscellaneous ]
Le. First Aid Basic Sciences General Principles. General Pharmacology. 3e. 2017. [ 16 pages ] [ Pharmacokinetics & Pharmacodynamics - Toxicology ]
Tellingen. Pharmacology Selected Topics from a Phenomenological Point of View. 1e. 2011.  [ ] [ 91 pages ] [ Info & Download ]
Neal. Pharmacology at a Glance. 9e. 2020. [ ]  [ 120 pages ] [ Download 8e ] [ Flashcards ]
Weiss. HY Pharmacology. 3e. 2009. [ 160 pages ] [ Download ]
Page. Crash Course Pharmacology. 5e. 2018. [ 260 pages ] [ Download 4e ]
Katzung. Katzung & Trevor’s Pharmacology : Examination and Board Review. 13e. 2021. [ 608 pages ] [ 12e Download  Download ]
Katzung. Basic & Clinical Pharmacology. 15e. 2020. [ 1328 pages ] [ Download ]
Baron. Lange Pharmacology Flash Cards. 2018. [ Download ]
Brenner. Pharmacology Flash Cards. 2017.
Lerchenfeldt. BRS Pharmacology. 7e. 2019. [ 384 pages ] [ Download ] [ Download ]
Whalen. LIR Pharmacology. 8e. 2022. [ 704 pages ] [ Download 7e ] [ Download 7e ] [ Download 7e ]
Ritter. Rang & Dale's Pharmacology. 10e. 2023. 9e. 2019. [ ] [ 872 pages ] [ Download 9e ] [ Download 9e ]
Loke. Rang & Dale's Pharmacology Flashcards. 2e. 2020. [ 561 pages ] [ Download 1e ] [ Download 1e ]
Jacob. NMS Pharmacology. 4e. 1996. [ 387 pages ] [ Read 2e ] [ Read 4e ]

Pazdernik. Rapid Review Pharmacology. 3e. 2010. [ 360 pages ] [ Read 2e ]
Tripathi. - kd-tripathi-essentials-of-medical-pharmacologyunitedvrg-2013.pdf - essentials-of-medical-pharmacology-d185808260.html  8e
Brunton. Goodman & Gilman's The Pharmacological Basis of Therapeutics.14e. 2022. [ 1664 pages ] [ Download 13e ] [ Download 13e ]
Brunton. Goodman Manual  2008 goodman-manual
Luellmann. Atlas of pharmacology. 4e. 2010. [ 404 pages ]
Fischer. Master the Boards USMLE Step 1 Pharmacology Flashcards. 2015.
Rebar. Clinical pharmacology made incredibly easy. 5e. 2022. 3rd-edition.pdf
Netter. Download
guidetopharmacology.org
https://bpspubs.onlinelibrary.wiley.com/
Memorizing Pharmacology - A Relaxed Approach (2016) https://docero.com.br/doc/nex1nce

Minimum Vital. Pharmacologie. 2002.
https://www.chu-toulouse.fr/IMG/pdf/lexique_2020.pdf  [ Excellent ! ]
https://commissionromandeformationambulanciere.files.wordpress.com/2020/12/glossaire-pharmacologie-corfa-v1.0.pdf
pharmacol-fr.org/
chups.jussieu.fr/polys/pharmaco/poly/Pharmaco.pdf
pharmacologie.u-bordeaux2.fr/documents/enseignements/poly_pharmacologie_generale.pdf

AUTHORS

TOPICS

CLASSIFICATION
ATC -  wikipedia - bioportal

PK
https://en.wikipedia.org/wiki/Pharmacokinetics
PD
https://en.wikipedia.org/wiki/Pharmacodynamics
https://en.wikipedia.org/wiki/Cell_surface_receptor

EMERGENCY
https://www.researchgate.net/publication/344637452_EMERGENCY_DRUGS

ADVERSE EFFECT
https://en.wikipedia.org/wiki/Adverse_effect

TOXICOLOGY
https://en.wikipedia.org/wiki/Toxicology
https://www.toxicology.org/
EMERGENCY TOXICOLOGY

PHARMACOMODULATION
https://en.wikipedia.org/wiki/Template:Pharmacomodulation
https://en.wikipedia.org/wiki/Receptor_modulator

AUTONOMIC DRUGS
https://en.wikipedia.org/wiki/Autonomic_drug
https://en.wikipedia.org/wiki/Sympatholytic

CHOLINERGIC

PRALIDOXIME
https://en.wikipedia.org/wiki/Pralidoxime
https://www.drugs.com/cons/pralidoxime.html
https://journals.lww.com/jopm/abstract/2014/60010/efficacy_of_pralidoxime_in_organophosphorus.7.aspx

ADRENERGIC

AUTACOID
Titier. 2018. nanopdf.com/download/pharmacologie-des-autacoïdes_pdf
pubmed.ncbi.nlm.nih.gov/27028114/
ncbi.nlm.nih.gov/pmc/articles/PMC5693806/

UNSORTED
https://www.medicosrepublic.com/easy-to-remember-pharmacology-mnemonics-with-pictures/

MORE REFERENCES

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