• reversible competitive antagonists: bind non-covalentlv to the receptor, thusincreasing

concentrations of agonist may overcome the antagonist (e.g. naloxone is a competitive antagonist

to morphine or heroin)

irreversible competitive antagonists:form a covalent bond with the receptor and cannot be

displaced, thus irreversibly blocking othersubstratesfrom binding (e.g. phenoxybenzamine

forms a covalent bond witn adrenergic receptors preventing adrenaline and NE from binding)

• non-competitive antagonism: antagonist (negative allosteric modulator) bindsto an alternate site on

the receptor which is distinct from the active site, producing allosteric effects that alter the ability of

the agonist to bind

Figure 3. The log(dose)-response

curve forirreversible antagonism

Se*

landmark Clinical Fhaimacology trials table

lor moie information go resultsfrom the EFIC trial,

whicli evaluates the eflect of chimerk monoclonal

anti bo dy Fa b fragment|c7E3 Fab) directed against

the platelet glycoprotein IMIa receptor,to treat

ischemic complications of coronary angioplasty and

atherectomy.

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CP9 Clinical Pharmacology Toronto Notes 2023

AGONIST BINDING

Agonist —SElicited effect

Receptor BINDING

ANTAGONIST BINDING

11 Competitive reversible binding

Agonist

Antagonist

Increased

concentration

ol agonist

i S overcomes

antagonist

binding

competition

Agonist concentration

Receptor Antagonist

binding

REVERSIBLE

BINDING

21 Competitive irreversible binding

Agonist

cannot bind

i

receptor which

1— i s irreversibly

blocked by

antagonist

Agonist

Antagonist*

Agonist concentration

IRREVERSIBLE

BINDING

Receptor Antagonist

binding Changes in agonist concentration

ellect cun/e produced by a

competitive agonist IA),and a

non-competitive agonist IB) When a

competitive antagonist is present, a

higher concentration of the drug

(agonist)is required to create an

effect. Therefore,the drug

concentration C'needed to create an

effect in the presence of

concentration [I] of an antagonist is

shifted to the right. High agonist

concentrations can overcome

inhibition in the presence of an

antagonist.This is not the case with

an irreversible (or a non-competitivel

antagonist,which reduces the

maximal effect the agonist can

achieve,although it may not change

the EOi

31 Non-competitive irreversible binding

Agonist

Antagonist ^

Antagonist

bound to

alternative

I site prevents

agonist from

binding to U ~*g~

receptor l

ALLOSTERIC

CHANGE

Receptor Antagonist

binding © Adrian Yen 2006

Figure 4. Mechanism of agonists and antagonists

Effectiveness and Safety

Effectiveness

• EDso (effective dose):the dose of a drug needed to cause a therapeutic effect in 50% of a test population

of subjects

Safety

• LD50 (lethal dose):the dose of a drug needed to cause death in 50% of a test population of subjects

• TDso (toxic dose): the dose of a drug needed to cause a harmful effect in 50% of a test population of

subjects

© CassieHW 2022

Figure 5. Agonist concentration

Therapeutic Indices

Therapeutic Index: TDso/EDso (LDso/EDso in animals)

• a measure of relative drug safety often used when comparing drugs to examine the likelihood of a

therapeutic dose to cause serious toxicity or death

• the larger the Tl, the safer the drug

• common drugs with a narrow therapeutic window or low IT that sometimes require TDM include

digoxin, theophylline, warfarin, lithium, and cyclosporine

• factors that can change the TT include presence of interacting drugs, changes in drug ADME, and

patient characteristics (e.g. age, pregnancy, and organ impairment)

Certain Safety Factor: TD1/ED99

• a comparison of the dose that is effective in at least 99% of the population and toxic in less than 1% of

the population

• regulatory agencies often like to see a certain safety factor or margin of safety above 100

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CP10 Clinical Pharmacology Toronto Notes 2023

Drug A

Toxicity

Efficacy Ellicac 100% Efficacy Toxicity 100%

i: —'A I

§ = 50%

O

C/3

. 50% sCil

O]

10%

EDio TO uLog Dose logIDose)

TheTIfTD a'EDs:|is a measure

of the margin of safety of a given drug

Drug A has a muchnarrowerTI than DrugB.The dose of Drug A

required to achieve a 100% therapeutic response will be toxic in

50% of patients,while drugB will only be toxic in10%

Figure 6. EDso, TDso, and the Tl

Therapeutic Drug Monitoring

• definition: using serum drug concentration data to optimize drug therapy (e.g. dose adjustment,

monitor compliance). Serum drug samples are usually taken when the drug has reached steady-state

(i.e. after approximately 5 half-lives)

• TDM is often used for drugs that have low T Is, unpredictable dose-response relationships,significant

consequences associated with therapeutic failure or toxicity, and/or wide interpatient PK variability

• nomograms are often used for low Tl drugs, particularly in the setting of patients with complex

clinical factors such as renal insufficiency, hepatic failure, dialysis, and hypoalbuminemia

• examples of drugs that sometimes require TDM include:

• vancomycin

• aminoglycosides (gentamicin, tobramycin)

» digoxin

phenytoin and other anticonvulsants

warfarin

• lithium

Tips to Reduce Drug-Related Adverse

Events in the Elderly

• Be mindful of longstanding

medications that have never been

adjusted for patient age or renal or

hepatic function

• Consider whether medications

initiated during hospital admission

are needed long term (and whether

the discharge dose is appropriate for

maintenance)

• Avoid polypharmacy by decreasing

the dose of or discontinuing

medications that are causing side

effects or are no longer indicated

• Verify adherence to medications

before automatically increasing the

dose of subtherapeubc treatment

• When prescribing medications,

preferentially use those with a high Tl

• Review the patient's problem list

and reconcile current medications

to avoid duplication or inappropriate

dosing/frequency

Adverse Drug Reactions

• definition:ADHs are events that occur while a patient is on a drug at either appropriate or

inappropriate dosage. A causal relationship is not required

• definition: AOKs are reactions to drugs that occur when a drug is used for the appropriate indication

at normal therapeutic doses

Table 2. Characteristics of Type A-F Adverse Drug Reactions

Classification Definition Characteristics

Predictable extension of drug's pharmacologic died (e g. |3 blockers causing

bradycardia)

>80%olall ADRs

Reachons unrelated lo the known pharmacological actions of the drug,generally

with a genelic basis

E.g.drug hypersensitivity syndromes.Immunologic reactions (e.g.penicillin

hypersensitivity),and idiosyncratic reactions (e.g.malignant hyperthermia)

Related lo cumulative doses

tlfeds are well-known and can be anticipated (e.g. alypical femoral Iradutc

Irom bisphosphonates.retinal toxicity from hydroxychloroquine)

Occurs some lime after use of drug (e.g.cardiovascular toxicity following

doxorubicin therapy)

May also be dose-related

Occurs alter cessation ol drug use (e.g. opioid withdrawal resulting from opioid

dependence)

the expected diedisnol produced.This is often due to pharinacogenetic

valiants (e.g.failure to biosclivate a prodrug such as dopidogrel)

A (Augmented) Dose-related

B (Bizarre) Nol dose-related

Antibiotic Allergies •What is the Risk of

Cross-Reactivity?

• In clinical practice.cross reactivity

between drugs presents a problem

for both patients and physicians

• In Use case of penicillin allergy,crossreactivity to cephalosporins is less

than 2%.However,in patients who

have a history of hue anaphylactic

reaction,cross-reactivity is closer to

40% depending on the side chain

• Cross-reactivity between penicillins

and carbapencms is <1%

• The term “sulfa allergy"is often

misused and has no formal definition.

Current evidence suggests crossreactivity between sulfonamide

antibiotics (e.g.sulfamethoxazoletrimethoprim) and non-antibiotic

sulfonamides,including loop

diuretics (e.g.furosemide).thiazide

diuretics (e.g. hydrochlorothiazide),

protease inhibitors containing an

arylamine group (e.g.darunavir),

carbonic anhydrase inhibitors (e.g.

acetazolamide). and sulfonylureas

(e.g.glipizide)

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C (Chronic) Dose - and lime-related

D (Delayed) Time-related

E (End of use) Withdrawal

F (Failure) Unexpected failure ol therapy

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CPI1 Clinical Pharmacology Toronto Notes 2023

Approach to Suspected Adverse Drug Reactions

• history and physical exam:signs and symptoms of reaction (e.g. rash,fever, hepatitis, anaphylaxis),

timing, risk factors,detailed medication history including all drugs and timing, de-challenge

(response when drug is removed), and re-challenge (response when drug is given again, if applicable)

* medication history should include prescription, non-prescription and over-the-counter, natural

health products/samples,supplements, creams, ear/eye drops, inhalers, and nasal sprays

dosage, frequency, route of administration, and duration of use should be recorded for each

• differentiate between drug therapy vs.disease pathophysiology

• treatment:stop the drug,supportive care, and symptomatic relief. Specific interventions (e.g. steroids,

immunosuppressants) used for some ADKs

• resources:check recent literature, Health Canada, and FDA; contact the pharmaceutical company;

call Poison Control (1-800-268-9017) if overdose or poisoning suspected;check with Mother'

i

’

oBaby

(https://mothertobahy.org/ ) in cases involving pregnant or breastfeeding women

• report all suspected ADKs that are: I ) unexpected, 2) serious, or 3) reactions to recently marketed

drugs (on the market <5 yr) regardless of nature orseverity

« Canadian Adverse Drug Reaction Monitoring Program available for online reporting

https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/

adverse-reaction-reporting/drug/health-care-providers.html

Examples of Clinically Relevant Drug

Interactions

Interaction Potential Mechanism

Effect ol

Interaction

Warfarin plus

ripratloiarin,

darithiccycin.

erythromron.

meCronniaiole.ee

trimethopricsuKamelhoiarole

Increased effect Italtiple

of warfarin proposed Pit and

PD mechanism

(including

antibiotic

teiference

nith enteric

flora mediated

Mamin 111

production and

alterations

img

eetaholiurl

Warfarin plus

acetaminophen.

Note that tlris is

not nth typical

use, bul with more

chrome and higher

dose use

Variability in Drug Response tcetairmcphen PD (reduction

IMPDO further ol Vitamin

increases IKK K dependent

clotting factcns

brHAPOl)

• recommended patient dosing is based on clinical research and represents mean values for a select

population, but each person may be unique in their dosing requirements due to age, genetics, disease

states,drug interactions, diet, environmental factors, etc.

• possible causes of individual variability in drug response include problems with:

intake:medication adherence

absorption:vomiting,diarrhea, orsteatorrhea;first-pass effect increased due to enzyme induction

or decreased due to enzyme inhibition or liver disease

• drug interactions(e.g. calcium carbonate complexes with iron, thyroxine, and fluoroquinolones

in the G1 lumen, impairing absorption)

distribution:very high or low percentage body fat, intact or disrupted BBB, patient is elderly or a

neonate, or hasliver dysfunction

• biotransformation and elimination: certain genetic polymorphisms or enzyme deficiencies

related to drug metabolism (e.g. acetylcholinesterase deficiency, CYP polymorphism), kidney or

liver dysfunction

PD:genetic variability in drug response (e.g. immune-mediated reactions), diseases that affect

drug PD, drug tolerance or cross-tolerance

Oral contraceptive Decreased PK (rHamycin

pllsphisrilampin elfeclivtoess ndu«sCVP3M.

of oral xhich increases

contraception hormone

metabolism)

Sildenafil plus Hypotension PDIbothPDSS

MriHon

and nitrates

potentiate cSIIIP

production)

SSRI plus St. John'

s Serotonin PD (concomiUM

syndrom use of

ntrales

•ort

serotonergic

medications)

PD (all decrease

metabolism ol

serotonin,so

acessserotonin

in synapticdeft)

SSRI plus sriegilme Serotonin

or nonseleelirt syndrome

"-,l Drug Interactions

• concomitant medications (including natural health products, e.g. St. (ohn'

s wort) or foods (e.g.

grapefruit juice):one drug alters the effect of one or more other drugs by changing PK and/or PD

• PK interactions involve changes in drug concentration when a new drug is added

absorption: alterations in gastrointestinal pH, gastric mucosa and/or emptying,intestinal

motility, and/or transporter function

distribution:alterationsin blood flow,plasma protein binding, anatomical and/or functional

barriers(e.g. drug transporters)

metabolism: alterations in drug metabolism

elimination: alterations in renal or hepatic elimination

• PD interactions are due to two drugs that exertsimilar effects (additive orsynergistic) or opposing

effects (antagonistic)

Some HMt-Cot PossHe

reductase

inhibitors phis

nacin, gemfibtonl.

erythromport or

(raconarole

PK (various

rhabdompotysis mechanisms

based on drugs

lsted;CYP3» cc

MtPIII.eg.

dirilhroerycin

-:i :s|

Sulfamethoxazole- Increased risk of PD (reduced

trimethoprim ®: hyperkalemia renal pulasslim

Kfls'

iRBs.ee excretion in the

presenceol

trimethoprim

realting from

decreased

spirgoofadone

sodium

reabsoephen

as a result of

nhitatiunol

sodium channels

n the distal

tubule)

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CP12Clinical Pharmacology Toronto Notes 2023

Autonomic Pharmacology

Poriphoral Norvous System

I

1

Somatic Autonomic (ANSI

|

I

Sympathetic (SNS)

fight or Flight

Figure 7. Subdivisions of the peripheral nervous system

Parasympathetic (PNS)

Rest and Digest

• most organs are innervated by both sympathetic and parasympathetic nerves,which have opposing

effects (see Neurology. N8)

• ACh and NE arc the main neurotransmitters of the autonomic NS

• ACh binds to many cholinergic receptorsubtypes,which include nicotinic and muscarinic receptors

• NE bindsto adrenergic receptors, which principally include pi,

P2, al, and a2

• ACh action is terminated by metabolism in the synaptic deft by acetylcholinesterase and in the

plasma by pseudocholinesterase

• acetylcholinesterase inhibitors (pyridostigmine, donepezil, galanlaminc, and rivastigminc) can be

used to increase ACh levels in conditionssuch as myasthenia gravis or Alzheimer’s disease

• NE action is terminated by reuptake at the presynaptic membrane, diffusion from the synaptic cleft,

and degradation by MAO and COMT

Parasympathetic Nervous System

Sympathetic Parasympathetic

• blood vessels,sweat glands, the spleen capsule, and adrenal medulla do NOT have parasympathetic

innervation

• parasympathetic pre-ganglionic fibres originate in the lower brainstem from cranial nerves 111, VII,

IX, and X, and in the sacralspinal cord at levels S2-S4. For this reason, it issometimes referred to as

the “craniosacral” nervoussystem. Ihey connect with post-ganglionic fibres via nicotinic receptorsin

ganglionic cells located near or within the target organ (e.g. ciliary ganglion)

• post-ganglionic fibres connect with effector tissues via:

M1 muscarinic receptorslocated in the CNS

M2 muscarinic receptorslocated in smooth muscle, cardiac muscle, and glandular epithelium

Preganglionic

neuron

I

Mia nr

icotinic

receptors Sympathetic Nervous System

voy • sympathetic preganglionic fibres originate in the spinal cord at spinal levels T1-L2/L3

• preganglionic fibres connect with postganglionic fibres via nicotinic receptorslocated in one of two

groups of ganglia:

1. paravertebral ganglia (i.e. the sympathetic trunk) that lie in a chain close to the vertebral

column

2. prevertebral ganglia (i.e. celiac and mesenteric ganglia) that lie within the abdomen

• post-ganglionic fibres connect with effector tissues via:

• pi receptors in cardiac tissue

p2 receptors in smooth muscle of bronchi and G1 tract

al receptors in vascularsmooth muscle

a 2 receptors in vascular smooth muscle

M3 muscarinic receptors located in sweat glands

Postganglionic

neuron

A

NE AC'

W '

Ws ^

<XK • t

Muscarinic

receptors

Adrenergic

receptors

©Woody Gu 2016

Figure 8. Autonomic nervous system

Table 3. Direct Effects of Autonomic Innervation on the Cardiorespiratory System efferent tracts

Organ Sympathetic NS Parasympathetic NS

Receptor Action Receptor Action

Heart

1.Sinoatrial

2.Atrioventricular node

3.Atria

4. Ventricles

Blood Vessels

1.Skin,splanchnic

2.Skeletal muscle

3.Coronary

31 Increased HR

Increased conduction M

Increased contractility M

Increased contractility M

M Decreased conduction

Decreased conduction

Decreased conduction

Decreased HR

PI

Si

31

j

1.82 Constriction

Constriction

32 (large muscles) Dilatation

Constriction

Dilatation

M Dilatation

Dilatation

Dilatation

Dilatation

Dilatation

Constriction

Stimulation

o M

M

01.32 M

--

M +

lungs

1. Bronchiolarsmooth muscle 32 Relaxation M

2. Bronchiolar glands 01.32 Increased secretion M

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CP13Clinical Pharmacology Toronto Notes 2023

Opioid Therapy and Chronic Non-Cancer Pain

Does Opioid Tapering in Chronic Pain Patients

Result in Improved Pain or Same Pain vs.

Increased Pain at Taper Completion

’

Pain Med 2019:20:2179-2197

Purpose:Support or refute the hypotheses that opioid

tapering in chronic pain patients(CPPsI improves pain

or maintainsthe same pain level Dp taper completion

but does not increase pain levels.

Methods: Structured systematic review searchirg

relevant subject headings. 20 studies met inclusion /

delusion enteria and were of type lll/IV level

evidence.Characteristics were abstracted foe

numerical analysis.

Results: fotal ol 2109 CPPstapeied HI allstudies

com bmed.8% ol the studiesshowed that by taper

completion, pain had improved.In15% of the studies,

pa m remaned the same.

Conclusions: I -ere is consistent type 3 and A

evidence that opioid tapering in CPPs reduces

or mamtainsthe same pain levels.Studies were

marginal in guafityand further controlled studies

needed.

General Management Principles

• when first considering therapy for patients with chronic non-cancer pain, optimize non-opioid

pharmacotherapy and non-pharmacologic therapy rather than starting a trial of opioids (strong

recommendation)

• general approaches to opioid use include avoiding high doses, and when possible, a slow, collaborative

approach when tapering

• for patients with chronic non-cancer pain beginning opioid therapy, restrict the prescribed dose to

<90 mg MMK, and ideally <50 MMK, especially at starting dose

for patients with chronic non-cancer pain who are currently using 90 mg MMK or more,

encourage a slow1

, collaborative taper of opioids to the lowest effective dose, potentially

discontinuing

• for patients with chronic non-cancer pain who are using opioids and experiencing serious challenges

in tapering, a formal multidisciplinary program issuggested

• please refer to national opioid guidelines for a comprehensive approach to opioid use (link: http://

nationalpaincentre.mcmaster.ca /guidelines.html)

Common Drug Endings

Table 4. Common Drug Endings

Ending Category Example

alii POE-S inhibitor

Inhaled general anesthetic

Benyodiaiepinc

Antifungal

local anesthetic

Monoclonal antibody

Small molecular inhibitor

p- blocker

Croton pump inhibitor

ACE inhibitor

sildenafil

•ane halothane

loratepam

ketoconazole

•azepam

•azole*

caine

mab

lidocaine

adalimumab

imatinib

propranolol

omepraiole

captopril

candesaitan

atorvastalin

albuterol

cimctidine

somatotropin

acyclovir

prazosin

- nib

•olol

prazoie

pril

sartan AR8

•slabn HMG CoA inhibitor

p2 agonist

H 2 antagonist

Pituitary hormone

Antiviral

d1anlagonist

-terol

- tidine

tropin

vir

•zosm

Note:This table providesthe most common drugendingsfor which there are only a tew exceptions (e.g.methimazole.an antithyroid:stanozotol is

an anabolic steroid) and is not exhaustive

'Unless ending Is -prazolu

Tor more information on medical pharmacology, please refer to our textbook product

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CPUClinical Pharmacology Toronto Notes 2023

Landmark Pharmacology Trials

Trial Name Reference Clinical Trial Details

MONOCLONAL ANTIBODIES or DRUG EFFECTS ON RECEPTORS

EPIC NEJM1994; 330:956 961 Title:Use ola Monoclonal Antibody (mab) Directed against the Platelet Glycoprotein lib:Ilia Receptor in High-Risk Coronary

Angioplasty

Purpose: To evaluate the effect of chimeric mab Fab fragment (c 7E3 Fab) directed against the platelet glycoprotein llb/llla receptor,

in patients undergoing angioplasty at highrisk for ischemic complications.

Methods:RCI involving 2099 high- risk patients scheduled to undergocoronaiy angioplasty or directional atherectomy.Patients

received 1of 3 combinations of c?E3 Fab (bolus and an infusionof placebo,a bolus ol c 7E3 Fab and an infusion of placebo,or a bolus

and an infusion of c7E3 Fab) or placebo.Primary endpoints included death,nonfatal Ml.intra aortic balloon pump insertion for

refractory ischemia or unplanned surgicalrevascularization,repeat percutaneous procedure orimplantation of a coronary stent.

Results:c7E3 Fab bolus and infusion resulted in a 35% reduction in rate of the primary end point vs.placebo.10% reduction was

observed with the c7E3 Fab bolus alone.Bleeding episodes and transfusions were more freguent in 7E3 Fab bolus and infusion group

vs.other two groups.

Conclusions:Ischemic complications of coronary angioplasty and atherectomy were reduced with a mab directed against platelet

llb/llla glycoprotein receptor.

mRNA VACCINES

BNT162b2 trial NEJM 2020:383:2603-2615 Title:Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Purpose: loreport safety and efficacy findings from the phase 2/3 of a global trial of BNI162b2 in preventing Covid-19 in persons 16

yr and older.

Methods:Eligible participants were randomly assigned in a1:1ratio to receive two doses.21d apart,of either placebo or the

BNI162b2 vaccine candidate (30 pg per dose).

Results:Among those eligible 43448 received injections.A totalol 21720 patients receivedBNT162b2 and the rest received placebo.

BNT162b2 was 95% effecbve in preventing Covid-19 (95% credible interval.90.3 to 97.6).Safety profile of BNT162b2 characterized

by short-term,mild-to-moderate pain at the injection site, fatigue,and headache.Incidence of seriousadverse events was lowand

similar inboth groups.

Conclusions: 8N116262 conferred 95% protection against Covid-19 in persons >16 yr. Safety over a median of 2 mo was comparable

to other viral vaccines.

INTRAMUSCULAR INJECTIONS or DRUG ADMINISTRATION

A1LAS NEJM 2020: 382:1112 1123 Title:Long -Acting Cabotcgravir and Rilpivirine for Maintenance of HIV -1Suppression

Purpose: to establish whether switching to long-acting cabotegravir plus rilpivirine isnoninlerior tocurrent oral therapy among

adults with virologically suppressed HIV-1.

Methods:Patients with plasma HIV-1RNA levels

"

50 copies/ml for 6 mo were randomly assigned to either continue standard therapy

(placebo) or receive monthly long-acting cabotegravir and rilpivirine.

Results: Treatment was initiated in 308participants/group.HIV-1RNAIevels >50 copies/ml were found in 5 participants in

intervention vs.3in placebo (0.6% points:95% CI:1.2-2.5). HIV-1RNA levels <50 copies/ml were foundin92.5% of participants in

intervention vs. 95.5% in placebo (-3.0% points:95% Cl:-6.7 0.7).Adverse events included injection-site pain (75%).Participants

who received intervention reported greater satisfaction and preferred long-acting therapy over previous oral therapy.

Conclusions:Monthly injections of long-acting cabotegravir and rilpivirine werenoninferior to standard therapy for maintaining

HIV-1suppression.Adverse events were common but medication withdrawal infrequent.

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SeithelA.Eberl S,Singer K,et al.The Influence of MacrolideAntibiotics on the Uptake of OrganicAnions and Drugs Mediated by 0A1P1B1and 0ATP183.Drug Metab Dispos 2007:35(5):779-786.

Shenoy ES.Macy E.Rowe T. Blumenthal KG etal.Evaluation and management of penicillin allergy.JAMA Review 2019:321112):188-199.

Suchowctsky 0,deVries JD.Interaction ol fluoxetine and selegiline. Can J Psychiatry.1990:35(61:571- 572.

Thijsscn HH.Soute BA.Ver voort LM.et al.Paracetamol (acetaminophen) warfarin interaction:HAP0I.the toxic metabolite of paracetamol,isan inhibitor of enzymes in the vitamin K cycle.Ihromb Haemost

2004;92(4):797-802.

Velazquez H.Perazella MA,Wright FS.et al.Renal mechanism of trimethoprim-induced hyperkalemia.Ann Intern Med1993:119(4):296-301.

Webb DJ.Freestone S.Allen MJ.elal. Sildenafil citrate andblood pressure lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999:83(5A):21C 28C.

Wen MA.Juuilmk DN.GomesI.etal.Beta blockers,trimethoprim-sulfamethoxazole. and therisk of hypeikalemia requiring hospitalization in the elderly:a nested case-control study.Clin JAm Soc Nephrol

2010;5|9):1544-1551.

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Dermatology

Natalie Kozlowski, Yuliya Lytvyn, and Sara Mirali, chapter editors

Ming Li and Dorrin Zarrin Khat, associate editors

Vijithan Sugumar, LBM editor

Dr. Patrick Pleming, Dr. Marissa Joseph, and Dr. Jensen Yeung,staff editors

Acronyms

Introduction to Skin

Normal Processes of Skin and Subcutaneous Tissue

Skin Anatomy

Skin Function

Morphology.

Primary Lesions

Secondary Lesions

Patterns and Distribution

Common Skin Lesions.

Cysts

Fibrous Lesions

Hyperkeratotic Lesions

Keloids

Pigmented Lesions

Vascular Lesions

Lipoma

Xanthoma

Acneiform Eruptions

Acne Vulgaris/Common Acne

Perioral Dermatitis

Rosacea

Dermatitis (Eczema)

Asteatotic Dermatitis

Atopic Dermatitis

Contact Dermatitis

Dyshidrotic Dermatitis

Nummular Dermatitis

Seborrheic Dermatitis

Stasis Dermatitis

Lichen Simplex Chronicus

Papulosquamous Diseases

Lichen Planus

Pityriasis Rosea

Psoriasis

Veskulobullous Diseases

Bullous Pemphigoid

Pemphigus Vulgaris

Dermatitis Herpetiformis

Porphyria Cutanea Tarda

Drug Eruptions

Exanthematous

Urticarial

Pustular

Bullous

Other

Heritable Disorders

Ichthyosis Vulgaris

Epidermolysis Bullosa

Neurofibromatosis (TypeI;von Recklinghausen's Disease)

Oculocutaneous Albinism

Vitiligo

Infections

Bacterial Infections:Epidermis

Bacterial Infections:Dermis

Bacterial Infections:Epidermis and Dermis

Dermatophytoses

Parasitic Infections

Viral Infections

Yeast Infections

Sexually Transmitted Infections

D2 Pre-Malignant Skin Conditions

Actinic Keratoses (Solar Keratoses)

Leukoplakia

Malignant Skin Tumours

Nonmelanoma Skin Cancers

Malignant Melanoma

Other Cutaneous Cancers

Diseases of Hair Density

Hair Growth

Non-Scarring (Non-Cicatricial) Alopecia

Scarring (Cicatricial) Alopecia

Nails and Disorders of the Nail Apparatus

Adnexal Disorders

Oral Diseases

Skin Manifestations of Systemic Disease .

PaediatricExanthems

Miscellaneous Lesions

Angioedema and Urticaria

Erythema Nodosum

Pruritus

Wounds and Ulcers

Sunscreens and Preventative Therapy

Topical Steroids

Dermatologic Therapies

Traumatic andMechanical Disorders

Landmark Dermatology Trials

References

D39

D2

D40

D4

D44

D8

D46

D47

D48

D49

D50

D14 D50

D16

,D55

D56

D57

D20

D23

D24

D27

D29

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D1 Dermatology Toronto Notes 2023

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D2 Dermatology Toronto Notes 2023

Acronyms

p-hCG p-human chorionic gonadotropin DRESS drug reaction with eosinophilia

ACEI angiotensin-converting enzyme and systemic symptoms

inhibitor DVT deep vein thrombosis

AGEP acute generalized EM erythema multiforme

exanthematous pustulosis

AD atopic dermatitis

actinic keratoses

ASO anti streptolysin 0

BCC basal cell carcinoma

BCG bacillus Calmette-Guerin

BSA body surface area

blood urea nitrogen

CMV cytomegalovirus

CNS central nervous system

creatinine

CXR chest x-ray

DIHS drug-induced hypersensitivity

syndrome

DLE discoid lupus erythematosus

diabetes mellitus

interferon SSRI selective serotonin reuptake

inhibitor

SSSS staphylococcal scalded skin

syndrome

STI sexually transmitted infection

tuberculosis

TEN toxic epidermal necrolysis

TMP/SMX trimethoprim-sulfamethoxazole

UC ulcerative colitis

URTI upper respiratory tract infection

UV ultraviolet

UVA ultraviolet A

ultraviolet B

UVC ultraviolet C

UVR ultraviolet radiation

VDRL venereal disease research

laboratory

V2V varicella zoster virus

IFN

IVIg intravenous immunoglobulin

MAOI monoamine oxidase inhibitor

MM malignant melanoma

Er:YAG erbium-doped yttrium aluminum NB DVB narrow band ultraviolet B

Nd:YAG neodymium-doped yttrium

aluminum garnet

NMN nevomelanocytic nevus

NMSC nonmelanoma skin cancers

'

garnet B

AK ESR erythrocyte sedimentation rate

Fe iron

FTA-ABS fluorescent treponemal

antibody-absorption

GAS group A p-hemolytic

Streptococcus

GVHD graft-versus-host disease

HHV human herpes virus

FIPA hypothalamic- pituitary adrenal

HPV human papillomavirus

HRT hormone replacement therapy

HSV herpes simplex virus

HZV herpes zoster virus

inflammatory bowel disease

OCP oral contraceptive pill

over-the-counter

para-aminobenzoic acid

psoriasis area and severity index UVB

purified protein derivative

psoralens and UVA

rheumatoidarthritis

squamous cell carcinoma

Stevens- Johnson syndrome

sun protection factor

OTC

BUN PABA

PASI

PPD

Cr PUVA

RA

SCO

SJS

SPF

DM IBD

Introduction to Skin

Normal Processes of Skin and Subcutaneous Tissue

Embryonic Development of the Skin

Basal cell bud

Primordial

eccrine gland

Layers of the Epidermis

— "Californians Like Going Sun Bathing"

Basal cell bud

Primordial OR

epidermis : ; i

K,.,3

•

air follicle "Canadians Like Good Sushi Boxes"

hair follicle

Eccrine

MesenchymalJ

cells

—Sebaceous

4 weeks 9 weeks 14 weeks IB weeks 18 weeks 23 weeks 30 weeks

(B) (Cl (A) (0) IEI ( F) (G|

Figure 1. Fetal maturation of the skin

(A) 4 wk gestation: fetal skin has two distinct layers - the basal cell layer and outer layer (i.e. periderm). (B) 9

wk gestation:keratinization begins. (C) 14 wk gestation: stratification of epidermal layer; primordial hair follicle

forms from the basal cell bud. (D) 16 wk gestation:local proliferation of mesenchymal cells associated with the

epidermal buds as hair follicles develop and elongate. (E) 18 wk gestation: sebaceous gland develops; hair follicle

elongates. (F) 23 wk gestation: continuous elongation of the hair follicle; primordial eccrine gland forms from the

basal cell bud.(G) 30 wk gestation: continuous elongation and foiling coiling of the eccrine glands.

Modified from FacialPlastic Surgery Clinics of North America. 21(1). King A. Balaji S.Keswani SG.Biology and Function of Fetal andPaediatric Skin.

1-6.Copyright (2020).with permission from Elsevier

• embryonic development and fetal maturation (see i-

'

igure I )

• neonatal changes

• full-term infants have skin with all five layers, similar to adults

• epidermal cells mature from columnar stratum basale to squamous keratinocytes of the stratum

corneum

maturation occurs more rapidly in facial skin than trunk or limb skin

neonatal skin is coarser and develops into a more smooth texture homogeneously during the first

30 d of life

• infants have smaller corneocytes and thinner stratum corneum until 2 yr old

from infancy to puberty, dermal thickness increases

• repair, regeneration, and changes associated with stages of life

• regeneration relies on tissue-specific stem cells and restricted progenitor cells

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regenerative abilities decline with age as both cell types undergo:

a loss of self-renewing capacities

altered proliferative activity

functional decline

with age, the skin becomes thinner and less able to withstand external stress because:

the epidermis attenuates with effacement of the rete ridges

keratinocytes lose proliferative abilities

the dermisloses volume

hyaluronic acid diminishesin the extracellular matrix of the dermis

these changes lead to loss ofskin and hair integrity, leading to conditionssuch assenile purpura

and male pattern baldness (i.e. androgenic alopecia, see D l l )

senile purpura (i.e.solar or actinic purpura):typically arise spontaneously;characterized by

non-blanchable red-to-purple patches that resolve over 1-3 wk,leaving residual brown-yellow

discolouration secondary to hemosiderin deposition

• the decline in regenerative ability can also be seen as postmenopausal hair changes (see D45 )

Skin Anatomy

Arrectorpilimuscle

Hair follicle

A B

\

Epidermal layer ‘

Stratum corneum \

Stratum lucidum

Stratum granulosum

Epidermis

* -J

Papillary layer

I ,

i> . t (Hi/ii

Dennis tlx1

-

'

.

Reticular layer

•

•

' Stratum spinosum

Subcutan

ad pose I

eous

ssue

Is- Sweat gland

,

. T = Stratum basale

Fig ure 2. Histologic layers of the skin.A. epidermal layers of theskin.B.all layers of the skin

Skin

• divided anatomically into epidermis, dermis, and subcutaneous tissue

• epidermis

• avascular:receivesits nutrition from the dermal capillaries

• derived from keratinocytes with the youngest presenting at the stratum basale

cells progressfrom stratum basale to stratum corneum in about 4 wk

stratum basale (i.e. germinativum): mitotic figures that give rise to keratinocytes

stratum spinosum (prickle cells):junctions in thislayer (tonofilaments) give the epidermis its

strength

stratum granulosum:flat cells containing basophilic granules

stratum lucidum:transparent layers of packed dead cells

stratum corneum:flat scales of the water-resistant protein keratin

cells of the epidermis:

keratinocytes:located in all layers of the epidermis except the stratum corneum; connected to

each other by desmosomes

melanocytes:located in the stratum basale; keratinocyte:melanocyte ratio in the basal layer

is 10:1; melanocyte number is equal among races; produce melanosomes containing melanin,

which are transferred to keratinocytes

Langerhans cells: dendritic cells which are important for immune surveillance

Merkel cells:located in the stratum basale; involved in touch sensation

• dermis

comprised of connective tissue divided into two regions

papillary: contains numerous capillaries that supply nutrients to the dermis and epidermis

reticular:provides a strong structure forskin;consists of collagen bundles woven together

along with elastic fibres, fibroblasts, and macrophages

cells of dermis

fibroblasts:produce collagen, elastin, and ground substance

mast cells: release histamines which mediate type 1 hypersensitivity

« other components of dermisinclude:blood vessels, nerves, pilosebaceous units, and sweat glands

• subcutaneous tissue (i.e. hypodermis)

consists primarily of adipose cells,larger calibre vessels, nerves, and fascia

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Epidermal Appendages

• epidermal in origin, can extend into the dermis; includes hair, nails, and cutaneous glands

• pilosebaceous unit = hair i hair follicle + sebaceous gland arrector pili muscle

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Cutaneous Glands

• sebaceous gland: part of pilosebaceous unit; produces sebum which is secreted into the hair follicle

via the sebaceous duct, where it covers the skin surface (protective function)

sebum has some antifungal properties

• these glands cover entire skin surface and are absent only in non-hair bearing areas(e.g. palms,

soles, lips)

• apocrine sweat gland: apocrine duct empties into hair follicle above sebaceous gland

• not part of pilosebaceous unit

found concentrated in axillae and perineum

likely a vestigialstructure, functionsin other species to produce scent (e.g. pheromones)

• cccrine sweat gland: not part of pilosebaceous unit

• found over entire skin surface except lips, nail beds,and glans penis

• important in temperature regulation via secretion of sweat to cool skin surface

Skin Function

• protection

• due to continuous recycling and avascularity of epidermis,as well as normalskin flora

barrier to U V radiation (melanin), mechanical/chemical insults (sensory/mechanoreceptors),

pathogens (immune cells), and dehydration (lipid rich barrier)

• thermal regulation

• insulation to maintain body temperature in cool environments via peripheral vasoconstriction,

hair,and subcutaneous adipose tissue

• dissipation of heat in warm environments via increased activity of sweat glands and increased

blood flow within dermal vascular networks

• sensation

• touch, pain, and temperature sensation

• metabolic function

• vitamin D synthesis

» energy storage (mainly in the form of triglycerides)

Morphology

Primary Lesions

Definition

• a de-novo initial lesion that has not been altered by trauma or manipulation, and has not regressed

Describe a Lesion with SCALDA

Table 1. Types of Primary Morphological Lesions Si ze andSurface area

Colour (e.g. hyperpigmented,

hypopigmented, erythematous)

Arrangement (e.g.solitary,linear,

reticulated, grouped, herpetiform)

Lesion morphology

Distribution (e.g. dermatomal,

intertriginous, symmetrical/

asymmetrical,follicular)

Always check hair, nails,mucous

membranes, and intertriginous areas

Profile <1cm Diameter a1cm Diameter

flat lesion

Raised Superficial Lesion

Deep Palpable (Dermal or Subcutaneous)

lesion

Elevated Fluid-Filled lesion

Macule (e.g. freckle)

Papule (e.g. wart)

Nodule (e.g. dermatofibroma)

Patch (e.g. vitiligo)

Plaque (e.g. psoriasis)

Tumour (e.g.lipoma)

Vesicle (e.g.HSV) Bulla (e.g.bullous pemphigoid)

Secondary Lesions

Definition

• develop during the evolutionary process of skin disease, created by manipulation, or due to

complication of primary lesion (e.g.rubbing,scratching,infection)

Types of Secondary Morphological Lesions

• crust:dried fluid (serum, blood,or purulent exudate) originating from a lesion (e.g. impetigo)

• scale:excess keratin (e.g. seborrheic dermatitis)

• lichenification: thickening of the skin and accentuation of normalskin markings (e.g. chronic AD)

• fissure: a linearslit

-like cleavage of the skin

• excoriation: a scratch mark

• erosion: a disruption of the skin involving the epidermis alone; heals without scarring

• ulcer: a disruption of the skin that extendsinto the dermis or deeper; may heal with scarring

• xerosis:pathologic dryness of skin (xeroderma), conjunctiva (xerophthalmia), or mucous membranes

(xerostomia)

• atrophy: histological decrease in size or number of cells or tissues,resulting in thinning or depression

of the skin

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Tf iff' m

Macule Patch Papule Plaque

-

*

m

r

m

Nodule Tumour Erosion Ulcer

r

i

***

%

Scale Fissure Vesicle Bulla

^

0

© ;#

k

, ;

A

_

< r

Lichenilication Annular Reticulai Tarqetoid Satellite

Figure 3.Examples of primary and secondary lesions

Other Morphological Terms

• cyst: an internally epithelial-lined structure containing semi-solid material or tluid

• pustule: an elevated lesion containing a collection of neutrophils (infectious or inflammatory in

nature)

• scar: replacement fibrosis of dermis and subcutaneous tissue (hypertrophic or atrophic)

• wheal: a special form of papule or plaque that is transient (<24 h) and blanchable, often with a halo

and central clearing,formed by edema in the dermis (e.g. urticaria)

• comedonc: a special collection ofsebum and keratin

open comedone (blackhead)

closed comedone (whitehead)

• petechiae: pinpoint extravasation of blood into dermis resulting in hemorrhagic lesions; nonblanchable, <3 mm in size

• purpura: larger than petechiae,3 mm-1 cm in size

• ecchymosis (i.e. bruise):larger than purpura, >1 cm in size

• telangiectasia:dilated superficial blood vessels; blanchable, reticulated, and of small calibre, can be

associated with benign or malignant entities

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D6 Dermatology Toronto Notes 2023

B. Pustule

C. Scar 0. Wheal

© Ariadna Villalbi 2020

Figure 4.Examples of other morphological terms: cyst,pustule, scar,and wheal

Wolff K.Johnson R. Saavedra A.Fitzpatrick's Colour Atlas and Synopsis olClinicalDermatology.Seventh Edition,copyright 2020.Modified by

Permission olMcGraw-HillEducation

A. B. %en

n

:

1I

-

A B. closed comedo (whitehead) . open comedo (blackhead)

Figure 5.Examples of other morphological terms:open and closed comedone

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A B

C D

g

CM

c5

s

-

-s

Figure 6. Examples of other morphological terms: A: petechiae, B: purpura, C: ecchymosis, and D:

telangiectasia

Patterns and Distribution

Table 2. Patterns and Distribution of Morphological Lesions

Pattern or Distribution Definition Example

Acral

Annular

Relating to the hands and feet

Ring- shaped

Involving hair follicles

lesions following a “drop-like" pattern

Kocbncr Phenomenon|i.e. Appearance of lesions at a site of skin injury

isomorphic response)

Morbilliform

Pcrniosis.secondary syphilis

Granuloma annulare

Folliculitis

Guttate psoriasis

lichen planus, psoriasis,vitiligo

Follicular

Guttate

literally means “measles-llke," an eruption composed of macules and

papules with truncal predominance

Lesions following a “net-like"pattern

Small lesions scatteredaround theperiphery of a larger lesion

lesions following a “snake-like"pattern

Concentric ring lesions,like a bullseye

Morbilliform drug eruption

Reticular

Satellite

Serpiginous

Target/Targeloid

Livedo reticularis

Candida diaper dermatitis

Cutaneous larva migrans

EM

Other descriptive terms:discrete, clustered,linear,confluent,dermatitic,indurated (i.e.hard or firm)

Differential Diagnoses for Common

Presentations

r -i

Table 3. Differential Diagnoses for Common Presentations L J

Lesion Infectious Inflammatory Drug/Toxin Miscellaneous

Post-inllammatoiy

hyperpigmentation

Brown

Macule

UV radiation,aclinic/ Congenital:cafd-au- lait macule, congenital nevus,epidermal/junctional nevus

solar lentigo,freckle Neoplasia:lentigo maligna.MM.pigmented 8CC

(i.e.ephelis)

Bites/slings

Other:melasma/chloasma (i.e.“mask of pregnancy”) +

Discrete Red folliculitis

Papule Furuncle

Scabies

Acne vulgaris

Rosacea

Psoriasis

Urticaria

Autoimmune:lichenplanus

Vascular:hemangioma,pyogenic granuloma

Other:dermatofibroma,miliariarubra

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D8 Dermatology Toronto Notes 2023

Table 3. Differential Diagnoses for Common Presentations

Lesion Infectious Inflammatory Orug/Toxln Miscellaneous

Red Scales Pityriasis rosea

Secondary syphilis

Tinea

Dermatitis (atopic,contact, Gold

nummular,seborrheic)

Discoid lupus

Psoriasis

Autoimmune:lichen planus

Neoplastic:mycosis fungoides

Cat scratch disease

Impetigo

Viral:HSV. HZV.V2V.Coxsackievirus

Scabies

Bullous impetigo

Vesicle Acute contact dermatitis

Dyshidrotic eczema

Other:dermatitis herpetiformis,porphyria cutanea tarda

Bulla Acute dermatitis

EM.SIE,SJSfTEN

Acne vulgaris

Rosacea

Dyshidrotic dermatitis

Pustular folliculitis

Pustular psoriasis

Nidradenilis suppurativa

Allergic stomatitis

Fixed drug eruption

SJSfTEN

AGEP (usually

secondary to drug

reaction)

Autoimmune:bullouspemphigoid,pemphigus vulgaris

Other:dermatitis herpetiformis,porphyria cutanea tarda

Candida

Dermatophyte

Impetigo

Sepsis

Varicella

Pustule

Oral Ulcer Aspergillosis Chemotherapy

Radiation therapy

SJSfTEN

Autoimmune:pemphigus vulgaris

Congenital:XXV

Hematologic:sickle cell disease

Neoplasia:BCC.SCC

CMV EM

Coxsackievirus

Cryptococcosis

HSV/HZV

HIV.TB.Syphilis

Plague

Syphilis

lichen planus

Seronegative arthropathies.SIE

Recurrent aphthous stomatitis

Behcet's disease

RA.SLE. vasculitis

UC, pyoderma gangrenosum

Skin Ulcer Autoimmune:necrobiosis lipoidica diabeticorum (e g. 0M|

Congenital:XXV

Hematologic:sickle cell disease

Neoplasia:SCC

Vascular: arterial,neurotrophic,pressure, venous,aphthous,leukoplakia,traumatic

IB

Tularemia

Common Skin Lesions

Cysts

Table 4. Cysts

Clinical Features Pathophysiology Epidemiology Clinical Course Management

Central punctum may rupture (foul,

cheesy odour,creamy colour) and produce Elective excision

inflammatory reaction

Can increase in sice and number over time

Rupture causes pain and inflammation No treatment

Elective excision

Epidermal Cyst Round,yellow/fleshcoloured. slowgrowing,

mobile,firm,fluctuant,

nodule,or tumour

Epithelial cellsdisplaced into dermis, epidermal

lining becomes filled with keratin andlipid-rich

debris

May be post-traumatic,rarely syndromic

Multiple,hard,variable Thick-walled cyst lined with stratified squamous

sized nodules under the epithelium and filled with dense keratin

scalp:lacks central punctum Idiopathic

Post

-trauma

Firm nodule mostcommonly Rare, congenital hamartomas,which arise from Rare

found at lateral third of inclusion of epidermis along embryonal cleft closure

eyebrow or midline under lines,creating a thick-walled cyst filled with dense

nose keratin

Usually solitary,rubbery,

translucent:a clear

gelatinous viscous fluid may on fingertip

be extruded

1-2 mm superficial,white

to yellow subepidermal

papules occurring on

eyelids,cheeks,and

forehead

Most common

cutaneous cyst in

youth-middle age

No treatment

2nd most common

cutaneous cyst

F>M.hereditary

Pilar Cyst

(i.e.

Trichilemmal)

Dermoid Cyst If nasal midlme.risk olextension into CNS No treatment

Elective excision

Ganglion Cyst Cystic lesion Ural originates from joint or tendon Older age

sheath,called a digital mucous cyst when found

Stable No treatment

Incision and expression of

contents

Elective excision

No treatment

Incision and expression of

contents

Electrodessication

Topical retinoid therapy

Associated with osteoarthritis

Milium Small epidermoidcyst,primarily arising from

pluripotential cells in epidermal or adnexal

epithelium

Can be secondary to blistering,ulceration,

tiauma,topical corticosteroidatrophy,or cosmetic

procedures

In newborns,spontaneously resolves in

first 4 wk of life

Any age

40-50% of infants

Fibrous Lesions

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DERMATOFIBROMA c J

Clinical Features

• firm dermal papule or nodule,skin-coloured to red-brown

• majority are asymptomatic but may be pruritic and/or tender

• sites: legs > arms > trunk

• dimple sign (i.e.l-itzpatrick'

ssign):lateral compression causes dimpling of the lesion

+