Pharmacology:
Pharmacodynamics = what drugs do to body
Pharmacokinetics = what body does to drugs as it moves around
Drugs bind receptors
-
Exceptions = antacids, osmotic diuretics, antibiotics/anticancer
ED50 = dose required for 50% of people to have effect
TD50 = dose for 50% to have toxicity
ADME = adsorption, distribution, metabolism, excretion
42L total volume
Liver metabolism – phase ½
-
-
Phase 1 = cytochrome p450 adds polar groups to increase water solubility = inactive
o Inducing means less drug
o Inhibiting means more drug
 Grapefruit juice inhibits it which is why sometimes it can cause overdose
Phase 2 = add large polar molecules to prepare for excretion
Kidney
-
Passive filtration = small drugs
Active = big drugs
Reabsorption = small drugs go back in
Autonomic Nervous System
Adrenal medulla = 85% E 15% NE
Nicotine = nicotinic receptor agonist
Muscarine/bethanechol = muscarinic receptor agonist
Epinephrine = all adrenoceptor agonist
Norepinephrine = all except B2 agonist
Phenylephrine = a1
-
Mydriasis, vasoconstriction, sphincter constriction
Salbutamol = B2
-
Bronchodilation, vasodilation, muscle tremor, decrease GI, gluconeogenesis, glycogenolysis,
lipolysis
Isoproterenol = B1/B2
-
B1 = increase cardiac rate/contractility
Ach won’t affect arterioles because it is not directly innervated, unless injected into blood = muscarinic
receptors release NO which causes vasodilation = lower blood pressure
Neostigmine = reversible cholinesterase inhibitor
Soman/sarin/malathion = irreversible cholinesterase inhibitor (lipophilic = stays in body)
Atropine/scopolamine = muscarinic blocker
-
Treat motion sickness, cause pupil dilation, treat asthma, irritable bowel, urinary urgency
Hexamethonium = nicotinic ganglion blocker
-
Effects depend on dominance of SNS or PSNS
Heart, eye, GI are more PSNS = increase heart rate, mydriasis, less GI
-
Blood vessels are more SNS = dilation
Tubocurarine = nicotinic NMJ blocker
Uptake 1 takes up NE from synapse by bringing it in with Na+ - then packaged into vesicles by vesicular
monoamine transporter
Cocaine = blocks uptake 1
Amphetamine/ephedrine = displaces NE from uptake 1 = releases NE not from exocytosis
NE also taken up into post synaptic membrane by uptake 2
Anaphylaxis = A/B
-
A1 = vasocontriction = increase BP, decrease secretion in mucous membrane
B1 = increase cardiac rate
B2 = bronchodilation
Decongestion = A1
-
Phenylephrine = vasoconstrict mucus membrane
Also vasoconstrict local blood vessels = prolong anesthetic action
Also used in eye to dilate
Cardiac arrest = B1
-
Epinephrine = Increase SA activity and conduction velocity in AV node
Asthma = B2
-
Salbutamol = bronchodilation
ADHD
-
Amphetamine = more NE/dopamine
Ephedrine used to decrease eating
Prazosin = a1 blocker = reduce blood pressure, nasal stiffness, dilation of veins = less blood to heart,
tachycardia = reflex to decreased pressure
Propranolol = B1/B2 blocker
-
B1 = less sympathetic activity
B2 = less tremor
Lowers heart rate, contraction, heart O2 demand
Be careful with people with weak hearts
Metoprolol = B1 blocker
Reserpine = blocks vesicular monoamine transporter = prevents uptake of dopamine/NE
Guanethidine = taken up via uptake 1 and stops AP = NE not released, eventually degraded
Respiratory
Allergic reaction = allergens are proteases, DerP1 = dust mite poop, fel d 3 = cat hair, mold = prtt
-
Can also be non allergic, like from cold air
Mild asthma = short acting B2 adrenergic agonist = SABA
-
Methyl groups = higher affinity for receptor
Severe asthma = LABA
-
Lipophilic group = embeds in cell = longer lasting
B2 = G protein receptor
-
Binding = release cAMP = remove Ca2+/uncouple filaments in smooth muscle = relax
On mast cell binding = stop release of inflammatory mediators
Also can affect B1 receptors = agitation, tremor, tachycardia
LABAs can desensitize B2 receptors = severe attacks, should use with corticosteroid to reduce
inflammation and dose of LABA
Corticosteroid
-
Transrepression = stops inflammatory transcription factors from going to nucleus
Transactivation = upregulates antiinflammation stuff
Side effects = oral infection, hoarseness, osteoporosis, obesity, hyperglycemia
Small particles = further in lung
Bacteria
Gram positive = purple, thick pep
-
Staph
Gram negative = pink, thin pep
-
E coli
Anaerobes
-
Bacteroides
B lactam
-
Penicillin
Inhibit peptidoglycan synthesis
Time dependent
Bactericidal
Macrolide
-
Erythromycin
Inhibit protein synthesis = bind reversibly to 50s subunit of ribosome
Time dependent
Bacteriostatic
Aminoglycoside
-
Gentamicin
Inhibit protein = bind irreversibly to 30s and 50s
Concentration dependent
Bactericidal
Tetracycline
-
Tetracycline
Inhibit protein = bind reversibly to 30s
Might also change membrane
Time dependent
Bacteriostatic
Sulfonamide
-
Sulfamethoxazole
Interfere with folic acid synthesis = inhibit dihydropteroate synthesase and stops additions of
PABA to folic acid
Time dependent
Bacteriostatic
Quinolone
-
Levofloxacin
Inhibit DNA topoisomerase = inhibits DNA replication
Concentration dependent
Bactericidal
Glycopeptide
-
Vancomysin
Inhibit cell wall synthesis in gram positive by binding D alanyl D alanine of cell wall units
Time dependent
Bactericidal, static at low concentration
Oxazolidinone
-
Linezolid
Inhibit protein = binding P site of 50s subunit
Time dependent
Bacteriostatic, cidal against some bacteria
Resistance:
-
Decrease entry
Increase export
Release enzymes to destroy
Alter prodrugs to stop effect
Alter target proteins
Make alternative pathway that is inhibited
Cancer
TNM = size, lymph node, distant metastasis
Chemo = damage DNA = kill cancer cell
-
-
Can be phase specific/non specific
Cancer has many different clones, use combo chemo to get them all
Left over cells from chemo can divide = resistant
o DNA repair
o Drug inactivation
o Less uptake
o More efflux
o Other pathways
o Alter target enzymes
Contraindications
o Hypersensitivity
o Carcinogenicity
o Mutagenicity
o Infertility
o Human fetal risk
o Avoid breastfeeding
Alkylating agents
-
Bind DNA = cross link DNA = less protein synthesis
Cyclophosphamide, cisplatin
Phase non specific
Epipodophyllotoxins
-
Inhibit topoisomerase 2 = stops DNA synthesis
Etoposide
Late S/G2
Taxane
-
Promote microtubules = inhibit replication
Docetaxel
G2/M
Antimetabolites
-
Like nucleotides, goes into DNA/RNA = interfere function
5-FU
S phase
Antitumour antibiotics
-
Insert between base pairs = uncoil = inhibit synthesis
May also inhibit polymerase
Doxorubicin
Non specific
Streptozocin
-
Alkylating agent/antitumour antibiotic
Decomposes, methylcarbonium ions alkylates DNA and stops mitosis
Non specific
Camptothecins
-
Bind topoisomerase 1 = stops relegation
Irinotecan
S phase
Vinca alkaloids
-
Stops tubulin polymerization
Vincristine
M/S
GI
Mucous cells = make mucus
Parietal cells = make HCl
ECL cells = near parietal = make histamine
Acid made by H/K ATPase
-
Histamine from ECL activates H2 receptors = basal secretion level
More released by stimulation from Ach (nervous system onto M3 receptor), or gastrin (enteric,
CCK)
They also increase ECL secretions
Mucus = has bicarbonate = protect from acid
PGE2/PGI2 produced (EP3 receptor) to stop acid production and increase mucous production = protective
-
Inhibited by NSAIDs
Ulcers = 90% H pylori, 10% NSAID
-
Fix by lower acid, or increase protection
Lower acid:
-
-
Antacids
o Hydroxide/carbonate salts = neutralize
o Side effects:
 pH change = change other drugs
 burping because of CO2
 Al3+ = constipation
 Mg2+ = diarrhea
 Give a mixture
H2 antagonist
o
o
o
Cimetidine
Blocks H2 receptors
Best at night, food secretion kinda bypasses H2
-
PPI
-
o Omeprazole
o Inhibit the pump itself = irreversible
o Could result in polyps
Less attractive = inhibit gastrin, already inhibited at low pH/antimuscarinic = side effects
Increase mucus:
Misoprostol
-
Similar to PGE1
Lowers acid release, increase mucus, same receptor (EP3)
Diarrhea
Contraindicated with pregnancy
Sucralfate
-
In acid it breaks apart to bind to the mucus layer
Sticky protective gel, empty stomach use
Constipation, reduce drug absorption
H pylori = PPI and antibiotics
Triple therapy = clarithromycin, amoxicillin, metronidazole
NSAID = stop NSAIDs
-
If not, misoprostol or PPI
GERD
-
Antacids with alginic acid = foam raft to protect top, short term
Chronic = PPIs
Prokinetic agents
o Domperidone = dopamine receptor antagonist = stimulate gastric emptying
Constipation
-
-
Laxatives
o Bulk = fiber, absorb water, induces movement
o Osmotic = poorly absorbed molecules (not fiber like) bring in water
o Stimulant = sennosides = anthracene compound stimulates the myenteric plexus = cause
poop
Diarrhea
o viral case, antivirals rarely used
o bacterial cases, antibiotics are ok but usually resolves on its own
o opiates = act on u receptors = less movement
 loperamide
Endocrine
Steroids = estrogen, progesterone, cortisol
Peptide = insulin
Tyrosine derivative = thyroid hormone, epi, norepi
Metabolism: steroid slow, peptide fast
Half lives: long steroid, short peptide
Receptor: intracellular steroid, cell membrane peptide
Mechanism: steroid gene expression, peptide signal transduction
HPA axis:
-
CRH from hypothalamus makes anterior pituitary secrete ACTH which makes adrenal cortex
make cortisol
Cortisol is negative feedback to ACTH and CRH
Insulin:
-
Increase of glucose makes B cells make insulin to reduce glucose
Oxytocin:
-
Sucking = oxytocin/prolactin release = make milk
Addisons disease = adrenal gland problem = not enough corticosteroids
Cushings syndrome = too much corticosteroids = buffalo hump
Thyroid hormone:
T3/T4 – metabolism
-
Hypothyroidism – levothyroxine = T4 replacement
Hyperthyroidism – radioactive iodine = shrink thyroid
Birth control:
-
Combo of estrogen/progesterone
Negative feedback on GnRH, FSH, LH
o No egg, no LH surge = no ovulation, thins lining of uterus
Estrogen = stops FSH/LH
Progesterone = thickens entrance of womb, thins uterus
Mini pill = only progesterone
Glucocorticoids
-
Inhibit hypothalamus/anterior pituitary
Farquharson phenomenon = exogenous hormone stops endogenous production = atrophy of organ
Psychiatric
Autism = excess synapses
Schizophrenia = fewer synapses
Drugs = lipid soluble
-
-
-
Antipsychotics
o Typical
 Affect dopamine/serotonin systems
 Dopamine D2 antagonist = stops positive symptoms, can cause involuntary
movement
 Schizophrenia = too much dopamine in mesolimbic reward path
 Reduce dopamine to fix
o Atypical
 Dopamine and serotonin antagonist
 Good for positive/negative symptoms
 Serotonin decreases dopamine in mesocortical system, blocking it increases it =
improve negative symptoms
Mood stabilizers
Antidepressants
o Monoamine hypothesis = caused by low serotonin/norepinephrine
o Monoamine oxidase inhibitors = MAOIs
 MAO breaks down monoamines = increase them
 Avoid tyramine or else hypertension (tyramine increases catecholamine even
more)
 Older versions non selective, newer versions more selective for MAOIA = safer
o Tricyclic antidepressants (TCAs)
 Prevent reuptake by inhibiting serotonin/NE transporter
 Not selective
 New version = selective serotonin reuptakes inhibitors (SSRIs)
 Only inhibit serotonin transporter
 Serotonin/norepinephrine reuptake inhibitors (SNRIs)
 Similar to SSRIs
o Atypical
 Bupropion
 Inhibits NE/Dopamine reuptake
 Mirtazapine
 Blocks presynaptic a2 receptors, and postsynaptic serotonin receptors to
increase release
 Trazodone
 Blocks serotonin receptors and stops reuptake
o More dopamine/NE release
Anxiolytics
Genomics
-
Only 1% of drug goes to disease site
Lots of drugs have biomarkers to predict biological state, but gotta use trial and error to figure out
which one works since we don’t know your genome
Pharmacogenomics
o Identify your genome variability
o
o
-
-
-
-
Individualize therapy to minimize risk – streamline drug development
 Decrease size of clinical trials, development costs, increase drugs that reach
market
Sequencing genome has become much faster, easier, cheaper
 Genes affect risk of diseases
Issues
o Single nucleotide polymorphism
 Change in single base
o Genetic polymorphism
 Difference in sequence between individuals, groups, populations
Guide prescriptions
o One on one in hospital
o Doctor can give simple genetic test to see if you have protein for Herceptin (trastuzumab)
to work
o But need this for more common OTC drugs like Tylenol
 Usually safe but can cause liver damage in people with mutation in CD44 gene
o Some drugs change dosage depending on genes
 Warfarin is metabolized poorly with CYP2C9/VKORC1 gene mutations
 40% white, 14% black, 90% yellow people have at least 1 allele variation
 90% of drugs broken by cytochrome p450
 Dose depends on expression of this
o Poor metabolism
 Active drug = more effective, need to lower dose
 Prodrug = less effective, prodrug might accumulate so need to lower dose or
another drug
o Ultra rapid
 Active drug = less effective, increase dose
 Prodrug = metabolite might accumulate so need lower dose
Biomarkers
o HER2 – human epithelial growth factor receptor
 Herceptin = monoclonal Ab that binds to HER2, overexpressed in 25% of early
stage breast cancer and can improve survival
 First do genetic test to see if you have more HER2, or else no effect for
trastuzumab
o ALK – anaplastic lymphoma kinase
 4% of people with non small cell lung cancer have mutation that causes cancer
growth due to protein that is product of 2 genes fused together
 Xalkori inhibits defective gene product of ALK and shrinks tumors with the gene
o CFTR – cystic fibrosis transmembrane conductance regulator
 Cystic fibrosis is caused by defect in CFTR gene
 Kalydeco binds to CFTR in 3-5% of people with cystic fibrosis that improves
function
o BRCA1 – breast cancer 1, early onset
 Codes for protein that repairs damaged DNA or causes apoptosis
 Mutation leads to cell proliferation unchecked = cancer
 Leads to 60% with breast cancer, 40% with ovarian cancer
 Angelina jolie found she was positive, got double mastectomy
Therapeutics
o Glybera (alipogene tiparvovec)
 Gene therapy that compensates for lipoprotein lipase deficiency (LPLD)
 Leads to pancreatitis
Uses adeno associated virus serotype 1 (AAV1) as vector to deliver copy of
lipase gene
 Treatment costs 1million a year
CRISPR
 Cas9 cuts double DNA strand at specific point
 CRISPR is messenger RNA strand
 CRISPR guides cas9 to bind with specific place and make a cut
 Can splice out part of gene or insert new sequence

o
NMJ
End plate = generated by nicotinic cholinergic receptors, graded
Action potential = voltage gated channels, all or none
Before NMBs, had to do complete knockout
General anesthesia = analgesia, amnesia, unconsciousness, immobility, reduced autonomic response
-
Also reduced ability to breathe, hypotension, reduced cardiac contractility, risk of hypothermia
NMBs reduces risk of respiratory/cardiac depression
Curare – tips of arrows
-
Now used to relax muscles
NMBs – bind to nicotinic cholinergic receptors at neuromuscular junction
-
-
-
Only block at skeletal muscles, nothing else
Temporary paralysis and relaxation
Classes = depolarizing/non depolarizing
o Succinylcholine = dep
o D tubocurarine/pancuronium = non
 Isoquinoline derivative = tubo
 Steroid = pan
Similar to ACh structure
o Has 1-2 quaternary nitrogens (N+(Ch3))3
o N+ attracted to alpha subunits of postsynaptic ach receptor
o Also decrease lipid solubility and limits CNS penetration
o Administers parenterally = due to low lipid solubility
 IV or intramuscular
Depolarizing
o SCh
o Very rapid action = 1min
o Short duration = 5-10 min
o Agonist at nicotinic receptor
 Sch hydrolyzed by butyrylcholinesterase/pseudocholinsterase = not in cleft
 Much slower breakdown than ach
 Potentiated by cholinesterase inhibitors = lower breakdown
 Side effects = bradycardia, hyperkalemia = high K+, muscle pain
o Mechanism
 Phase 1


Paralysis preceded by twitches = fasciculations
Blocks transmission by causing persistent depolarization, receptors don’t
close
Membrane unresponsive to more impulses = channels inactivated

Phase 2
 After prolonged exposure to SCh
 Repolarization happens but SCh broken slower, so it can desensitize the
receptors
 Then they become less sensitive to Ach too
 Kind of like blockade from non depolarizing blockers
Non depolarizing
o Slower action = 2-3min
o Longer duration = 20-120min
o Competitive antagonists
o Prevent ach binding
o Can be stopped by cholinesterase inhibitors = more Ach can compete
o Mechanism
 Prevent end plate potential from thresholding = no action potential
o Examples
 Isoquionline – tubocurarine
 High potency
 Lack of vagolytic effects
 Release histamine = hypotension, tachycardia, bronchospasm
 Excreted by kidney
 Steroid – pancuronium
 High potency, vagolytic effects = tachycardia
 No histamine
 Metabolized by liver, excreted from kidney
o Clinical uses
 Tracheal intubation
 Improve surgical conditions
 Decrease anesthetics needed
 Suppress spontaneous ventilation when they need mechanical ventilation

-
Anesthesia
-
-
Phases
o Transduction
 Stimuli into AP
o Transmission
 AP through neurons
o Modulation
 Inhibition (glycine/GABA) or augmentation of pain signals (norep, sero,
endorphin)
o Perception
 Integration of input into somatosensory/limbic cortices
Modulation
o Inhibition from mechanoreceptor fibers to nociceptor tracts
Allodynia = pain to regular stimulus
Hyperalgesia = excessive pain to painful thing
-
-
-
-
-
Treatment
o Nsaids
 Blocks cox1/2
o Acetaminophen
 Blocks cox3
 Large TI
o Opiates
 Block Ca2+ from entering presynaptic terminal = no neurotransmitters
 Open potassium channels = hyperpolarize and prevent spike activity
 Side effects = CONSTIPATION, respiratory depression, difficulty urinating,
fuzzy thinking, pupil narrowing
 Fentanyl = 100x morphine
o Regional anesthesia
 Fentanyl used here
 Local anesthetic = lidocaine
 Na channel blocker = prevent propagation of nerve action
 Epidural
 Inject into epidural space = labour pain, postoperation, after
abdomen/chest surgery
 Use less general anesthetic/opiates systemically
Overdose
o Naloxone = antagonist for opioid receptor
Cannabis
o Activate CB1 receptors by THC = more dopaminergic activity in mesolimbic circuit
 Short term can increase reward system
 Long term decreases reward system
o Adolescent use associated with lower educational attainment, more drugs, but not with
school/psychological health when controlled for alcohol/tobacco
o Impairs attention, concentration, episodic memory, associative learning
o Chronic use = schizo, bipolar, anxiety, depression
o Can treat nausea from chemo, epilepsy, refractory pain, spasticity for MS
General anesthesia
o Amnesia, analgesia, anesthesia
o Upregulate inhibitory, downregulate excitatory pathways
o Excitatory = acetylcholine, nmda, glutamate
o Inhibitory = GABA, glycine
o Most important = GABA chloride channels
Dose
o Alpha phase = distribute to peripheral
o Beta = metabolism/excretion
o Context sensitive half time = to decrease by half in plasma
 Diazepam very long
 Etomidate very fast
Propofol
o Promote GABA
o Goes to liver for metabolism = cleared by renal
Ketamine
o Nmda antagonist
o Inhibit excitatory
o Dissociate thalamus from limbic cortex
-
-
-
o Liver converts to metabolites, some have activity still
Benzos
o Promote gaba
o Liver breakdown
Opioid
o Mu, kappa, delta, sigma
o Liver, renal failure
Remifentanil
o Half life less than 10 min
o 3 minutes lasting
o Ester hydrolysis by esterases
Inhalational agents
o Gas = NO
o Volatiles = desflurane, sevoflurane
o Activate GABA channels, inhibit calcium channels and prevent some neurotransmitters
or glutamate
o Decrease BP, increase brain blood, decrease tidal volume, increase respiratory rate
IV/inhalational
o IV more common, faster, loss of airway control, extravasation
o Inhalation needle phobia, maintain ventilation until airway controlled, slow, irritating,
apnea
Diabetes
Type 1 = insulin injections, careful diet, activity
-
No insulin, so sugar builds up
Autoimmune destruction of beta cells – cant be prevented = must have insulin to survive
May be triggered by high sugar foods
Type 2 = lifestyle change, oral meds, maybe insulin
-
Insulin resistance
Beta cell dysfunction
Obesity
No ketoacidosis
Less insulin secretion
More glucagon
More hepatic glucose
Less glucose uptake
More glucose reabsorption
More lipolysis
Symptoms
-
More sugar in urine = water loss = thirst
o Weight loss
Hunger
Dry mouth
More pee
Blurred vision
Infections
-
Slow healing
Insulin
-
-
-
Pancreas makes half after meals = need short acting
Other half during day/night = long acting
Aim is to inject like the body
Issue is if not used well = hypoglycemia
Rapid
o Clear
o Very fast
o Aprida, humulog, novorapid
Short
o Clear
o Humulin r
Intermediate
o Cloudy
o Humulin n
o Novolin nph
Long
o Clear and colourless
o Lantus
o Levemir
Treating type 2:
-
-
Lifestyle change
o Exercise
o Diet
o If no change, gotta use drugs
Drugs
o Sulfonylurea
 Close k atpases in beta cell membrane = release insulin
 Glyburide, glipizide, glimepiride
o Biguanides
 Metformin
 Increase sensitivity
 Decrease glucose storage
 Decrease glucose absorption from gut
 Side effects = digestive problems, b12 deficiency, weight loss
o Alpha glucosidase inhibitor
 Acarbose
 Inhibit alpha glycosidase hydrolase enzymes in intestine
 Slow down carb digestion
o Thiazolidinediones
 Rosiglatzone, pioglitazone
 PPAR activators = increase sensitivity
 Peroxisome proliferator activated receptors
o Incretins
 Mimic incretin = stimulate insulin release after meals
 Rapidly inactivated by DPP 4

o
GLP1 – from ileum, most effect in type 2
 Exenatide = resistant to DPP4
 Liraglutide = binds albumin, slow metabolism
 GIP – from jejunum, affect beta cells of pancreas
DPP4 inhibitors
 DPP found in all major organs
 Can help incretins work longer
Renal
Carbonic anhydrase inhibitors = rarely used
Osmotic diuretics
-
Increase osmotic pressure in proximal tubules/loop of henle
Prevent reabsorption of water
More osmotic force out = water/na excretion
Mannitol
Loop diuretic
-
Inhibit na/k/2cl transporter in ascending loop = transports ions in
Furosemide
Treats edema, hypertension
Also leads to hypokalemia, drug interactions
Thiazide
-
Inhibit reabsorption of na and cl in distal
More k, na, cl excretion
More excretion
Chlorothiazide
Hypokalemia
K sparing diuretics
-
Doesn’t affect K
Aldosterone antagonists, spironolactone
Use with k wasting diuretics
SGLT2 inhibitors
-
Sodium glucose co transporter 2 inhibitor cause body to excrete more glucose
Weight loss, good for type 2 diabetes
Canagliflozin
*don’t remember the drug names, just the classes
Cardio
Hypertension
-
Primary = no underlying cause
Secondary = has cause
Pressure = CO times resistance
RAAS
-
Aii = increase aldosterone = constrict blood vessels = more pressure
o Aldosterone = more sodium, more water = more pressure
o ACE converts renin to Aii
ACE inhibitors = treat high blood pressure
-
Prevents angina = low blood to heart
Congestive heart failure
-
Cant pump enough blood with each contraction
Shortness of breath, fluid retention
Caused by damage to heart, need digitalis, ace inhibitors, diuretics…
Digitalis glycosides
o Inhibits na k atpase at sarcolemma
o Increase stroke volume, and CO
Antiarrhythmic
Extrasystole = an additional beat, could be harmless, or it could trigger or indicate something more
serious
Tachycardia = beating too fast
-
Atrial flutter = only atria
o Not in sync with ventricle = blood moves slowly = clotting/stroke
Ventricular tachycardia = from ventricle
Supraventricular = somewhere above the ventricle
Fibrillation = random volleys
-
Can be minor, or can lead to blood clots
Ventricular is more serious, lethal if untreated
o CPR and defib
Arrhythmia = from disturbance in impulse formation, conduction, or both
-
Ectopic pacemaker
o Injury can trigger other cells to do pacemaking activity = send random signals
Early/delayed after depolarizations
o Early
 Spikes during phase 2/3
 Abnormal calcium handling
 Usually during slow rate
o Delayed
 Phase 4
 Abnormal calcium handling by SR
 Fast rate
-
-
o Can trigger Aps in other cells that lead to arrhythmia
Disturbance in impulse conduction
o Conduction block
 AV block
 Damaged tissue
 Only beats once every few times
 Bundle branch block
 Block or slow the branch in septum
o Scar tissue
o Reentry
 Obstacle to propagate around
 Area of unidirectional block
 Conduction time greater than refractory period
 Wolff Parkinson white syndrome = impulse travel too fast to ventricle, then can
go back to atria
 Treated by ablation = destroy accessory tissue
Drugs
o I = sodium channel blockade
 Block pacemaker current = stop ectopic
 Block sodium = increase threshold = stop ectopic
 Prolong ap = stop ectopic
 Use dependent = prefer to block sodium channels that are open/inactivated
 Better effect when heart rate is high or ischemia = slow drug dissociation
 Reentry
 1a prolongs apd
 1b shorters
 1c no effect
 Focus on slowing conduction = gives time for unidirectional block to
recover
 Can also lengthen APD and prolong refractoriness
o Premature beat will be blocked coming back as well
o Slow conduction
o Ii = b adrenergic blockade
 Propranolol = slow tachy
 Beta blockers stop arrhythmia from atria to go to AV node = supraventricular
 Slow conduction
o Iii = potassium channel blockade
 Slow ap = stop ectopic
 Reentry
 Reverse use dependent = better at slower heart rate
o Don’t target ischemic tissue
 Prolong refractoriness in normal tissue = no premature beat can
propagate or it will cycle around and then get blocked then
o Iv = calcium channel blockade
 Slow ap = stop ectopic
 Slow conduction and increase refractory at av node
 Treat av node reentry or supraventricular tachyarrhythmia
o Misc
 Atropine = muscarinic blocker for speeding brady

Hypokalemia = low potassium means lower resting potential = stop ectopic = not
therapeutic
Experimental design
Experimental unit = smallest unit where data can be obtained
-
Like an individual, a cell, a receptor etc
Treatment = apply to unit, in different levels = different doses
-
Independent variable
Outcome = dependent
Steps
-
-
Research question
o Make a hypothesis based on this
Study population
o Collection of experimental units
o Gotta take a sample
Treatment
o Iv vs dv
Sample size
o Power = probability of detecting treatment effect when one exists
o Hypothesis testing = use stat analysis to see probability that its true
 Null vs alternate
 Either reject or don’t reject null hypothesis
 Type 1 error = reject when its true
 Tell a man hes pregnant
 Type 2 error = don’t reject when it’s not true
o Power = probability of type 2 error = 1-B
 High power = low chance of type 2 error
 Improve power with:
 Effect size = bigger differences between groups
 Low variance = error bars don’t overlap
 Significance level = alpha = type 1 error
o Increase alpha to decrease beta = more power
No confounding variables
o Sampling
 Random = random
 Block = break into genders, then randomly assign treatment
 Paired = match pairs, one gets treatment and one doesn’t
o Control groups
 No treatment
 Sham
 Standard treatment = already well characterized
o Blindness
 Blind = treatment or control idk for experimenter
 Double blind = treatment or control idk for both experimenter and subject
 Triple blind = experimenter, subject, and analyzer all don’t know
o Crossover = deal with temporal effects
Natural health products
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Less likely to be scammed in Canada lmao
NHP is same as dietary supplement in us
o Must be safe as otc, no prescription needed
o Checked for efficacy
FDA only checks for safety, not efficacy = only checked after problems reported
NNHPD deals with all NHPs
In US, no preapproval needed, companies need to report effects
o DSHEA excludes dietary supplements from regulation
o Just say that its not approved by FDA and ur good
In Canada, you can say efficacy by anecdote
License with NPN or DIN-HM (homeopathic)
o Also need site license for where you make them
Examples
o Vitamin d
 Mostly from sun in skin
 Increase ca/mg absorption, hormone for metabolism, bone, etc
o Calcium
 Dairy, grain, veggies
 Physiology of organs
o Magnesium
 Almonds, cocoa, spinach
 Catalyst for lots of stuff
o Alpha linoleic acid
 Seeds
 Metabolism of cardiac cells
o Docosahexaenoic acid
 Oily cold water fish, algae
 Phospholipid in CNS
o Eicosapentaenoic acid
 Oily cold water fish, algae
 Turns to eicosanoids = prostaglandins, thromboxanes, etc
o Kava
 Anxiety
o Maca
 Super food
o St johns wort
 Antidepressant
o Antioxidants
 Sketchy, no trials
o Homeopathic = witchcraft
Drug development
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Drugs not always regulated
1906 = label adulterated, misbranded as illegal
o Thalidomide = birth defects
o Led to proof of efficacy
Canada = HPFB = controls what is sold, level of control, drug abuse
Steps
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Discovery
o Find disease, find drug
 New use for old drug
 Exogenous natural source, endogenous natural source
 Systematic design
 Molecular targeting
o Target specific protein
o High throughput screening = detect thousands of interactions
o Combinatorial chemistry = make lots of molecule for HTS
o Molecular modelling = make best possible candidate
 Disease targeting
o Test in vitro/in vivo
 Pharmacodynamics = what does it do to body
 Pharmacokinetics = what does body do to it
o Toxicity = from dose
 Which organs are toxic
 Is it reversible
 Safe starting dose
 Prrephase 1
 Figure out how its toxic
 Dose range
 How it damages genes
 Respiratory, cardio, cns
 After phase 1
 Reproductive toxicity
 ADME
 Metabolite toxicity
 Drug interactions
 Carcinogen
 Something that isn’t toxic to rodents can be toxic to us
 Try to design something that is consistent
Human testing
o Only if the risk is low
o Submit IND or CTA with all info so far
o Phase 1
 Small amount of healthy people
 Very low dose
 See what happens
 Could be dangerous
o Phase 2
 Hundreds of people
 Months to years
 Figure out dosage
o Phase 3
 In patients
 Very rigorous
o Pivotal
 Control
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 Blind
 Random
 Sample size
Submit new drug app, new drug submissions, marketing authorization app
o Have all the info
o Phase 4
 Post marketing surveillance to see safety
 Could be recalled if things are found
 Must be done in approved label range
Drug response
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Compliance
o Was the prescription filled
 If it’s a clear issue, more likely to fill
o Meds taken
 More likely if low dose
 Less likely if side effects
 Women prefer red, men prefer pink pills
 Small pills also better
 Also more likely to stop using if it changes color or shape
o How to improve
 Longer lasting = less doses
 Generic ones
 Pill organizers
 Clear instructions
Interactions
o P450 = sub therapeutic or toxic
o Disease affects itself
 Gi tract problems = less absorption
 Liver disease = less metabolism
 Kidney = less excretion
 Circulation = less adme
o SNPs can affect metabolism of enzymes
 Ex. Asian flush = aldh2 point mutation = less alcohol tolerant
 Converts to acetaldehyde, but slow conversion to acetate
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Age
o
o
Pediatrics
 Little clinical data
 Drugs used by experience
 Higher pH stomach
 Erratic gastric emptying time, less surface area in neonates
 Skin = thinner stratum corneum = more absorption
 Higher surface area mass ratio
 More water = 80%, less plasma protein and fat 10%
 Higher doses of hydrophilic drugs, lower dose since more free drugs
without plasma protein, and lower dose of hydrophobic drugs
 Less metabolism, phase ½ enzymes immature = greater half life
 Less excretion = greater half life
 Decrease dose, or increase interval
Geriatrics
 Much more toxic
 Less clinical data
 More illness
 More meds
 Higher pH stomach
 More fat, less water, less plasma protein
 Need more hydrophobic, less hydrophilic, less overall (less bound to
albumin)
 Smaller liver, blood flow
 Higher half life
 Phase 2 mostly unchanged
 Kidney excretes less
 Higher half life