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James’ Pharmacology Study Notes 11/6/2018 6:54:00 AM

Module 1 – General Principles of Pharmacology

Pharmacology – a branch of medicine dealing with interaction of drugs within


living animals, mechanisms of drug action as well as therapeutic and other
uses of the drug

Brand names, generic names and chemical names

Drug-Receptor Interaction
K1 = D + R -> DR
K2 = DR -> D + R

Ka = affinity constant
Kd = dissociation constant
Kd = K2/K1
The lower the Kd, the more affinity the drug has for the receptor

Dose response curve – measurement of drug-receptor interaction


EC50 - Concentration of drug that causes 50% of maximal response/efficacy

Log dose-response curve is easier to analyze mathematically and


compresses the scale

EC50 = dose/concentration of a drug that produces 50% of maximal


response
Emax = max effect produced by a drug; a measure of efficacy of a drug
Efficacy/Intrinsic activity = ability of a bound drug to change the receptor in
a way that produces an effect; some drugs have affinity but not efficacy
(just occupy the receptor)
Kd = concentration of a drug that occupies 50% of the total number of
receptors at equilibrium

Potency of the drug


 Potency is determined by the affinity plus intrinsic activity of the
drug
 A more potent drug is not clinically superior
o Low potency is a disadvantage only if the dose is so large that
it is awkward to administer
 If the dose-response curve is shifted left and steep, its considered
more potent

Spare receptors
If EC50 = Kd there are no spare receptors
If EC50 < Kd then it suggests the existence of spare receptors
 Spare receptors allow maximal response without total receptor
occupancy – increased sensitivity of the system
 Spare receptors can bind and internalize extra ligand preventing an
exaggerated response if too much ligand is present

Agonist – has affinity and efficacy


Partial agonist – has affinity but less efficacy (compared to a full agonist);
would therefore have a lower Emax
Antagonist – has affinity but NO efficacy
 Can be competitive (reversible) or non-competitive (irreversible)

A partial agonist acts as an antagonist in the presence of a full agonist


 Good because they have some efficacy and at the same time block
the endogenous full agonists ex: Pindolol for high BP and abN heart
rhythms

Competitive Antagonism
 Require a higher dose of agonist in the presence of competitive
antagonist to produce the same effect
 Can still get to Emax but require a higher concentration

Non-competitive Antagonism
 In the presence of non-competitive antagonist even a higher dose
of agonist cannot produce the original Emax
 Emax is depressed in the presence of a non-competitive antagonist

Quantal dose-response curve – indicates sensitivity of a given population to


the doses of a drug for a given effect
 Frequency distribution or cumulative frequency

Therapeutic Index
ED50 = effective dose in 50% of ppl
TD50 = toxic dose in 50% of ppl
LD50 = lethal dose in 50% of ppl
Therapeutic Index/TI = TD50 or LD50/ED50
 Higher the ratio, safer the drug

Therapeutic window – reflects [plasma] range that provides efficacy w/o


unacceptable toxicity
 TW is the difference between the minimum effective concentrations
(ED) for desired response and an adverse response (LD)

Signal Transduction Pathways


 Ion channel receptors/Ionotropic
 G-protein coupled receptors (half of all known drugs work through
this mechanism)
o Subsequently cAMP, IP3, DAG
 Enzyme receptors (tyrosine kinase, etc)
 Nuclear receptors

Up/Down-Regulation of Receptors
 Agonists tend to desensitive receptors
o Homologous – decrease receptor #
o Heterologous – decreased signal transduction
o Ex: Overuse of B2 agonists in asthma
 Antagonists tend to upregulate receptors

Pharmacokinetics

 Drug absorption
o Passage of drug from site of admin into general circulation
(except for drugs applied directly to target tissue)
 A drug given IV is immediately and completely 100%
absorbed
o Generally:
 Better absorbed
 Non-charged, small, lipid soluable drugs
 Poorly absorbed
 Charged, large molecules
o Ionization: Effect of pH on absorption
 pKa of a drug is defined as the pH at which the
drug is half ionized
 most drugs are either weak acids/bases
 acidic drug in a basic medium gets ionized and is
less well absorbed
 basic drug in acidic medium gets ionized and is
less well absorbed
 Ion trapping
 At steady state, an acidic drug will accumulate on
the more basic side of the membrane and a basic
drug on the more acidic side (trapped in the
compartment)
 Signifcant for fetus and in poisoning
 Acidification or alkylation of urine can
accelerate excretion of basic or acidic drugs
that have reached toxic concentrations in
blood (respectively)

First Pass Metabolism


 phenomenon where a drug is prevented from reaching the systemic
circulation due to metabolizing enzymes (especially in the GI
epithelium and liver)
 Ex: Wine and cheese reaction – high in tyramine – normally
tyramine is metabolized by MAO, but if pt takes a MAO inhibitor,
tyramine will get absorbed and stimulate adrenergic receptors
causing tachycardia and high BP

Bioavailability
 The fraction of orally given drug that reaches the circulation
 = (AUC orac/AUC IV) x 100

 some drugs bind to plasma proteins, displacement of a drug from


plasma protein binding generally causes no change in overall effect
except for drugs with very SMALL volume of distribution (like
warfarin, low Vd)

Distribution
 The REVERSIBLE movement of a drug b/w body
compartments
 Fx’s affecting drug distribution
o Ionization
o Capillary permeability (in liver and spleen, they are very
leaky)
 Drugs leave capillaries regardless if they are poorly lipid
soluable, large or polar
 Only lipiphilic drugs diffuse across the blood brain
barrier (tight junctions) unless they are transported
across by active transport
o Blood flow
 More blood flow more drug (brain, liver, kidneys >
muscle > fat)
o Plasma protein binding

Volume of Distribution (Vd) = dose administered / [plasma]


 High Vd indicates that most of the drug is in the extravascular
compartment, low Vd means most is in vessels, like warfarin (99%
bound to plasma proteins

Redistribution of Drugs
 Organs that are highly profused (brain and kidney) get a lot of
drug, but over time drug is redistributed to storage areas with less
perfusion (fat and muscle) removing the drug from the brain and
kidney; drug wears off
 Ex: anesthetics like thiopental used to induce anesthesia, where
induction and recovery of anesthesia are rapid and lower
concentrations are given to take advantage of redistribution

Biotransformation (Drug Metabolism)


 Chemical modification of drugs
 Drugs metabolizing enzymes found in LIVER, GI wall, lungs,
kidneys, etc
Prodrugs – are inactive, after metabolism are converted to an active form
 Ex: Olsalazine – for Tx of IBD, and PPI for ulcers

2 Phase Biotransformation
 Phase 1/Functionalization rxns
o Oxid/reduction and hydrolytic rxns – tend to make drug more
polar, but not necessarily deactivate
o Microsomal cytochrome P450 monooxygenase family of
enzymes
Oxidize drugs
Metabolize widest range of drugs, in most cases
inactivates them
o CYP Polymorphism – genetic variations in population
 Mutations in drug metabolizing enzymes in some pts
 Most common one is CYP2D6 in Caucasians; lack this
enzyme:
 Slowly metabolize b-antagonists, neuroleptics,
anti-depressents and codeine
 Prone to get bradycardia during BB Tx
 Codeine not good for analgesia in these pts, as it
needs to be metabolized to morphine to work
 Also CYP2C9
 Warfarin (also CYP1A) and phenytoin are
substrates for this enzyme
 Drugs with narrow therapeutic windows must be
given with caution in these pts
o Factors Affecting Drug Biotransformation
 Induction/inhibition of cytochrome P450 enzymes
 Inducers – expression of more CYP enzymes and
faster elimination
 Lower drug levels than usual result in treatment
failure
 Ex: Rifampin (Abx), St. Johns Wort
 Inhibitors – inhibit CYP enzymes and decrease
elimination of drugs
 Higher drug levels than usual can cause toxicity
 Ex: Grapefruit juice, cimetidine,
erythromycin

 Phase 2/Conjugation rxns


o Conjugation to polar groups (glucuronate, sulfate, acetylate)
– most result in inactivation of drug
o Conjugated drugs are rapidly excreted, and required enzymes
are usually located in cytosol
o Autosomal variations: 50% of Americans have reduced
expression of acetylating enzyme (slow acetylators)
 Slowly metabolize isoniazid (TB drug), and caffeine

Significance of Drug metabolism


 If a pt is taking 2 or more drugs, possibility of interactions should
be considered
 When a pt is taking a single Rx metabolized by cytochrome P450
enzymes, interactions due to food or herbs should be considered
 In cases of drug toxicity or treatment failure, genetic variation in
metabolizing enzymes should be considered

P-Glycoprotein
 An ATP efflux pump that pumps compounds from inside to
outside
o Plays a role in drug resistance to cancer chemotherapeutic
agents
 Over expressed in tumors and pumps out anti-cancer
drugs
o CCB’s inhibit P-glycoprotein and may be useful to reverse
resistance
o St. Johns Wort and Rifampin induce more expression of P-
glycoprotein
 Also found on CNS BBB to protect it from unwanted compounds
 Digoxin is transported by P-glycoprotein so inhibition of it can
elevate plasma digoxin levels to toxic range (verapamil, quinidine,
erythromycin – can cause dig toxicity)

Enterhepatic Recirculation
 Compound conjugated in liver, excreted in bile, deconjugated in
intestine by bacteria and reabsorbed into circulation
 This phenomenon prolongs the half-life of a drug
 Significance: 95% of bile acids are reabsorbed and are used in
cholesterol synthesis; bile acid binding resins like cholestyramine,
interrupts bile acid recycling and reduces cholesterol synthesis and
its level in plasma
 Also, OCPs and antibiotics, abx removes intestinal bacteria,
preventing deconjugation and interrupts recycling of estrogen

Clearance
 The volume of blood from which a drug is irreversibly
removed per unit of time (ml/min/kg)
o Cl = rate of constant elimination (k) x Vd
 Used to calculate maintenance dose of a drug
o Maintenance dose/rate of admin = rate of elim
 Systemic clearance of a drug is the sum of the clearance by all
organs (kidney, liver, lungs, etc)

Renal Clearance
 Only FREE drug is filtered, not protein bound drug
 Net removal = filtered + secreted – reabsorbed
 Creatinine Clearance
o Kidney function is usually assessed by GFR
 Creatinine clearance used to estimate GFR
 Creatinine plasma concentrations are stable and is
produced endogenously so doesn’t have to be
administered
 Freely filitered by the kidneys, not reabsorbed and
minimally secreted, therefore good to measure GFR
 Urine and serum creatinine levels measured along with
urine volume in 24 to calc clearance
 Clearance (ml/min) = ([Urine] (mg/ml) x Urine
flow rate (ml/min) / [plasma creatinine] mg/ml)

Drug Elimination Kinetics


 First-Order
o Constant fraction of drug is eliminated per unit time
 Rate of elim is proportional to plasma concentration
o Blood concentration declines in a linear fashion
o Most drugs eliminated this way
 Zero-Order
o A constant AMOUNT of drug is eliminated per unit time
o Because it is the maximum rate of elimination when the
pathway for elimination is saturated

Half-Life
 The time required for the plasma concentration of a drug to be
reduced by 50%
 It takes about 5 half-lives for more than 90% of a drug to be
effectively eliminated from the body
 If a fixed dose of drug is given repeatedly at fixed intervals, it takes
about 5 half-lives for that drug to achieve steady state plasma
concentration
o Ex: if half-life is 20 hours for a drug, it will reach steady state
in 100 hours
 Time to reach steady state depends only on the half-life
 t1/2 = 0.693 x Vd/Cl

Loading Dose
 Dose of a drug sufficient to produce a plasma concentration of drug
that will fall w/in therapeutic window after only one or very few
doses over a very short interval. It is larger than the dose rate
needed to maintain the concentration w/in the window and would
produce toxic concentrates if given repeatedly
 IV Loading Dose = (target [plasma]) x (volume distribution)
 Oral loading dose = (target [plasma]) x (volume distribution) / F
o F = fraction bioavailable (0-1)

Maintenance Dose
 Dose needed to maintain the given concentration w/in the
therapeutic window when given repeatedly at a constant interval
 Maintenance dose = steady-state plasma concentration x
clearance of the drug
o For oral dosing, divide by fraction bioavailable
 If clearance does not change, doubling the dose will double the
blood concentration of the drug
 Steady State Concentration = rate of admin/clearance

Drug Development and Therapeutics

Drugs in Children
 Hepatic enzymes not fully developed in infants, esp premature ones
 Gray Baby syndrome – side effect of IV admin of abx
chloramphenicol
o Blue discolouration of skin and lips and CV collapse
o UDP-glucuronyl transferase enzyme system of infants is
immature and incapable of metabolizing the excessive drug
load
 Changes in clearance
o Clearance increases from birth till age 1, then plateaus
till puberty, decreases a bit then plateaus again in
adulthood

Drugs in The Elderly


 Physiologic changes
o Reduced GI motility – reduced drug absorption
o Increased body fat – increased Vd
o Reduced GFR – decreased clearance of water soluable
drugs
o Reduced hepatic blood flow – decreased clearance of
some drugs

Drug Development
 Patent life = 20 yrs
 Preclinical ->Clinical ->Marketing ->Generic

QALY – Quality Adjusted Life Year – involves both quantity and


quality of life generated by healthcare interventions

Interchangeability
 The area under the curve for the plasma concentration and
the maximum plasma concentration need to be within 80 to
125% of the original drug. Time to reach Cmax would also
be taken to account.
o Tmax and Cmax should be within 80-125% of the
original innovator drug.
Autonomics 11/6/2018 6:54:00 AM

 ANS innervates smooth muscle, glands, and organs that aren’t


under conscious control (functions like breathing and HR, etc)
 ANS divided into sympathetic and parasympathetic
o Function in parallel to maintain homeostasis
 Enteric NS (ENS) considered third division of ANS and consists of
nerves innervating the GI tract, pancreas and gall bladder
o Innervated by both parasympathetic and sympathetic
o But local control seems to predominate its function

 Sympathetic Preganglionic NT = Acetylcholine


 Sympathetic postganglionic NT = NE
 Parasympathetic Preganglionic and post ganglionic NT =
Acetylcholine
 Sympathetic postganglionic fibers are longer and non-myelinated
therefore have a more diffuse effect that parasympathetic because
their postganglionic fibers are shorter and closer to effectors.
 Exceptions: Adrenal medulla is innervated directly by sympathetic
preganglionic fibers, causing the release of Epi; also postsynaptic
fibers of sympathetic acting on sweat glands uses acetylcholine

Catecholamines

 Biosynthesis
o From tyrosine -> DOPA -> Dopamine -> NE -> Epi
 Metabolism
o Very brief activity b/c metabolized rapidly
o Circulating catecholamines metabolized by catecholamine-O-
methyltransferase (COMT) to metanephrine on
postsynaptic membrane
o NE metabolized to normetanephrine
o Monoamine oxidase (MAO) converts them to VMA and
MAO is in neuronal mitrochondria
o Liver and GI conjugate them with sulfate or glucuronide and
excrete them in urine by kidney
o Levels of VMA and metanephrine provide a measure of
catecholamine production in medullary or sympathetic
system
o Uptake 1 – Neuron takes up NE; Uptake 2 –
tissue/effector takes up NE
 Physiological Actions of Catecholamines on receptors:
o A1 (IP3 pathway)
 Vasc. Smooth muscle (vasocontriction); increase
TPR and BP
 Nose (decongestion)
 Eye (mydriasis/pupil dilation)
o A2 (decrease cAMP)
 Presynaptic receptor on sympathetic nerve (decrease
NE release)
o B1 (increase cAMP)
 Heart (increase HR, contractility, automaticity)
 Kidney (increase renin)
o B2 (increase cAMP)
 VSM (vasodilation)
 BSM (bronchodilation)
 Liver (glycogenolysis)
 Uterus (relaxation)
 Mast cells (decrease histamine release)
o B3 (increase cAMP)
 Brown adipose tissue (increase lipolysis)

Catecholamines:
Agonists
 Epinephrine
o A and B receptors
 B1, A1, B2
o Good for emergency bronchospasm treatment (acute
asthma or anaphylactic shock) and open-angle glaucoma
o Also gives longer duration of anesthetic action via
vasocontriction and reducing systemic absorption
o Increases sBP lowers dBP
 Norepinephrine
o A and B in therapeutic doses, most A receptor influence
o Good to increase peripheral resistance (A1)
o Good for shock treatment (increase TPR and BP); increases
sBP and dBP
 Isoproterenol
o Synthetic: B1 and B2, little A stimulation
o Strong cardiac stimulation (b1), dilation of skeletal vessels
(b2), and bronchodilation (b2)
o Increases sBP lowers dBP
 Dopamine
o Precursor to NE; A and B activity and dopamine receptors
in renal and mesenteric vasculature causing
vasodilation
o B1 stimulation of the heart
o Therapeutic: choice drug for shock as it increases BP via
cardiac stimulation and also increases kidney blood
flow (increased GFR and Na diuresis)
 Dobutamine
o Synthetic B1 agonist
o To increase CO in CHF
o Watch out in Afib as it may increase AV conduction
 Phenylephrine
o Synthetic A1 agonist – for nasal decongestion
 Methoxamine
o Synthetic A1 agonist – for hTN in surgery
 Clonidine
o A2 agonist
o Used to lower pressure in essential HTN (via CNS effect,
diminishing sympathetic outflow)

In-direct Agonists
 Amphetamine
o A on vasculature and B on heart stimulation
o Acts via release of stored catecholamines therefore
indirect
 Tyramine
o Not a useful clinical drug, but found in fermented foods (ripe
cheese and wine)
o It enters nerve terminal and displaces stored NE and may
cause vasopressor episodes

Antagonists
 Prazosin, terazosin, Tamulosin
o A1 blockers
o Good for HTN, and benign prostatic hypertrophy
 Propanolol
o Nonspecific BB (B1 and B2)
o Bronchoconstriction, depresses heart, decreases sBP and dBP,
decreased glycogenolysis and glucagon secretion
o Not for asthmatics/COPD or DM
o Good for lowering BP in HTN by decreasing CO
 Timolol, Nadolol
o Nonspecific B1 and B2 blocker
o More potent than propanolol and longer duration of
action
o Timolol used topically in treating chronic open angle
glaucoma
 Atenolol, acebutolol
o Preferentially block B1 at low concentrations w/o
blocking B2 (cardioselective)
o Good in diabetic HTN
 Carvediol, Labetalol
o A and B antagonist
o Decreases lipid oxidation and vasc wall thickening
o Has some anti-arrhythmic properties

Drugs affecting NT Release


 Reserpine
o Blocks Mg2+ ATP-dependent transport of biogenic amines
(like NE, dopamine) from cytoplasm to storage vesicles
in sympathetic nerves
o Therefore depletes NE stores as MAO metabolizes
cytoplasmic NE
o Slow onset and long duration of action
 Guanethidine
o Blocks release of stored NE

Uptake Inhibitors
 Cocaine
o Blocks Na/K ATPase which is necessary for uptake of NE
o NE accumulates in cleft and potentiates actions of NE or
epi
 Increases duration of action of NE
 Causes exaggerated catecholamine response
 Amytriptyline
o Tricyclic antidepressant
o Prevents uptake of NE and serotonin

MAO inhibitor
 Phenelzine
o Irreversibly inactivates MAO

Cholinergics:
Synthesis
 Acetate + Acetyl-CoA + Choline acetyltransferase = Acetylcholine
 Ach transported into synaptic vesicles by Ach-H exchanger
 Uptake of choline into nerve fiber is rate-limiting step

Termination
 Acetylcholinesterase cleaves Ach into choline and acetate in the
synaptic cleft
 Choline taken up by a Na-coupled high affinity uptake system that
transport it into the neuron, where it is acetylated and then stored
until released by subsequent action potential

Receptors
 M1 – Neural (CNS, parietal cells)
 M2 – Cardiac (SA/AV nodes), presynaptic ganglia
 M3 – Glandular/Smooth muscle (secretion and contraction of
visceral smooth muscle)
 M4, M5 – CNS
 Nicotinic – Ganglionic and NMJ

Muscarinic Agonists
 Acetylcholine
o M (M2, M3) and N activity
o No therapeutic importance due to multiplicity of action and
rapid inactivation
 Carbachol
o Carbamic acid ester of Ach
o M and N activity
o Poor substrate of AChEsterase
o Rarely used therapeutically, except in glaucoma for pupil
constriction
 Pilocarpine
o Alkaloid containing tertiary amine resistant to AChEsterase
o Less potent than Ach
o Muscarinic activity
o Causes miosis
o Drug of choice for both closed and open-angle
glaucoma (cause opening of canal of schlemm thus dropping
intraocular pressure by increased drainage of acqueous
humor); timolol (B1 blocker used in chronic treatment)

Muscarinic Antagonists
 Atropine – blocks all muscarinic receptors
 Scopolamine
o For motion sickness
Cholinesterases:
Acetylcholinesterase – specific for ACh
Butyrylcholinesterase – non-specific, in plasma and other tissues

Anticholinesterases:
 Effects are due to enhancement of cholinergic transmission at
autonomic synapses and at NMJ
 Short acting – Edrophonium – used in Dx of myasthenia gravis
 Reversible:
o Physostigmine
 Duration 2-4 hours
 Can cross blood brain barrier and stimulate
cholinergic sites of CNS (increase intestinal and
bladder motility; good for atony of either organ)
o Neostigmine
 Synthetic, more polar so doesn’t get to CNS like
physostigmine
 Shorter duration (30 min)
 For Sx Tx in myasthenia gravis
 Pyridostigmine for chronic Tx of myasthenia
gravis (longer activity, 3-6 hours)
 Irreversible:
o Organophosphate compounds, bind covalently with AChE;
long lasting increase in Ach
o Many are highly toxic and are used as nerve agents
o Ex: Isoflurophate aka DFP (diisopropylflurophosphate)
 Pralidoxine can reactivate AChE but it can’t get into
CNS; but has to be given before the “aging” of
DFP; once DFP ages, its hard to break the bond.
Neuromuscular blocking drugs
 Block choline uptake:
o Hemicholinium, trieythlcholine (neither used clinically)
 Block ACh release:
o Aminoglycoside antibiotics, botulinum toxin

Nondepolarizing and depolarizing drugs


o Non-depolarizing block is reversible by
anticholinesterases; depolarizing is not
 Tubocurarine (Non-depolarizing)
o Reversible by high conc ACh or antiAChE’s like neostigmine
o Small rapidly contracting muscles (like face and eye) are
most susceptible to blockade
 Succinylcholine (depolarizing)
o 2 phases of activity
 1 – succinylcholine binds, resulting in initial
depolarization causing transient fasiculations then
flaccid paralysis
 2 – membrane repolarizes but receptor is now
desensitized to effects of ACh
o no ganglionic block unless at high doses
o used when rapid tracheal intubation required to induce
anesthesia (avoid aspiration of gastric contents)
 These are drugs used to cause paralysis during anesthesia
(Succinylcholine and tubocurarine)

Ganglionic Stimulators:
 Nicotine
o Stimulatory at low conc., blockade at high concentrations
o No therapeutic uses
 DMPP
Ganglionic Blockers:
 Block nicotinic receptors on sympathetic and
parasympathetic autonomic ganglia
 Nicotine
 Hexamethonium
 Trimethaphan, Tubocurarine
o The above block ALL autonomic and enteric ganglia
 hTN and loss of CV reflexes, inhibit secretions, GI
paralysis, impaired micturition
 Clinically obsolete

Drug Review:

Catecholamines:
Agonists
Epinephrine – a1, b1, b2 – good for anaphylactic shock; increase sBP,
decrease dBP
Norepinephrine – a and b, mostly a1 at therapeutic doses – increase TPR,
sBP and dBP increase
Dopamine – a and b, also d1 d2 (dopamine receptors) – for shock b/c also
vasodilates renal vasculature
Phenylephrine – a1 – for nasal decongestion
Methoxamine – a1 – prevent hTN in surgery
Dobutamine – b1 – for HF
Clonidine – a2 – for essential HTN, decreases sympathetic outflow
Salbutamol/salmeterol – b2 – bronchodilators

Indirect agonists
Amphetamine – release of stored catecholamines (a and b)
Tyramine – displaces stored NE (wine and cheese)

Antagonists
Phentolamine – a1 and a2 competitive antagonist – postural hTN
Phenoxybenzamine – nonselective a noncompetitive antagonist –
pheochromocytoma (catecholamine secreting tumor in adrenals); given prior
to surgical removal
Prazosin, terazosin, tamsulosin – a1 blocker – for benign prostatic
hypertrophy, hTN
Propanolol – nonspecific b blocker – for HTN by decreasing CO, glaucoma,
migraines, hyperthyroidism, angina, MI prophylaxis; not for
asthamtics/COPD or pts with DM; withdrawal syndrome
Timolol/Nadolol – nonspecific b blocker – more potent than propanolol; for
open-angle glaucoma
Atenolol/Acebutolol – b1 blocker – cardioselective, lower BP in HTN; good for
diabetic HTN
Carvediol/Labetalol – a/b blocker – decrease BP and lipid oxidation and vasc
wall thickening
Butoxamine – b2 blocker

Drugs affecting NT release/uptake:


Reserpine – blocks transfer of catecholamines into storage vesicles, gets
broken down by MAO.
Guanethidine – blocks stored NE release
Cocaine – blocks NE uptake 1; increases NE duration of action
Amitriptyline – inhibits NE and serotonin uptake – antidepressant
Phenelzine – MAO inhibitor

Mixed-Agonist:
Ephedrine – causes release of NE and also stimulates sympathetic receptors
on post-synaptic

Cholinergics:
Cardiovascular Drugs 11/6/2018 6:54:00 AM

Regional Ischemia
 Double Product
o Exercise tolerance test, pt runs on treadmill until they get
angina
o Double product is a clinical index of myocardial O2
demand/consumption
o Double Product = HR x sBP

 Angina
o Exertional/Stable – CP on exertion or excitement,
depression of ST segment
 Stable Angina occurs at the SAME double product
o Variant – CP resting assoc with ST elevation
 Due to spasm of coronary artery
 Angina occurs at variable double products
o Unstable – change in character, freq, and precipitating
factors in patients with stable angina, and when there
is pain at rest
 Signals impending MI
 Determinants of O2 supply/demand
o O2 Supply
 Diastolic perf pressure
 Coronary vasc resistance
 O2 carrying capacity
o O2 Demand
 Wall tension
 HR
 Contractility
 Aims of Therapy
o Decrease O2 demand (same double product)
 Most drugs we have decrease O2 demand
o Increase O2 supply (higher double product)

Anti-Anginal Drugs
 Nitrates
o Liberation of NO
o Cause venodilation, decrease VR and ventricular filling
pressure and wall tension; therefore decrease O2
consumption
o Problem with Tolerance – fix with intermittent
administration (patch 12hrs on 12hrs off)
o Often offered sublingually or transdermally
 Beta-Blockers
o Reduce myocardial O2 demand by decreasing HR and
contractility; blocking B1
o Contraindicated in variant angina, good for chronic
prophylaxis of stable angina
 Calcium Channel Blockers
o All existing CCBs block L-Type channels
o 1st Generation; 3 Classes:
 Phenylalkalamines (ex: Verapamil)
 Benzothiazepinones (ex: Diltiazem)
 Dihydropyridines (ex: nifedipime)
 Less depressant activity on heart than the
other 2
 Assoc with reflex-tachycardia from
baroreceptors
 Problem in pts with angina

Intermittent Claudication
 Vasodilators and BBs contraindicated
 Pentoxiphulline – reduces blood viscosity and thus
resistance and improves blood flow to ischemic area

Antihypertensives

 Essential/Primary HTN – due to unknown factors


 Secondary HTN – due to known cause
 BP = CO x TPR
 Labile HTN – BP elevated b/c of increased CO
 Established HTN – BP elevated b/c of increased TPR
o Eventually in labile HTN, increased CO causes over perfusion
of tissues causing autoregulation and subsequent increase in
TPR (evolution to established to HTN)
o Possible causes for increases in CO in labile HTNs
 Increased contractility
 Increased venous return (decreased venous
capacitance, increased plasma volume)
 Increased HR
 Control of BP
o Short term – sympathetic NS, RAAS, ADH system,
endothelin, etc
o Long-term – kidney fluid and electrolyte balancing

Anti-HTN Rx

 Diuretics: Thiazide and Thiazide-like Diuretics


o Decrease BP by decreasing blood volume and venous
return; this causes underperfusion of tissues (decrease CO)
and causes autoregulatory vasodilation and decrease in
TPR
o 50% of patients do not respond to these diuretics, they
tend to have exaggerated activity of RAAS system
o Adverse effects
 K+ depletion
 Lipid hostile
 Impaired glucose tolerance
o Often used in combo with other anti-HTN to prevent the
increase in plasma volume as a result of the other drugs
o Used for HTN
 Beta-Blockers (Propanolol, acebutolol, atenolol)
o Initially reduce CO but long term reduce TPR
 Block renin release
 Decreases SNS activity
 Peripheral pre-synaptic inhibition of NE release
from sympathetic nerve terminals
o BP lowering effect more pronounced in pts with normal
or high renin activity; but in those with low renin, a BB
+ a diuretic is good
o Adverse effects
 Lipid hostile (increase plasma TAGs, and reduce
HDL-cholesterol)
 Withdrawal syndrome (tachycardia, increased BP,
severe angina, and sometimes MI)
 b/c upregulation of B-receptors
 Alpha1-Blockers (Prazosin, Tamulosin)
o Dilates resistance vessels and capacitance vessels
 b/c they dilate capacitance vessels they reduce BP more
in standing position than in supine
 adverse effects
 Postural/orthostatic hypotension
(venodilator)
 Commonly on first dose
 Vasodilators
o Hydralazine, Minoxidil
Weak anti-HTN b/c of reflex increase in CO (b/c
reflex venoconstriction, sympathetic increase in renin.
 Adding a diuretic and a BB will block the changes
above
o CCBs (Nifedipine, verapamil, dilitiazem)
 Less of a problem with RAAS compensation than with
BBs
 Good in elderly and preferred over BB and ACE-I’s
o ACE-Inhibitors
 Block formation of ANG II, and secondarily b/c it
potentiates bradykinin
 Severe hTN can occur in hypovolemic patients and
cause renal failure in patients with renal artery
stenosis
 Adverse Effects:
 Cough, could be b/c of higher bradykinin
o ANG II Antagonists
 Share common effects and adverse effects of ACE-
Is
 Not assoc with cough

Heart Failure
 Most common causes are HTN, CAD and Diabetes

 Drugs to Decrease Preload


o Diuretics, venodilators
 Help reduce congestion in HF
 Drugs to Increase Contractility
o Digitalis glycosides
 Inhibition of Na/K ATPase
 Favors increased movement of extracellular
Ca2+ into the cell
 Direct increase in automaticity, decrease in conduction
velocity and shorter refractory
 Indirect “vagal” effect reducing conduction
through AV node
 Protects ventricles from A-fib (a therapeutic
use for dig)
 Narrow therapeutic window
 Problem with toxicity, esp in pts in renal
failure
 Hyperkalemia exacerbates dig toxicity
 Drug is cleared primarily by the kidneys, half-life
~40hrs
 Drugs to Decrease Afterload
o Prazosin – A1 blocker
o Hydralazine – dilates resistance vessels not capacitance
vessels; decreases TPR but causes reflex increase in CO
 These 2 drugs increase CO by decreasing afterload
o ACE-I’s
 Decrease afterload and preload, but increase in
CO due to reduction in TPR
o BBs
 Prevent cardiac remodeling from sympathetic
stimulation
o Aldosterone Receptor Blockers aka Spironolactone
 K+ sparing
 SEs - gynecomastia

Antiarrhythmics

 Phase 0 in myocytes due to Na influx, in nodal cells due to


slow Ca2+ influx
 The number of Na channels open and therefore the slope of 0
is decreased and the recovery time is increased as the cell
becomes more depolarized
o Antiarrhythmics often exaggerate these

 Antiarrhythmics drugs
o Class I – Na+ Channel Blockers (ex: Quinidine)
 Have a greater effect when cells are depolarizing
rapidly b/c these cells spend greater time in
activated and inactivated states than in resting
state
 Also true in ischemic tissues
 Reduce slope of phase 0
 b/c they depress conduction in areas with already
depressed conduction (ischemic areas) they make
a bidirectional block -> abort reentry b/c it needs
unidirectional block
 In Afib, quinidine has atropine like effects (M
blocker) and increase conduction through AV
node and worsen ventricular rate
 Therefore before giving quinidine, give
digitalis, its indirect effect on AV node will
protect the ventricles from high atrial rate
o Class II – BB’s
 More effective in conditions with high sympathetic
activity
o Class III – K+ Blockers (ex: Amiodarone, sotalol – BB with
class III activity)
 Prolong QT interval
 Can lead to TdP
o Class IV – CCBs
 Drug of choice for SVTs
 Recall verapamil (phenylalkalmine) and diltiazem
(benzothiazepine) are more affect on cardiac
tissue than vascular tissue
 Nifedipine (dihyrdopyridine) – more effect on
vascular; also reflex baro-receptor tachycardia
Drugs Affecting the Lung or the Kidney 11/6/2018 6:54:00
AM
KIDNEYS!

Classes of Diuretics & Site of Action

 Carbonic Anhydrase inhibitors (Acetazolamide) – PCT


o Prevent HCO3- formation, increased bicarb excretion ->
meta. Acidosis (low pH with low plasma HCO3-)
o Less bicarb formed means less H+, preventing Na+
reabsorption in PCT
 Distal channels get more Na and pump out more K+
o Therefore Weak natriuresis, hypokalemia + meta.
Acidosis
o Used in glaucoma
 Loop Diuretics (furosemide) – ThickAHL
o Reduced Na/K/2Cl reabsorption
 Distal channels get more Na and pump out more K+
 Na+, K+, Cl-, H+ loss
 Bicarb retention
 Decreased Ca2+ reabsorption
o High ceiling natriuretic, hypokalemia, hypochloremia,
meta. Alkalosis (high pH with high plasma HCO3-)
o For CHF and hypercalcemia
 Thiazide Diuretics (Hydrochlorothiazide/HCTZ) – early DCT
o Reduce NaCl reabsorption
 Distal channels get more Na and pump out more K+
 Na+, K+, Cl-, H+ loss; bicarb retention
o Similar to loop diuretics, a bit less natriuresis, also uric
acid retention; b/c they use the same transporter
o For HTN
 Potassium sparing diuretics (spironolactone) – late DCT
o Aldosterone antagonist
o Reduce Na-K, H+ exchange
 Na+ loss, K+ and H+ retention
o Weak natriuresis, hyperkalemia and acidosis
o Also reduces androgen activity (blocks androgen
receptors and inhibits 5alpha-reductase)
 Side effect = gynecomastia
o Usually used w/ other diuretics, and with digoxin to
prevent hypokalemia
 Osmostic diuretics (mannitol) – in DLoH
o Osmotic diuretic
o Prevent water reabsorption in PCT and DLoH
o For cerebral edema/to decrease intracranial pressure
 ADH antagonists (lithium, demeclocycline) – Collecting Duct
o Used is chronic SIADH (Syndrome of Inappropriate
ADH secretion)

Uses of Diuretics:
 Thiazides and loop diuretics – to decrease volume, preload
thereby decreasing CO (for CHF and HTN)
 Spironolactone – prevent or treat low K+
 CA inhibitors not used as diuretics but in glaucoma (reduce
intraocular pressure)
 Uses lowest dose!... Why?
o b/c of starling’s law of heart (increasing preload too much
eventually overwhelms the heart, decreasing CO)
o and b/c low K+ can cause death!

Tolerance to Diuretics
 Reasons:
o Reduced GFR (b/c volume depletion)
o Increased Na reabsorption in unaffected sites of tubule
o Increased RAAS
 Overcoming tolerance:
o Increase dose
o Reduce Na/H2O intake
o Add another diuretic

Respiratory!

Functions of Resp System


 Maintains PO2 and H+ (via PCO2)
o H+ = 25 x PCO2/HCO3-
 Protection from irritants
 Hypoxic vasoconstriction to prevent V/Q mismatch
(redirecting blood from poorly ventilated parts of lung)

Cough Suppressants
 Opiates (Codeine, morphine) – suppress cough
o Use lower doses than ones for analgesia
 Dextromethorphan not an opiate, for OTC use
 Recall, ACE-I side-effect is cough

Asthma
 Recurrent SOB, cough, wheezing (exhalation)
o Due to small airway narrowing b/c of bronchospasm,
edema and mucus (obstruction)
o Airway inflammation (inflammatory cells and mediators)
 People with methylcholine sensitivity tend to get asthma

Measurements in Resp Medicine:


 Peak Expiratory Flow Rate (PEFR)
o <200L/min is bad
 FEV1/FVC
o <70% = obstructive

Drugs Used in Asthma


 Beta2 Agonists
o Bronchial smooth muscle relaxation (via increased cAMP
and reduced [Ca2+]intra)
o Most common for asthma
o Inhaled or systemic
o B2 and some B1; also stimulate receptors in other sites (side
effects: tachycardia, etc)
o Salbutamol (short), Salmeterol (long-acting); albuterol
 Methylxanthines (Theophylline)
o Bronchodilator
 Lots of actions (adenosine antag, phosphodiesterase
inhibit., NE release, stim CNS resp center to increase
RR)
o Low Therapeutic Index
o Less effective in asthma than B-agonists, additive effect
o Good for COPD with Bronchospasm
 Muscarinic Antagonists (ipratropium)
o Block M3 on bronchial smooth muscle
o Inhaled
o Additive effect with B-agonists; as good as beta2
agonists in COPD w/ bronchospasm
 Leukotriene Receptor Blockers (montelukast)
o Blocks LTD4 receptors
o Steroid sparing
o Oral only
o Good for aspirin induced asthma
 Not as good as B2’s, or steroids for asthma
 Release Inhibitors (cromolyn, nedocromil)
o NOT BRONCHODILATORS
 Hyperpolarize cells (vagus nerves and mast cells)
preventing release of mediators
 Inhaled only, can cause bronchospasm
 For allergic rhinitis, conjunctivitis
 Corticosteroids
o Reduce # of inflamm cells and inhibit release of
cytokines
o Not bronchodilators
o Take longer to act
o Systemic initially, topical later
o Lowest dose possible
 Oral candidiasis (Thrush)
o Inhibits growth in kids
Pharmacology of Anesthesia 11/6/2018 6:54:00 AM

Local Anesthetics

Types:
 Esters
o Cocaine, benzocaine, etc
o Hydrolyzed by esterases (broken down quick in the blood
and tissues)
o Allergic reactions
 Safe to give amides if allergic to esters
 Amides
o Lidocaine, Bupivicaine, etc
o Metabolized by microsomal enzymes (liver)
 Slower therefore systemic toxicity more likely
than esters
 Way to distinguish the 2:
o Amides have an “I” in prefix, prior to the “caine”

Mechanism of Action:
 Prevent conduction of AP
o Block Na channels from intracellular side (when drug is
in protonated form)
o The non-protonated form allows it to enter axon

Factors affecting Local Anesthetic Action


 pH
o Acidosis
 Acidic environment protonates drug and reduces
ability to enter nerves
 Ex: Infection
o Alkalosis
 Adding HCO30, favors non-protonated form
increasing drug uptake into nerves
 Lipid Solubility
o Lipid soluable/high protein binding – longer acting
o Less lipid soluable/less protein binding – shorter acting
 Blood flow
o To and from site
o Vasoconstrictors prevent systemic absorption +
vasodilation; makes drug stay around longer; so you
can get away with lower doses of anesthetic
 Ex: Epinephrine
 Misc.
o Bulk flow
o Diffusion
o Non-specific binding

Nerve Fibers & Local Anesthetics


 Small axons > large w/ regards to sensitivity
o Pain > temp > touch/pressure > motor (size of axons)
o Allows for concept of differential blockade
 Ex: epidural local anesthetic giving in dilute
concentration that only affects the small pain fibers;
leaving motor intact (epidural during labor)
o Rapidly firing axons more sensitive than slow ones
o Myelinated more sensitive than non-myelinated
o Large nerve trunks
 When given, anesthesia works proximally first
and spreads distally

Adverse Effects
 Amides > esters b/c of difference in metabolism
 CNS
o Dizziness, seizures, coma
 CV
o Heart depressed, vasodilation, arrhythmias
 Toxic range is different for diff anesthetics
 See H&N Sx’s first because they get a lot of blood
 Tx:
o ABCs
o Raise seizure threshold (benzodiazepines, hypervent)
o Supportive
 O2, secure airway
 Support circ. If CV effects
 Lipid emulsion/albumin to bind excess

Clinical Applications of Local Anesthetics


 Less disturbance with co-existing diseases than with general
anesthetic
 Less systemic effects (resp, CV)
 Good for post-op analgesia
 Cheap
 Good outcomes

Techniques
 Topical (skin: EMLA, wounds: TAC)
 Infiltration (injection)
 Peripheral nerve blocks (specific nerve blocks or plexus)
o Surgeons often do these
 Intravenous Regional Anesthesia
o Ex: Tourniquet on arm to stop blood flow and give high
volume local anesthetic for hand surgery
 Neuaxial anesthesia
o Epidural, spinal
 Intravenous
o Continuous throughout surgery
 Results showed decreased narcotic use post-
surgery
o Danger of systemic toxicity

General Anesthesia

Consists of:
 Inhaled agents (sevoforane, nitrous oxide, halothane)
 Induction/IV agents (Pentohal, Propofol)
 Benzodiazepines (Lorazepam, diazepam)
 Opiods (Demorol, morphine)
 Muscle Relaxants (depolarizing/non-depolarizing) – recall,
neuromuscular blockers from Autonomics: tubocarine,
succinylcholine
o Depolarizing – succinylcholine (irreversible)
o Non-depolarizing – pancuronium (reversible)
 Reversal drugs
o NM reversal (neostigmine) – Anti-Ch-E
o Benzodiazepine antag (anexate)
o Opiod antag (Naloxone)

GOALS of General Anesthesia


 Amnesia/Hypnosis
o Impaired perceptive awareness/don’t remember
anything
 Inhalants and benzos
 Analgesia
o Lack of pain
 Narcotics, opiods
 Akinesia
o Loss of movement
 Muscle relaxants
 Control physiological parameters
 Goal is to control the first 3 factors and blunt sympathetic
responses to adverse stimuli during procedures
o If patient is not deep enough, will see sympathetic
responses (increase HR, rise/drop in BP, etc)

Balanced Technique
 One agent can achieve all goals, so use a combo of inhaled
and IV agents

Mechanism of Action of Inhalational Agents? -> We don’t really know!

Minimum Alveolar Concentration (MAC)


 Miminum alveolar concentration at 1 atm that causes
immobility in 50% of patients exposed to a noxious stimulus
o Considered a measure of potency
o 1.3 MAC = 95% of pts are immobile
o MAC values for gases are ADDITIVE
 Add MACs together for multiple drugs, gives you
an idea of the depth of anesthesia
 Ex: nitrous oxide (1 MAC = 104%); Desflurane (1 MAC = 6.0%)
o so you need A LOT of nitrous to get to 1 MAC, so its not good
for general anesthesia

 Factors affecting MAC:


o Age (younger people tend to need more)
o Temperature (colder need less)
o Pregnancy
o Extreme physiological states (hTN, acidosis, etc)

Pharmacokinetics
 Concentration Gradient
o Delivered > inspired > alveolar > arterial > brain
 Factors:
o Inspired concentration of drug (how much you gave)
o Alveolar ventilation (pt’s breathing or if you ventilate them
with positive pressure)
o Solubility (decreased solubility means faster onset of
anesthesia)
o CO (low CO makes it easier to saturate blood with drug,
better transit time)
o Pa-Pv gradient

Systemic Effects of Inhaled Anesthetics


 Resp
o Rapid shallow breathing (decrease TV, increase RR)
o Decrease drive to breathe (blunted body’s response to
higher PCO2)
o Bronchodilation! (sometimes given to asthmatics who
aren’t responding to other Rx)
 CV
o Vasodilation (hTN)
o Decrease CO (decreased contractility and BP)
 CNS
o Decreased cerebral metabolic rate and O2 demand
o Increased cerebral blood flow
 Cerebral vasodilation
 Also Renal, hepatic, uterus etc
 Malignant Hyperthermia
o Autosomal dominant hypermetabolic disorder
 When exposed to certain gases, every cell in body
goes hyperactive; bad prognosis
11/6/2018 6:54:00 AM

Anticoagulants

Maintenance of blood fluidity


 Balance b/w
o Procoags:
 Thrombin (factor II)
 Tissue factor (extrinsic pathway)
 Thromboxane (from arachidonic acid,
vasoconstrictor, from plts)
 ADP (from act. Plts, plt aggregation)
o Anticoags:
 Heparan sulfate (on endothelium, potentiates
antithrombin III)
 Prostacyclin (from arachidonic acid)
 Nitric Oxide

Drugs:
 Antiplatelet
o Aspirin/ASA
 Works on Cyclo-oxygenase (AA -> thromboxane)
 Low dose (80-160 mg/day) irreversibly inhibits plt
COX, and they can’t make new COX b/c they have
no nucleus
 Some inhibition of endothelial COX but not much,
therefore prostacyclin (anti-coag) synthesis isn’t
affected much
 Benefit is greater after thrombolysis
 SE is bleeding
Prophylaxis for MI or TIA (80mg/day), higher
doses for post-MI/TIA (160-325mg/day)
 Contraindications (bleeding risk):
 Vit. K def., Hemophilia,
Hypoprothombinemia, pregnancy & child-
birth
o Clopidogrel/Plavix
 ADP antagonist
Competes with ADP for P2Y receptor
(prevents lowering of cAMP)
 Less incidence of neutropenia/thrombocytopenia
 Used in combo with ASA
o Ticlopidine
 ADP antagonist, prodrug
 Often used in combo with ASA (synergistic)
 May cause severe neutropenia (1%)
o Dipyridamole
phosphodiesterase inhibitor (prevents cAMP
breakdown)
o GpIIb-IIIa inhibitors
 Eptifibatide, Abciximab, Tirofiban
 Block the receptor for fibrinogen blocking plt
aggregation

 Heparin (& derivatives)


o Stimulates natural anticoags (antithrombin)
o Heparin
 Monitor using aPTT (add negative charges)
 Negatively charged, therefore cannot cross
membranes (given IM, IV, parentally)
 Good for pregnancy
 Eliminated by RES & macrophages
 Potentiates AT III (in the plasma) – inhibits IIa,
Xa, IXa and VIIa
 Toxicity – hemorrhage
 Antidote – protamine sulfate (1mg for every
100 units of heparin)
 Heparin-Induced Thrombocytopenia (HIT) –
occurs 5-10 days after, stop heparin immediately;
use alternatives lepirudin/danaparoid
 Good for PE and DVT and during pregnancy

o LMWH – better bioavailability, can be given subcut.


w/o lab monitoring as outpatient, less risk of bleeding
More expensive, not good in renal failure, not for
pregnancy
 DOES NOT inhibit IIa (but inhibit Xa)
 Good for DVT, PE and UA
o Danaparoid – promotes inhibition of Xa by AT (for HIT)
o Lepirudin – direct thrombin inhibitor (for HIT)

 Coumarin (Oral) anticoags


o Warfarin
 Monitored using PT (add tissue factor)
 Inhibit Vit. K Epoxide reductase in liver
 Prevents carboxylation of Vit.K dependent factors
 Takes 4-5 days to get effective (carboxylated fx’s
in plasma need to be cleared before inactive ones
take over)
 Small volume of distribution, steep dose-response
curve (small therapeutic window)
 Teratogenic
 For DVT and PE, prosthetic heart valves or Afib, MI
 Metabolized by CYP1A and CYP2C9
 Efficacy measured by INR, pt’s PT time divided by
PT time in pooled plasma
 INR = (PTpt/PTref)^ISI (target is 2.0 – 3.0)
 Warfarin overdose
 Give Excess Vit.K, goes through a diff
enzyme that isn’t inhibited by warfarin
(Diaphorase)

 Fibrinolytics (lyse formed thrombi)


o Streptokinase – turns plasminogen -> plasmin
 Plasmin breaks down fibrin (lysis of formed clot)
Dissolves clots post-MI/DVT/PE
 SE – bleeding (systemic plasminogen activation),
allergy, hTN, fever
 Streptokinase has an additive effect with ASA
o Tissue plasminogen activator (tPA) – acts on fibrin and
circulating plasminogen -> plasmin
 Less systemic plasmin
 Same indications as streptokinase
 More expensive

Hyperlipidemia & Obesity

Lipid Cycling:
 Dietary fat + cholesterol in GI -> chylomicrons cleaved by
LPL in plasma into FFAs (used by muscle or stored in
adipose) and remnants broken down by liver.
 Liver -> VLDL -> IDL -> LDL (Apo B)
o 75% of plasma LDL cleared by liver through LDL
receptors

Lipoprotein particle structure:


 Apoprotein – ligand for receptors
 Hydrophobic core – TAGs and cholesteryl esters
 Outer layer – phospholipids & free cholesterol

HDL = 20% cholesterol


LDL = 60% cholesterol

Hyperlipidemia
 Risk factors for CV dz:
o High LDL, total cholesterol, total cholesterol/HDL, high 1/HDL
 Macrophages take up LDL and form foam cells and
atherosclerotic lesions
 HDL picks up cholesterol from cells and takes it back to liver
(reverse cholesterol transport)
o High HDL Protective, low HDL is atherogenic

Synthesis and Metabolism of Cholesterol


 Made from Acetyl-CoA -> HMG-CoA and HMG-CoA reductase -
> mevalonate -> Cholesterol
 Cholesterol incorporated into bile acids and into GI and
reabsorbed (enterohepatic recycling)
 Also used for hormone synthesis

Drugs:
 Statins
o Most effective and best tolerated for hyperlipidemia
 Except when LDL receptor is dysfunctional
o Inhibits HMG-CoA reductase (helps with cholesterol
synthesis)
 Reducing cholesterol and VLDL (and subsequent LDL) in
the liver
o Ex: Atorvastatin, simvastatin
o Statins inhibit cholestrol synthesis, but liver needs it so
it increases LDL receptors and picks up more
cholesterol reducing its plasma levels
o other protective effects:
 increase NO
 plaque stability
 anti-inflammatory
 decrease LDL oxidation (form macrophages take
up)
 reduce plt aggregation
o Given at bedtime (most cholesterol made b/w midnight
and 2am), not with bile-acid binding resins
o Do not use during pregnancy/breastfeeding
o Extensive first pass metabolism
o Work better in combo with bile-acid binding resins,
fibrates or niacin
o Side effects:
 Hepatotoxicity – check ALT (alanine
aminotransferase)
 Myopathy – when other drugs metabolized by CYP3A4
are given (erythromycin, azole antifungals,
cyclosporine)
 Fibrates (Gemfibrozil, Bezafibrate)
o Work via transcription factor receptor (Peroxisomal
proliferation activated receptor; PPAR-a)
 Increase LPL activity, decrease TAG/VLDL synthesis,
etc
o Primarily in liver and adipose tissue
o Better absorbed with meals
o Fibrates + statins = myopathy (so monitor with CK,
myoglobin)
o Not for kids, pregos, and breast-feeders; renal failure or liver
disease

 Niacin (Nicotinic acid)


o Water soluable B-complex vitamin
o Cofactor for many rxns
o Best agent to increase HDL (30-40%)
 Also reduces TAGs and LDL
o Lots of side effects that decrease pt compliance
 Flushing (give ASA)
 Dyspepsia/indigestion (take after meals)
 Hepatotoxicity
 Not for pregos -> birth defects; or pts with peptic ulcer
or gout
o Binds receptor in adipose, reduces breakdown of TAGs
and release of FFA to liver, thereby reducing TAG/VLDL
synthesis in liver. Also decreases HDL clearance in liver
o Statins + niacin = myopathy (monitor)

 Bile Acid Binding Resins (Cholestyramine, colestipol)


o Decrease reabsorption of bile acids
o Positively charged molecules that bind neg charged bile
acids
o Liver has to make new ones, therefore lowers plasma
cholesterol by increasing LDL receptors
o Safe b/c not absorbed (stays in GI lumen)
o Only one recommended for children
o Not used in patients with hyper-TAG-emia
o Side effects:
 Inhibits absorption of lipid soluable vitamins (AEDK)
and drugs
 Bulk of resins = discomfort – bloating and dyspepsia
 Suspend resin in liquid before ingestion

 Ezetimibe
o Prevents absorption of dietary cholesterol from the
intestines
o Not a bile acid bind resin

Obesity
 BMI = kg/m^2 (N 20-25, obese > 30)
 Waists: Male > 100cm or female > 90cm
 Higher risk of DM, MI and HTN

Anti-Obesity Drugs
 Orlistat (xenical)
o OTC drug, for Tx of obesity, not to decrease cholesterol
o Inhibits pancreatic and intestinal lipases in GI lumen
(safe)
 Inhibits breakdown of dietary fat
 Prevents FA absorption by 30%
o Side effects:
 Bloating, oily spotting, fecal urgency
 Vitamin deficiencies (AEDK)
 Sibutramine
o Anorectic – decreases appetite
o Inhibits reuptake NA, 5-HT, and dopamine; increasing
their concentrations in the brain
 Activates sympathetic system, higher
metabolism?
o Side effects:
 Dry mouth, headache, constipation, increased HR and
BP (related to dose)

 Rimonabant
o Anorectic, not approved here yet
 Symlin (Pramlintide)
o Analogue of Amylin, secreted by pancreas after eating
 Delays gastric emptying and causes satiety
o Given to DM pts
 Leptin
o From adipocytes as they stores fat (also placenta, stomach)
o Release also stimulated by insulin
 Leptin receptors in hypothalamus
 Decreases neuropeptide Y, causing decrease
hunger and food intake
 Results in higher energy expenditure
and lower energy intake (weight loss)
 Also reduces size and # of adipocytes
 Also increases GnRH secretion (increased LH/FSH)
 Explains why anorexics can get infertile
o Most obese patients are resistant to leptin
Module 8 – Antibiotics & Antifungals 11/6/2018 6:54:00 AM

Ideal Drug
 Selective toxicity
o High LD50, vs MIC and/or low MBC
 Bactericidal/Bacteriostatic
 Favorable pharmacokinetics
o Reach target site with effective concentration
 Spectrum of activity
o Broad vs narrow
 Lack of “side-effects”
o Therapeutic Index = LD50/ED50; therefore higher is better
 Little resistance development

Antibiotic
 Product produced by a microorganism or by chemical synthesis,
which in low concentrations inhibits the growth of other
microorganisms
o Old antibiotics were not chemical/synthetic, only products of
microorganisms

Mechanism of Action
 Inhibit/Damage cell wall (Penicillins, Cephalosporins,
Carbapenems, monobactams, bacitracin, vancomycin)
 Inhibit/damage cell membrane (Polymyxins, amphotericin
B)
 Disrupt nucleic acid synthesis/metabolism (quinolones,
rifampin, nitrofurantoins)
 Disrupt protein synthesis (Macrolide, Tetracyclines,
Chloramphenicol, Aminoglycosides, Clindamycin, linezolid)
 Disrupt energy metabolism (ex: Folic Acid – TMP-SMX;
dapsone, isoniazid)
Bacteriostatic Bactericidal
Sulfonamides Quinolones
Trimethoprum Penicillins
Choramphenicol Cephalosporins
Tetracycline Most Aminoglycosides
Macrolides/Erythromycin
 Fluoroquinolones and aminoglycosides have more killing at higher []
and have a post-antibiotic inhibitory effect (beyond the MIC)
o Means their action continues past their ½-life; they can be
administered less frequently
 Beta-lactams don’t have concentration-dependent killing or post-
antibiotic effect
MIC – Minimal inhibitory concentration
 Use un uncomplicated infection where host immunity can help
eliminate the microorganism
 Peak [ ] of the drug at the site of infections should be at least 4X
the MIC

MBC – Minimal bactericidal concentration


 Neutropenic patients
 Infection is in an area protected from host immunity (CSF, brain,
eye prostate)

Pharmacokinetic Factors in IV-administered drugs (determine the amount of


antimicrobial that reaches the extravascular tissues or fluids where the
infection is):
 Concentration (gradient b/c plasma and target tissues)
 Degree of drug binding to plasma and tissue proteins
 Molecular size
 Ionization
 Lipid soluability
 Rate of elimination/metabolism of drug

Special Cases:
 These require usually higher concentration antibiotics for
longer periods:
o Abscesses
o Endocarditis
o Osteomyelitis
o Mycobacterium infection

Host Factors:
 Allergy
 Age
o Ex: Tetracyclines stain growing teeth and bone
o Declining renal function in elderly
o Sulfonamides in newborns  CNS disorder
 Renal Function – adjust dosage for aminoglycosides, vanco,
penicillins, cephalosporins, carbapenems, quinolones
 Hepatic Function – adjust dosing of chloramphenicol, macrolides,
rifampin
 Pregnancy
o Almost all antimicrobials cross the placenta to some
degree; greatest risk in first trimester
 Genetic/Metabolic Factors
 Host defenses
o Bacteriostatic agents in often ineffective in
neutropenic/immunosuppressed hosts

Reasons for using >1 antimicrobial agent in a patient:


 Life-threatening infection
 Polymicrobial infection
 Achieve synergy
 Prevent resistant strains
 Permit lower dose of one of the antimicrobial agents

Synergistic effects have been documented for 3 combos of antibiotics:


 Ampicillin + Gentamicin (cell wall inhibitor + aminoglycoside
protein synthesis inhibitor)
 Trimethoprim + Suflamethoxazole (sequential steps of a
metabolic pathway)
 Amoxicillin + Clavulanate (b-lactam + lactamase inhibitor)
Antibiotic Resistance
 Intrinsic or acquired
o Intrinsic – ex: Pseudomonas aeruginosa intrinsically resistant
to many b/c they can’t cross outer membrane or bind target
sites
o Acquired
 Mutation
 New genes
 Exchange of genetic information b/w bacteria

Mechanisms of Resistance:
 Altered receptors/targets – drugs can’t bind
 Decreased rate of entry or increased rate of removal of drug
 Enhanced destruction/inactivation of drug
 Resistant metabolic pathways

Antibiotics

Bacterial Cell Wall Inhibitors


 B-lactams (bactericidal)
o Penicillins (amoxillicin, cloxacillin, penicillin, oxacillin,
methacillin)
o Cephalosporins
o Carbapenems
o Monobactams
o Glycopeptides

 B-lactamase inhibitors
o Often given with penicillins
 Clavulanate
 Tazobactam
Cephalosporins
o 1st – do not enter CSF
 Cefazolin – moderate spectrum
o 2 nd
 Cefuroxime – greater gram – spectrum + some
gram + cocci
o 3nd – enter CSF
 Cefatriaxone – broad spectrum, some gram -
o 4th - many cross into CSF
 Cefepime – similar to 1st
 Carbapenems
o Highly resistant to B-lactamases
 Imipenem – broad spectrum
 Monobactams
o Azetreonam
 Glycopeptides
o Vancomycin – gram +
o Bacitracine – topical gram +

Inhibitors of Protein Synthesis


 Tetracyclines
o Tetracycine
o Doxycycline
 Macrolides
o Erythromycin
o Ketolides
o Azithromycin
 Aminoglycosides
o Streptomycin
o Gentamicin
 Clindamycin
 Chloramphenicol (serious side-effect = aplastic anemia)

 Mechanisms of Protein Synthesis Inhibition


o Blocking amino-acyl-tRNA binding to ribosome
o Inhibit formation of ribosomes
o Block peptide bond formation
o Block translocation step of ribosome
o Misread mRNA to add wrong aminoacid
o Prevent release of growing peptide from ribosome
Inhibition of Metabolism
 Folic acid synthesis
o Sulfonamides
 Sulfamethoxazole
o Trimethoprim
o Synergistic effect:
 Trimethoprim/Sulfamethoxazole
 Sulfa – inhibits synthesis of dihydropteric
acid by competing with PABA (Para-
aminobenzoic acid)
 Trimeth – blocks production of THF by
inhibiting dihydrofolate reductase
 This combo blocks 2 consecutive steps and
usually bactericidal

Inhibiting/Damaging Nucleic Acids/DNA


 Fluoroquinolones – inhibit DNA topoisomerases (DNA gyrase
and Topoisomerase IV)
o Ciprofloxacin (2nd)
o Norfloxacin (2nd)
o Levofloxacin (3rd)
o Gatifloxacin (4th)
o Moxifloxacin (4th)
 Nitrofurans (banned in Canada)

Inhibiting/Damage Cell Membrane


 Colistin (Polymyxin E)
 Polymyxin B – poke holes in membrane and cause leakage

Actinobacteria
 Mycobacterium is a class of actinobacteria
o TB (always treated with multi-drug b/c of risk of
resistance
 1st Line Drugs for TB
 Isoniazid (INH) – inhibit mycolic acid/waxy
synthesis
 Rifampin – inhibits RNA Polymerase
 Pyrazinamide (PZA) – disrupt plasma
membrane
 Ethambutol
 2nd Line
 Fluoroquinolones
 Streptomycine (Aminoglycoside)
o Leprosy
 Rifampin – inhibits RNA polymerase
 Dapsone – inhibits dihyrdopteric acid (Like SMX)
in folic acid synthesis
 Clofazimine

Anti-Fungals
 Fungi more complex b/c:
o Different ribosomes
o Different cell wall
o Discrete nuclear membrane
 Principle antifungals:
o Inhibits Cell wall
 Capsofungin
o Inhibit Cell membranes
 Polyenes
 Amphotericin B (most widely used
antifungal)
 Messes with ergosterol and causes ion leak
 Nystatin
 Azoles – inhibit synthesis of ergosterol
 Allylamines – inhibit synthesis of ergosterol
o Inhibit nuclear division
 Griseofulvin – inhibits microtubule function
therefore inhibits mitosis
o Inhibit DNA synthesis
 Flucytosine – pyrimidine analogue
Module 9 – Antivirals, AntiCancer 11/6/2018 6:54:00 AM

Viruses
 Nucleic acid core surrounded by a protein capsid; some have an
envelope
 Attach then enter cell (endocytosis or penetration)
 SS or DS RNA or DNA genomes

Viral Infection
 Lytic, latent or chronic
 Is characterized by an incubation period
 Is prevented primarily by cell-mediated immunity

Overview for Tx:


 Block virus attachment
 Block uncoating of virus
 Inhibit viral DNA/RNA synthesis
 Inhibit viral protein synthesis
 Inhibit viral enzymes
 Inhibit viral assembly
 Inhibit viral release
 Stimulate host immune system

Respiratory Virus Infection


 Influenza A and B and RSV
 Viral Uncoating Inhibitors (Amatadine and rimantadine)
o For Influenza A ONLY
 Immunization is the preferred approach
 Neuraminadase Inhibitors (Oseltamivir [oral] and Zanamivir
[inhaled])
o Prevents attachment
o For Influenza A and B
 Ribavirin – Guanosine analog
o In RSV and HCV

Hepatic Viral Infections


 Hepatitis B and C most common for chronic hepatitis,
cirrhosis and HCC
 Hepatitis B
o IFN-a – inhibit viral RNA translation, degrades it and
stimulates host immune system
o Lamivudine – inhibit HBV DNA polymerase and HIV
reverse transcriptase
 Hepatitis C
o IFN-a + ribavirin

Herpes Infections
 HSV 1 and 2 (Oral and genital)
 VZV
 Acyclovir
o Analog of endogenous substrate deoxyguanosine;
premature termination of viral DNA
o Choice drug for HSV1, HSV2 and VZV
o Most commonly used for genital herpes infections
 Valacyclovir (oral)
 Famiciclovir – acyclovir analog w/ longer duration of action
 Peniciclovir (topical)
 Ganciclovir
o Guanosine analog
o Good vs HSV, VZV, EBV, CMV
o 100x better for CMV than acyclovir
 Foscarnet
o Pyrophosphate derivative
 Inhibits viral DNA and RNA polymerases
o For CMV retinitis, acyclovir-resistant HSV

Retroviral Infections
 HTLV-1, HTLV-2
 Lentiviruses (HIV-1, HIV-2)
o Attach to CD4+ cells
o Has a reverse transcriptase (RNA->DNA)
o Inactivates CD4+ cells -> deficient cell-mediated
immunity
o Therapeutic Regimen:
 HAART (Highly active anti-retroviral therapy)
 Use combination (3 or more) to suppress HIV
replication and restore immuno-competency
 NRTIs (Nucleoside/tide reverse transcriptase Inhibitors)
o Prodrugs, and analogs of native nucleosides/tides
o Incorporated into viral DNA and prematurely
terminates elongation
 Zidovudine (AZT- Azidodeoxythymidine)
 Decreases viral load and increases CD4+
cells
 Introduced into viral DNA by reverse
transcriptase
 Metabolized by liver and excreted in urine
 Didanosine (ddI, dideoxyinosine)
 Pancreatitis (monitor amylase)
 Zalcitabine (ddC, didoxycytosine)
 Peripheral neuropathy (major toxicity)
 Lamivudine (3TC, deoxy-thiacytidine)
 Used with AZT, but not ddC
Terminiates synthesis of proviral DNA and inhibits
reverse transcriptase
 For HCV and HIV
 NNRTIs (Non-nucleoside/tide reverse transcriptase inhibitors)
o Lack affinity for HIV-2
o Don’t need activation by cellular enzymes (like NRTI’s
do)
 Nevirapine
 Substitute for AZT
 Inducer of CYP3A4 of cytochrome p450
(drug interactions!)
 Increases metabolism of: OCPs,
ketoconazole, methadone,
metronidazole, warfarin, theophylline
 Delavirdine
 Inhibitor of cytochrome p450 metabolism
(drug interactions!)
 Protease Inhibitors
o Inhibit HIV aspartyl protease (formation of reverse
transcriptase, protease, integrase and other structural
proteins) and block viral maturation
o Synergistic with NRTIs + NNRTIs
o Substrates and inhibitors of cyp3A4 of p450
 Rx interactions are common and problematic
 Midazolam/Triazolam etc – excessive
sedation
 Warfarin – bleeding
 Fentanyl – resp distress
 Inducers of cytochrome p450 (rifampin,
barbituates, carbamazepine) – failure of
protease inhibitor
o Saquinavir
 Poor bioavailability, need to be taken with meals
(absorption increases with high fat meals and
grapefruit juice)
o Ritonavir
Inhibits p450 (drug interactions)
Pharmacokinetic enhancer for other protease
inhibitors
o Indinavir
 Nephrolithiasis can occur

Viral Fusion Inhibitor – Enfuvirtide


 Binds gp41 and prevents conformational changes that occur
with HIV tries to fuse with host membrane
 Combines with other antivirals
 Given SC

2 New Drugs for HIV:


 Raltegravir
o Inhibits Integrase (prevents viral DNA integrating with host
DNA)
o Active against HIV resistance to other anti-retrovirals
 Miraviroc
o CCR5 (CC chemokine receptor 5) antagonist
 Only for adults with CCR5-tropic HIV-1 (R5 Virus)
 CCR5 is major receptor involved in viral entry
o Binds CCR5 preventing entry
o Active against HIV resistance to other anti-retrovirals

Anti-Cancer Drugs

4 Features of Cancer/Neoplasm
 uncontrolled cell prolif
 impaired apoptosis
 loss of normal functions
 metastasis

Goals of Cancer Tx
 Primary Goal – Cure (long term disease free survival) – eradicate all
neoplastic cells
 Secondary Goal – palliation, reduce Sx’s, delay tumor growth,
preserve normal function

Treatment Modalities
 Surgery
 Radiation
 Chemotherapy
o Indications:
 Cancer disseminated and not amenable to surgery
 Tumor close to vital organ and other modalites
not feasible
 Vs micrometastasis following surgery and
radiation Tx

Tumor Susceptibility & Growth Cycle


 Cancer cells have more cells in replicating cycle
 Normal cells tend to be in G0 (resting phase)
 Solid tumors in vivo initially grow rapidly but slow down b/c
O2 and nutrients can’t keep up
 Recruitment:
o Reducing tumor burden via surgery/radiation,
promoting recruitment of remaining cancer cells into
active replication thereby increasing their susceptibility
to chemotherapeutic agents
 Significance of a 1g Tumor Mass
o 10^9 cells is the smallest tumor burden that is
physically detectable
o Clinical Sx’s usually first appear at this stage
 1 Kg tumor burden, usually death

Treatment Regimens & Scheduling


 Log Kill
o Chemotherapeutic agents follow 1st order kinetics:
 A given dose of drugs destroys a constant
FRACTION of cells
 Pharmacologic Sanctuaries
o Tumor cells can find sanctuaries in tissues like CNS
 May need radiation to craniospinal axis or
intrathecal Rx administration to eliminate tumors
there
 Drugs may be unable to penetrate certain areas of
solid tumors (usually cells at the center)
 Treatment protocols
o Cytotoxic agents are usually combined at full doses
o Advantages of combinations:
 Maximal cell killing within range of tolerated
toxicity
 Effective against broader cell lines in
heterogenous tumor population
 Delay or prevent development of resistant cancer
cell lines
o Usually identified by acronym (ex: POMP: Prednisone,
oncovin, methotrexate, purinethol)
o Examples:
 Hodgekin’s Disease
 MOPP (Mechlorethamine, oncovin,
procarbazine, prednisone)
 ABVD (adriamycin, bleomycin, vinblastine,
dacarbazine)

Problems with Chemotherapy


 Resistance – minimized by short-term intensive intermittent
tx with combo of drugs
 Multi-drug resistance – expression of P-glycoprotein
(permerability glycoprotein) pumping drugs out of the
cancer cells
 Toxicity
o Common adverse effects:
 Bone marrow – pancytopenia
 GI tract – ulceration, diarrhea
 Hair – alopecia
 Gonads – menstrual irregularity, impaired
spermatogensis
 Wounds – impaired healing
 Fetus – teratogenesis (esp 1st trimester)
o Many of these are due to drug effects on non-tumor
cells that are usually growing (GI tract, gonads, hair,
bone marrow, etc)
 Treatment-induced tumors
o Anti-neoplastic agents are mutagens and new cancers
may arise years after chemoTx
o Esp with alkylating agents that can X-link DNA

Anti-Cancer mechanisms
 Impair nucleic acid synthesis
 Impair DNA function
 Impair protein synthesis
 Inhibit mitosis
 Stimulate immune system
 Impair endogenous cell growth regulating mechanisms
 Inhibit angiogensis and metastasis

Cell-cycle specificity of Drugs:


 Cell-cycle specific – only effective vs replicating cells
 Cell-cycle non-specific – useful vs tumors with low % of
replicating cells also vs replicating cells

Antimetabolites
 Struct. Related to normal compounds in the cell
 Interfere with availability of pyrimidines/purines by
inhibiting synthesis or competing with them
 Maximal cytotoxic effects in S-phase and are Cell-cycle
Specific
o Methotrexate (MTX)
 Structurally related to folic acid; inhibits
dihydrofolate reductase (converts folic acid to active
THF)
 Decreases synthesis of nucleic acid precursors
 Usually used in combo with other cancer Rx
 Low dose MTX is anti-inflammatory and
immunosuppressive (ex: Crohn’s Disease, SLE )
o 6-Mercaptopurine (6-MP) + 6-Thioguanine (6-TG)
 Purine analogs and inhibit purine synthesis
o 5-Fluorouracil (5-FU)
 pyrimidine analog

Antibiotics
 Cell-cycle specific
 Interact with DNA, leading to disruptions in DNA function
o Doxorubicin (Adriamycin)
 Belongs to anthracycline family of abx
Used in drug combos
Blocks DNA and RNA synthesis, binds to cell
membranes and generates O2 radicals (causing
breaks in DNA)
 Tumors and heart tissue low in supraoxide
dismutase
 Cardiotoxicity
o Dactinomycin (actinomycin D)
 1st abx to find application in cancer Tx
 Forms complex with DNA
 Also immunosuppressive
o Bleomycin
 Mixture of copper-chelating glycopeptides causing
scission of DNA via oxidative processes (like
doxorubicin)
 Cell-cycle specific
 Pulmonary toxicity (Fibrosis)

Alkylating Agents
 Alkylating DNA (covalent binding) lethal to tumor cells
 Cell-cycle non-specific
 Mutagenic + carcinogenic and can cause secondary
malignancy
o Mechlorethamine
 Mustard gas in WW1
 Causes lymphocytopenia
 Alkylates guanine and causes x-linking b/w
guanines in DNA
o Cyclophosphamide
 Most commonly used alkylating agent
 Transformed by body into active phosphoramide
mustard, which alkylates DNA

Microtubule Inhibitors
 Mitotic spindle needed for moving organelles during cell
division
o Vincristine (VX, oncovin), vinblastine (VBL)
 From plant Vinca rosea
 Cell-cycle specific and phase-specific
 Bind to Tubulin blocking the polymerization to
microtubules
o Paclitaxel (Taxol)
 Promote polymerization and hyper-stabilizes the
microtubules and blocks the ability to use
cytoskeleton in a flexible manner
 Chromosomes don’t segregate and cell death occurs

Steroid hormones & Their Antagonists


 Some tumors are steroid hormone sensitive, hormone-
responsive, hormone-dependent or both.
o Tamoxifen
 Estrogen antagonist
 Blocks estrogen stimulation of breast cancer
growth
o Prednisone
 Potent synthetic anti-inflammatory steroid, with
less mineralocorticoid activity than cortisol
 For Lymphoma and ALL

Antibodies
 Polyclonal, monoclonal (mAbs), humanized and chimeric antibodies
o Monoclonal Antibodies (mAbs)
 Naming:
 “zu” in the name = humanized
 “muro” = murine antibody
 “xi” = chimeric antibody
 Identify malignant cells as targets for attack by
complement-dependent cytotoxicity and antibody-
dependent cell-mediated cytotoxicity
 Trastuzumab
 Targets human epidermal growth factor
(hEGF) receptor protein 2 (HER2) and
inhibits prolif of HER2 expressing cells
o For regression of breast cancer
 Others:
 Rituximab - (anti-CD20) for malignant
B-cells
 Bevacizumab – anti-VEGF
 Cetuximab – anti-EGFR

Antivirals
 Influenza A & B
o Uncoating inhibitors (only for A)
 Amatadine, rimantidine
o Neuraminidase inhibitors (block attachment) – A & B
 Osteltamivir
 RSV
o Ribavirin (guanosine analog)
 RSV, HCV

Hepatic
 HBV & HCV most common for chronic hepatitis, cirrhosis and HPCC
o HBV – IFN-a and lamiduvine
o HCV – IFN-a and ribavirin

Herpes Viruses
 HSV 1 and HSV 2
o Acyclovir – choice for HSV and VZV
o Valcyclovir - oral
o Ganciclovir – better for CMV and EBV
o Famiciclovir – longer duration that acyclovir
o Foscarnet – pyrophosphate derivative
 For CMV retinitis and acyclovir-resistant HSV

Retroviral
 HTLV 1 and HTLV 2
 HIV1 and HIV2
o NRTIs
 Zidovudine/AZT
 Lamiduvine
 Didanosine - pancreatitis
 Zalcitabine – peripheral neuropathy
o NNRTIs
 Nevirapine
 Substitute for AZT
 Inducer of CYP3A4 p450
 Delavirdine
 Inhibitor of p450
o Protease Inhibitors (substrates and inducers of p450)
 Saquinovir
 Ritonavir – inhibitor of p450
 Indinavir – nephrolithiasis
 Viral Fusion Inhibitor
o Enfuvirtide
 Binds gp41 and prevents conformational changes
that occur with HIV tries to fuse with host
membrane
 New HIV Drugs
o Raltegravir
 Inhibits integrase
o Miraviroc
 CCR5 receptor antagonist – prevents viral entry
 For resistant HIV

Anti-Cancer
 Antimetabolites
o Methotrexate – messes with folate
o 5-mercaptopurine + 6-thioguanine – purine synthesis
o 5-fluorouracil – pyridimine
 Antibiotics
o Doxorubicin
o Dactinomycin
o Bleomycin
 Akylating Agents
o Cyclophosphamide
o Mechlorethamine
 Microtubule Inhibitors
o Vincristine, Vinblastine
o Paclitaxel
 Antibodies
o Trastuzumab
o Ritixumab
o
CNS Pharmacology 11/6/2018 6:54:00 AM

Functional Neuroanatomy
 Spinal cord
o Relays info b/w brain and rest of body
 PONS/Medulla
o Crucial physiological reflexes
o CO2 centers for breathing
o CTZ reduces absorption of toxic compounds from GI tract
 Hypothalamus
o Thermoregulation and autonomic NS
o Controls pituitary
 Basal Ganglia
o Extrapyramidal system
o Smooth coordinated muscle activity
o Removes unwanted movement
 Limbic System
o Amygdala, hippocampus, habenula, septal area
o Memory, emotions
o Focusing by inhibiting irrelevant sensory and cognitive activity
o Judgement, evaluation, inhibition of inappropriate thoughts
and behaviours
 Cortex
o Sensory and motor activity
o Language, concept manipulation
o Thoughts, ideas, consciousness
o Long-term memory storage

Chemical Neurotransmission
 In PNS its ACh and Norepi
 In brain theres much more
o Neurotransmittiers - released from nerve terminal and acts on
receptor near site of release
 Dopamine
 Extrapyramidal system
 Parkinson’s Disease
 Limbic, hypothalamus, CTZ
 Norepi
 Reticular activating system
 Arousal, alertness, wakefulness
 Limbic, hypothalamus, pons/medulla
 Epi
 Pons/medulla – CV control
 Serotonin
 Limbic, hypothalamus
 ACh
 Limbic
 Extrapyramidal
 Glutamate/glutamic acid
 Everywhere - main excitatory NT
 GABA
 Everywhere – main inhibitoryNT
 Endorphin, enkephalin, dynorphin
 Limbic, Spinal cord, thalamus
 Addiction, analgesia
 Substance P
 Pain
 Capsaicin in chili peppers stimulates these
receptors
 Histamine
 RAS - arousal
 Neuromodulator – chemical that alters neuron activity by acting on
a receptor located some distance away from site of release

Steps in Neurotransmission
 DNA/RNA/Protein synthesis
 Axo-plasmic transport
 AP – tetrodotoxin
 NT Synthesis
 NT Storage
 NT Release
 NT Receptor coupling/binding
 NT Removal
o Reuptake or breakdown
CNS Pharmacokinetics
 Blood Brain Barrier
o Physical – brain capillaries have different structure
 Lack fenestrae + intercellular clefts
 Tight junctions
 Surrounded by astrocytic endfeet (more layers of lipid)
o Chemical – enzymes
 Capillary endothelium has more mitochondria w/
enzymes (MAO to break down neuroactie monoamines)
o Physiochemical – plasma protein binding
 Keeps neurotoxic lipid soluable compounds (bilirubin)
out
 Nutrients enter brain by active transport (Glucose, AA, FFAs)
 For a drug to enter brain it must be lipophilic or carried by active
transport across BBB

Neuropsychiatry
 Neurosis
o Maladaptive learned behaviour
 Ex: fears/phobias
 Psychosis
o Loss of contact w/ reality
o Disrupted brain function
o Neurochemical imbalance
 Induced by:
 Drugs/chemicals
 Neurodegeneration
 Genetic abN’s
 Schizophrenia
o Symptoms
 Negative
 Affective flattening
 Alogia (poverty of speech)
 Avolition-apathy
 Anhedonia-asociality
 Reduced attention
 Positive
 Hallucinations
 Delusions
 Bizzare behaviour
 Positive formal thought disorder
 Most common
 Unchanging facial expression
 Persecutory delusions
 Lack of persistence at work/school
 Impaired grooming/hygiene
 Few recreational interests
 Few relationships w/ friends/family
o Dopamine Hypothesis
 Anti-schizoprenia drugs are D2 (dopamine) antagonists
 DA receptor overstimulation mimics schizophrenia
 Amphetamine psychosis
 Schizo an adverse effect of Tx in Parkinson’s Dz
 DA antagonists reduce + Sx’s
 5HT antagonists reduce – Sx’s

Neuroleptics
 Phenothiazines
o Not all of them are neuroleptics
 Chlorpromazine
o DA antagonist
o A-adrenergic antagonist
o Muscarinic antagonist
o Histamine antagonist
 Thioxanthenes
o Structural analogues of phenothiazines
 Main effect and side effects are similar
o Flupenthixol
o Flupenthixol decanoate
 Depot IM injection, maintain therapeutic levels for 2-4
weeks
 Butyrophenones
o Differ from phenothiazines in structure and side effect profile
o Block dopamine receptors, no affinity for others
o Haloperidol
 Only butyrophenone used as a neuroleptic
 D1 and D2 receptor blocker
 Has only dopamine related SE’s
 Extrapyramidal symptoms, hyperprolactinemia,
anti-emetic, tardive dyskinesia

Atypical Neuroleptics
 Clozapine
o D1, D2, 5HT2 antagonist
 For + and – Sx’s
o Little or no EPS?
o SE’s
 Bone marrow suppression -> agranulocytosis + death
 Weekly blood tests
 Respiridone
o D2 + 5HT2 antagonist
 + & - Sx’s
 little or not EPS or SE’s
 Olanzapine
o D2 + 5HT antagonist
 + and – Sx’s
o Halts progression of schizo
o SE’s
 Weight gain, dizziness, dry mouth
 Quetiapine
o D1, D2, 5HT1a, 5HT2 antagonist
 Similar to respiridone and olanzapine but cheaper
o Neuroprotective actions

Depressants, Anti-depressants, Stimulants


 Anxiety
o Is good for you
o Is a negative enforcer
o Keeps us out of danger (escape and avoidance)
o Crucial for learning and memory
o Has a “bell”-shaped effect on performance
 Anxiety Disorders
o Panic disocer w/ or w/o agoraphobia
o Agoraphobia
o Social phobia
o Specific phobias
o OCD
o Post-traumatic Stress Disorder
o Substance-Induced

Axiolytics
 Benzodiazepines
o Pharmacological Effects
 Anxiolytic, hypnotic, anticonvulsant, muscle relaxant
o Neurochemical Effects
 Increased GABA
 Down-regulated benzodiazepine receptors
 Up-regulated downstread receptors for noreepi, 5HT,
etc
 Increasing GABA induces release of the same,
which upregulates receptors, and so on
 Overdose of benzodiazepines is not lethal but can
potentiate the actions of other depressants like EtOH
and narcotics
o Anxiolytics
 Alprazolam (high potency)
 Chlordiazepoxide
 Diazepam
 Oxazepam
o Hypnotics
 Triazolam (high potency)
 Flurazepam
 Temazepam
 Tolerance and Addiction
o Due to altered receptor density – neural system goes back to
pre-drug functioning level
o Effects of withdrawal is exact opposite of direct drug effects
o Withdrawal syndrome lasts until enough receptors have
returned to previous pre-drug state to maintain normal nerve
impulse traffic
o Withdrawal syndrome is more severe with short halflife drugs
 All active drug mocules eliminated before receptors can
return to pre-drug densities
o Benzodiazepine withdrawal
 Severe with short half-life drugs (Triazolam)
 Not a problem with long half-life (Diazepam)
 To discontinue a short half-life drug, switch patient to a
comparable dose of a long half-life drug and reduce the
amount of a drug given by 10% a week

 Atypical Anxiolytics
o Buspirone
 Not a benzo
 Partial agonist at 5HT inhibitory presynaptic
autoreceptors
 A selective anti-anxiety drug
 Lacks hypnotic, anti-convulsant or muscle relaxant
effects
 Does not potentiate the resp depressant actions of
alcohol, narcotics, etc
 Little, or no withdrawal syndrome
 But takes 2-3 weeks for its effects

Sleep Disorders
 Insomnia
o Less sleep needed for daily activities
o Excessive daytime sleepiness
 Sleep is an active brain process
 Chemically induced sleep is not normal
 Many drugs suppress REM sleep
 Hypnotic drugs are rarely needed but help in: but use only for 2-3
nights
o Jet lag
o Shift work
o Bereavement
 Ideal sleeping pill
o Short half-life, drug gone by morning
o Rapid onset (sleep w/in an hour)
o Little effect on brain activity during sleep

Hypnotic Agents
 Benzodiazepines
o Triazolam (1/2 t = 2-3 h)
o Temazepam (1/2 t = 8-10 h)
 Atypical
o Zopiclone (5 h)
o Zolpidem (2 h)
o Less sleep effects than benzos but still not normal sleep

Sleep Hygiene
 To get bed at same time each night
 Get up at same time each morning
 Don’t do other things in bed, just sleep
 Don’t nap; if you do, it counts toward total sleep time
 No caffeine before bed
 Analgesics if sleep disturbed by pain

Major depressive Disorder


 Heterogenic genetic disorders
 10% of population
 Symptoms
o Emotional (sad, frustrated, hopeless, apathetic)
o Cognitive (negative thoughts and ideas, impaired
concentration, pseudo-dementia)
o Neurovegetative (loss of apetite, libido, motivation, interest in
anything)

Antidepressant Interventions
 Electroconvulsive Therapy
o Currently safe and effective
 MAO Inhibitors
o MAO
 Mito enzyme helps to maintain neural activity be
preventing buildup of neuroactive amines
 Chemical part of Blood brain barrier
 2 forms
 MAO-A
 Highest affinity for 5HT
 Less for NE, dopamine, trace amines like
tyramine
 MAO-B
 Highest affinity for dopamine
 Less for NE and tyramine
Wine-Cheese Reaction
 Contain tyramine and MAO inhibitors will cause
buildup of tyramine and displaces NE from
sympathetic nerve terminals
o Tranylcypromine
 Irreversibly binds MAO
 Inihibts MAO A and B
o Moclobemide
 Reversible binding and selective for MAO-A
 Not usually a problem b/c short half-life and reversible
 NT Reuptake Inhibitors
o Nonselective Reuptake Inhibitors (NSRIs)
 Inhibit NE and 5HT reuptake (broad-spectrum)
o Selective Serotonin Reuptake Inhibitors (SSRIs)
 Inhibit only 5HT
 Fluoxetine
 Inhibits p450 enzymes
 Fluvoaxamine
 Paroxetine
o Selective NE Reuptake Inhibitors
 Desipramine
 Nortriptyline
 Active part of amitriptyline
 Maprotiline
 Neurotransmitter Release Enhancers
o Increase NE and 5HT release
 Mirtazapine

Antidepressant Mechanism
 Uptake blockade maximal w/in a few hours
 Clinical improvement not seen for 2-6 weeks
o Therefore acute drug reaction is not the theapeutic action of
antidepressants
 Down-regulation of b-adrenergic receptorcs common to all
antidepressant interventions

Other uses for Anti-depressants/Mood Stabilizer


 Panid disorder
 OCD
 General anxiety disorder

Stimulants/Sympathomimetics
 Caffeine
o Blocks adenosine receptors (an inhibitory NT)
 Cocaine
o Blocks reuptake of NE and dopamine
 Amphetamine
o Stimulates release of NE,dopamine and serotonin
 Methylphenidate
o Similar to amphetamine
 Adverse Effects
o High doses stimulates dopamine “reward” pathways
o Amphetamine psychosis
o Appetite suppression
o Suppression of growth hormone

Narcolepsy
 Patient enters REM sleep instantly
 Methylphenidate
o Drug of choice

Bipolar Disorder (Manic Depression)


 Higher in professionals and entertainers
 Mood swings b/w depression and mania
 Genetic
 Drugs useful as Mood Stabilizers
o Lithium
 Reduce neuronal inositol 2nd messenger system
o Carbamazepine
 Anticonvulsant (reduce excitatory NTs)
o Clonazepam
 Anticonvulsant (Benzo – therefore increase GABA)
o Valproate
 Anticonvulsant (increase GABA)

 Glutamate
o Main excitatory NT
o 4 receptors
 NMDA – opens Ca2+ channel
 Over-stimulation of NMDA causes massive
increase in intracellular Ca2+ killing neuron

Epilepsy
 Abnormal synchronous APs of groups of neurons in various parts of
brain
 Many casues (infection, fever, tumors, injury, lyte imbalance, etc)
 Therapy aimed to reduce excitability of neurons
o Increasing GABA
 Benzodiazepines (Clonazepam, Diazepam)
 Diazepam used for status epilepticus
 Barbiturates (Phenobarbital)
 Benzos and Barbituates increase GABA channel
hyperpolarization of neurons
 Gabapentin
 Increases gaba release
 Valproic acid
 Increases GABA, also blocks Na+ and Ca2+
channels, and increase K+ conductance
o Alter transmembrane flow of ions
 Phenytoin
 Blocks Na+ channels
 Carbamazepine
 Blocks Na+ channels and potentiates post-
synaptic effect of GABA
 Ethosuximde
 Blocks Ca2+ channels
 Iamotrigine
 Blocks Na+ channels
o Decrease glutamate excitatory tone
 Glutamate antagonists have too many side effects and
none are on the market as anticonvulstants yet

Pain Sensory System


 Endogenous opiod preptides (EOP) modulate pain sensory
transmission
o Also modulate GI function
 Stimulation of opiod receptors in intestine causes
contractions of GI muscle and blocks propulsive
transport of GI contents = Constipation

EOPs
 Products of 3 separate genes:
o Pro-opiomelanocortin
 B-endorphin, ACTH and MSH
o Prepro-enkaphalin
 Met-enkephalin, leu-enkephalin
o Prepro-dynorphin
 Dynorphin

EOP Receptors
 3 classes (mu, kappa, and delta)
 Mu has highest affinity for B-endorphin
o Mu stimulation:
 In brain and spinal cord– produces analgesia
 In GI – constipation
 Limbic system – euphoria
 Kappa – highest for dynorphin
o Kappa stimulation
 Brain and spine – analgesia
 Selective kappa agonists are underdevelopment as Non
addicting analgesics
 Deta – highest for met-enkephalin and leu-enkephalin
o Brain and spine – analgesia

Pharmacological Actions of Opiod Analgesics


 Dose-dependent
 Mood changes (mellow, pleasant, euphoria, etc)
 Analgesia w/o sedation
 Constipation (reduced GI propulsive motility)
 N+V, drowsiness
 Respiratory Depression
o Reduced responsiveness to CO2 in brain stem
 The cause of death in opiod overdose
 Tolerance includes down-regulated EOP receptors and up-reg
downstream receptors
 Withdrawal has exact opposite symptoms
o More severe with short half-life (ex: morphine and heroin vs
methadone)
 EOPs released from acupuncture
o Also physical activity (running, ex: second wind during long
run)
EOP Receptor Agonists (Opiod Analgesics)
 Morphine
o Constituent of opium
o Mu agonist
 Codeine
o Also from opium
o Less potent than morphine at mu receptors
o Converted to morphine by Cyp 2D6
o Good cough suppressant
 Meperidine
o Synthetic mu agonist
o Less resp depression than morphine
 Methadone
o Synthetic mu agonist
o Used in addiction treatment programs
o Good analgesic profile, and for chronic pain syndrome

Non-Opiod Analgesics
 NSAIDs (inhibit COX I and II)
o Aspirin/ASA
o Ibuprofen
 Selective COX II inhibitors (don’t mess with GI or plts)
o Celecoxib
o Rofecoxib
 BUT increased clots and MIs in patients with CV risk
factors
 Due to thromboxane A2 made from COX I causing plt
aggregation
 Other analgesics
o Acetominophen (Tylenol)
 Weak inhibition of PG synthesis
 Lacks anti-inflamm actions
 Analgesic and anti-pyretic actions same as ASA
 N-acetylcysteine is antidote for overdose
Addiction to Opiod Analgesics
 Drugs potentially addictive if:
o Pleasant enjoyable drug action (euphoria, pain relief)
o Rapid onset (IV gets to brain in 20 sec)
o Short half-life (morphine)
 Once tolerance to morphine occurs, (down-reg EOP receptors)
withdrawal is quick in onset and severe
 Taking drug to avoid withdrawal is final step in addiction

EOP Receptor Antagonists


 Naloxone
o Blocks all EOP receptors
o Used in opiod overdose
 Naltrexone
o Blocks all EOP receptors
o For narcotic addiction
o Reduces craving of EtOH in alcoholics

Parkinson’s Disease
 Motor
o Akinesia
o Bradykinesia
o Muscle rigidity
o Tremor at rest
o Mask-like facies
o Cog-wheel locomotion
 Other
o Dementia + depression
 Pathology
o Due to degeneration of Parkinson’s Disease
o Death of dopamine cell bodies in substantia nigra

Extra-pyramidal System (EPS)


 Regulation of fine motor activity
 For smooth and coordinated movement
 When dopamine inhibition b/c deficient, acetylcholine excitation is
unchecked and GABA output becomes excessive
 Dopamine/ACh balance can be restored by augmenting dopamine
inhibition or by reducing acetylcholine excitation

Treatment of Parkinson’s
 Dopamine Replacement Therapy
o Dopamine can’t cross BBB
o Levodopa
Precursor of dopamine can cross
Restores dopamine/ACh balance and normal output of
EPS
 Adverse Effects
 Peripheral – HTN, tachycardia, arrhythmia, N+V
 Central – psychosis, dyskinesias

o Selegiline – MAO-B inhibitor, inhibits braindown of dopamine
 Dopmaine Receptor Agonists
o Bromocriptine
o Pramipexole, Ropinirole
 Anticholinergic Therapy
o Benzotropine – muscarininc ACh antagonist
 Antioxidant Therapy

Alzheimer’s Disease
 Dementia
o Memory loss, impaired judgement and evaluation, labile and
inappropriate emotions
o Motor functions intact until late stages
o Pathology
 Plaques and tangles in brain

Treatment of Alzheimer’s
 ACh Replacement Therapy
o AChE inhibitors
 Donepezil, Galantamine, Rivastigmine
 Antioxidant Therapy
o Block neurotoxicity of B-amyloid
o Vitamin E, C, blue berries, strawberries, ethanol

The Alcohols
 Methanol
o Metabolized to formaldehyde
o Metabolites are harmful to living tissue – blindness, acidosis,
death
o Methanol poisoning treatment
 Saturate alcohol dehydrogenase with ethanol and bicarb
to reduce acidosis
 Initate hemodialysis
 Also Fomepizole – alcohol dehydrogenase inhibitor
 Ethanol (beverage alcohol)
o Suppresses neuronal excitability in concentration dependent
manner
o Moderate consumption has health benefits due to antioxidant
effects
 Ethylene Glycol (anti-freeze)
o Severe metabolic acidosis, if they survive go on to get
hypocalcemia and renal failure -> death
o Treatment is ethanol, fomepizole, bicarb and dialysis
o Also fluids and calcium

Calculation of Blood Alcohol Concentration (BAC)


 Grams of ethanol consumed form time Y to X (minus) grams of
ethnol metabolized (average metabolism = 124mg EtOH / kg
weight/hour) from time Y to X (divided by) WIdmark Factor (WF)
o WF = kg body weight x (.55 for females) or (.68 for males)
Smooth Muscle & Migraines 11/6/2018 6:54:00 AM

Emetics & Anti-emetics

Vomiting
 Physiological protective anti-peristaltic response in a forceful
expulsion of GI contents

Sequence of Events in Vomiting:


 Nausea – increased salivation, sweating, pallor, etc
 Wretching – abd muscles contract + antiperistalsis
 Vomiting – contraction of diaphragm and expulsion through mouth

Causes of Vomiting
 Drug Induced
 Infectious GI disorders
 Non-infectious
 Early pregnancy
 CNS related

Emetic Center
 In medulla
 Receptors for:
o Dopamine
o Acetylcholine (muscarinic)
o Histamine
o 5-hydroxytryptamine (5-HT/serotonin)

Anti-emetics
 Antihistamine
o Dimenhydrinate (Gravol)
o Most effective in Motion sickness and inner ear dysfunction
(Menier’s disease – excess fluid in ear; and Labrynthitis)
o SE
 Drowsiness, sedation, dry + blurred vision (block
muscarinic receptors)
 Anticholinergics
o Scopalamine
o Used in motion sickness
o Same SE as above + tachycardia (blocks muscarinic)
 Dopamine Antagonists
o Non-selective dopamine antagonist (Phenothiazines)
 Decrease vomiting caused by gastric irritants
 SE’s
 Dystonic reactions, extrapyramidal side effects
o D2 Selective antagonists (Metoclopramide, domperidone)
 During cancer chemotherapy to control nausea and
vomiting
 Benzodiazepines
o Lorazepam, Alprazolam
o Prevent central cortical induced vomiting
o For anxiety and anticipatory emesis (ex: Chemotherapy)
 5-HT3 Selective Antagonist
o 1st gen (Ondasetron, Granisetron)
o 2nd gen (Palonoseron) – more potent and longer acting
 used for vomiting from chemotherapy
 Cannabinoids
o Tetrahydrocannabinol, nabilone
o Control of vomiting when all other agents fail
o SE’s
 Hallucinations, bulimia
 Corticosteroids
o Dexamethasone
o Motion sickness, mountaineering
o Effective when combined with dopramine and 5-HT
antagonists
o SE’s
 Osteoporosis, cushingoid features, adrenal suppression,
susceptibility to infection
 Substance P Antagonist (NK-1 antagonist)
o Aprepitant

Combination Treatment for Chemotherapy-Induced Nausea-Vomiting (CINV)


 When cisplatin and oher anti-cancer drugs are used there is severe
intractable N+V
o Combination with Palonosetron + Aprepitant + corticosteroid
 Long lasting relief in adv cancer patients with severe
pain and N+V

Migraine
 Unilateral pulsating or throbbing headache associated with N+V,
photophobia, phonophobia, osmophobia
 Common migraine (w/o aura) 85%
 Classical migraine (w/ aura) 15%
o Visual scotomas, hemianopias, or speech abnormalities
 Triggers
o Stress, sleep deprivation, bright light, diet changes, menses
and food (chocolate and cheese)
 Pathophysiology
o Vascular hypothesis
 Increased venous draining causes inadequate perfusion
causes vessels in anoxic regions to dilate and stretch
perivascular nerve fibers and cause pain
 Goal – selective vasoconstrict vessels using 5HT
agonists and dihydroergotamine (a1 and 5HT-
receptors)
o Neurogenic Hypothesis
 Pain transmitted by serotoninergic nerve fibers
 When 5-HT agonists fiven, it cuz down the pain
tranmission by acting on an interneuron

 Treatment
o Symptomatic (for acute attack)
 Mild – non-narcotic analgesics
 Acetominophen, aspirin
 Moderate
 NSAIDS + dichlorophenazone
 Triptans
 Ergotamine (Ergot alkaloids)
 Butorphanol
 Severe
 Ergot or Triptan + antiemetic
 Narcotic of meperidine if above fail
o Prophylactic (if >3 attacks/month)
 BB’s (Propanalol)
 CCBs (verapamil)
 Tricyclic antidepressants (Amitriptyline)
 Anti-epileptics (Valproic acid)
 Cyproheptadine (5HT and histmine antagonist

Ergotamine
 Constricts vessels, redistributing flow and no pain generation
 No for pregnant women, PVD CAD, HTN or sepsis
 Can cause N+V as SE

Triptans
 5-HT selective agonists
 Activate 5HT1b receptors to reduce rapid draining to the venous
side by vasoconstriction of unwanted collaterals
o redistribution of blood to anoxic underperfused regions and
reduces vasodilation and pain
 Triptans also act on 5HT1d receptors and cuts down level of
endogenous 5HT release which is required for activation of pain
sensitive fibers.
 Contraindicated in angina and PVD (Peripheral vascular disease)
GI Tract Pharmacology 11/6/2018 6:54:00 AM

Physiology of Gastric Acid Secretion


 Regulated by neural (ACh – muscarinic), endocrine (Gastrin) and
paracrine (Histamine) secretory factors
o Gastrin and ACh work through ECL secretion of histamine
causing Parietal cell secretion of acid
 Secreted products:
o HCl
o Pepsin
o Mucus
o HCO3
 Aggressive Factors
o HCl, Pepsin, H. pylori infection
 Protective Factors
o Mucus, HCO3, PGEs (PGE1 and PGE2)

Pharmacology of Anti-Ulcer Agents


 Agents that Neutralize Acid
o Antacids
 Weak bases that form salts with HCl causing chemical
neutralization to buffer the acid
 Advantage – immediate relieve
 Disadvantage – short duration, rebound acid secretion
 Compounds
 NaHCO3
 CaCO3
 Al(OH)3
 Agents that reduce acid secretion
o H2 receptor antagonists
 Ranitidine
 Good for gastric/duodenal ulcers and in Zollinger-Ellison
Syndrome
 Cimetidine
 Many side effects (CNS, Immune, Gondal, inhibits
Cyp450
o Proton Pump Inhibitors (PPIs)
 Inhibit H+/K+ ATPase
 Omeprazole
o Cytoprotective Mucosal Defensive Agents
 Sucralfate: Sucrose Octasulfate Aluminum Hydroxide
 Gives a protective coating over ulcerated region
and prevents erosion
 Also stimulates PGE1 production, absorbs pepsin
 SE – dry mouth + constipiation
 Misoprostol
 PGE1 analog
 Enhances mucus and HCO3 production
 Good for ulcers from NSAIDs
 Not for pregnancy
 Bismuth chelate
 Protective coating
 Increases mucus and PGE
 Kills H. Pylori

Management of H. Pylori Infection


 Gram – rod
 Causes erosion of protective epithelial cells -> gastritis or peptic
ulcer
 H2 antagonist or PPI + Abx
o Metronidazole or amoxicillin/clarithromycin
 PPI + 2 or 3 antimicrobials is standard
 Ex: Ranitidine + Peptobismol + Clarithromycin +
Amoxicillin 7-14 days
 Add bismuth if resistant H. pylori
o Ex: PPI + BMT (Bismuth + Metronidazole + tetracycline) 7
days

Treatment for ZE Syndrome


 Gastrinoma of the duodenum or pancreas
 Elevated gastrin levels
o Peptic/gastric ulcers
 Treatment
o High dose PPI until resorting to surgery or chemotherapy for
tumor removal

Drugs that Promote Upper GI Motility (Prokinetic Agents)


 Increase gastric emptying, relieve gastric stasis
 Prevent reflux esophagitis/heart burn/GERD
 Decrease N+V

 Modulate ACh release to promote opening of gastroduodenal


sphincter and selectively increase duodenal motility to promote
gastric emptying
o Metoclopramide (D2 blocker), Cisapride (5-HT agonist),
Erythromycin (Motilin agonist) are prokinetics via
increasing ACh release
 Cholinomimetics (Bethanachol) and Anti-AChE
(Neostigmine) also promite GI motility but the effects are
non-specific and many side-effects
o Therefore use selective D2 (Dopamine) blockers, 5-HT
(serotonin) and Motilin agonists as prokinetics

Metoclopramide
 D2 antagonist/blocker
 Crosses BBB
 Prokinetic and also anti-emetic
 CNS SE’s
o Parkinsonian Sx’s (Extrapyramidal) +
hyperprolactinemia

Domperidone
 D2 antagonist
 Doesn’t cross BBB
 Prokinetic and moderate anti-emetic effects
o Therefore few CNS effects
 Can cause hyperprolactinemia (b/c pituitary is outside BBB)

Erythromycin
 Macrolide abx
 Also activates motilin receptors
 Not an anti-emetic
 Also causes diarrhea (effect on lower GI motility)
o Can help with constipation

Cisapride
 5-HT agonist
 Not an anti-emetic
 Not used now b/c blocks K+ channels and can cause long QT
syndrome (TdP)
 Cardiotoxicity when combo’ed with clarithromycin (which is
a CYP3A4 inhibitor and decreases metabolism of cisapride –
toxicity)
Smooth Muscle Pharmacology 11/6/2018 6:54:00 AM

Drugs Affective Uterine Motility


 Oxytocics
o Uterine stimulants
 Oxytocin
 From Post. Pituitary
 Targets
 Cervix (Opens)
 Myometrium (Contracts)
 Myoepithelial cells of breast (Milk let down)
 Stimulus
 Positive feedback mechanism
 Afferent info from target tissues
 Uses
 At term – induce labor
 Preterm – augment incomplete abortion
 Postpartum – control hemorrhage
 Postpartum to enhance milk let down
 Risks
 At high doses: H2O intoxication and
hyponatremia (OT similar to ADH, can can
activate renal ADH receptors)

 Prostaglandins
 PGF2a and PGE2 (intravaginal, IV)
 To ripen and dilate cervix and increase
uterine contraction at term
 Given with OT to induce labor intravaginally
 With mifepristone to terminate pregnancy in
1st trimester (con contraction to clear fetus)
 SE – N+V
 Ergot alkaloids
 Ergonovine, Egometrine (IV or IM)
 Stimulate pregnant/non-pregnant uteri
 Activates adrenergic A1 receptors in
myometrium
 Used to control post-partum
hemorrhage/uterine atony
 SE – Angina
 NOT USED IN CANADA
 Tocolytics
o Uterine Relaxants
 Ca2+ Channel Blockers
 Nifedipine
 COX Inhibitors
 NSAIDs (Diclofenac, ketorolac)
 B2 Selective Agonists
 Terbualine, ritodrine
 Oxytocin Antagonists
 atosiban
 MgSO4 IV (Mg2+)
 17-a hydroxyprogesterone caproate
o Order in management:
 CCBs>>NSAIDs>>B2 selective agonists > OT
antagonists> MG2+ IV > Progesterone
o In Canada we use NSAIDs, Corticosteroid (for lung maturation
of fetus) and MgSO4 (Mg2+)
o Mg2+ prevents neurological defects in neonates if premature
labor occurs, decreases seizures and neurological symptoms
in patients with pre-eclampsia

Urinary Pharmacology
 Ach -> M3 muscarinic receptors promotes micturition
o Contraction of the Detrusor
o Relaxation of trigone + urethral sphincter
 Sympathetics do the opposite of above

Stress Urinary Incontinence (urine voiding w/o control)


 Antimuscarininc like Oxybutynin to reduce micturition
 Duloxetine
 SSNRI (Selective Serotonin-Norepi Reuptake Inhibitor
o Antidepressant
 Increases Epi and closes urethra (but increases BP)

Bladder Neck Obstruction/Benign Prostatic Hypertrophy (BNP)


 Selective A1 antagonist – to relieve spasm and relaxation of urethra
o Tamsulsoin/Flowmax or Prazosin – problem w/ postural
hypotension
 Selective A1 antagonist + 5-a reductase inhibitor (Finasteride)
 A1 blocker + anticholinergic (Oxybutynin-ditropan)

Nocturnal Enuresis in Children/Elderly


 Desmopressin
o V2 selective agonist to reabsorb water
 Tricyclic antidepressant (amitryptiline)
o Antimuscarinic and norepi uptake inhibition effects
o Decrease micturition

Diabetes Insipidus (DI)


 Lack of reabsorption of water in renal collecting ducts
o Lack of ADH
 Desmopressin acetate
o More potent V2 agonist than ADH
o Good for neurogenic DI (no ADH)
 But not nephrogenic DI (ADH insensitivity)
o Also used for hemophilia and Von Willebrand’s Disease

Renal Colic
 1st line
o Opiod analgesics (Meperidine) then NSAIDs
 Opiod for pain and for anticholinergic, NSAIDs to
decrease motility and pain
 2nd line
o besides opiods give A1 blocker (Tamsulosin/Flowmax)
 expulsive therapy to promote urine flow
o Or CCB (Nifedipine) to relax smooth muscle
o Combo treatment
 Analgesic + NSAID + A1 antagonist + nifedipine
Toxicology 11/6/2018 6:54:00 AM

Toxidromes
 Agitated delirium
o Sympathimometic or anti-cholinergic
o HR, BP, Temp, RR elevated
o pupils dilated
o Skin sweaty or dry
 Sedative hypnotic
o Opiod or benzo’s or EtOH
o Above depressed
o Pinpoint pupils or small pupils
 Fluids out of every orifice
o Cholinergic
 Slow HR
 N or increased RR
 DUMBELS
 Diarrhea
 Urination
 Miosis
 Bradycardia, bronchospasm, bronchorrhea (Killer
B’s)
 Emesis
 Lacrimation
 Salivation

Two main toxidromes you will encounter:


 Sedatative hypnotic
o By far most common toxicologic cause is EtOH
o Also benzos, opiods, anti-depressants
o Also trauma (ICH), infectious, or metabolic (hypoglycema,
hyponatremia) can cause coma
o “DON’T forget to reverse a coma” mnemonic:
 Dextrose 1amp or 50ml D50W
 Oxygen (maintain SaO2 > 92%)
 Naloxone 0.1-0.4mg IV, repeat PRN (opiod antagonist)
 Thiamine 100mg IV or IM
o Actual approach to coma should be:
 1) Assess ACBDs and vital signs
 2) Get IV access, give O2 and connect cardiac monitors
 3) Give glucose if hypoglycemic; thiamine first is
pt has normal glucose
 4) Naloxone if pinpoint pupils and RR <12
 Agitated delirium
o Most common toxicologic cause is EtOH (from disinhibition)
o Also sympathimometic (cocaine, ecstacy, crystal meth)
o Anticholinergics (gravol, mushrooms, Jimsonweed, etc)
o Also Psychosis (Schizoprhenia), traumatic (ICH), infectious
(meningitis, encephalitis) and metabolic (Thyroid storm)
o If certain it’s a psych cause (known psych Hx with N vitals)
consider using neuroleptic (Haloperidol)
o In most cases sedate with high dose benzos:
 Lorazepam (Ativan)
 Diazepam (Valium)
o Sympathimometics – work by increasing circulating
catecholamines
 You’d think to give BB’s but if u block all the B’s, then
catecholamines flood the A receptors and cause HTN
crisis
 Give benzodiazepines, effetive in countering Sx of
sympathimometic toxicity.
o Anticholinergics – treat by increasing amount of ACh to
overcome the blockade
 Cholinesterase inhibitors – like physostigmine – rsk of
causing cholinergic syndrome (DUMBELS) and the killer
B’s therefore used infrequently
 Most managed supportively w/o antidotal therapy
 Cholinergic (fluids out of every orifice)
o Infrequent and hard to miss clinically
 Ex: farmer who works with pesticides presents with
DUMBELS and killer B’s you should suspect cholinergic
toxicity
o Antidote = Atropine, blocks ACh activity; dose is 1mg, PRN
Decontamination
 2 main methods
o Activated Charcoal
 1g/kg up to 50g/dose, 1st one given with sorbitol
 if aspirated can cause pneumonitis, so pt must be
awake, alert and stay that way
 Indications
 Toxic ingestion w/in 1-2 hours of presentation or
longer if enteric coated preparation
 Potentially lethal injestion with any suspicion of
Rx still in GI tract
 Contraindications
 Rx that don’t bind charcoal (PHAILS)
 Pesticides
 Hydrocarbons (chloral hydrate)
 Alcohols
 Iron
 Lithium
 Solvents
Pt is drowsy (risk of aspiration) unless airway

protected by endotracheal tube
 Non-intact GI tract (caustic ingestion, kid with TE
fistula)
 Bowel obstruction
o Whole Bowel Irrigation (Polyethylene Glycol or “Go-lytely”)
 Dose 25-50ml/kg/hour up t 1L/hour
 Usually used when substance can’t bind charcoal
(Iron/lithium) and body packers (Human drug
trafficking)
o Induced vomiting
 Ipecac and gastric lavage (stomach pump) not routinely
used

Investigations
 Some tests are routine for poisoned patient work-up and others
used selectively
 Remember, most blood/urine tests take 1-2 hours to get back and
decisions often need to be made well before results get back
 Routine Tests
o CBC, INR/PTT
o Lytes, Urea, Creatinine
o Liver enzymes
o CK, Troponin
o Lipase
o Acetominophen level
o Salicylate level
o EtOH level
o Serum osmolarity
o ECG
 Tricyclic anti-depressant (TCA) toxicity shows up nicely
as ECG changes b/c blocking of Na channels
 Earliest finding is terminal R wave in aVR > 3mm
in height
 The > the QRS widening, the > the
potential for seizure and arrhythmia
 Treatment for wide QRS = NaHCO3 (1mp or
50mEq) IV bolus repeatedly until QRS narrows

Antidotes
 Toxin : Antidote:
o Acetominophen : N-acetylcysteine
o Cholinergic (Organophosphates) : Atropine
o Methanol or Ethylene Glycol : Ethanol or fomepizole
o Benzodiazepines : Flumazenil (compet. Inhibitor of
GABA receptor)
 Not routinely used unless you give benzos to someone
who has never had them before and you over-sedate
them (respiratory depression), flumazenil will reverse it
 Not routinely used b/c in people who take benzos
regularly or with mixed-overdose the removal of the
benzo effect may cause the patient to seize
o Opiod : Naloxone (opiod inhibitor)
o Anticholinergic : Physostigmine
o TCA : Sodium bicarbonate (NaHCO3)

Elimination
 Some meds can have their rate of elimination enhanced
o Alkalination of urine/serum
 Helps keep meds in ionized state and in the blood and
out of the tissues so they can’t exert their effects
 Also helps kidney enhance elmination of certain drugs
 Salicylate, ethylene glycol, phenobarbitol,
methotrexate
o Dialysis
 Methanol, ethylene glycol, salicylate, litium
 These need to have a fairly LOW volume of distribution
 With meds with HIGH Vd, most of the drugs is in the
tissues and dialysis can’t remove those
 Ex: Digoxin (high Vd)

Summar y– Approach to the Poisoned Patient


 1) Resuscitation
 2) History – use all potential sources
 3) Physical exam – search for a TOXIDROME
 4) Supportive Care and Management of Agitation, consider
antidotes
 4) Decontamination – consider charcoal if indicated
 5) Investigations – almost all patients need to be tested for
Acetaminophen
 6) Antidote – if indicated
 7) Enhance elimination – if indicated

Acetominophen (Tylenol) Toxicity


 N-acetyl-para-aminopheno (APAP)
 APAP overdose is #1 cause of liver failure in US
 Many formuations (Tylenol, Nyquil, Percocet, etc)
 Actions:
o Centrally – analgesic (inhibits prostaglandins)
o Peripherally – analgesic (blocks pain impulse generation)
o Antypyretic – inhibiton @ hypothalamus
 90% APAP metabolized to non-toxic metabolites by the liver and
excreted in urine
 10% metabolized to N-acetyl-para-amino=benzoquinomeimine
(NAPQI)
o reduced by glutathione into non-toxic mercapturic acid
o when glutathione stores depleted, NAPQI binds to liver
proteins causing dysfunction and cell death (liver toxicity)
o Inducers of CP450 have increased risk b/c increased
production of NAPQI
 Ex: Smoking, barbituates, phenytoin, ING, chronic
EtOH, Carbamezapine

 Clinical stages of Toxicity


o Stage I: 0-24 hours
 minimal symptoms, but may have nausea, vomiting and
anorexia
 for this reason Acetaminophen is considered a ‘Toxic
Time Bomb’…by the time you manifest real symptoms,
it is too late to reverse the toxicity
 - for this reason it is crucial that all suspected
overdose patients get an APAP level!
 Stage II: 24-48 hours
o RUQ pain, elevation of liver enzymes (usually in the
thousand’s), elevated INR/PTT and bilirubin
 Stage III: 48-96 hours
o hepatic dysfunction: acidosis, bleeding, cerebral
edema/coma, death
 5% of patients with APAP levels above the treatment
threshold who do not receive N-acetlycysteine within 8
hours will die of liver failure without a transplant
 Stage IV: 96 hours to 2 weeks
o resolution of hepatic dysfunction

 Testing
o Acetaminophen is potentially toxic at 150mg/kg
o A toxic 4 hour level would be 1300 umol/L
o A Toxic 8 hour level would be 800 umol/L
 Treatment
o Decontaminiation
 Activated charcoal if indicated
o Antidote
 N-acetylcysteine (NAC/mucomyst)
 In Canada given IV
 Loading dose over 60 min, then 2 infusions
(4 and 16 hours) so total duration is 21
hours
 Glutathione precursor
 Converts NAPQI to non-toxic metabolite
 Crucial to start within 8 hours
 If > 8 hours, start anyway b/c it will reduce
chance of liver failure and death
Endocrine Drugs 11/6/2018 6:54:00 AM

Insulin & Anti-DM Agents


 Diabetes Mellitus
o Impaired glucose homeostasis characterized by elevated
blood glucose
o Due to inadequate insulin production or impaired action or
both
 Insulin secreted from islet B-cells in pancreas
o Glucose (or AAs or FAs) stimulate B cell receptors and are
broken down into ATP, causing closing of K+ channels
 Depolarization from increase in K+ opens V-G Ca2+
channels and the release of insulin containing vesicles
o Catecholamines also regulate insulin release
 A receptors on B-cells – decrease insulin release
 B receptors on A-cells – increase glucagon release
o Actions
 Increase glucose uptake of cells
 In Liver via Glut2
 In muscle and fat via Glut4
 Glycogen, lipid and protein synthesis
 Mitogenesis

Classification of DM
 T1DM (10% of DM)
o Childhood or puberty onset
o Moderate genetic predisposition
o AI destruction of B-islet cells
o Often undernourished at onset of dz
o Ketonemia and ketoacidosis common
 T2DM (90% of DM)
o Adult onset (>35)
o Very strong genetic predisposition
o Insulin resistance, reduced insulin secretion
o Obseity common

 Complications of DM
o Retinopathy – blindness
o Nephropathy – dialysis or renal transplant
o Neuropathy – neuropathic pain, ulcers, impotence
o CV – CAD, HTN, Stroke

DM Treament
 T1DM – insulin, intensive therapy, Edmonton protocol
 Insulin delivery system – standard is SC injection

Drugs for T1DM


 In increasing time of onset and duration of action:
 Lispo-> Regular insulin -> NPH -> Lente -> Ultralente
 All these preparations contain zinc and the ratio of zinc : insulin
influences rate of release and duration

 Insulin Lispro
o Enters circ twice as fast as regular
 Ultra-rapid onset and very short duration (3-4 hours)
 Suitable to use immediately before meals
 More drug only increases intensity, not duration
 Regular insulin
o Rapid onset and short action (5-7 hours)
o Used IV in emergencies
 Intermediate-acting insulin
o Includes:
 Isophane insulin suspension (Netural Protamine
Hegadorn or NPH insulin)
 Lente insulin (18-24 hours)
o Both SC, not for IV
 Ultralente insulin
o To provide basal insulin level (>30 hours)
o Usually given in the morning only or morning and evening to
provide basal level for 12-24 hours
o Can be supplemented with injection of lispro or regular to
meet requirement of carb intake

Hazards of Insulin Use


 Hypoglycemia / insulin shock
o Treatment with glucose (sugar or candy by mouth, glucose
IV) or glucagon IM
 Insulin induced immunologic complication
o Insulin antibodies form -> insulin resistance

T2DM Management
 Weight reduction/Exercise
o Increases insulin sensitivity and lowers blood glucose
o Central obesity = waist circumference >88 or >102 cm in
women or men, respectively
 Dietary control
 Oral antidiabetic agents (monotherapy)
 Combination therapy

Oral Antidiabetic Drugs


 Insulin secretalogues
o Sulfonylureas
 Stimulate release of endogenous insulin
2nd gen:
 Glyburide (Diabeta)
 Inhibit Katp channels causing release of insulin
 Decrease glucagon, and may increase insulin
receptors in peripheral tissues
 SE’s – hypoglycemia, rash, allergy
o Repaglinide
 Stimulate release of insulin by same mechanism
 No effect in pts who lack working B-cells
 Different from sulfonylureas b/c faster onset and short
action – take just before meals
 Biguanides
o Metformin
 Unclear mech
 Decrease liver gluconeogenesis, stimulate tissue
glycolysis, decrease GI absorption of glucose
 Does NOT stimulate insulin release
 Therefore doesn’t cause hypoglycemia
 SE – GI distress (N+D), lactic acidosis in renal or liver
dz
 Thiazolidinediones (TZD)
o Ex: Rosiglitazone
 Mech
 Activates PPAR-y regulating transcription of genes
of proteins for carb and lipid metabolism
 Causing increased insulin sensitivity, glucose
uptake, deceased liver gluconeogenesis
 Reduces fasting and postprandial glucose
 Monotherapy or combo wih insulin or other anti-DM
drugs
 SE’s – edema, anemia, induces CP450 3A4 – can affect
concentrations of OCPs and cyclosporine
 a-Glucosidase Inhibitors
o acarbose (Prandase)
 inhibits enzyme in gut that converts starches to smaller
sugars for absorption
 reduces post-prandial glucose and no effect on fasting
sugar
o Mono or combo therapy
o SEs are gas, diarrhea and cramping

Thyroid
 Thyroid Hormone Synthesis
o Uptake of iodide ion
o Iodination
 MIT, DIT
o Coupling
 DIT+DIT = T4
 MIT+DIT = T3
 Thyroid hormone release
o Thyroglobulin is endocytosed and cleaved to release T3/T4
o T3/T4 bound to Thyroid-binding globulin (TBG) transport
protein in blood
o TSH and TRH stimulate release of hormones
o 80% is T4, 20% is T3
 T3 5-10x more potent than T4
 T4 converted to T3 in target cells, liver and kidney
 Effect of Thyroid hormone
o Growth & Development
 Absence of thyroid hormone – Cretinism
o Calorigenic effect – heat production
 Increased O2 consumption
o CV effects
 Augments sympathetic NS function
 Thyroid Disorders
o Hypothyroidism – low T4, high TSH
o Hyperthyroidism – high T4, low TSH

 Hypothyroidism
o Primary Hypothyroidism
 Hashimoto’s Disease (most common)
 AI attack on thyroid cells
 Thyroid surgery
 Dietary Iodine deficiency
 Thyroid hypoplasia or enzume defects
o Secondary hypothyroidism
 Pituitary or hypothalamus dysfunction
o In kids – cretinism
 Due to iodine deficiency or failed thyroid development
o In adults – impaired physical and mental activity, slowing of
CV, GI and NM function
Lethargy, cold intolerance, weight gain, constipation,
skin-coarse and dry and cold
 In severe hypothyroidism – clinical syndrome called
Myxedema occurs
 Dry and waxy swelling of skin (non-pitting
edema)
o Treatment
 For all forms: T3/T4 replacement therapy
 Synthetic Levothyroxine (T4) is the form of choice
 Careful when giving it to older patients, more sensitive
to effects of thyroid hormones on their heart
 Drug Interactions:
 Anticoags – thyroid hormones increase catabolism
of vit.K clotting factors, they potentiate effects of
warfarin – bleeding
 Anti-DM Rx – may require more insulin or more
anti-DM rx b/c thyroid hormone will return BMR to
normal
 Female hormones – increases circulating TBG
therefore pts on OCP or pregnant may need more
thyroid hormone
 Hyperthyroidism
o Grave’s Disease (most common)
 abN production of Thyroid-stimulating immunoglobulin
(TSI)
 goiter common
o also TSH secreting tumors, toxic nodular goiter, overdose for
hypothyroid treatment
o Manifestations of hyperthyroidism or thyrotoxicosis
 Nervousness, emotional lability, weight loss, heat
intolerance, proximal muscle weakness, increased freq
of BMs, irregular menses
 Acute thyrotoxicosis/aka Thyroid Storm
 Usually provoked by infection, surg, trauma in
hyperthyroid pts
 Life-threatening emergency
o Treatment
 Anti-thyroid agents to inhibit synthesis and secretion of
T3/T4
 Thiourea drugs
 Propylthiouracil (PTU)
o Inhibits synthesis and conversion of
T4->T3
o For Grave’s disease
o SE – rash (common), immune
reaction rare
o Caution in pregnant and nursing
women; can cross placenta and breast
milk (can cause Cretinism)
 Iodide Salts
 Lugol’s solution (iodine and potassium iodine)
 Inhibit iodination of tyrosine
 Used for short-term to treat thyroid storm
 Rapid onset but transiet effects (thyroid
escapes the block)
 Iodinated Radiocontrast media
 Ex: Ipodate
 Prevent conversion of T4->T3
 Radioactive Iodine (RAI) Therapy
 Taken up and concentrated in thyroid gland and
emits beta particales that destroy thyroid tissue
w/o damaging other tissues
 Iodide salts used to inhibit iodine release after
 Not in pregnant or nursing women
 Surgery
 Thyroidectomy
 Reduce functional thyroid mass
 Beta-blockers
 Propranolol
 Controlling tachycardia and other cardiac abN of
thyroid storm
 Thyroid hormone and sympathetic NS work
synergistically on CV function, so increased
thyroid hormones can cause tachycardia and
arrhythmia

Bone
 25% organic/cells
 75% inorganic (hydroxyapatite)
o 99% calcium in body is stored in skeleton

Bone Mineral Homestasis


 Involves 2 elements
o Ca2+ and Phosphate
 3 Organs (intestines, bone, kidney)
 4 Hormones
o PTH, Vit. D, calcitonin, and estrogen

Vitamin D
 Vit.D converted to active form by hydroxylation in liver and kidney
o 1,25-(OH)2-D3
 Osteomalacia/Rickets due to Vit. D Deficiency
 Vit. D functions like a hormone (circulates and acts at different
places)
o Ultimately causing increased circulating Ca2+ and Phosphates
 GI – increased absorption
 Kidney – increased reabsorption
 Bone – increased bone resorption

Parathyroid Hormone
 Acts on G-protein coupled receptors to increase cAMP in bone and
renal tubules
o Net effect is increase levels of Ca2+ and decreased PO4- and
increased osteoclast activity
 Release inhibited by high Ca2+ and enhanced by low Ca2+ or high
Phosphate
o b/c phosphate can complex with ionized Ca2+
 A major stimulus for synthesis of active Vit. D
o Negative Feedback to decrease PTH
 No clinical use as a drug
o Vit. D and calcium supplement substitute for PTH replacement

Calcitonin
 Secreted by C cells of thyroid in response to plasma Ca2+ lelvels
o Kidney – decreases Ca2+ and PO4- reabsorption
o Bone – opposite of PTH and Vit. D
 Inhibits osteoclasts and decreases bone resorption
 Protects against Ca2+ los during pregnancy or lactation
 Good for management of hypercalcemia and Paget’s Disease of
Bone where there is increased resorption of bone -> bone pain and
deformity
 Injection or nasal spray

Estrogens
 Estrogens and Selective Estrogen Receptor Modulators (SERMs-
raloxifene) can prevent or delay bone loss post-menopause
o Inhibition of PTH stimulated bone resorption
 Decreases osteoclast differentiation/activation by
inhibiting IL-1 and TNF

Osteoporosis
 Most common bone disorder
o Gradual reduction in bone masss weaknening bone and ->
fracture
 Most common in post-menopausal women
o Most rapid BMD loss in 1st 5 years of onset of menopause
(generally at age 50)
 Treatment
o Vit. D, Calcium
o Estrogen Replacement Tx
 First line drug in post-menopausal women
o Raloxifene (SERMs)
 Prevents osteoporosis w/o increasing risk for
endometrial cancer and estrogen positive breast cancer
o Alendronate (used in place of or in addition to estrogen) – a
bisphosphonate

Paget’s Disease of Bone


 2nd most common bone dz
 bone deformities, bone pain and fractures
 unknown cause
 Treatment
o Calcitonin (intranasal)
o Bisphosphonates
 Alendronate, Risedronate
 Adsorb to hydroxyapatite and become permanent part
of bone structure
 Reduce bone resorption by inhibiting osteoclast
activity

Osteomalacia/Rickets
 AbN mineralization of bone matrix due to vit. D deficieincy and
osteoblast dysfunction
 In kids = Rickets
 Treatment
o Vit. D or Cacitriol

Bisphosphonates
 Indications
o Osteoporosis
o Paget’s Disease
o Hypercalcemia and osteolytic bone lesions (cancer)
 SE’s
o Esophageal ulceration (if PO)
o Mild nausea, dyspepsia, constipation/diarrhea

Bone Anabolic Agents


 Fluoride
o A mitogen for osteoblasts
o Increases bone mass
o But leads to hydroxyapatite -> fluoroapatite which is denser
but more brittle
 PTH (1-34)
 1-34 fragment of PTH shown to be powerful anabolic agent to make
new bone
 SC injection
 Increased osteoclast activity (continuous PTH)
 Increased osteoBLAST activity (one-daily PTH)

Steroids
 Hypothalamo-pituitary axis with regard to CRH->ACTH -> Cortisol,
Aldosterone and androgens (DHEA)
 Synthesized from Cholesterol

Glucocorticoids
 Enter cell and nucleus and alter gene transcription and protein
synthesis
 Effects of Nutrient Metabolism (Generally, increase circulating
nutrients)
o Stimulate gluconeogenesis (anti-insulin) and lipogenesis
o Activate protein catabolism
o Excessive glucocorticoid may lead to abN fat distribution,
muscle wasting
 Anti-inflammatory Effects
o Inhibit macrophage cytokine release
o Inhibit T cell activiation and cytokine production
o Prevent mast cells and eosinophils from releasing inflamm
mediators
o Cause vasoconstriction and decrease capillary permeability
 Other Effects
o Increase bone catabolism -> SE is osteoporosis
o Behavioral changes, peptic ulcers

Corticosteroids
 Cortisol (Hydrocortisone)
o Major natural glucocorticoid
o Circadian rhythm (peak in am, and trough around midnight)
o 95% bound to corticosteroid-binding-globin in plasma
o small mineralcorticoid effect – salt-retaining
o Important cause of HTN in patient with cortisol secreting
tumor or pituitary ACTH-secreting tumor (Cushing’s
Syndrome)
 Aldosterone
o Major natural mineralcorticoid
o Important in regulating blood volume and BP
 Synthetic Glucocorticoids and Mineralcorticoids
o Glucocorticoids
 Triamcinolone
 Dexamethasone
 Prednisone
o Mineralcorticoids
 Fludrocortisone

Glucocorticoids
 Indications
o Adrenal insufficiency
 Primary Adrenal Cortical Insufficency (Addison’s
Disease)
 All regions of cortex destroyed
 Deficiencies in cortisol, aldosterone and
androgens
 Hypoglycemia, fatigue, hypotension,
hyperpigmentation
 Hydrocortisone used orraly in a manner that
mimics circadian rhythm or cortisol
 Secondary Adrenal Insufficiency
 Caused by prolonged use of exogenous
glucocorticoid
Therefore, chronic glucocorticoid Tx should
whenever possible, be tapered slowly; decreasing
doses
o Congenital Adrenal hyperplasia
 Specific enzy,e deficiencies that impair synthesis of
cortisol and aldosterone
o Diagnosis of Cushing’s Syndrome
o Nonadrenal Disorders
 Inflammatory or immunologic in nature (Asthma, organ
transplant rejection, collagen Dz)

Cushing’s Syndrome
 Caused by hypersecretion of glucocorticoids
o Excessive ACTH (pituitary adenoma most common) or Adrenal
adenomas
 Dx often based on:
o Free cortisol level in urine
o Results of dexamethasone suppression test (not for adrenal
adenoma)
 Given dexamethasone PO and measure serum cortisol
over 4 days
 If plasma [cortisol] decrease to less than 50% of
baseline, pituitary adenoma indicated
 b/c giving glucocorticoid will
 If not, adrenal tumor or ectopic ACTH-producing tumor
is indicated
 Clinical Features
o Moon face
o Buffalo hump
o Weight gain
o Hirsutism
o Muscle wasting
o Thinning of skin
 Treatment
o Surgical excision
o Adrenal steroid inhibitors
Corticosteroid Antagonists
 Receptor Antagonists
o Spironolactone
 Aldosterone receptor antagonist
o Mifepristone
 Glucocorticoid and progesterone receptor antagonist
 Used in Tx for Cushing’s
 Synthesis Inhibitors
o In Tx of adrenal cancer, if surgery impractical or mets
o Ketoconazole (antifungal)
 Inhibits p450 enzymes, therefore inhibiting synthesis of
all steroids
 For adrenal carcinoma, hirsutism, breast cancer
o Aminoglutethimide
 Blocks cholesterol -> pregnenolone
o Metyrapone
 Inhibits cortisol synthesis
 Dx test of adrenal function

Gonadotropic and Gonadal Hormones


 GnRH
 FSH
o Ovarian follicle development
o Secretion of estrogen
o spermatogenesis
 LH
o Estrogen and progesterone synthesis in ovaries
o Testerone synthesis in testes

Ovarian Hormones
 Estrogens (Estradiol, major in women)
o Indication
 Primary hypogonadism
 HRT in menopause
 Compnent of OCPs
o SEs
 When used as HRT, risk of endometrial cancer
(Prevention w/ Progestin)
 Progestins (Progesterone, major in humans)
o Indications
 Component of OCPs and implantable contraception
 In HRT to prevent endometrial cancer
 Suppress ovarian function in Tx of dysmenorrheal,
endometriosis, uterine bleeding

Hormonal Contraceptives
 OCPS
o 3 types
 Monophasic – constant dosage
 Biphasic & Triphasic
 Progestin doses rise during the month (mimics
natural cycle)
 Progestin only
 Prevents LH surge that simulated ovulation
o Cause feedback inhibition of gonadotropin release from
pituitary (LH, FSH)
 Post-coital
o Prevent pregnancy if used w/in 72 hours after unprotected
intercourse
 Adverse Effects
o Thromboembolism
 Major toxic effect
 Increased blood coag, -> MI, stroke, DVT and PE
o Breast Cancer

Selective Estrogen Receptor Modulators (SERMs)


 Mixed estrogen agonists that have estrogen agonist effects in some
tissues and act as partial agonists or antagonists of estrogen in
other tissues
o Tamoxifen & Raloxifene
 Estrogen receptor antagonists in breast tissue to
prevent or treat Breast Cancer
 Agonist effect in bone – prevent osteoporosis in post-
menopause
 But tamoxifen is an agonist at endometrium ->
risk of cancer
 Ramoxifene – no effect on endometrium

Estrogen and Progesterone


 Clomiphene
o Non-steroid
o Increases FSH and LH
o Block estrogen receptors in puiitary, reducing negative
feedback
o Used to induce ovulation
 Mifepristone
o Synthetic steroid
o Progesterone antagonist, used in medical abortion

Androgens
 Testosterone & Methyltestosterone
o Indications
 HRT in hypogonadism
 Anabolic steroids used illicitly by athletes to increase
body mass, strength and performance
o SEs
 Male – decrease testicular size and function, impotence
 Female – hirsutism, masculinization
 Anti-androgens
o Leuprolide – GnRH analog
o Ketoconazole, Spironolactone – inhibit steroid synthesis
o Finasteride
 5a-reductase inhibitor
o Flutamide, cyproterone – receptor inhibitors

Oral Contraception
 Mechanism of action
o Gross inactivity of ovarian functions: Inhibition of ovulation or
ovum production by decreased release of pituitary
gonadotropins (FSH, LH) NO OVULATION – high dose
estrogen and progestin combined effect
o Cervical mucus and Decreased uterine motility: Makes the
mucus thick and viscous, which inhibits the penetration of
sperms- progesterone effect
 Contraindications
o CHF
o Vascular disease
o HTN
o Liver dz, Cholestatic Jaundice, severe depression
 Drug Reactions
o OCP with anticonvulsants (barbiturates, Phenytoin) reduce
the efficiency of the former due to increased hepatic
metabolism of OCP due to induction of p450.
o OCP with antibiotics (eg. Ampicillin/amoxcillin) reduce the
OCP efficacy due to increased intestinal excretion and reduced
enterohepatic reabsorption of estrogens.

 Mifepristone
o A steroid antagonist that competes with progesterone
and cortisol at their receptors and block their effects.
o It is Helpful in the termination of pregnancy (during the first
53 days only).
o It is also useful in the Pharmacological management of
Cushings Syndrome (Excess Cortisol or Tumor of the Adrenal
Cortex) and Endometriosis.
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11/6/2018 6:54:00 AM