Professional Documents
Culture Documents
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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
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
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)
Distribution
The REVERSIBLE movement of a drug b/w body
compartments
Fxs 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
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
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 doesnt have to be
administered
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
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
Autonomics
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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-Omethyltransferase (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
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
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
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)
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:
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:
Cholinergics:
Cardiovascular Drugs
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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
Intermittent Claudication
Vasodilators and BBs contraindicated
Pentoxiphulline reduces blood viscosity and thus
resistance and improves blood flow to ischemic area
Antihypertensives
Anti-HTN Rx
Heart Failure
Most common causes are HTN, CAD and Diabetes
Antiarrhythmics
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 BBs
More effective in conditions with high sympathetic
activity
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KIDNEYS!
Classes of Diuretics & Site of Action
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 starlings 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)
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
Pharmacology of Anesthesia
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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
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 Sxs first because they get a lot of blood
Tx:
o ABCs
o Raise seizure threshold (benzodiazepines, hypervent)
o Supportive
O2, secure airway
of:
Inhaled agents (sevoforane, nitrous oxide, halothane)
Induction/IV agents (Pentohal, Propofol)
Benzodiazepines (Lorazepam, diazepam)
Opiods (Demorol, morphine)
Amnesia/Hypnosis
o Impaired perceptive awareness/dont 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 dont really know!
Minimum Alveolar Concentration (MAC)
Miminum alveolar concentration at 1 atm that causes
immobility in 50% of patients exposed to a noxious stimulus
Pharmacokinetics
Concentration Gradient
o Delivered > inspired > alveolar > arterial > brain
Factors:
o Inspired concentration of drug (how much you gave)
o Alveolar ventilation (pts 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 bodys response to
higher PCO2)
o Bronchodilation! (sometimes given to asthmatics who
arent responding to other Rx)
CV
o
o
CNS
o
o
Vasodilation (hTN)
Decrease CO (decreased contractility and BP)
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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:
Drugs:
Antiplatelet
o Aspirin/ASA
Works on Cyclo-oxygenase (AA -> thromboxane)
Low dose (80-160 mg/day) irreversibly inhibits plt
COX, and they cant make new COX b/c they have
no nucleus
Some inhibition of endothelial COX but not much,
therefore prostacyclin (anti-coag) synthesis isnt
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 & childbirth
o Clopidogrel/Plavix
ADP antagonist
o GpIIb-IIIa inhibitors
Eptifibatide, Abciximab, Tirofiban
Block the receptor for fibrinogen blocking plt
aggregation
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
o
o
o
o
o
o
o
the liver
Ex: Atorvastatin, simvastatin
Statins inhibit cholestrol synthesis, but liver needs it so
it increases LDL receptors and picks up more
cholesterol reducing its plasma levels
other protective effects:
increase NO
plaque stability
anti-inflammatory
decrease LDL oxidation (form macrophages take
up)
reduce plt aggregation
Given at bedtime (most cholesterol made b/w midnight
and 2am), not with bile-acid binding resins
Do not use during pregnancy/breastfeeding
Extensive first pass metabolism
Work better in combo with bile-acid binding resins,
fibrates or niacin
Side effects:
Hepatotoxicity check ALT (alanine
aminotransferase)
Myopathy when other drugs metabolized by CYP3A4
are given (erythromycin, azole antifungals,
cyclosporine)
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
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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
Trimethoprum
Choramphenicol
Tetracycline
Macrolides/Erythromycin
Quinolones
Penicillins
Cephalosporins
Most Aminoglycosides
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
Reasons
Antibiotic Resistance
Intrinsic or acquired
o Intrinsic ex: Pseudomonas aeruginosa intrinsically resistant
to many b/c they cant cross outer membrane or bind target
sites
o Acquired
Mutation
New genes
Exchange of genetic information b/w bacteria
Mechanisms of Resistance:
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
nd
o 2
Glycopeptides
o Vancomycin gram +
o Bacitracine topical gram +
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 (Paraaminobenzoic acid)
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
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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:
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 Dont need activation by cellular enzymes (like NRTIs
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
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 Sxs, 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 cant 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 Sxs usually first appear at this stage
1 Kg tumor burden, usually death
o Examples:
Hodgekins 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
Anti-Cancer mechanisms
Impair nucleic acid synthesis
Impair DNA function
Impair protein synthesis
Inhibit mitosis
Stimulate immune system
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)
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
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
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
11-05-14 4:46 PM
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
Parkinsons Disease
Limbic, hypothalamus, CTZ
Norepi
Steps in
Epi
Pons/medulla CV control
Serotonin
Limbic, hypothalamus
ACh
Limbic
Extrapyramidal
Glutamate/glutamic acid
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 abNs
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
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 SEs
Extrapyramidal symptoms, hyperprolactinemia,
anti-emetic, tardive dyskinesia
Atypical Neuroleptics
Clozapine
o D1, D2, 5HT2 antagonist
For + and Sxs
o Little or no EPS?
o SEs
Bone marrow suppression -> agranulocytosis + death
Weekly blood tests
Respiridone
o D2 + 5HT2 antagonist
+ & - Sxs
little or not EPS or SEs
Olanzapine
o D2 + 5HT antagonist
+ and Sxs
o Halts progression of schizo
o SEs
Weight gain, dizziness, dry mouth
Quetiapine
o D1, D2, 5HT1a, 5HT2 antagonist
Similar to respiridone and olanzapine but cheaper
o Neuroprotective actions
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
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
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
Dont do other things in bed, just sleep
Dont 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)
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)
o Alter
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
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 (dont 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
Parkinsons 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 Parkinsons Disease
o Death of dopamine cell bodies in substantia nigra
Extra-pyramidal System (EPS)
Regulation of fine motor activity
For smooth and coordinated movement
Treatment of Parkinsons
Dopamine Replacement Therapy
o Dopamine cant 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
Alzheimers 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 Alzheimers
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
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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
(Meniers disease excess fluid in ear; and Labrynthitis)
o SE
Drowsiness, sedation, dry + blurred vision (block
muscarinic receptors)
Anticholinergics
o Scopalamine
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%
Butorphanol
Severe
Ergot or Triptan + antiemetic
Narcotic of meperidine if above fail
o Prophylactic (if >3 attacks/month)
BBs (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
11-05-14 4:46 PM
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
Metoclopramide
D2 antagonist/blocker
Crosses BBB
Prokinetic and also anti-emetic
CNS SEs
o Parkinsonian Sxs (Extrapyramidal) +
hyperprolactinemia
Domperidone
D2 antagonist
Doesnt 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)
11-05-14 4:46 PM
Uses
Risks
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
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
Toxicology
11-05-14 4:46 PM
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 benzos 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
Bs)
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 DONT 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:
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 dont 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 cant 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 cant 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 cant 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)
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
11-05-14 4:46 PM
Complications of DM
o Retinopathy blindness
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
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
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
Thyroid Disorders
o Hypothyroidism low T4, high TSH
o Hyperthyroidism high T4, low TSH
Hypothyroidism
o Primary Hypothyroidism
Hashimotos 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
Hyperthyroidism
o Graves 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 Graves disease
Iodide Salts
Lugols 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)
Bone
25% organic/cells
75% inorganic (hydroxyapatite)
o 99% calcium in body is stored in skeleton
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
Estrogens
Estrogens and Selective Estrogen Receptor Modulators (SERMsraloxifene) can prevent or delay bone loss post-menopause
o Inhibition of PTH stimulated bone resorption
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
Pagets
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 Pagets Disease
o Hypercalcemia and osteolytic bone lesions (cancer)
SEs
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)
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
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 (Cushings
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 (Addisons
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 Cushings Syndrome
o Nonadrenal Disorders
Inflammatory or immunologic in nature (Asthma, organ
transplant rejection, collagen Dz)
Cushings 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 Cushings
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
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
HTN
Liver dz, Cholestatic Jaundice, severe depression
Reactions
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.
o
o
Drug
o
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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