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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
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
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
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
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)
Bioavailability
The fraction of orally given drug that reaches the circulation
= (AUC orac/AUC IV) x 100
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
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
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
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)
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
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
Drug Development
Patent life = 20 yrs
Preclinical ->Clinical ->Marketing ->Generic
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
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
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
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
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
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 – 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!
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!
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
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
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
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)
Balanced Technique
One agent can achieve all goals, so use a combo of inhaled
and IV agents
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
Anticoagulants
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
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
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
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
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
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
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
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 +
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Vomiting
Physiological protective anti-peristaltic response in a forceful
expulsion of GI contents
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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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