Module 4 Pharmacology

! 3. Antimitotics (Chemo Drugs)!

! ! a. Taxanes!
!Basic Principles of Pharmacology • Paclitaxel!
! • Docetaxel!
PHARMACOLOGY! • Cabazitaxel! !
• study of drugs! ! b. Vinca Alkaloids!
• articles used in the prevention, diagnosis, • Vincristine!
mitigation, treatment and cure of diseases in • Vinblastine!
men and other animals! • Vinorelbine!
• Division :! • Vindesine!
! a. Pharmacodynamics ! ! c. Estramastine!
! b. Pharmacokinetics! !
! c. Pharmacotherapeutics - study of ! B. Regulatory Proteins!
! rational use of drugs in the ! ! • regulate cell activity or function!
! management of diseases.! !
! CHANNELS (Voltage-gated)!
! • conduct changes in electrical signals!
! PHARMACODYNAMICS
• present in all cells!
• study of physiologic and biochemical effects !
of drugs in living systems and the !
Cells at rest are (-) or polarized, once excited, cell

mechanisms by which these are produces! !

becomes less negative or (+) it will become

! !
depolarized and repolarizes (-) to reach equilibrium!

!
TYPES OF MECHANISM OF DRUG ACTION! !
Hyperpolarization of cells renders the cell more

I. Target Protein Mediated! !!!

negative (-) or less excitable!

• biologic site of action, “action site” or “active Dominant anions/cations:!

site”! !
PISO (K, Na)!
• target a physiologic protein! !
MICO (Mg, Ca)!
! !!!
PIChO (PO4-, Cl-)!
A. Structural Proteins!
ex. microtubules - made of alpha and beta !
Importances of Ions:!
units of tubulin. ! !
Na, Cl - for tonicity!
function: keep organelles in place (in !
Ca - structural component in bones, muscle

eukaryotic cells)! !
contraction, release of neurotransmitters from the

! chemotaxis - cell movement via !

pre-synapse!

chemical stimulus! !
Mg or MgSO4 (Epsom salt) - natural CCB, used for

! axonal release of neurotransmitters! !

eclampsia (IV/IM: anticonvulsant, PO: cathartic)
competes with Ca at binding sites
! mitosis/cell division (metaphase)! !
! 1. Voltage-gated Na-channels!
DRUGS THAT INHIBIT MICROTUBULES! ! Inhibitors: !
! CLASS I ANTI-ARRHYTHMICS
1. Griseofulvin !
• antifungal! IA IB IC
• management of dermatomycosis1!
Disopyramide Tocainamide Moricizine
• arrest fungal mitosis!
• enzyme inducer! Quinidine Mexilitine Flecainide
• increased absorption with fatty food!
! Procainamide Lidocaine Propanfenone
2. Colchicine! Phenytoin Encainide
• 1st line for acute gout and acute gouty
attcks! • Class IA - prolong action potential (AP)!
• inhibits chemotaxis of immune cells that • Class IB - shorten AP!
• Class IC - no effect on AP!
!
causes inflammation!
!
1 infection of skin and appendages
1
 LOCAL ANESTHETICS • exception: Aripiprazole which is an
atypical antipsychotic!
ESTER TYPE AMIDE TYPE !
ENZMYES!
Procaine Lidocaine
!
Cocaine Bupivacaine 1. Eicosanoid Pathway:!
• Phospholipase A2 (PLA2)!
• Ester-containg : short acting!
• Inhibitors: corticosteroids (eg.
• Amide-containg : long acting!
! Prednisone)!
• Cyclooxygenase (COX)!
• Some anti-convulsants!
! Phenytoin! • 5-lipoxygenase (5-LOX)!
• Inhibitor: Zileuton (anti-asthma)!
!
!
Carbamazepine!
!
! Phospholipids - precursor for Arachidonic acid, in
2. Voltage-gated K-channels!
! turn giving Prostaglandin and Leukotriene
• Class III Antiarrhythmics (Amiodarone)!
! (eicosanoids) with the action of COX and LOX
• Insulin Secretagogues (Sulfonylureas:
! respectively!

!
Glimeperide)!
! Prostaglandin - cytoprotection, pain and

! inflammation!
3. Calcium-Channel Blockers (CCB)!
! Leukotrienes - bronchoconstriction
• Dihydropyridines “-dipines” (eg.
Nicardipine) - vasoselective (arteries)!
!
2. Cyclooxygenase (COX) - lahat daw ng
• Non-DHP class IV antiarrhythmics !
NSAID COX-inhibitor!
• Verapamil - cardioselective tx for
! Inhibitor:!
arrhythmia !
! NSAIDS!
• Diltiazem - heart and blood vessels
(intermediate effect)! • ASA (Aspirin)!
contraindicated sa px with heart failure2! • Ibuprofen!
•
! • Naproxen!
3. Angiotensin Converting Enzyme (ACE)!
CARRIER MOLECULES!
• aka “Kinase II” or “dipeptidyl
• cell membrane proteins with specific binding
decarboxypeptidase”!
sites that undergo conformational change!
! ! Inhibitor:!
• ACE-inhibitors “-prils”!
1.
•
Na/K-ATPase Pump!
found in the cardiac myocytes!
!
4. Monoamine Oxidase (MAO A, MAO B)!
• responsible for Ca extrusion!
! Inhibitors:!
• activation of NCX is dependent on NKAP
activation! MAOIs
! Inhibitor:!
Selective Selective Non-selective
! Cardiac Glycosides!
MAOI A MAOI B MAOI
• Digoxin (from Digitalis lanata) -
inotropic! Moclobemide Selegiline Phenelzine
• Digitoxin (from D. purpurea)!
! Rosagiline Isocarboxazid
2. H/K-ATPase Pump or Proton Pump!
• mediates release of gastric acid! Tranylcypromi
ne
• ACh, gastrin, histamine in the parietal cells
of the stomach (triggers the release of HCl)! • MAO A - metabolizes, NE, EPI, 5-HT3!
! Inhibitor:! • MAO B - metabolizes dopamine!
! Proton Pump Inhibitor (PPI)! • Clinical Depression - serotonin and
• “-prazoles” eg. Omeprazole! norepinephrine are deficient!
• most effective during hyperacidity! • Parkinsonism - low dopamine!

2 inefficient force of contraction of the heart

3 aka serotonin
2
5. Catechol-O-methyltransferase (COMT)! Serotonin blockers: -setron
! Inhibitors:! (Ondansetron) tx for cancer-induced nausea!
• COMTIs “-capones”! !
• Tolcapone! !
• Entacapone! 2. Type II or Metabotropic Receptors!
! • G-protein linked, coupled receptors!
I. Drug-Target Protein Mediated • 7-transmembrane spanning receptors!
Mechanism of Action! • location: cell membrane!
! • increase or decrease of secondary
RECEPTORS! messengers!
• functional macromolecular cell components • onset: secs!
with specific stereochemical configuration !
with which a ligand interacts, usually in a G-receptors / ANS
lock and key fashion!
! Gs Gi Gq
1. Type I or Ionotropic Receptors!
• associated with ion channels (ligand-
gated ion channels)! B1, B2 a2 a1
• location: cell membrane! H2, V2 M2 M1
• onset: ms!
GABA receptor complex - associated with Dopa2 Dopa2 Histamine-1!
Cl- channels! Vasopressin-1
! receptors!
• GABA A receptor!
!
Secondary Messengers:!
• Stimulators: BZDs, Barbiurates!
a. cAMP (cyclic adenosine
• Barbiturates - prolongs duration of Cl
channel opening! monophosphate)!
b. cGMP (cyclic guanosine
• C Benzodiazepenes - increases the
frequency of Cl channel opening ! monophosphate)!
! • aforementioned secondary messengers
! utilizes same signalling cascades.!
!Barbiturates and benzodiazepenes enhances • intestinal mucosa & blood vessels!
!GABAa receptor binding with GABA. Hence, c. IP3 (inositol triphosphate)!
!opening of Cl channels, influx of Cl, resulting to
!
d. DAG (diacylglycerol)!
!hyperpolarization of the cell. (CNS Depression)

! Types of G-proteins:!
a. Gs - stimulates adenylyl cyaclase (AC)!
Nicotinic Receptors - associated with Na-
channels! • ex. Beta-receptors!
• Nn (neural/neuronal)! • stimulators: Epi, NE!
• Nm (neuromuscular) - skeletal m. ! • Blockers: Beta-blockers (-olols)!
! Stimulators:! b. Gi - inhibits adenylyl cyclase (decrease
cAMP)!
• Nicotine!
• Lobeline! • ex. Pre-synaptic Alpha2 receptors!
• Varenicline! • stimulators: Clonidine, Methyldopa,
! Inhibitors:! Guanfacine, Guanabenz!
• ex M2 receptors!
• Nm blockers (skeletal muscle
relaxants):! c. Gq - stimulates Phospholipase C (PLC)!
• Tubocurarine! • PLC stimulates the formation of IP3 &
DAG from PIP2. (increased
• Succinlycholine!
intracellular Calcium ions =
• Atracurium “-curium”!
contraction)!
• Pancuronium!
• Rocuronium “-curonium”! • ex. Alpha1!
! • blockers: -zosin (Alprazosin)!
• ex. M1, M3!
Glycine blocker: strychnine!
! ! • ex. Post-aynaptic Alpha2!

3
“KISS
! KICK” Gq Gi Gs Gs (alpha and beta), Gq Gi
• Chelating Agents !
! !!
Gq (M-receptors)!
! ex. British Anti-Lewisite (BAL) or
dimercaprol (IM) for Hg & As toxicity (peanut
!
In what body fluid is prostaglandin derived?!
oil as vehicle)!
!
Answer: Semen
• Penicillamine (Cuprimine) for Cu
! Wison’s disease!
3. Type III or Enzyme-linked Receptors! • Deferoxamine (Desferal) for Fe !
• location: cell membrane! !
• insulin receptor - tyrosine kinase linked! C. Counterfeit or Incorporation Mechanism!
• onset: minutes! • ex: Antimetabolites!
• effects: stimulation of glucokinase • purine and pyrimadine base analogues
(glycolysis)! (also used as anti-cancer drugs)!
• translocation of glucose transporters • e.g. 5-fluorouracil!
(GLUT2, GLUT4) into the cell !
membrane! !
• ex. Insulin receptors, Platelet-derived !
Growth factor, epidermal growth factor! !
DRUG-RECEPTOR INTERACTION
! I. Characteristics!
4. Type IV / Gene Transcription-linked ! Affinity - ability to bind to receptor!
Receptor / Nuclear Receptors / Intracellular ! Intrinsic activity - ability of a ligand to
Receptor (DNA to RNA)! evoke an active response.constitutive activity/
• location: intracellular (cytoplasm, effect; (+)effect even in the absence of ligand!
nucleus)! !
• onset: hours! II. Types of Ligands!
• modulate gene transcription! ! A. Agonist - has affinity and intrinsic !
• DRUGS: sex hormones, thyroid ! activity [increase intrinsic activity (IA)]!
hormones, Vit D, steroidal hormones ! B. Antagonist - no effect on IA!
(corticosteroids)! ! C. Inverse Agonist - decrease IA!
! !
II. Non-Target Protein Mediated Mechanism! !
! !
A. Colligative Mechanism / Mass Effect! !
• Colligative properties - dependent on the !
number of solute particles! !
! ex. VP lowering, BP elevation, FP ! !
! depression, Osmotic pressure! !
! !
Mannitol - osmotic diuretic/aquaretic! !
MOA (IV Infusion): inhibits water !
reabsorption in the water permeable regions in !
the renal tubules (descending limb of loop of III. Types of Agonist!
Henle) by increasing the osmotic pressure.! ! A. Full Agonist - produces all of the
MOA (PO) : osmotic diarrhetic! effects of receptor (ex. Morphine - mu
! receptor) IA=1!
B. Chemical Antagonism / Direct Chamical ! B. Partial Agonist - produces some of
Interaction! the effects of the receptor; has a mixed agonist
• Local Antacids - neutralization reaction! and antagonist action. (IA > 0 but < 1)!
! ex. Mg(OH)2, Al(OH)3! ! ex. Nalbuphine - mixed agonist-
• Systemic Antacids - NaHCO3 for antagonist; acts as a full antagonist in the
metabolic acidosis! presence of a full agonist (morphine)!
• Protamine sulfate for heparin toxicity ! Tamoxifen - management of
(neutralization din yielding ionized4 estrogen receptor in breast CA; partial agonist
heparin)!

4 when a drug is ionized, it is rather excreted than absorbed

4
 of estrogen with allosteric5 (full agonist is Based on the Type of Interaction!
endogenous estrogen)! 1. Reversible Antagonism!
! • temporary (duration of interaction
! <24h)!
! • non-covalent bonds (weak forces of
! attraction like VDV, H-bond)!
!
NOTE: A partial agonist in the presence of a full
!
!
agonist will act as an antagonist.!
2. Irreversible Antagonism!
!!!
ex. Morphine + Nalbuphine!
• as long as the receptor is viable, effect
still present!
!
Morphine is a full agonist to mu receptors while
Nalbuphine is a partial agonist for same receptor, • permanent (DOI: days-weeks)!
!
when taken together, result is reduction of • covalent bond!
!
analgesia • !
! C. Inverse Agonist (IA<0)! Based on Surmountability!
! 1. Competitive / Surmountable!
IV. Types of Antagonist! • completely overcomes the effect of the
! antagonist by increasing the dose of the
Based on Mechanism of Antagonism! agonist!
1. Functional or Physiologic - produces • quantity based (kung sino mas marami
opposite effects by binding to different siya ang magbbind sa receptor)!
receptors; 2 ligands acting on different !
receptors, producing opposite effects! 2. Non-competitive / Non-surmountable!
! • kahit gaano mo damihan ang dose ng
ex. Epinephrine in the management of ligand, hindi na niya maka-counteract
anaphylaxis ! yung effect ng isa pang ligand!
! • allosteric !
! !
!
An allergic reaction would trigger IgE and mast cell
!
!
production, which in turn would release your
!
THEORIES

!
histamine. Binding of histamine to your H1
A. Hypothesis of Clark!
!
receptors, will cause bronchoconstriction, and
• all receptors are occupied to experience
!
vasodilation of blood vessels, giving you
full effect!
!
anaphylactic shock (low BP).!
Epinephrine would bind to the following receptors B. Hypothesis of Paton!
!
to produce these corresponding effects! • aka Rate Theory!
!! Alpha1 - vasoconstriction! • the action of the drug depends on
!! Beta2 - bronchodilation! STIMULUS!
! C. Hypothesis of Ariens and Stephenson!
2. Pharmacologic or Receptor Antagonism - • pharmacologic effects of drug remain as
produces opposite effects by binding to same long as receptors are occupied!
or similar receptors.! !
ex. Histamine in allergic reactions (H1 !
Receptors) using antihistamines like !
Diphenhydramine (first generation) will inhibit !
binding of your histamine.! !
ex. Epinephrine & Beta-blockers !
(epinephrine is a beta-agonist)! !
! !
3. Chemical ! !
ex. Protamine sulfate - used for the !
management of heparin (acidic) toxicity! !
MOA: neutralization reaction! !
! !
5allosteric site - site other than the agonist binding site. allosteric agonism increases the binding of
an agonist, while an allosteric antagonist inhibits its binding
5
DOSE RESPONSE GRAPHS PHARMACOKINETICS

I. Graded Dose-Response Graph! • what the body does to the body!

• Plot: Degree of Response VS Dose or Log • study of the processes a drug undergoes as
Dose! it reaches and leaves the site of action!
• Log dose (sigmoidal) dose (hyperbolic)! • Processes invloved (LADME) :!
! 1. !Transport!
! Parameters:! 2. Liberation!
• Efficacy or ceiling effect - 3. Absorption!
maximum achievable response! 4. Distribution!
• Potency - dose that produces 50% 5. Metabolsim!
of the efficacy! 6. Excretion!
• Slope - degree of change in • Biopharmaceutics !
response with a change in the dose! • “bio”= bioavailability!
• Steep slope : drastic response; • “pharmaceutics” = dosage forms,
start low, go slow! physicochemical properties of a drug
• Not steep : dose can be (pKa, pH, etc), routes of administration
adjusted! (PO,IV,IM,etc)!
• Ceiling dose - smallest dose that !
produces the maximum achievable TRANSPORTATION!
response ; limit dose ! • movement through the cell membrane!
! • basic requirement: drug must be in aqueous
Applications (see appendix)! solution except in pinocytosis where drug is
a. Efficacy vs Potency (hanap table)! in micelle form!
b. Full, Partial and Inverse Agonists! !
c. Competitive Antagonist (shifts to the right, Mechanisms of Transport!
with the same height for efficacy)! 1. Passive diffusion !
d. Non-competitive Antagonist (increases • dominant, most common; slowest; no
amount of agonist and non-comp. energy requirement!
antagonist, but never reaching max • along concentration gradient (high to low)!
efficacy)! • governed by Fick’s Law of Diffusion!
! !
II. Quantal Dose-Response Graph! ! dQ Di Aik
• Plot: Cumulative number of Px vs Log ! dt = h
(CGI − C p )
Dose (all or none) ! ! !
! Parameters:! ! where:!
• Median effective dose (ED50) - ! dQ/dt = rate of diffusion!
dose that produces the beneficial ! C1-C2 = concentration gradient!
response in 50% of the study ! d = diffusion coefficient!
population! ! A = surface area!
• Median toxic dose (TD50) - dose ! h = membrane thickness!
that produces the toxic response in ! k = partition coefficient!
50% of the study population. !
NOTE: LD50 is used in death !
responses in pre-clinical trials, i.e. Factors affecting passive diffusion:!
in animals! a. Concentration gradient & rate!
• Therapeutic Index (TD50/ED50) - b. Surface area & rate!
relative measure of safety (higher c. Diffusion coefficient & rate!
TI, safer drug) ! • property of the drug in relation to the
• Margin of Safety ! property of the membrane!
! d. Membrane thickness & rate (indirect)!
! !
! !
! !
! !
! !
! !
! !
6
Diffusion Coeffecient is determined by:! ! c. Convective Transport / Bulk Flow -
a. Particle size & diffusion k. (indirect)! ! drug passes through water filled pores;
! ! only paracellular transport mechanisms!
b. Lipophilicity & diffusion k. (direct)! ! ! Features:!
• 2 Factors:! • pore size 7-10Å MW
• Degree of Dissociation / Ionization! <150-400!
UNIONIZED[HA] IONIZED H+ A • pore lining is charged (drugs
with opposite charge may
lipophilic hydrophilic pass through)!
• Movement is by solvent drug!
non-polar polar • Movement is along
absorbed excreted
concentration gradient (no
ATP)!
“LUNA” ‘HIPE" !
! d. Ion-Pair Transport - important for
! kB = base dissociation constant! ! movement or transport of large ions. !
! kA = dissociation constant acid! ! papasok sa cell via passive transport
! pKa = -logkA (increased pKa favors ! ! because walang charge!
! diffusion)!
! !
!
!
!
ex. tert. NH4 (+) + mucin (-) !
makes use of a combination or
• Partition Coefficent (increased K ! ! neutralization reaction first !
increased diffusion)!
! !
!
! before passive diffusion!
! K=
Coil
! ! e. Pinocytosis or Phagocytosis - !
! Cwater
! vesicle mediated ; energy requiring. !
! ! basic requirement: micelle6 form of !
! !
!
drugs!
! ex. Griseofulvin!
2. Carrier-mediated Transport! ! ! Fat soluble vit. (A,D,E,K)!
• Selectivity / specificity - carriers recognize !
specific molecules ex. Levodopa crosses ! Body surfactants:!
the BBB bc of a large neutral AA ! ! BILE which is produced in the liver and
transporter (LNAAT)! ! stored in the gall bladder. The contraction of the
• subject to competition, inhibition or ! gallbladder is stimulated by cholecystokinin
antagonism (Levodopa given before meal)! ! (enzyme from pancreas) which is on the other
• Saturability - basis is limited number of ! hand stimulated by fatty food.!
carriers! !
• Michaelis-Menten Kinetics / non-linear !
kinetics / capacity-limited! !
! Start:! !
• First Order - elimination is !
dependent on drug concentration! !
• Zero Order - drug clearance is on a !
constant rate (independent of drug !
concentration)! !
! ! !
! a. Active Transport - energy-requiring; !
! against concentration gradient (uphill) ; !
!
!
fastest! !
!
! b. Facilitated Diffusion - no energy ! !
! requirement; along concentration ! !
! gradient ; passive diffusion with carrier! !
6 micelle - oil globules stabilized by surfactants
7
 LIBERATION! ! Factors Affecting Absorption!
• release of drug from the dosage form! 1. dose size & rate and extent (direct)!
• end product: drug in aqueous form / sol’n! 2. pH of absorption site - stomach
• highly modifiable (i.e. controlled-release absorption : ASA [WA], EtOH &
dosage forms)! upper segment of small intestine!
• exemptions: true solutions (RLE: absorption)! !
• factors (pharmacotechnical)! DRUG STOMACH Small
1. formulation! Intestine
2. quality!
3. disintegration rate! Weak Acid Absorbed Excreated
4. dissolution rate!
! !
Weak Base Excreted Absorbed

ABSORPTION!
• Physiologic : rate and extent of drug 3. Surface Area of the absorption
disappearance from the site of administration environment & BA!
ex. Tablet PO ! ! ! SI > stomach!
! ! lungs > SI > stomach!
GIT to bloodstream (portal circulation)!
!
• Pharmacokinetic : rate and extent of drug
! The small intestine’s surface area is 120 sq. m
entry into the systemic circulation!
! making it the main site of drug absorption. The
!
!
Peripheral to liver to systemic!
! small intestine has vili & microvilli that increases its
! SA.
Bioavailability [BA] or [F] is the measure of
rate and extent of drug entry into the systemic !
circulation / pharmacokinetic absorption! ! 4. Degree of Perfusion !
! ! ! SI > stomach!
• local anesthetics / vasoconstrictors
2 Methods:!
a. Cumulative Urinary Excretion Data! (epinephrine)!
b. Drug Plasma Concentration vs Time Graph! • to minimize systemic
! ! absorption!
! 3 Parameters:! • to minimize systemic toxicity!
1. Cmax - maximum plasma • prolong duration of action of
concentration; both rate and extent; local ones!
• minimize bleeding!
most variable!
2. Tmax - time it takes to reach !
Cmax; rate only; least important! ! 5. Gastric Emptying Time (GET) - time
3. AUC - area under the curve; extent ! ! it takes the stomach to empty
only; most important! ! ! its contents into the small !
! ! ! intestine!
• normal: 2-3 hours!
! Types of BA [F]:!
! 1. Absolute Bioavailability ! • Faster emptying, faster absorption,
! (same dose, different routes)! lower GET.!
! • you need gastric emptying because
! Fabs =
AUCnon−IV the stomach has a small surface
! area, degree of perfusion and thick
! AUC IV mucous membrane making it
! ! !
inefficient for absorbing drugs!
! 2. Relative Bioavailability - used
!
when comparing a generic drug to a reference
!
standard.!
!
(same dose, same route particularly PO)!
! !
! AUCnon−IV !
! Frel = !
! AUCnon−IV !
! !
! !
8
Factors increasing GET (slower absorption)!
!
• high fat / protein meal, heavy meal!
2. Regional Blood Flow - fraction of the
!
• stress!
cardiac output that reaches a specific
!
• strenuous exercise (heavy)!
organ or tissue (direct with D.)!
!
• gastric ulcers!
• 100% lungs!
!
• lying on the left side!
• drugs decreasing GI motility ! • 25% liver!
!
• (anticholinergics, opioids, morphine, • 25% kidney!

! !! nalbuphine)!
! • <1% bones and adipose tissue!

!
Factors decreasing GET (faster absorption)! !
!
• extreme temperature of food! ! That’s why a lung infection would only take 7-10
!
• mild exercise! ! days to treat while a bone infection would take
!
• DM ! ! longer ( at least 6 weeks).
!
• lying on the right side!
!
!
• drugs that increase GI motility!
!
!
• cholinomimetics, !
PHARMACOKINETIC PARAMETERS:!
!
• prokinetics : domperidone, metocloproamide!
!
! 1. Volume of Distribution (Vd) is a
Bioequivalence is the similarity of BA of hypothetical value of body fluid required to
generic and innovator or standard drug. *AUC dissolve a given amount of drug to a
Ratio, Cmax Ratio, Tmax Ratio! concentration equal to that of plasma
! concentration. unit = Litres!
Terminologies:! !
a. Pharmaceutical Equivalents!
!
!
Ab(dose)
• same API, salt / ester / complex!
• same dosage form and strength! ! Vd =
• may differ in excipients used (flavorants,
colorants)!
! Cp
Where Cp = plasma concentration!
b. Pharmaceutical Alternatives! !
• same API! Applications:!
• may differ in any of the ff: ! • to estimate the loading dose!
• salt/ester/complex (eg Diclofenac Na, • to estimate the actual distribution of drugs
Diclofenac K)! in the body!
• dosage form, ! !
• dosage strength! 2. Protein Binding !
c. Therapeutic Equivalents! a. Blood Proteins:!
• pharmaceutic equivalents! • Albumin - weak acids!
• bioequivalent! • Alpha1-acid Glycoprotein - weak bases!
d. Therapeutic Alternatives! • Globulins - for hormones!
• different API, same drug class! b. Consequences:!
• eg, Ibuprofen and Naproxen (same • long duration of action!
NSAID, same propionic acid derivative)! • limit access to certain body
! compartments!
DISTRIBUTION! • potential for drug plasma displacement
• reversible transfer of a drug from the interaction (ADR)!
systemic circulation to the site of action and c. Drugs that undergo extensive protein
to the other compartments! binding:!
• goal is to reach the biological site of action! • Warfarin!
! • NSAIDs (Phenylbutazone)!
Factors Affecting Distribution:! • Midazolam!
1. Cardiac Output - volume of blood • Sulfa drugs!
pumped by the heart per minute is !
directly related to the extent of !
distribution. (normal: 2.2-3.5 L/min/ !
!
sqm) higher CO, better distribution! !
!
9
 PHASE I METABOLISM : FUNCTIONALIZATION

METABOLISM! • aka Asynthetic Phase!

• biotransformation! • goal: to add or unmask functional group!
• primary goal: to convert drugs into an • increase polarity of drug, increasing
inactive / less active non-toxic / less toxic hydrophilicity, favoring excretion!
polar, water soluble! !
• Exceptions:! A. Oxidation - dominant!
1. Prodrug - initially inactive! 1. CYP mediated - CYP450!
! ex. long-acting ACEI ! CYP1A2 APAP, Theophylline, caffeine
! enalapril to enalaprilat!
! CYP2C9 s-warfarin, phenytoin
• All ACEIs except Captopril, Lisinopril,
Enalaprilat (acute drugs)!
CYP2C19 PPIs, clopidogrel, propranolol
• eg. Clopidogrel, Dipifevrin (for Epi)!
! CYP2D6 codeine, tamoxifen!
2. Formation of Toxic Metabolites!
! ex. Acetaminophen undergoes some antipsychotics, anti-
depressants, B-blockers
oxidation to form NAPQI (N-
acetylparabenzoquinoimine) ! CYP3A4,5,7 azole antifungals!
• unmasking addition of polar functional CCBs!
gaps to parent drug or metabolite! macrolides!
! antivirals (HIV)!
tyrosine kinase inhibitors (anti-
3. Active to Active!
• eg. Diazepam to Oxazepam! cancer)
!
Organs Capable of Biotransformation:!
1. Liver - dominant organ for metabolism!
!
2. Non-CYP mediated!
2. Kidneys! ! ex. Monoamine Oxidase, aldehyde
3. GIT! dehydrogenase!
4. Placenta!
5. Plasma!
!
B. Reduction - addition of H, removal of O!
! ! Mechanisms:!
First Pass Effect:! 1. Nitroreduction (eg.
• aka pre-systemic metabolism! chloramphenicol)!
• for PO drugs (decreases oral BA)! 2. Carbonyl reduction (eg.
• Drugs:! Naloxone, methadone)!
• Propranolol! 3. Azo reduction (eg. prontosil)!
• Opiates (natural) and Opioids (synthetic)! !
• Catecholamines (eg. Epi, NE, DA)! C. Hydrolysis !
• Felodipine (CCB-DHP)! ! ex. Ester-containing : local anesthetics,
• Lidocaine! ! ! ! ! ACEI, ASA!
! ! Amide-containing: lidocaine, !
! ! ! ! ! procainamide!
! !
! !
! !
! ! What inhibits the formation of T3 to T4? !
! ! Answer: Propranolol (MOA: Beta-blocker)
! !
! !
! !
! !
! !
! !
! !
! !
!
10
PHASE II METABOLISM : CONJUGATION / SYNTHETIC

• goal: addition of polar conjugate! EXCRETION!

! • final loss of drug from the body!
Reactions:! • requirement: polar, water soluble!
A. Glucoronidation ! !
• dominant phase II metabolism in adults! Routes:!
• enzyme is efficiently expressed! 1. Kidneys!
• neonates: Sulfation! • main excretory organ!
• enzyme: Uridine-5’- • urine !
diphosphoglucoronosyl transferase ; • requirements: polar, low MW <400-600!
glucoronosyl acyl transferase! • Processes involved in Urine Formation:!
! • Glomerular Filtration - passive
B. Acetylation! process!
• enzyme: N-acetyltransferase! • CrCl = approximate GFR!
• substrates: hydralazine, INH, • Cockroft-Gault Equation!
procainamide! !
! ! CrCl =
140 − Age(yr)xBW (kg)
= ml / min
C. Miscellaneous ! ! SerumCr(mg / dL)x72
• Glycine Conjugation : carboxylic acid, !
salicylic acid and benzoic acid! ! *female x 0.85!
• Methylation: catecholamine (COMT)! • Tubular Secretion - active (carrier)!
• Sulfation : Paracetamol! • peripheral capillaries to lumen of
• Glutathione conjugation : free radicals! renal tubules!
• Glutamate conjugation! !
! 2. Biliary excretion!
! • stool!
! • requirements: polar, high MW!
!ENZYME INDUCTION AND INHIBITION
• limitations: biliary recycling / enterohepatic
! circulation (reabsorption of drugs)!
I. Enzyme Induction! • may undergo metabolism on its way into
• enhancing or stimulating enzyme activity! the small intestine rendering drugs less
• consequences:! polar, entailing reabsorption!
! a. Inactivation (decrease efficacy)! • biliary recycling (enterohepatic recycling)
! b. Activation of prodrug (increases ! increases the risk of toxicity!
! efficacy and toxicity)! !
! c. Formation of toxic metabolite ! 3. Miscellaneous!
! (increases toxicity)! • Lungs - non-polar volatile drugs!
! • Sweat gland - sweat!
II. Enzyme Inhibition! • Mammary gland - milk!
• inhibition of enzyme activity! !
• consequences:! Additional:!
! a. no enzyme present to inactivate drug CYP2D6 Polymorphism / Genetic
! increasing its efficacy and toxicity! Polymorphism - variation in the expression or
! b. no enzyme to activate prodrug ! production of specific enzymes!
! rendering it less efficient! • EM (Extensive Metabolizers) normal!
! • PM (Poor Metabolizers) decreased
! enzyme activity!
! • UM (Ultra Metabolizers) increased
! enzyme activity!
! NAT2 !
! • Slow Acetylators (Caucasians) PM!
! • Fast Acetylators (Asians) EM!
! !
! !
! !
! !
! !
11
!
Autonomic Nervous System
Anatomy & Physiology ! Anatomy Sympathetic Parasympathetic
• effector of CNS (brain and spinal cord)!
• other effector: somatic nervous system!
! origin / roots Thoracolumbar
(T1-12, L1-5)
Craniosacral !
(CN 9, 10, 7, 3,
Difference between SNS & ANS!
! S1-4)
Synaptic Neurotransmission - mechanism of
impulse transport across a synapse!
length of
preganglionic
!
shorter
!
longer
• Synapse - communication between 2 nerves fiber
or a neuron and target organ!
• Parts:!
length of
postganglionic
!
longer
!
shorter
1. Pre-synapse!
fiber
• synthesis, storage, release of
neurotransmitters! location of near the spinal near the target
• autoreceptors or presynaptic ganglion cord organ
receptors; for modulation or
Neurotransmitters
regulation of NT release!
• metabolizing enzymes (ex, MAO)! pre ganglionic ACh ACh
! postganglionic NE, Epi Dopa ACh
2. Synaptic cleft!
• metabolizing enzyme containing! Receptors Adrenergic Cholinergic
• responsible for inactivating NTs!
! ganglion Nn Nn
3. Post-synapse! target organ α , β, D M, N
• receptors’ primary location!
• metabolizing enzymes!
! Response fight, flight, fright rest, digest

! eyes mydriasis miosis

! DIVISIONS OF PNS (dilation) (constriction)
! bronchi bronchodilation bronchoconstriction
I. Enteric NS!
• motility and secretions of the GIT! heart tachycardia bradychardia
• intrinsic autonomic innervation of the GIT
(Motility, secretions)! GIT (Wall) relaxation (ileus) contraction
(diarrhea)
• Neurotransmitters:!
• VIP (Vasoactive Intestinal Peptide)! GIT (Sphincter) closure opening
• ATP!
• Neuropeptide y! Bladder Wall relaxation contraction
• Substance P! bladder sphincter closure opening
• Plexus (nerve network)! and trigone
• Myenteric (Auerbach)!
• Submucosal (Meissner)! sweat glands apocrine (palms/ eccrine (diffuse)
! soles)!
! for
! thermoregulation!
!
! increased
! sweating increase sweating
! !
! !
! !
! !
! !
! !
! !
! !
! !
12
! SYMPATHETiC NERVOUS SYS: DRUGS

! (70%) via transporters in the pre-

Biosynthesis of Catecholamines:! synapse; prevents premature metab.!
• precursor: TYROSINE! • transporter: Norepinephrine
• site: ! Transporter or Uptake-1
• post-ganglionic sympathetic nerves! Transporter!
• brain/cns! • Inhibitors: !
• adrenal medulla! • TCAs (NE > 5-HT) !
• STEPS! • Cocaine (causes
1. Uptake of Tyrosine! vasoconstriction)!
2. Conversion of Tyrosine to DOPA • NERI (Norepinephrine Reuptake
(dihydroxyphenylalanine) by tyrosine Inhibitors) ex. Reboxetine!
hydroxylase! 4. Formation of L-DOPA!
3. Formation of the first catecholamine • Inhibitor: Metyrosine!
(Dopamine) by DOPA Decarboxylase! 5. Vesicular Trasport of Dopamine!
4. Vesicular storage and uptake of • Inhibitor: Reserpine - inhibits storage
Dopamine! of Dopamine !
• prevents premature metabolism 6. Release of Norepinephrine (exocytosis)!
of dopamine! • Stimulators: Tyramine, Ephedrine,
• transporter/carrier: VMAT Amphetamine, Angiotensin II, alpha-
(Vesicular Monamine Transporter)! latrotoxin!
• inhibitor: reserpine! • Inhibitors: Guanethidine, Guanadrel,
! Bretylium!
5. Conversion of Dopamine to NE by !
dopamine-B-hydroxylase! !
6. Exocytotic release of NT! RECEPTORS!
• requires Calcium ion! Alpha!
• Inhibitors:! 1. Alpha 1!
• guanethidine! • Vascular Smooth Muscles -
• guanadrel! vasoconstriction (increased BP,
• bretylium! hypertension)!
• Stimulators:! !
• ephedrine! • Urinary Bladder, Trigone, & Sphincter
• amphetamines! - closure (urinary retention)!
• angiotensin II! !
• alpha-latrotoxin - explosive • Prostatic Smooth Muscles -
release of catecholamines! contraction (urinary retention)!
! !
7. Conversion of NE to Epi by • Radial Muscles of the Iris -
phenylethanolamine-N- contraction (mydriasis)!
methyltransferase (PENMT) occurs in !
the medulla! • Pilomotor smooth muscles -
! piloerection (goosebumps)!
!Recap: (enzymes)!
!
!1. Tyrosine hydroxylase!
2. Alpha 2!
!2. L-DOPA decarboxylase!
• Pre-synaptic Alpha 2!
!3. Dopamine-B-Hydroxylase!
• location: vasomotor center (CNS) -
!4. Phenylethanolamine-N-methyltransferase
responsible for maintaining blood
! (PENMT)!
pressure (baroreceptors) !
! • effect: Autoregulation!
! • inhibits further release of NE!
Fate of Norepinephrine in the S. Cleft! • anti-sympathetic!
1. Bind to post-synaptic receptors! • consequences:!
2. Metabolized by MAO or COMT! • Central: sedation & depression!
3. Reuptake into the synapse - major • Peripheral: Vasodilation!
mechanism for termination of activity !
• Post-synaptic Alpha 2!
13
 Receptors Location Responses

α 1 (Gq) smooth muscles! contraction!

• location: blood vessels! vascular vasoconstriction!
• Effect: Vasoconstriction! (cutaneous, mydriasis!
Beta! splanchnic)! urinary retention!
1. Beta 1! - radial muscles hair erection
• Heart:! of iris! (goosebumps)
• (+) Inotropy - force of contraction! - bladder, trigone
• (+) Chronotropy - heart rate! & sphincter!
• (+) Dromotropy - conduction - prostate!
velocity ! - pilomotor
! α 2 (Gi) CNS inhibition of NE
• Kidneys (Juxtaglomerular Apparatus)! (presynaptic) release!
• causes the release of the enzyme central:
Renin! depression/
! sedation!
!
2. Beta 2!
• Smooth Muscles! peripheral:
vasodilation
• Bronchial SM: bronchodilation!
• Uterine SM: relaxation (tocolysis)! Gq vascular smooth vasoconstriction
• Vascular SM (supplying blood to muscles
skeletal muscles): vasodilation! (postsynaptic)
! β1 (Gs) Heart ! (+) inotropy -
• Skeletal Muscle Cell Membraes!
• increased inward conductance of K - SA node! strength of force
- AV node! of contraction!
(potassium influx): hypokalemia
occurs!
- Bundle of His! !
! - Purkinje fibers!
! (+) chronotropism
- inc. HR!
• Neuromuscular Endplates!
• skeletal muscle contraction!
Kidney! !
! - juxtaglomerular
apparatus for
(+) dromotropism
inc. conduction
3. Beta 3! renin release velocity thru AV
• Location: Adipose tissues! node!
• effect: lipolysis!
! β 2 (Gs) smooth muscles! relaxation!
Dopamine!
1. D1! - bronchial! bronchodilation!
- uterine! tocolytic!
• Location: renal & splanchnic vessels! - blood vessels vasodilation!
• Effect: renal vasodilation (increased
GFR, entailing diuresis)!
supplying !
! skeletal
muscles!
contraction!
intracellular K+
2. D2! - skeletal shift
• Peripheral! muscles! (hypokalemia)!
• location: GIT! - muscle cell
• effect: relaxation (Ileus7)! membrane
• eg. Metoclopramide MOA peripheral
D2 blockade (pro-motility)! β3 fat cells (adipose) lipolysis
! D1 (Gs) renal vasculature! vasodilation
• Central!
splanchnic blood
• location: CNS (brain)! vessels
• effect: !
• modulation of motor activity! D2 (GI) GIT, CNS increase GIT
• perception & behavior!
! motility!
motor activity
! regulation!
behavior &
perception
7 loss of peristalsis modulation
14
SYMPATHOMIMETICS / ADRENERGIC AGONISTS
! • management of glaucoma (Dipivefrin:
I. Direct Acting - bind to and stimulate pivalic ester of Epi)!
adrenoceptors! !
! !
II. Indirect Acting - increases concentration b. Norepinephrine or Noradrenaline /
of catecholamines in the cleft ! Levarterenol!
• increases sympathetic effect! • 1st line inotropic agent for septic
• increases exocytosis of NE! shock!
• inhibits reuptake of NE! !
! c. Dopamine!
III. Centrally Acting! • Doses:!
• CNS! • 1-3 mcg/kg/min: D1 activation!
• Habit-forming! • 2-5 mcg/kg/min: B1 activation!
! • > 5 mcg/kg/min: A1 activation!
DIRECT ACTING! • Uses:!
• Non-selective - stimulate more than one type • management of Septic Shock!
of receptor (alpha, beta, dopa)! • management of cardiogenic shock!
• Selective - stimulate only one type of • management of AHF8, complicated
receptor ! by oliguria or anuria!
! !
Non-Selective (alpha, beta, dopamine)! !
! ! Oliguria: < 500 mL/day!
1. Natural Catecholamines - NE, Epi, DA! ! Anuria: < 50 mL/day!

! !
Pharmacodynamics:! Adverse Effects:!
• higher affinity at Beta Receptors than • Alpha1 Overstimulation: digital necrosis!
Alpha (mas madikit sa beta kesa alpha)! • Beta1 Overstimulation: tachyarrhythmias!
• low dose: Beta effect! !
• high dose: alpha effect may manifest! Selective (alpha, or beta, or dopa)!
• Epinephrine: B1 = B2 > A1! !
• Norepinephrine: B1 > A1! 1. Non-selective B Agonist !
• Dopamine: D1 > B1 > A1! • ex. Isoproterenol/Isoprenaline!
! • uses: !
Pharmacokinetics:! • alternative during shock states!
• undergo extensive first pass effect • management of AHF (pwedeng Beta1
(decreased oral BA)! agonist)!
• Routes: IV, SQ, inhalation! • historically used for the management of
• Metabolism by MAO & COMT: bronchial asthma (can cause
(degradation products)! tachyphylaxis9 leading to ventricular
• NE & Epi! tachyarrhythmias)!
• 3-methoxy-4-hydroxy-mandelic acid! !
• aka vanillyl mandelic acid (VMA)! 2. Beta1-selective Agonist !
! • cardioselective!
• Dopamine! • eg. Dobutamine!
• Homovanillic acid! • uses:!
! • 1st line for cardiogenic shock!
Clinical Uses:! • management of AHF ([+]inotrope)!
a. Epinephrine or Adrenaline! • pharmacologic stress test!
• 1st line cardiac stimulant! !
• 1st line for anaphylaxis & anaphylactic !
shock! !
• local vasocinstrictor! !
8 acute heart failure
9 rapid development of tolerance to B2 effects
15
3. Beta2-selective Agonist! 5. Alpha2-selective Agonists!
• SABA (short-acting beta agonists)! • Clonidine!
• Albuterol/Salbutamol! • Methyldopa!
• Terbutaline! • Guanfacine!
! • Guanabenz!
• LABA (long-acting)! • effect: autoregulation!
• Salmeterol - slow onset of action! !
• Formoterol - fast onset of action! Clonidine:!
• Bambuterol! • Phases of Effects:!
• Indacaterol! • Initial: Vasoconstriction (post-synaptic
! alpha2 activation), transient!
• Tocolytics! • Final: Vasodilation (pre-synaptic), lasting
• Ritodrine! effect!
• Isoxsuprine - most common! • uses:!
• Terbutaline (SQ) - off-label! • alternative for HTN!
! • alternative for ADHD!
• Uses:! • management of Clonidine withdrawal
• management of bronchial asthma & induced HTN (alt. Captopril, Labetelol)!
COPD! !
• management of pre-term labor! Methyldopa:!
• adjuncts in the management of • prodrug!
hyperkalemia (hypokalemic kasi ang • alpha-methynorepinephrine!
B2)! • false neurotransmitter!
• Terbutaline - used in the management • alpha-2 agonist!
of symptomatic bradycardia, promotes • use: management of hypertension in
(+) chronotropic effect, enhances pregnancy!
baroreceptive reflex (increase • AE:!
sympathetic tone)! • sedation (most common)!
! • hepatotoxicity!
4. Alpha1-selective Agonists! • (+) Coomb’s test (hemolytic anemia)!
• Phenylephrine (decongestant)! !
• Methoxamine! 6. D1-selective Agonist!
• Propyhexedrine! • Fenoldopam!
• Tetrahydrozoline! • use: hypertension crisis!
• Oxymerazoline! !
• Nafazoline! INDIRECT ACTING!
• Uses:! a. Releasers!
• management of hypotension! • Tyramine, Ephedrine*, Amphetamine!
• management of nasal congestion! b. Reuptake Inhibitors!
• local vasocinstrictors! • TCAs, COCaine, Reboxetine!
• Adverse Effects (local intranasal)! !
• rhinitis medicamentosa - rebound !
congestion (remedy: do not use ! *Ephedrine has mixed action. DIrectly
decongestant for more than 3 days)! ! activates alpha, beta and dopamine

• Adverse Effects (systemic)! ! receptors. Indirectly it increases the

• exacerbation of hypertension! ! releases of norepinephrine from the pre-

• urinary retention (BPH10 px)! ! synapse.

• tolerance (increases the risk of toxicity) !

remedy: use A1 agonist for nmt 5 days! !
! !
! !
! !
! !
10 benign prostatic hyperplasia
16
 Ephedrine! Pheochromocytoma!
• management of hypotension! • tumor/hyperplasia in adrenal medulla due
• local vasoconstriction! (causes hypersecretion of Epi < NE)!
• Management of bronchial asthma! • SSX:!
• Ephedra sinica (Ma Huang)! • agitation!
• S/E! • confusion!
• Exacerbation of HTN! • tachycardia!
• Urinary retention (BPH px)! • palpitation!
• Ventricular tachyarrhythmias! • paroxysmal HTN!
! • Dx:!
CENTRALLY ACTING! • VMA Assay (Vanillymandelic Acid) in
• Phentermine, Phenmetrzine, serum/urine!
Phenylpropanolamine (PPA), AMphetamine, • Imaging Studies (MRI, CT)!
Methylphenidate! • Treatment:!
• Uses:! • initial control: alpha, beta blockers!
• management of ADHD! • surgical incision!
• 1st line: Methylphenidate! !
• alt. : Amphetamine! Carcinoid’s Syndrome!
• Anorexiants! • neuroendocrine condition associated with
• phentermine, phenmetrazine, PPA! malignancy affecting enterochromaffin cells
• management of narcolepsy (Phentermine)! (secretes 90% of 5-HT)!
• S/E! !
• increased risk of addiction! Raynaud’s Syndrome!
• PPA - increases risk of hemorrhagic stroke! • digital vasopressin in response to stress/cold
• Phentermine - increases risk of pulmonary environment (vasoconstriction causes
hypertension! necrosis)!
! • Treatment: CCBs!
!
SYMPATHOLYTICS / ADRENERGIC ANTAGONISTS !
! Side Effects Associated with Alpha-
ALPHA BLOCKERS! Blockers!
a. Non-selective ! • First dose Phenomenon!
• Phenoxybenzamine - irreversible • selective alpha-1 blocker!
(antihistamine)! • orthostatic hypotension & syncope !
• Phentolamine - reversible! • Triggers:!
b. Selective! • initial dose!
ALPHA1 ALPHA2 • big dose!
• use of another anti-HTN!
Prozacin Rauwolscine • Remedies:!
• give 1st dose at bedtime!
Doxozacin Yohimbine • give 1/2 or 1/4 of usual dose!
Terazocin
!
BETA BLOCKERS!
Tamsulosin a. Selective B-1 Blockers!
• cardioselective B-blockers!
• Clinical uses:! • less likely to cause bronchospasm!
• management of hypertension (secondary • BEAM!!
to pheochromocytoma), nonselective,
• Bisoprolol, Betaxolol!
selective A1!
• Esmolol (shortest t1/2, given IV)!
• in patients with BPH (selective A1)! • Atenolol, Acebutolol!
• management of carcinoid syndrome • Metoprolol!
(phenoxybenzamine DOC)!
• Celiprolol!
• management of Raynaud’s syndrome !
!
(nonselective, selective A1)! !
! !
! !
!
17
 • Nebivolol! • CLAP!
• most cardioselective! • Carteolol, Caliprolol!
• vasodilator! • Labetalol!
• increases NO or EDRF11! • Acebutolo!
• 1st line for HTN in px with hx of MI! • Penbutolol, Pindolol!
• Management of Angina Pectoris! !
• management of stable heart failure 2. Alpha-blocking Effect (vasodilation)!
(bisprolol, metoprolol, carvedilol)! • Carvedilol!
• management of arrhythmia (Class II)! • Labetalol!
• management of glaucome (timolol, • Nebuvolol!
betaxolol)! !
• management of sympathetic symptoms !
of hyperthyroidism (Propranolol - inhibit ! PARASYMPATHETIC DRUGS
the peripheral conversion of T4 to T3 Biosynthesis of ACh!
[deiodination] enzyme: 5-deiodinase)! • Sites:!
• anaphylaxis of migraine headache! • preganglionic fiber!
• management of stage fright • parasympathetic post-gagnglionic fibers!
(Propranolol)! • CNS!
• AE:! • Somatic nerves!
• bradycardia, heartblock! • Steps:!
• bronchospasm (non-selective)! 1. Active uptake of choline (rate
• decrease exercise tolerance! limiting step, inhibited by
• metabolic: dyslipidemia! hemocholiniums)!
• erectile dysfunction! 2. Formation ACh from AcetylCoA +
! Choline (enzyme: choline
Caution! acetyltransferase)!
• DM & hypoglycemics! 3. Vesicular Storage / uptake of ACh
• Ssx! (inhibitor: vesamicol)!
• tachycardia! 4. Quantal release of ACh (inhibitor:
• palpitatios! Botulinium toxin)!
• tremors! !
• coma, death! Fate of Acetylcholine!
• Remedy: monitoring of blood sugar 1. Bind to receptors (M, N)!
level (CBG)! 2. Metabolism by Acetylcholinesterase
! (AChE)!
Contraindications! 3. Reuptake into the synapse!
• anaphylaxis history! • AChE aka RBC Cholinesterase, True
• heartblock! Cholinesterase!
• unstable heart failure! • butyryl cholinesterase (plasma
• non-DHP CCBs! pseudocholinesterase)!
• active BA! !
! !
b. Non-selective (everything else) NSTP! !
• Nadolol! !
• Satolol! !
• Timolol! !
• Propranolol! !
! !
c. Beta-blockers with Special Properties! !
1. Intrinsic Sympathomimetic Activity! !
• less likely to cause rebound !
hypertension/tachycardia when !
withdrawn! !
11 endothelium derived relaxing factor
18
 PARASYMPATHOMIMETCS

Receptors Location Responses Direct Acting!

• bind to stimulate receptors (N, M)!

M1 (Gq) nerves that gastric acid

!
A. Choline Esters (ABC,M)!
supply the secretion • Acetylcholine (N,M)!
gastric glands Bethanecol (M)!
•
(CNX)
• Carbachol (N,M)!
• Methacholine (N,M)!
M2 (Gi) nerves that
supply the
(-)
dromotropism! !
heart (CN X) bradycardia B. Cholinergic Alkaloids !
• Pilocarpine (M) Pilocarpus jaborandi!
M3 (Gq) Smooth !
Muscles:! ! •
•
Muscarine (M) !
Nicotine (N) Nicotiana tabacum!
• eyes - • contraction
circular & (miosis)! • Lobeline (N) Lobelia inflata!
cilliary
muscles!
!! • Arecolne (N,M) Areca catechu; betel nut,
nga nga!
• Bronchial! constriction! • Varenicline (N) - smoking cessation!
• GIT wall!
•
• contraction! !
• Sphincter! • opening! Indirect Acting!
• Bladder Wall • contraction & • increase concentration of ACh in the cleft!
(detrussor)! opening! • MOA: Inhibition of AChE!
• Trigone/
Sphincter!
• urination!
!! !
!
Exocrine !!
A. Short-Acting (Edrophonium)!
• duration of action: 15-30 mins (average of
Glands! 20 mins)!
• Lacrimal • increased • chemical structure: Aminoalcohol!
glands! secretion! • Edrophonium (Tensilon)!
• Reversible inhibitor!
• Salivary
glands!
• lacrimation!
• salivation! !
• Sweat • sweating! B. Intermediate Acting (-tigmines)!
glands! • duration of action: 2-8 hours!
• Gastric & • chemical structure: Carbamates /
Bronchial Carbamyl Esters!
Glands
• Stigmine:!
Nn ganglion stimulation • Physostigmine!
• Neostigmine!
• Pyridostigmine!
Nm Neuromuscular skeletal • Demecarium!
End-plate muscle
• Amberonium!
contraction
• reversible inhibitor!
!
! !
C. Long-acting !
! • chemical structure: Organophosphates!
! • Echothiopate (Medically useful)!
! • Isofluorophate!
! • Malathion!
! • Parathion!
! • Nerve gases (Sarin, Tabun, Soman)!
! • duration of exposure:!
! • <24-48 hours = potentially reversible
! inhibition!
! • > or = 24-48 hours = irreversible!
! !
! !
! !
! !
19
D. Drugs for Alzheimer’s Disease! 2. Association of MG with Thymoma
• Rivastigmine! (Thymic hyperplasia)!
• Galantamine! • increased size, activity of the thymus
• Donepezil! gland!
• Tacrine! • dapat after age 4, involute na yan!
! !
Clinical uses: ! 3. Diagnosis!
• diagnosis and treatment of Myasthenia • progressive symptoms!
gravis! • serologic test: Anti-ACR antibodies!
• dx: Edrophonium (Tensilon/Edrophonium • Imaging studies: thymoma!
test)! • Tensilon/Edrophonium Test!
• Tx: Neostigmine, Pyridostigmine, • differentiate cholinergic and
Ambenonium! myasthenic crisis!
• managment of atropine toxicity !
(Neostigmine)! 4. Treatment!
• management of neuromuscular blocking • immunosuppresants (Prednisone)!
toxicity (edrophonium, neostigmine)! • Thymectomy!
• management of non-obstructive Ileus • Acetylcholinesterases!
(physostigmine, pilocarpine)! !
• management of urinary retention !
(Betanechol)! ! PARASYMPATHOLYTICS
• management of glaucoma (Echothiopate, !
Isocarbachol, Pilocarpine)! Antimuscarinics / Anticholinergics!
• smoking cessation (Varenicline, Nicotine)! • Prototype: Atropine (inhibits M1, M2, M3)!
• management of Alzheimer’s disease! !
• Memantine - binds to glutamate receptor Effects of Atropine:!
N-methyl-D-aspartate (NMDA)! • M1-block (decreased acid secretion)!
! • M2-block (vagolytic effect; tachycardia)!
Side Effects/Toxicity (DUMBBELSS)! • M3-block (mydriasis)!
Diarrhea! • ***Cycloplegia - loss of near vision due to
Urination! increased intraocular pressure (failure to
Miosis! drain of aqueous humour) !
Bradycardia! !
Bronchoconstriction! “Blind as a Bat”!
Emesis! • increase intraocular pressure (glaucoma)!
Lacrimation! • CI: Narrow-angle glaucoma (over-production
Salivation! of aqueous humour)!
Sweating! • Bronchi: bronchodilation!
! • GIT: Ileus & constipation!
Management of Toxicity! • Bladder: urinary retention!
• If Organophosphate:! • Exocrine glands: decrease secretions!
• enzyme regeneration! !
• pralidoxime! “Dry as a Bone”!
• Diacetylmonoxime (DAM)! • anhydrosis (decreased sweating)!
! • hyperthermia!
Myasthenia Gravis! !
• autoimmune condition! “Hot as Hell”!
• antibodies targeting ACh receptors! • cutaneous vasodilation!
• anti-ACh receptor antibodies! !
• targets Nm! “Red as a Beet” - flushing!
! “Mad as a Hatter”!
1. Signs and Symptoms! • CNS effects: agitation, seizure, confusion,
• Initial: late afternoon muscle weakness, psychosis!
ptosis! !
• Final: diaphragmatic muscle weakness! !
! !
20
Uses:! Antinicotinics!
• management of symptomatic bradycardia! !
• mydriatic - cycloplegia! Nn - inhibited by ganglionic blockers!
• pre-medication for diarrhea! • Mecamylamine!
• formulated atropine + diphenoxylate • Trimetophan!
(Lomotil) anti-diarrheal! • Hexamethonium!
! !
Adverse Effects! Uses!
Opposite of DUMBBELLSS! • management of hypertension!
! • non-specific effects!
Management of Toxicity! !
• Mild to Moderate - Neostigmine, Pilocarpine! Nm - inhibited by neuromuscular blockers
• Severe - Neostigmine/Pilocarpine (NMB)!
(Peripheral) Benzodiazepine (CNS Effects)! !
! A. Depolarizing Neuromuscular Blockers!
Others:! !
a. Mydriatics / Cycloplegics! • Succinylcholine (Suxamethonium)!
• Tropicamide! • MOA: Irreversibly stimulates Nm
• Cyclopentolate! receptors !
• Homotropine! • Dual effects:!
! • Stimulation!
b. Centrally-Acting! • Inhibition (flaccid paralysis)!
• Scopolamine! !
• Sedative (+ morphine) = twilight sleep, B. Non-depolarizing Neuromuscular Blockers!
management of motion sickness! !
• Benztropane (Congentin)! • Isoquinolines - Tubocurarine!
• Biperiden (Akineton)! • “-curium”!
• Trihexyphenidyl (Artane)! • Atracurium!
• management of Parkinson’s disease! • Cistracurium!
• management of EPS • Mivacurium!
(pseudoparkinsonism, akathisia, acute !
dystonia)! • Steroidal - “-curonium”!
! • Rocuronium!
c. Bronchi / Bronchodilators! • Pancuronium!
• Ipratropium! • Vecuronium!
• Oxitropium! • Inhibition: flaccid paralysis!
• Tiotropium! • Uses: !
• 1st line relievers: COPD! • skeletal muscle relaxant (surgery)!
• Alternative relievers: Bronchial Asthma! • px with spastic disorder (cerebral
! palsy)!
d. Selective M1-blockers! • AE: diaphragmatic muscle paralysis!
• Prenzepine! • Tubocurarine - anaphylactoid reaction!
• Telenzepine - adjunct in management of • Succinylcholine!
acid peptidc disease! • myalgia!
! • myositis!
e. Selective M3-blockers! • rhabdomyolysis!
• Hyoscine-N-butylbromide! • skeletal muscle breakdown!
• Clidinium! • hyperkalemia, myoglobinemia (toxic
• Dicycloverine! to renal tubule, myoglobinnuria)!
• Glycopyrrolate! • acute tubular necrosis!
• Uses: ! • malignant hyperthermia!
• spasmolytics - renal and biliary colic! • hypersecretion of Ca ions by the
• hypermotility disorder & urinary sarcoplasmic reticulum (muscle rigidity)!
incontinence! • Tx:!
! • Dantolene!
! • Ryanodine - to prevent hypersecretion!
21
 CENTRAL NERVOUS SYSTEM

Excitatory NT : 5-HT (serotonin), glutamate, ANTIPSYCHOTICS / NEUROLEPTICS /

NE! MAJOR TRANQUILZERS!
Inhibitory NT : GABA, glycine! !
Both NT : Dopamine (major NT)! GOAL: decrease Dopamine & Serotinin!
! !
Termination of NTs! I. First Generation / Typical
1. Diffusion! Antipsychotics / Traditional!
2. Reuptake! • MOA: Block D2 receptors!
3. Metabolism by MAO & COMT! • Other Blocking effect: anti-HAM!
! • Histamine (sedation)!
CNS Disorders! • alpha receptors!
A. Psychosis! • muscarinic!
• increased dopamine and serotonin! !
• Treatment of psychotic disorder: • Potency:!
Schizophrenia***! • directly proportional with D2 receptor
! affinity!
!! Hallucination (auditory) • Inversely proportional with HAM
receptor affinity!
!! Delusions (false belief)!
• paranoia /
• Butyrphenones = Piperazines >
Piperidines > Thioxanthines > Aliphatic!
!! persecutory! !
• Grandiose ! D2 affinity
Positive Symptoms !
Disorganized thoughts /
speech ! HaM affinity
!
Bizarre behavior !
a. Phenothiazines (-azine)!
• Aliphatic (-promazine)!
!! Alogia (low verbal
output)
• eg. Chlorpromazine!
• Piperazines (-phenazine)!
!! Anhedonia - unable to
• eg Fluphenazine!
• Piperidines (-ridazine)!
! feel pleasure
• eg.Thioridazine!
Negative Symptoms Avolition - lack of !
motivation / drive b. Butyrophhenones!
• Haloperidol!
Associality
• Droperidol!
Flattening of affect - !
c. Thioxanthines (-thix-)!
monotonous voice /
one facial expression !
! II. Second Generation / Atypical
! Antipsychotics!
! • MOA: blocks D4 receptors & 5-HT
! receptors!
! • ***D4 receptors are less lkely associated
! !
with Extrapyramidal Syndome (EPS)!
!
! a. -zapine!
! • Clozapine!
! • Olanzapine!
! ! • Quetiapine!
!
! b. -xapine!
! ! • Loxapine!

22
 c. -peridone! 3. Neuroleptic Malignant Syndrome (NMS)!
• Risperidone - first line; dows not have • Malignant Hyperthermia:!
muscarinic effects! • Succinylcholine!
• Paliperidone! • Inhalational anesthetics!
• Ziprasidone! • management:!
! • Dantrolene (Ca antagonist, uscle
Others:! relaxant)!
• Apipiprazole! • Bromocriptine (D2 Agonist)!
• Amisulpride! !
• Molindole! 4. Tardive dyskinesia!
! • potentially irreversible!
Advantage: Lower EPS effects! • uncontrolled muscle movement!
Efficacy:! • due to hypersensitivity of D2 receptors!
• in treating positive symptoms: 1st Gen = • management: discontinue drug and give
2nd Gen! Clozapine or Olanzepine (only anti-
• in treating negative symptoms: 2nd Gen > psychotics that do not cause EPS)!
1st Gen! !
Adverse Effects: Dopamine receptor blockade! 5. Alpha-receptor Blockade!
! • orthostatic hypotension!
1. EPS - movement disorders due to !
cholinergic stimulation! 6. Muscarinic receptor blockade!
a. Akathisia (uncontrolled restlessness)! • anticholinergic effects!
• most difficult to treat, only EPS that is !
not treated with anticholinergics.! 7. Histamine receptor blockade!
• management: BZD, Beta-blokers! • sedation!
! !
b. Dystonia / Retrocollis / Torticollis / Other effects:!
Twisting of the neck! 1. Seizure - Clozapine!
• 1st EPS seen, easier to treat, but • all anti-psychotics can lower seizure
can be fatal! threshold!
• management: ! !
• Anticholinergics! 2. Agranulocytosis!
• Biperidine! • low basophil, neutrophil, eosinophil count!
• Benztropine! • Neutropenia effect : (bacterial infection)!
• Trihexyphenidyl! • ***Clozapine - requires WBC monitoring
• IV Diphenhydramine! every week for the 1st 6 months of
• ***typical anti-histamines have therapy and every 3 weeks thereafter!
anti-muscarinic effects! !
! 3. Cardiac Effects!
c. Pseudoparkinsonism! • myocarditis - Clozapine!
• due to severe depletion of Dopamine! • QT prolongation:!
• TRAP ! • Thioridazine!
• Tremors, Rigidity, Akinesia, Postural • Ziprasidone!
Imbalance! !
! 4. Corneal/Lens deposit!
2. Hyerprolactinemia! • Chlorpromazine (does not lead to
• increased prolactin in the blood! blindness)!
• dopamine is a prolactin inhibiting 5. Retinal deposits!
hormone! • Thioridazine (can cause blindness)!
• px manifests with galactorrhea alog with !
the ff:! 6. Weight gain!
• amenorrhea! • common to 2nd generation
• gynecomastia! antipsychotics except AMA:!
• impotence! • Aripiprazole, Molindole,
! Amsulpride!
! 7. Increased risk of DM!
23
 MOOD STABILIZERS! B. SECOND GENERATION
• Norepinephrine, Serotonin! ANTIDEPRESSANTS!
! !
Anti-Depressants! Trazodone!
! Nefazodone!
A. TRADITIONAL! • withdrawn; causes severe hepatotoxicity!
! • MOA: inhibition of 5-HT 2A receptors!
1. Tricyclic Antidepressants! C. NEWER GENERATION!
• Drugs end in “-tryptiline” eg Amitryptiline! !
• “-pramine” eg Imipramine (tx for Enuresis)! 1. Selective Serotonin Reuptake Inhibitor
• MOA: inhibition of NE, 5-HT reuptake! (SSRIs)!
• Imipramine! • Drugs:!
• Effect: HAM (Histamine, Alpha, • Fluoxetine!
Muscarinic) blockade = leads to urinary • Fluroxamine!
retention, hypotension, inhibits • Sertraline!
sedation ! • Paroxetine!
• AE: ! • Citalopram!
• Weight gain! • MOA: inhibits reuptake of 5-HT!
• ECG abnormalities! • AE:!
• Insomnia! • Serotonin Syndrome!
• Amitriptyline! • fever, tremors, agitation!
• for Pseudobulbar palsy! • management: Cyproheptadine (5-HT
• CM: weakened facial muscles! receptor blocker)!
! !
2. Tetracycline (MaAmMia)! 2. Serotonin Norepinephrine Reuptake
• Mianserine! Inhibitor (SNRI)!
• Maprotiline! • Drugs:!
• Amoxapine! • Venlafaxine - less affinity to NE
• MOA: Inhibits reuptake of NE and 5-HT! reuptake (more selective to 5-HT
! reuptake)!
3. Non-Selective MAOI! • Duloxetine!
• inhibits the enzyme that degrades • similar MOA to TCA, however, TCAs have
catcecholamines! an effect on HAM.!
• Phenelzine, Isocarboxazid, • No effects on HAM!
Tranylcypromine (PIT)! !
• Drug Interaction:! 3. Noradrenaline Reuptake Inhibitor (NaRI)!
• Tyramine - induces the release of • Drugs:!
neurotransmitters. induces • Raboxetine!
hypertension crisis (increases !
sympathetic effect)! 4. Noradrenergic and Specific
• food rich in Tyr: cheese, wine, Serotonergic Anti-depressants (NASSA)!
fermented fish, meat products, pickled !
vegetables, chicken liver! • Myrtazapine*** - alpha2 receptor
! (presynaptic) antagonist!
! !
! 5. Reversible Inhibitor of MAO-A!
! • Moclobemide!
! !
! 6. Noradrenaline / Dopamine Reuptake
! Inhibitor (NDRI)!
! • Bupropion!
! !
! !
! !
! !
!
24
Bipolar disorder! ANXIOLYTICS!
! !
1. Lithium! Anxiety disorders:!
• DOC: Mania! a. General anxiety d/o!
• not for rapid cycling (> 4 cycles per year)! b. Panic d/o!
• MOA: not known! c. Obsessive Compulsive d/o!
• proposed: inhibits membrane d. Post-traumatic d/o “Warshock Syndrome”!
phosphoinositides (eg PIP2)! !
! ! GABA receptors (Allosteric Sites)!
! ! 1. BZD!
! IP3, DAG are products of PIP2, ! 2. Barbiturates!
! classified as secondary messengers, ! ! 3. Zolpidem!
! essential for neurotransmission !
! ! binding of drug to above receptors agonizes
• AE:! ! the binding of GABA to the receptors, making

• Nausea, Vomiting! ! the membrane hyperpolarized (more neg

• Poyuria, polydipsia! !
• tremor! !
• ***common even at normal doses! Effects:!
• Idiosyncratic Reactions:! 1. Benzodiazepines - increase the
• nephrogenic DI! frequency of opening of Chloride channel!
• Thyroid abnormalities! 2. Barbiturates - increases the duration of
• Ebstein Anomaly! opening !
• insufficient development of tricuspid !
valve, thus, backflow of blood! A. Benzodiazepines!
• Alteration Levels! !
• Acetazolamide! 1. Short-Acting!
• “xanthine” drugs! • Midazolam!
• Sodium competes with Li excretion • Triazolam!
(opposite levels pakagi)! !
• Increased levels of ACEi, NSAIDs, 2. Intermediate-Acting!
Thiazide diuretics! • Oxazepam!
! • Lorazepam!
2. Valproic Acid! • Alprazolam!
• for rapid cycling bipolar disorder! !
• better safety profile than Lithium! 3. Long-Acting!
! • Diazepam (Valium)!
3. Carbamazepine (Tegretol)! !
• for acute mania! 4. Active: Metabolite!
• prophylaxis for depressive phase of • Diazepam to Nordiazepam (N-
bipolar disorder ! desmethyldiazepam)!
! • “nor-“ means NO methyl group in the N-
4. Antipsychotics (Atypical)! position!
• Quetiapine (under Benzodiazepine)! 5. No metabolites (COLA)!
• Olanzapine (under 2nd gen)! • Clonazepam!
! • Oxazepam!
! • Lorazepam!
! • Alprazolam!
! !
! Side Effects:!
! • CNS Depression!
! • Anterograde amnesia!
! • “Flunitrazepam” (Rohypnol) - date-rape
! drug!
! !
! !
25
B. Barbiturates! ANTI-SEIZURES!
! !
1. Ultra short-acting (Thiol-containing)! 2 Types of Seizure:!
• very lipid-soluble (nakakapasok, !
nakakalabas agad)! 1. Partial Seizure!
• Thiopental! • simple!
• Thioamylal! • complex!
• Methohexital! • 1st Line: Carbamazepine, Phenytoin!
! !
2. Short-Acting! 2. Generalized Seizure!
• Secobarbital! • tonic-clonic seizure (Grand Mal) !
• Hexobarbital! • DOC: Valproic Acid!
• Pentabarbital! • Absence Seizure (Petit Mal) !
! • DOC: Ethiosuxide !
3. Intermediate-Acting! • alt: Valproic Acid!
• Amobarbital! • Atonic Fall - loss of tone!
• Butabarbital! • Myoclonic Jerk or “Muscle Jerking”!
! !
4. Long-Acting! 3. Status epilipticus!
• Phenobarbital - enzyme inducer (for • New DOC: lorazepam!
hyperbilirubinemia)! • Old DOC: Diazepam!
• Barbital! !
! 4. Febrile seizure!
Uses:! • DOC: Phenobarbital!
• management of seizures! • alt: Primidone!
• adjunct in anesthesia (specifically Ultra !
Short-Acting)! PARKINSONISM!
• Neonatal Hyperbilirubinemia! • Dopamine is decreased!
! • ACh is increased (responsible for tremors
C. Buspirone! and rigidity)!
• 5-HT 1A partial agonist! !
• Advantage over BZDs and Barbs:! TRAPS!
• no potential for abuse! Tremors!
• no euphoric effects! Rigidity!
• no dependence! Akinesia (Pill rolling)!
• no muscle relaxant effect! Postural imbalance!
! Shuffling gait!
! !
! !
! 1. Levodopa !
! • dopamine precursor!
! • converted to dopamine via DOPA
! decarboxylase!
! • transporter: L-amino acid transporter
! (transports L-DOPA)!
! • used in combination with Carbidopa
! (Sinemet)!
! !
! 2. Dopamine Agonists!
! • can be used as monotherapy or adjunct
! to your levodopa!
! • !
! a. Ergot Derivatives!
! • Bromocriptine!
! • Pergolide!
! !
26
 b. Non-Ergot Derivatives! b. Intravenous!
• Pramipexole! • SABZDs!
• Ropinirole! • Midazolam!
! • USABarb!
3. MAO-B Inhibitors! • Thiopental!
• Selegiline! • Propofol!
• Rasagiline! • emulsion (larger particles causes a
! milky appearance)!
4. COMT Inhibitors! • Ketamine!
• Tolcapone! • dissociative anesthesia!
• Entacapone! • “out of body” like feeling!
! • similar to Phencyclidine aka Angel Dust!
5. Amantadine! • Opioids!
• used as management for Influenza A ! • analgesia, sedation!
• MOA: increases the release of Dopamine, • neuroleptanalgesia (Fentanyl +
decreases the reuptake of Dopamine! Droperidol)!
! • neuroleptanesthesia (Fentanyl +
6. Apomorphine! Droperidol + NO)!
• D2 agonist activity! !
• mimics dopamine in the body! Local!
• adjunct for parkinsonism! a. Ester!
! • Procaine!
7. Anticholinergics! • Benzocaine!
• Benztropine! b. Amide!
• Trihexyphenydyl! • Lidocaine!
• Biperiden! • Bupivocaine - most cardiotoxic!
! !
ANESTHETICS! Most serious AE:!
! • Seizures!
Stages:! !
1. Cortical! All are vasodilators except for COCAINE!
• analgesia! !
2. Delirium! MOA: inhibition of Na-channels. sodium is
• excitation of neurons! important for maintaining the tone of blood
3. Surgical ! vessels!
• respiratory relaxation! !
• skeletal muscle relaxation! ***Cocaine: inhibits the reuptake of
4. Medullary! neurotransmitters (similar to the effect of
• respiratory depression! Amphetamine)!
! !
Types! !
! !
General! !
a. Inhalational! !
• Nitrous oxide (highest MAC12) - least !
potent! !
• Desflurane! !
• Isoflurane! !
• Halothane! !
• Methoxyflurane (lowest MAC) - most !
potent! !
! !
! !
12 minimum alveolar concentration, minimum amt. to cause effect
27
 ANTI-CANCER! Drugs:!
! !
Traditional anti-cancer drugs’ action is on the 1. Alkylating Agents!
cell cycle:! • makes the H-bonds of DNA covalent,
! rendering the DNA incapable of
G0 - no division happens (no chemo drugs can replicating!
act on them)! a. Platinum Compounds!
G1 - preparatory for synthesis! • Cisplatin!
S - synthesis of DNA! • Carboplatin!
G2 - preparatory for mitosis! b. Nitrogen Mustards!
M - mitosis (PMAT)! c. Cyclophosphomide!
! d. Busulfan!
Tumor Growth! !
• “Gompertzian” growth cycle / curve! 2. Anthracyclines!
• tumors are capable of angiogenesis (what • cleaves the DNA, breaking the strand,
makes them capable of growing)! rendering the DNA once again incapabale
! of replication (no DNA synthesis)!
Fate of Tumors:! • Doxorubicin - cardiotoxic anticancer!
1. Some tumor cells may die (incapability na !
for angiogenesis)! 3. Podophyllin!
2. Reaching G0! • “-poside”!
! • Etoposide!
<10^9 - subclinical manifestetations • Teniposide!
(asymptomatic)! !
! 4. Antimetabolites!
10^9 - (+) symptoms or 1cm in diameter! • purine, pyrimidine analogs!
! • 5-Fluorouracil (mimics uracil, RNA
10^12 - Fatal size tumor (1 kg)! synthesis, no transcription, translation, no
! DNA synthesis)!
Objective of Chemotherapy:! • Antifolate: Methotrexate!
• < or = 0.01% probability that a cell is !
cancerous! 5. Enzymes!
• for every session, 99.9% of CA cells should • leukemic cells feed on Asparagine which
be killed! is metabolized by Asparaginase!
! !
Intermittent Dosing:! 6. Mitotic Spindle!
• allow recovery of normal cells! • “-taxols”!
• cells will receive blood supply, escaping • vinca drugs!
from G0, making chemotherapy effective! • Estramustine!
! !
99.9% or 3 Log Hypothesis:! Adverse Effects:!
! !
1st Session 10^11 10^8 • Cyclophosphamide/Ifosphamide -
Hemorrhagic cystitis!
2nd Session 10^9 10^6 • Busulfan, Bleamycin, Amiodarone -
pulmonary fibrosis!
3rd Session 10^7 10^4 • Mitomycin, EHEC - HUS (Hemolytic
10^5 10^5 10^2
Uremia Syndrome)!
• Vincas - Neuropathy!
5th Session 10^3 10^0 !
!
6th Session 10^1 10^-2 = 0.01 !
! !
! !
! !
!
28
Nonselective (COX1, COX2)! !
Disadvantage: increased risk in gastritis! • CNS Effects:!
! • serum level 50-80mg/dL!
1. ASA & Salicylates! • salicylism (dec. hearing, tinnitus,
• Pharmacokinetics:! vertigo)!
• Absorption: stomach, upper small • hyperventilation (decreased CO2)!
intestine! • respiratory alkalosis (normal:
• Excretion:! 7.35-7.45 pH)!
• < 600mg/day (first order)! • serum level 80-110mg/dL!
• > or = 600mg/day (zero order)! • metabolic acidosis!
! • hyperthermia!
• Pharmacokinetics:! • dehydration!
• anti-inflammatory (3.2-4g a day)! • serum level 110-160mg/dL!
• analgesic (nmt 600mg/day)! • hypoprothrombinemia (risk: bleeding)!
• MOA: inhibition of the synthesis of • serum level >160mg/dL!
peripheral prostaglandin! • respiratory and renal failure!
• antipyretic (0.3-2.4g/day)! !
• MOA: alteration of response to • Hypersensitivity reaction!
interleukin 1 (endogenous pyrogen)! • ASA induced bronchial asthma!
• antiplatelet (nmt 325mg/day)! • Arachidonic Acid is shunted to LOX
• MOA: irreversible acetylation of COX in pathway, producing more leukotrienes
platelets, leading to decreased TXA2.! (bronchococnstriction) LTC4/LTD4OC!
• potential anticancer (decrease number of !
colonic polyps)! • Reye’s Syndrome!
! • hepatic failure & encephalopathy!
• Adverse effects:! • viral infection!
• GI nonselective COX inhibitor! !
• GI intolerance! 2. Pyrazolone derivatives!
• hyperacidity symptoms! ! !
• no mucosal injury! ! Phenylbutazone!
• Px: intake of NSAIDs after a full meal! ! Dipyrone! NSAIDS!
!!
• Gastritis (erosive) & GI bleeding! ! ! Oxyphenbutazone!
• (+) mucosal bleeding! !
• Px: PPI (DOC), Misoprostol (alt.)! ! ! Sulfnpyrazone! used for gouty

! ! arthritis

• Increase Serum Ureate Level! !

• ASA, Salicylates, Tolmetin (AST)! • powerful anti-inflammatory and analgesics!
• dose: dapat < or = 2g/day! • Adverse Effects:!
• uricosuric effect: > 4g/day ! • Hematoxicities!
! • aplastic anemia (bone marrow:
• Renal! hypocellular)!
• decrease GFR (reversible)! • pancytopenia (dec. RBC, WBC, Plt)!
• afferent arteriole: dilated by • agranulocytosis (dec. granulocytes eg
prostaglandin (use of NSAIDs inhibits basophils, eosinophils, neutrophils), thus
de novo synthesis of prostaglandin, increasing risk in bacterial infection!
thus, constriction of the AA)! • thrombocytopenia!
• Clinical Significance:! • Hepatotoxicty!
• NSAIDs may predispose px to acute • Nephrotoxicity!
renal failure)! • nephrotic syndrome!
• pre-existing renal impairment! • proteinuria (results to edema,
• elderly! decreased oncotic pressure)!
• NSAIDs & diuretics (lowering of • acute tubular necrosis!
diuretic effect! • anasarca13!

13 generalized edema
29
3. Pyrrole alkanoic acid Derivative! 8. Propionic acid derivatives!
• Tolmetin:! !
• CI: gout! ! Ibuprofen! Flurbiprofen
! ! Ketoprofen!
4. Indole derivative! ! Naproxen!

• Indomethacin:! !
• COX1 > COX2 preferential inhibition! • Ibuprofen, Naproxen:!
• higher risk of gastritis! • antipyretics!
• management of gout! • Naproxen is used for the management of
• management of Patent Ductus Arteriosus fever of malignancy (CA)!
(closure of PDA)! • Naproxen test: no lowering of temp with
! APAP, or ASA; suspected CA!
5. Oxicam derivative! !
• Piroxicam! 9. OTC NSAIDs!
• Cox1 >>>> Cox2! !
• highest risk of gastritis! !
! ! ASA! Naproxen (low
6. Fenamates! ! Ibuprofen (low dose)!
• Mefenamic Acid! ! dose)!

• Meclofenamic acid! !
• management of acute pain (nmt 5days)! Selective / Specific COX2 Inhibitors!
• high risk of gastritis! !
• CI: < 14 yrs old (no studies on this age 1. Meloxicam (Mobic) - selective!
group)! 2. Celecoxib (Celebrex) - specific!
! 3. Etoricoxib (Arcoxia) - specific!
7. Phenylacetic Acid derviative! 4. Rofecoxib (Vioxx) - specifc (withdrawn)!
! 5. Valdecoxib (Bextra) - specific (withdrawn)!
! !
! Sulindac! Etidolac!
***differ in the preferential degree of inhibition
! DIclofenac! Nabumetone!
of COX2. !
! Ketorolac! Alclofenac
!
! • Adverse Effect:!
• Sulindac! • not associated with increased risk of
• AE: SJS-TEN (Steven Johnson gastritis!
syndrome associated with Sulfa-drugs; • Disadvantage:!
Toxic Epidermal Necrolysis)! • utilized in the endothelial cells for PGE1,
• Diclofenac! PGI2 (prevents platelet aggregation)!
• anti-inflammatory; analgesic! • increases risk of acute thrombotic events:!
• Nabumetone! • stroke!
• only NSAID that is not a weak organic • myocardial infarction!
acid! !
• acetic acid derivative (active metabolite)! !
! !
! All active NSAIDs are weak organic !
! acids except Nabumetone. !
! !
• Ketorolac! !
• management of post-op pain (acute pain)! !
• nmt 5 days! !
• AE: nephrotoxicity! !
! !
! !
! !
! !
! !
! !
30
 NARCOTIC ANALGESICS

! 2. Biliary!
! Opioids: semi/synthetic!
• contraction of the biliary tract (sphincter of
! Opiates: natural!
Oddi)!
!
Sources:!
• CI: acute pancreatitis (backflow of
!
1. Papaver somniferum!
2. Papaver brateatum - source of thebaine (synthesis pancreatic enzymes, bile etc)!
!
of naloxone) • except: Meperidine (no biliary effects)!
! !
Mechanism Of Action:! 3. GIT!
• stimulate the release and mimic the action of • constipation!
endogenous peptides:! • GIT has mu receptors, when stimulated
• endorphins! caues dec. peristalsis!
• dynorphin! • tx: laxative (Lactulose)!
• endomorphin! • Oxycodone + Naloxone (opioid antagonist)
• len- & met- enkephalins! = Targin!
! • ***Naloxone oral BA 30%!
Receptors:! !
1. mu - major! 4. Mast Cells!
• analgesia! • anaphylactoid reaction (Tubocurarine &
• euphoria! Opioids)!
• sedation! • tx: Epinephrine!
• respiratory depression! !
• bradycardia! 5. Uterus!
• vasodilation! • relaxation (tocolysis)!
• miosis! !
• constipation! Uses!
• addiction! • management of pain (depends on severity of
• truncal rigidity! pain)!
! • mild: Tramadol!
2. kappa! • moderate: Codeine (or its derivatives)!
3. delta! • severe: Morphine!
*** stimulation of kappa and delta lead to • CA px!
additional analgesia! • management of acute pulmonary edema
! (accumulation of fluid in lung tissues and air
Others:! spaces = impaired gas exchange)!
1. D2! • Morphine (peripheral venodilation)
• hallucinations, psychosis! decreased venous return, decreased
2. NMDA (N-methyl-D-aspartate)! hydrostatic pressure (pupunta yung
• convulsions! surfactant sa vascular space)!
! • management of diarrhea!
Summary of Effects! • Difenoxelate & Loperamide!
! • anesthetic adjuncts !
Central! • fentanyl, fentanil!
• analgesia! • Antitussives (codeine)!
• euphoria! !
• sedation! Adverse Effects!
• respiratory depression! • Tolerance!
• miosis! • unresponsiveness to a given dose of a
• addiction! drug after continuous use!
• truncal rigidity! • 2-3 weeks before developing tolerance!
! • may be shorter if higher dose is given
Peripheral! within a short period of time!
! • lahat ng effect mawawala except: Miosis,
1. Cardiovascular! Convulsions, constipation and antagonist
• Cardiac - bradycadis! effect!
• Vascular - venodilation! • there is cross-tolerance among the full
• except: meperidine (tachycardia)! agonists !
31
• Physical dependence! Semisynthetic!
• withdrawal symptoms: (abstinence !
syndrome)! 1. Heroin!
• frequent yawning! • derivative of morphine!
• rhinorrhea! • diacetylmorphine/diamorphine!
• hyperventilation! • acetylation of morphine!
• Mydriasis! • drug of abuse!
• hostility! !
• Precipitants:! 2. Apomorphine!
• abrupt discontinuation after chronic use • not a narcotic!
(onset: 2-3 days)! • derivative of morphine!
• administration of an opioid antagonist • D2 agonist!
(onset: minutes)! • adjunct: management of parkinsonism!
• delivery of a baby by a chronic opioid • AE: emesis (tx: Trimethobenzamide di
user! pwede Metoclopramide because it is a D2
• Convulsions! antagonist)!
• NMDA usually! !
• from its metabolites! 3. Oxymorphone & Hydromorphone!
• Normeperidine (N-desmethylmeperidine)! • same activity as morphine!
• morphine-3-glucoronide (M-3-G)! • 8-12x more potent than morphine!
! !
Contraindications / Cautions! 4. Oxycodone & Hydrocodone!
• pregnancy! • same activity as codeine!
• head trauma (or any condition that increases • 8-12x more potent than codeine!
Intracranial Pressure or ICP)! !
• do not give full agonists with partial agonists Synthetic!
(makes the partial agonist act as a full !
antagonist: cancellation of effects)! 1. Methadone!
! • same activity as morphine!
Natural Agents (Opiates)! • higher oral BA!
! • longer duration of action!
1. Morphine! • later development of tolerance!
• low oral BA (25-30%)! • uses:!
• oral dose is 4x IV dose! • to wean off patients addicted to morphine !
• has 2 active metabolites ! • analgesic!
• M-3-G: causes convulsions! !
• M-6-G: active analgesic! 2. Meperidine!
• metabolites normally do not cross the • same activity as morphine!
blood brain barrier, unless the patient has • no cardiovascular and biliary effects!
renal insufficiency or renal failure (may • active metabolite: Normeperidine (effect is
cause seizures)! convulsions) !
! !
2. Codeine! 3. Fentanyl / Alfentanil / Sufentanil /
• 3-methylmorphine! Remifentanil!
• product of methylation of morphine! • commonly used as anesthetic adjuncts!
• compared to morphine, it is less active ! • same activity as morphine.!
• antitussive! • Fentanyl: 100x more potent than morphine!
• metabolized by CYP2D6 via oxidation to !
be converted to Morphine ! 4. Antidiarrheal!
3. Thebaine! • Diphenoxylate (Rx) - crosses the BBB!
• synthesis of naloxone (full antagonist)! • Loperamide (DOC)!
! • Diphenoxylate + Atropine (Lomotil)!
! !
! 5. Tramadol!
! • weak opioid agonist!
! • derivative of codeine!
32
6. Pentazocine! Psoriatic Arthritis!
• partial kappa agonist! !
! 1. Analgesics!
! • 1st Line: OA (Paracetamol)!
Strong Opioid Agonists (Full Agonists) - M! • non-ASA NSAIDs!
• Morphine! !
• Hydromorphone! 2. Glucocorticoids!
• Oxymorphone! • Oral:!
• Meperidine! • Prednisone, Prednisolone!
• Fentanyl (-fentanil)! • management of RA (low dose)!
• Levorphanol! • management of mild SLE!
! • IV:!
Mild-moderate Opiod Agonists! • Methylprednisolone!
• Codeine! • Pulse Therapy/Treatment (high dose
• Hydrocodone! over a short period of time)!
• Tramadol! • 1g/day for 3 days IV infusion!
! • management of life threatening SLE!
Partial Agonists (Mixed agonist/Antagonist • Intrasynovial!
effect) - B! • Triamcinolone!
• Nalbuphine! • minimum interval between doses: 4 mos.!
• Butorphanol! !
• Buprenorphine! 3. DMARDs (Disease Modifying Anti-
• Pentazocine! rheumatic Drugs)!
! • drugs able to retard joint destruction!
Full Antagonists (Nal-), L! • modify the natural cause of the disease!
• Naloxone! • SAARDs (slow-acting anti-rheumatic
• Naltrexone! drugs)!
• Nalorphine! • 2 weeks to 6 months before clinical benefit
• Nalmefene! is evident!
• Levallorphan! • Methotrexate (1st line)!
! • MOA: Inhibits pyrimidine synthesis by
! inhibiting 2 enzymes:!
! DRUGS FOR GOUT • thymidylate synthase!
! • AICAR transformylase!
! • dose: 7.5-25mg/week!
Rheumatoid Arthritis (RA)! • MOA (for CA): inhibition of dihydrofolate
! reductase (folic acid synthesis)!
Osteoarthritis (OA) - most common joint • dose: 100mg/day!
disorder! • AE:!
• no redness, warmth! • mucositis (most common)!
• risk factors:! • hepatotoxicity (management: folinic
• Age! acid, leucovorin)!
• joint injury / trauma! • Anti-malarials (Chloroquine &
• 2 types:! Hydroxychloroquine)!
• primary - seen among elderly px! • AE:!
• secondary - joint injury px (athletes/ • retinal toxicity!
dancers/obese)! • optic neuritis!
Systemic Lupus Erythematosus (SLE)! • cardiotoxicity!
! • hyperpigmentation!
Ankylosing Spondylitis! • annual eye examination to monitor AE!
• sacroiliac joint! • Sulfasalazine!
• young males! • metabolites:!
! • 5-aminosalicylate (management of
! inflammatory bowel disease or IBD)!
! • IBD: Crohn’s disease, ulcerative colitis!
! • sulfapyridine (useful for RA)!
33
• Gold Compounds! • (+) hyperuricemia!
• Auranofin (PO)! • (+) monosodium urate (MSU) crystals in
• Aurothiolucose (IM)! the joints (arthrocentesis)!
• Aurothiomalate (IM)! !
• Au Na Thiomalate! Clinical Presentations!
• MOA: inhibits chemotaxis, modify the 1. Acute Gout - newly diagnosed!
morphology/function of phagocytes! • Acute Gouty Attack !
• CI: pregnancy, hypersensitivity! • most commonly affected joint: 1st
• AE: ! metatarsophalangeal joint (MTP joint) aka
• hypersensitivity reaction! Podagra initial presentation!
• nephrotic syndrome! • monoarthritis (only one joint is inflamed) !
• Penicillamine! • elderly women usually present with
• metallic aftertaste! polyarthritis !
! !
4. Biologic Agents! 2. Chronic gout!
• TNF-alpha inhibitors:! • 2 forms:!
• adalimumab (fully human)! • Gouty nephropathy (+) UA stones!
• infliximab (chimeric)! • Chronic Tophaceous Gout (tophi)!
• certolizumab (humanized)! • SQ deposits of MSU crystals (chalk
• etanercept! like)!
• used in the management of RA, !
refractory to DMARDs (unresponsive to Drugs!
DMARDs) and px with contraindictions 1. Analgesics!
with DMARDs! a. NSAIDs (except A, S, T)!
• AE:! • preferred: short-acting, lipophilic!
• increased risk of serious infections! • eg. Indomethacin, Ibuprofen!
• hypersensitivity (premedication with !
antihistamine with or without b. Glucocorticoids!
glucocorticoids)! • management of polyarthritis!
• Interleukin-1 Inhibitor! • short course only (to prevent
• Anakinra! mineralocorticoid effect)!
• CD20 Inhibitor / B-cell inhibitor! • < 7 days!
• Rituximab! !
• T-cell depleting! c. ACTH injection!
• Abatacept! • management of refractory gout!
! !
5. Immunosuppresants! d. Colchicine!
a. Leflunomide! • MOA: inhibits microtubule synthesis
• prodrug! leading to inhibition of chemotaxis!
• active form: A77-1726! • 1st line in management of acute gout!
• MOA: inhibits dihydroorotate • 1st line initial treatment for chronic gout!
dehydrogenase (pyrimidine • AE:!
synthesis)! • nausea & vomiting!
! • diarrhea (early sign of toxicity)!
b. Cyclophosphamide! • rashes!
c. Mycophenolate! • rare:!
d. Azathioprine (more on lymphocyte)! • hemolytic anemia, agranulocytosis!
! • Dosing:!
! • initial - 1-2 tablets q8h, then 1-2 tabs/
! day (0.6mg/tab)!
Gout : metabolic disorder characterized by 2. Hypouricemic drug!
increased body stores of urate (uric acid / UA) • any change in the serum urate level leads
in serum and in body tissues! to an cute gouty attack (flare) !
! • Colchicine for 4-6 weeks!
Dx: ! • overlap for > than or = 9 months!
• clinical presentation! • goal: <300-360 mmol/L!
34
 a. Xanthine Oxidase Inhibitors! b. Mucolytics!
• Allopurinol, Febuxostat! • lysis of mucous!
• management of chronic gout! • MOA: inhibits disulfide linkage between
• prevention & treatment of mucousmolecules!
hyperuricemia associated with tumor • Example: N-acetylcysteine (NAC)!
lysis syndrome (condition seen in px • route: direct instillation into the tracheal
undergoing chemotherapy)! bronchial tree!
b. Urate Oxidases (Uricases)! !
• uric acid to allantoin via uricase (di c. Expectorant!
kaya ng humans na de novo)! • MOA: stimulates bronchial gland to
• mammalian or avian urate oxidase! increase water secretion!
• Pegloticase! • example: guaifenesin (Glyceryl
• management of refractory gout! gulacolate)!
• prevention and treatmen of TLS! !
• Rasburicase! d. Antitussives!
• management of TLS! • cough suppresants!
c. Uricosuric Agent! • uses: useless cough / dry
• Probenecid, Suldinpyrazone! nonproductive / harmful cough (px with
• increase the excretion of UA by TB)!
increasing tubular secretion! • Examples:!
• AE:! • Peripherally Acting!
• predisposes px to renal stone • levopropizine !
formation! • MOA: decreases sensitivity of
• prevention: adequate hydration, peripheral cough!
urinary alkalinization! !
! • Centrally Acting!
! • Opioid derivative: Codeine,
! RESPIRATORY DRUGS Dextrometorphan, Noscapine!
! • Non-opioid Derivative: Butamirate
! citrate, (Sinecod)!
Drugs for Colds! !
! Drugs for Bronchospastic Disorders!
a. Common Colds! !
• caused by virus (Coronavirus, Reliever medications: PRN!
Adenovirus, Rhinovirus)! Effect: provides immediate relief of symptoms
• Management: alpha-1 agonist! of bronchospasm!
• avoid antihistamines (prolonged use of !
antihistamines can cause drying effects)! Controller medications: Maintenance!
• Topical: NMT 3 days! Effect: reduce severity, frequency & duration
• Oral: NMT 5 days! of subsequent episodes of bronchospasm!
• risk: Rhinitis medicamentosa! !
! a. Bronchodilators!
b. Allergic Colds! • Methylxanthine: inhibits PDE and
• management: combination of Adenosine!
antiistamines and nasal decongestants! • Antimuscarinic: inhibits ACh!
! • B2 Agonist: inhibits cAMP!
Drugs for Cough! !
! 1. B2-Agonists!
a. Mucoregulators! !
• MOA: increase water layer of mucous • Short-Acting B-Agonists (SABA) -
that aids expectoration! relievers!
• Examples:! • Examples:!
• Ambroxol! • Albuterol, Salbutamol, Picoterol!
• Bromhexene! • Use: !
• Carbocisteine! • reliever meds!
! • 1st line: BA!
35
 • 2nd line: COPD!
• Route: Inhalational, MDI,
nebulization, PO, SQ (Terbutaline)!
• AE:!
• tachycardia!
• tremors!
• muscle weakness!
• palpitations!
• hypokalemia!
! degradation of histamine from mast cell!
• Long-Acting B-Agonists!
• Examples: Formoterol, Salmeterol!
• Use:!
• in BA, combined with
corticosteroids!
• If given alone in BA increases risk
of hospitalization and morbidity!
• in COPD, can be given as a single
agent!
• not to be given to children!
• Route: MDI!
! !
2. Methylxanthines!
• MOA: inhibits PDE; increasing cAMP,
inhibits adenosine even at low doses,
can have anti-inflammatory effects;
given to inhibit late phase allergic
reaction!
! Churg-Strauss syndrome!
! • Recent: increased suicidal
! Characterized by bronchospasm in early
! stage (bronchodilation), late phase
! means there’s inflammation (anti-
! inflammatory)
! the macrophage!
• Examples:!
• Theophylline - PO controller!
• Ammophylline - IV reliever (salt of
Theophylline)!
• Use:!
• Alt. in BA!
• respiratory stimulant in COPD!
• AE/SE:!
• Central: over-stimulation of CNS,
anxiety, confusion, agitation seizure!
• Cardiovascular: palpitation,
tachycardia, tachyarrhythmia!
• diureses!
! <1000-1200 ncg/day!
3. Antimuscarinics!
• Quaternary Ammonium Compounds!
• Short-Acting Anti-muscarinic
(SAMA) - reliever!
• ex. Ipratropium!
• use: !
• 1st line reliever for COPD!
36
• add-on in BA, not responding well
with SABAs!
!
b. Mast Cell Stabilizers!
• ex: “Cromores”!
• Nedocromil !
• Cromolyn Na!
• MOA: induces hyperpolarization of the
mast cell membrane, therefore, prevents
• increases Cl- influx and K+ efflux!
• AE: bronchial irritation (bronchospasm)!
• management: SABA!
!
c. Anti-inflammatory!
1. Anti-leukotriene / Leukotriene
Modifiers!
• Lipooxygenase Inhibitor!
• decreases the formation of
leukotrienes!
• ex. Zileuton!
• LTD4 Antagonist!
• ex. Montelukast, Zafirlukast!
• Uses: first line controller of BA
especially in children!
• AE:!
• Historical: unmasking of
tendency, psychotic reactions!
!
2. Glucocorticoids!
• MOA: inhibits cytokine release from
• triggers status asthmaticus:!
• Eosinophilic Cationic Protein (ECP)!
• Major Basic Protein (MBP)!
• Use: late-phase allergic reaction!
Examples:!
!
• Inhaled Corticosteroids!
• Budesonide, Fluticasone,
Triamsinolone!
• Use: Controller; combined for BA,
controller for COPD!
• AE:!
• Systemic: minimal if dose is
• Local: Oral thrush, hoarseness of
the voice. !
• *remedy: gargle after each dose!
!
• Systemic Oral Corticosteroids!
• Prednisone, Prednisolone,
Methylprednisolone!
 • Use:! End Prodruct: Platelet Plug!
• in BA, combined controller in • aka primary hemostasis /
patients with severe exacerbation! white thrombus!
• In COPD, may have same benefit • unstable clot!
as with BA! !
• AE: increased risk of infection, HTN, 2. Activation of blood coagulation
hyperglycemia! cascade (clotting factors)!
! • Goal: activate clotting factor I
• Systemic Parenteral Corticosteroids! (fibrinogen) to form factor Ia (fibrin)
• Hydrocortisone (IV) - synthetic which is its stable form!
counterpart of cortisol! • 2 Pathways involved:!
• Methylprednisolone (IV)! • Extrinsic (Factors VII, III)!
• Use: ! • Intrinsic (Factors VIII, IX, XII, XI)!
• px with severe asthma • Product:!
exacerbation! • secondary hemostasis / red
• DOC for prevention of status thrombus!
asthmaticus! • stabilized clot!
• AE: HTN, hyperglycemia, increased !
risk of infection! C. Regulatory Mechanisms!
! 1. Antithrombin-III (AT-III)!
3. Anti-IgE! • endogenous anticoagulant (inhibits
• example: Omalizumab! FIIa)!
• MOA: antibody against IgE! !
• Use: poorly controlled BA with 2. Protein C & S!
increased serum IgE! • endogenous anticoagulant!
! !
! 3. Plasmin!
! • serine protease!
! DRUGS FOR COAGULATION • activated from plasminogen via tPA!
! DRUGS:!
! !
Physiology of Clot Formation:! Antithrombotics!
! !
A. Triggers:! Anticoagulants!
1. Endothelial injury! MOA: interfere in the blood coagulation
2. Blood stasis! cascade by acting on clotting factors!
3. Presence of foreign material! !
! 1. Direct Thrombin Inhibitors (DTIs)!
B. Protein & Cellular Events in Clot Formation! • MOA: directly inactivates Factor IIa,
! impeding the activation of Factor I to
1. Platelet Migration & Aggregation! fibrin!
a. Pro-aggregants! !
• TXA2, ADP, 5-HT! a. Parenteral!
• platelet-derived! !
! • Hirudin: from Hiruda medicinalis
b. Anti-aggregants! (medicinal leech)!
• PGE1, PGI2 (Prostacyclin), cAMP! !
• endothelial cell derived! • Lepirudin: recombinant form of
! Hirudin; less associated with
c. Receptors! hypersensitivity reactions!
• GPIa - binding of platets to collagen! • Use: 1st line for HIT (Heparin-
• GPIb - binding to Von Willebrand Induced Thrombocytopenia)!
Factor (VWF)! !
• GPIIb / GPIIa - for interplatelet
binidng through fibrinogen bridge!
!
37
 • Bivalirudin: used in the • Contraindications: Active bleeding,
management of acute thrombosis Thrombocytopenia!
post-angioplasty14! !
! • Unfractionated Heparin (UFH) /
• Argatroban: alternative to Lepirudin Regular Heparin!
for HIT! • MOA: forms an active complex with
! ATIII by 1000-fold; inactivation of
b. Oral! IXa, Xa, XIa, XIIIa!
• Dabigatran! • Effect: within 6 hours!
• use: alternative to Warfarin in the • Routes:!
following conditions:! • IV bolus (80M/kgBW) or IV
• stroke prophlaxis, prevention in infusion (180 units/kgBW/hr)!
px with atrial fibrillation! • for the management of venous
• management of vascular thromboembolism, DVT,
thromboembolic events! embolism!
• Deep Vein Thrombosis (DVT)! • IV Bolus (50M/kBW) or IV
• Advantage:! Infusion (12-15mg)!
• no PT-INR monitoring required! • management of acute coronary
• no significant drug interaction syndome (MI)!
(drug-food)! • Monitoring for IV infusion:!
• AE: Hemorrhage! • aPPT: activated partial
! prothrombin time!
2. Indirect Thrombin Inhibitors! • goal: 60-85 sec delay!
• MOA: destroys clotting factor that • <40: underdose!
activate prothrombin II! • >40: overdose!
! !
a. Parenteral: Heparin (acidic)! • Low Molecular Weight Heparin
• mixture of sulfated (LMWH) !
mucopolysaccharides! • Enoxaparin, Dalteparin, Trinzaparin!
! • Heparinoid: Danaproid!
• Clinical Uses:! • Synthetic LMWH: Fondaparinux!
• when initiating anticoagulation • MOA: Inactivates Xa!
therapy! • Route: SQ!
• management of acute coronary • Monitoring: None required!
syndrome! !
• management of DVT, VTE (venous !
thromboembolism), pulmonary b. Oral: Warfarin!
embolism! • Wisconsin Alumni Research
• note: If anticoagulation is needed Foundation (Arin = Coumarin)!
in pregnancy regular heparin is • MOA:!
used! • inhibits enzyme: Vit K Epoxide
! Reductase Complex (VKERC)!
• Adverse effects:! • inhibition of hepatic synthesis of Vit
• Hemorrhage/Bleeding:! K dependent clotting factors (IX, X,
• tx: protamine sulfate! VII, II)!
• Heparin-Induced Thrombocytopenia • inhibits Protein C & S (endogenous
(HIT)! anticoagulants/anticlotting factors)!
• immune-mediated response! !
• decreased platelet count = • Effects:!
thrombosis! • Initial - inhibition of protein C & S
• tx: Levoridan! (t1/2 = 6-24 hrs)
• Osteoporosis! PROCOAGULATION!
• Alopecia!

14 PTCA - precutaneous transluminal coronary angioplasty

38
 • Final - inhibition of vit K dependent • Decreased PT-INR (Thrombosis)!
clotting factors (t1/2 = 6-60 hrs) i. Pharmacokinetic!
ANTICOAGULATION! • enzyme induction (Warfarin +
! Phenobarbital)!
• Dosing for Caucaseans: 5mg daily! • use of cholestyramine!
• Dosing for Asians: 1-2 mg daily ii. Pharmacodynamic!
(lower dose because there is less • intake of green leafy vegetables
expression of VKERC)! (rich in Vit K)!
! • hypothyroidism!
• Use:! !
• when chronic anticoagulation is NOTE: Newer Oral Anticoagulants (NOACs/
needed except during pregnancy NOVEL)!
(teratogenic) such as px with the • Rivaroxaban, Apixaban!
following:! • MOA: inactivate Factor Xa!
• chronic atrial fibrillation! • no monitoring required!
• prosthetic heart valve! !
• rheumatic heart disease (RHD)! Antiplatelets!
• DVT, VTE! !
! A. TXA2 Synthesis Inhibitor!
• Monitoring:! • Aspirin (< 325mg/day) - lower doses
• PT-INR (prothrombin time - have better antiplatelet effect!
international normalized ratio)! • MOA: irreversible acetylation of COX!
• Goal: 2-3 (most patients)! • Duration: entire lifespan of platelets
• 2.4-3.5 : patients with prosthetic (8-10 days)!
heart valve! • Uses:!
• > 2 : underdose (thrombosis)! • 1st line antiplatelet!
• > 3.5 : overdose (hemorrhage)! • primary & secondary prevention of
! thrombotic events (MI, stroke)!
• Adverse Effects:! !
• Hemorrhage (tx: Vit K1)! B. ADP Inhibitors!
• Cutaneous Necrosis due to 1. Thienopyridines!
procoagulant effect! • MOA: irreversible ADP inhibitor!
• remedy: co-administration with • Examples:!
Heparin! • Ticlopidine!
• Purple Toe Syndrome: 2-3 weeks • 250mg BID!
use of Warfarin! • full effect is seen in 11 days!
! • Use: alternative to ASA in stroke
• Contraindications:! prophylaxis!
• pregnancy hemorrhagic disease of • AE: neutropenia,
the newborn)! thrombocytopenia (monitoring of
! WBC and platelets weekly for 3
• Drug Interaction:! months)!
• Increased PT-INR (Hemorrhage)! !
i. Pharmacokinetic! • Clopidogrel!
• enzyme inhibition (Warfarin + • 75mg OD!
Cimetidine), thus there is • not associated with neutropenia &
decreased metabolism of thrombocytopenia!
Warfarin! • Use: alternative to ASA in stroke
ii. Pharmacodynamic! prophylaxis!
• use of broad spectrum • metabolized by CYP2C19 to its
antibiotics kills intestinal flora active form!
(synthesise Vit K)! 2. Non-thienopyridines!
• use of other antithrombotics (eg • MOA: reversible ADP inhibition!
ASA)! • eg Ticagrelor!
• liver disease, hyperthyroidism! !
! !
39
C. Phosphodiesterase Inhibitors! Prothrombotics!
• MOA: Inhibits PDE! !
• Dipyridamole, Cilostazol! 1. Vitamin K!
• Effect: Potentiate PGI2 levels! • Types:!
• Uses:! a. Vit K1 (Phytonadione) - clinically
• antiplatelet but have to be combined useful!
with other antiplatelets (eg Aspirin)! b. Vit K2 (Menaquinone) - synthesized by
• Dipyridamole - for pharmacologic colonic bacteria!
stress test! c. Vit K3 (Menadione) - water soluble!
• Cilostazol - management of !
intermittent claudication! • Uses:!
! • prevention of hemorrhagic disease in
D. GPIIb / GPIIa Inhibitor! newborn!
• Use: management of acute thrombous • tx of bleeding associated with vit K
post angioplasty! deficiency (Warfarin Toxicity, wherein
• Examples: Eptifibatide, Abciximab, Vit K1 is the antidote)!
Tirofiban! !
• Adverse Effect: Hemorrhage! 2. E-aminocaproic Acid!
! • analog: Tranexamic Acid!
! • MOA: Inhibits plasminogen activation!
Fibrinolytics! • use: prevention & treatment of post-
• MOA: accelerate activation of plasminogen procedural bleeding!
to plasmin ! !
• Clinical Uses: ! 3. Aprotinin!
• management of STEM (St Segment • MOA: inhibits serine protease (plasmin)!
Elevation Myocardial Infarction)! • Use: management or to minimize
• management of massive pulmoembolism! bleeding in px undergoing CABG!
• management of acute ischemic stroke! !
• management of central DVT! !
• SE: Hemorrhage / Bleeding (tx: Tranexamic !
acid)! !
! !
! !
1. Streptokinase! !
• from Beta-hemolytic sreptococcus! !
• SE: Hypersensitivity (tx: !
Diphenhydramine IV)! !
! !
2. Anisoylated Plasminogen Streptokinase !
Activator Complex (APSAC)! !
• Anistreplase! !
! !
3. Recombinant tPA! !
• Alteplase, Reteplase! !
• non-antigenic! !
! !
4. Urokinase ! !
• from mammalian kidneys ! !
! !
! !
! !
! !
! !
! !
! !
! !
40
 AUTACOIDS
! b. Betahistine!
• local hormones! • MOA: H1 Agonist; a central H3
• Site of Action: within area of secretion! antagonist (leads to the
! vasodilation of middle ear =
Histamine! resorption of endolymph)!
! • Use: For the management of
A. Biosynthesis! vertigo (Meniere’s Syndrome)!
• Location: mast cells, basophils, stomach, !
brain/CNS! 2. Antagonists!
• Step: 1-histidine undergoes a. Physiologic - Epinephrine!
decarboxylation to produce histamine! b. Pharmacologic !
! • H1-antagonists / antihistamines!
B. Receptors-Effects! • H2-antihistamines!
1. H1! !
• vascular smooth muscle: vasodilation! H1 Antagonists / Antihistamines!
• extravascular smooth muscle: ! • Summary of Effects: anti-allergy, anti-
• Bronchi: bronchospasm! muscarinic!
• GIT: contraction of walls! !
• sensory nerve endings: itch or pain; Classifications:!
wheal or flare (reflex vasodilation of !
cutaneous vessels)! A. First Generation (Classical)!
• endothelial cells (capillaries): contraction! • common effect: sedation!
! 1. Ethanolamine!
! • Diphenhydramine!
! Triple Response of Lewis is elicited by stroking
• Dimenhydrinate (salt of
! the skin. or intradermal injection of Histamine!
! diphenhydramine)!
! • Carbinoxamine!
!1. localized redness (red dot)!
2. spreading erythima! • Doxylamine!
!3. swelling ! !
! • Diphenhydramine - antral
! antimuscarinic effect!
2. H2! • additional use: management of
• Gastric Glands - basal gastric acid parkinsonism & some forms of EPS
secretions (peaks at the height of (pseudoparkinsonism, dystonia)!
sleep)! • DOC for acute distonic crisis
• Mast Cells - stimulate histamine (twisting of the neck) “torti coilis”!
release! • Route: IV!
! • additional use: sleeping aid
3. H3 (presynaptic receptor)! (Unisom)!
• H3 is regulatory, inhibiting! • soft gel (Diphenhydramine)!
• Brain - myenteric plexus (inhibits • tablet (Doxylamine)!
histamine release???)! !
! • Doxylamine !
C. Drugs Acting at H receptors! • use: sleeping aid (Unisom tablet)!
1. Agonists! !
a. Histamine (obsolete, diagnostic 2. Ethylenediamine!
agent)! • Pyrilamine!
• pulmonary function test; • Tripennelamine!
“challenge test”! !
• diagnosis of airway hyper- 3. Alkylamines!
responsiveness (AHR)! • Chlorphenilamines!
• determine adequacy of gastric • Brompheniramines!
acid secretion in achlorydia! • use: Components of cold medication!
! !
! !
! !
41
 4. Piperazines! H2-Antihistamines!
• Cyclizine & Meclizine! !
• use: for motion sickness! Examples:!
• Hydroxyzine (Iterax)! 1. Cimetidine!
• prodrug; active form is cetirizine! 2. Ranitidine!
! 3. Famotidine!
5. Phenothiazines! 4. Nizatidine!
• Promethiazine (Phenargan)! !
• use: anesthetic adjunct; minimize Use: !
stage 2 anesthesia (excitation); • management of Acid Peptic Diseases: mild
minimize “emergence phenomenon”! GERD, mild dyspepsia!
• AE: EPS! • alternative in the management of peptic
! ulcer disease!
6. Piperidines! • Note: time of administration is at bedtime
• Cyproheptadine! (adjunct anti-allergy)!
• additional MOA: Serotonin !
antagonist; antimuscarinic1! Adverse Effects:!
• Use: management of Serotonin • Cimetidine - anti-androgenic!
Syndrome! • Males: gynecomastia, loss of libido,
! sterility!
B. Second Generation! • Females: loss of libido, infertility!
1. Less sedating! • enzyme inhibitor!
a. Piperazine! • all H2-blockers: risk of Vit B12 deficiency!
• Cetirizine! !
• Levocetirizine! !
! Serotonin!
2. Non-sedating! A. Biosynthesis!
a. Piperidine! • Locations:!
• Loratidine! 1. Enterochromaffin Cells (90%)!
• Desloratidine! 2. Brainstem!
• Fexofenadine! 3. Platelets!
! !
!
Note: Only H1-antihistamines are allowed to be • Steps: L-tryptophan undergoes
!
used by pilots. 2nd generation is less effective for hydroxylation and decarboxylation to
! allergic rhinitis compared to 1st generation form 5-hydroxytryptamine aka
! Serotonin!
3. Miscellaneous: Ketotifen! !
• Additional MOA: Mast Cell Stabilizer B. Summary of Effects!
(inhibits release of Histamine from 1. Central Effects!
Mast Cells)! • Mood regulation!
• Use: seasonal allergic rhinitis (4-6 • BP, temp regulation!
weeks before allergy season)! • Appetite!
• AE:! • nausea and vomiting!
• non-sedating but it can enhance !
depression effects of CNS drugs! 2. Peripheral Effects!
• Headache - most common! • Vasoconstriction (all blood vessels
• Rhinitis! except a normal coronary artery &
! normal skeletal muscle artieries)!
! !
! 3. Other effects!
! • Peristalsis!
! • platelet aggregation!
! !
! !
! !
! !
42
C. Receptors! • can be combined with caffeine to
1. 5HT 1A! improve absorption!
• Location: Presynaptic (CNS/Brain)! • most effective route is rectal!
• inhibits serotonin release! • Use: !
! • management of migraine but at a
2. 5HT 1B / 1D! maximum of 2 doses per week!
• Location: vascular smooth muscle! • management of duster headache
• vasoconstriction! (can be given daily)!
! • Note: risk of rebound headache if
3. 5HT 2A! given more than 2 doses a week!
• Location: smooth muscle! !
• vascular smooth muscle constriction! • Adverse Effect:!
• GIT: peristalsis! • Ergotism: !
• Bronchi: bronchospasm! • Paresthesia!
! • HTN!
4. 5HT3! • digital vasospasm (necrosis)!
• Location: Brain (area postrema); CTZ • management: vasodilator for 24h!
(Chemoreceptor trigger Zone)! • GI discomfort!
• vomiting center, emesis! • nausea & vomiting!
! • Retroperitoneal Fibrosis -
5. 5HT4! development of mass at the back
• GIT: peristalsis! (area of kidney)!
! !
D. Drugs! 4. 5HT3!
1. 5HT 1A! • Antagonists:!
• partial agonist: Buspirone! • Ondansetron!
• Effect: decrease serotonin release in • Granisetron!
the CNS! • Ramosetron!
• Use: Anxiolytic! • Palonosetron!
! • Use:!
2. 5HT 1B / 1D! • Chemotherapy induced N & V
• Full Agonist: “-triptans”! (CINV)!
• Sumatriptan! • premedications!
• Naratriptan! • Routes:!
• Zolmitriptan! • PO - all except Palonosetron!
• Route: All PO! • IV - ALL!
• Sumatriptan: PO, SC, Intranasal! • ID Patch: Granisetron (Sancuso)!
• Bioavailability:! • effects 2-7 days; given 24 hours
• Naratriptan: Most BA (70%)! before scheduled chemo!
• Sumatriptan: Least BA (20%)! !
• Metabolism:! ! Palonosetron - given as a single IV dose; however
• MAO - all except Naratriptan ! its effects lasts for around 5 days
(metabolized by CYP)! !
• Use: management of acute migraine 5. 5HT4!
attack! • Agonists: Tegaserod!
• AE:! • Use: management of irritable bowel
• increased BP! syndrome & dominant constipation!
• angina pectoris! !
• muscle pain (peripheral vascular !
occlusive disease) aka claudication! !
! !
3. 5HT 2A! !
• Agonists: Ergots! !
• Ergotamine (PO, SL, Rectal)! !
• Dihydroergotamine or DHEA (IM, !
SC, IN)! !
43
Eicosanoids! C. Analogues & related drugs!
A. Synthesis - various cells! 1. Misoprostol (Cytoprotective)!
• PGE analogue!
• Use:!
• management of NSAID-induced
peptic ulcers!
• Off-Label:!
• ripening of cervix (labor induction)!
• renal protectant!
!
2. Alprostadil!
• PGE Analogue (vasodilators)!
• Use: management of erectile
dysfunction!
!
3. Epoprostenol!
• PGI2 analogue (vasodilators)!
• Use: acute management of
symptoms of primary pulmonary
hypertension!
!
! 4. Dinoprostol!
• PGE2 analogue (abortifacient)!
• Leukotrienes: SRSA (Slow Reacting
• Use: induce abortion!
Substances of Anaphylaxis)!
• LTD4 - humans!
!
5. PGI2 alpha-analogues!
• LCT4 - animals!
• LTB4 - chemotactic factor! • eg. Latanoprost!
! ! • Use: management of Glaucoma!
B. Effects!
!
1. Blood Vessels!
!
• Vasoconstriction: TxA2, 8Epi,
!
PGF2D, PGF2a!
!
• Vasodilation: PGI2 (prostacycline),
!
!
PGI!
!
!
2. Bronchi!
!
• Bronchospasm: TxA2, PGF2a, SRSA!
!
! • Bronchodilation: PGI2, PGE!
!
!
3. Uterus!
!
• Oxytotic, Dysmenorrhea!
!
! • PGE, PGFa, PGD!
!
!
4. Platelets!
!
• Aggregation: TxA2!
!
! • Inhibit Aggregation: PGI2, PGE!
!
!
5. Eyes!
!
! • Lowering of IOP: PGF2a, PGE!
!
! !
! !
! !
! !
! !
!
44
 CARDIOVASCULAR DRUGS
! • for long-term BP regulation!
Antihypertensives! • triggers:!
! • Beta1 activation (heart and
A. Blood Pressure Control & Regulation! juxtaglomerular apparatus)!
BP = CO X SVR! • renal hypotension!
! • renal hypoperfusion!
Factors Affecting BP! !
1. Cardiac Output - volume of blood pumped C. Blood Pressure Categories!
out by the heart per minute! !
• CO = HR x Stroke Volume (vol/min)! JNC 7
• HR = chronotropy!
a. Stroke Volume - volume of blood Systolic BP Diastolic BP
pumped out by the heart per
contraction or beat! Normal < 120 mmHg < 80 mmHg
• Factors:! Prehypertension 120-139 80-80
i. Strength of Myocardial Contraction
(inotropy) - direct relationship with HTN Stage 1 140-159 90-99
SV, CO, BP!
! HTN Stage 2 > or = 160 > or = 100
ii. Preload!
JNC 8
• also known as end diastolic volume
/ venous return! BP GOAL
• volume in the heart prior to
contraction or end of relaxation! < 60 y/o < 140 / < 90 mmHg
• Factors:!
> or = 60 y/o < 150 / < 90 mmHG
• Tone of the veins (pressure) /
Capacitance! !
• Fluid content of the blood D. Types of Hypertension!
(increased Na+ and Water 1. Essential HTN / Primary HTN!
increases preload)! • no identifiable cause!
! !
! 2. Secondary HTN!
! Highest pressure in the arteries!
• with identifiable cause!
! Lowest pressure in the veins
!
! 3. Special Types of HTN !
2. Systemic Vascular Resistance / Total a. HTN in Pregnancy!
Peripheral Resistance / Peripheral • renal hypertension at the
Vascular Resistance! beginning of pregnancy!
• “afterload:! • albuminuria!
• pressure required by the blood to be • pre-eclampsia, eclampsia ([+]
ejected from the heart! seizure) tx: Magnesium Sulfate
• Factors affecting Aferload:! Epsom Salt IV!
i. Tone of the arteries (resistance) eg • note: Methyldopa, Hydralazine,
arteriolar vasoconstriction (inc. SVR, Nifedipine, Labetalol!
BP)! • considered safe with
! hypertension; safe for
B. Mechanisms of BP Control! pregnant women!
1. Baroreceptor Reflex! !
• for short term BP control! b. Hypertensive Crisis!
• for rapid BP regulation! i. Hypertensive Urgency!
• Sensory Organs: Carotid Sinus, • DBP < or = 120 mmHg!
Aortic Arch! • asymptomatic!
• Stimulus: change in arterial pressure! • no target organ damage!
! • tx: rapid acting antihypertensive!
!
2. Renin-Angiotensin-Aldosterone System!
45
 • PO/SL: Captopril or Drugs:!
Clonidine / Nifedipine! a. PCT:!
• IV: Nicardipine (bolus)! • Carbonic Anhydrase Inhibitors (CAIs)!
! • Osmotic Diuretic (Mannitol)!
ii. Hypertensive Emergency! • Methylxanthine (Caffeine)!
• malignant HTN! • Acidifying salts (NH4Cl)!
• symptomatic with target organ b. TDL: Osmotic diuretic (Mannitol)!
damage! c. TAL: Loop Diureics!
• S/Sx: AHF, ARF, d. DCT: Thiazide diuretics!
Encephalopathy, Papiilledema15! e. CD: Potassium Sparing Diuretics!
• Tx: Anti-hypertensive (IV !
infusion)! Carbonic Anhydrase Inhibitors (CAIs)!
! • sulfonamide-like compounds!
E. Therapeutic Goals! • active moiety: Sulfonamoyl (SO2-NH2)!
• to lower BP by altering the ff: CO, SVR, • ex:!
BV! • Acetazolamide!
• to delay or limit subsequent organ • Dorzolamide!
pathology! • Brinzolamide!
! • Diclorphenamide!
DRUGS! !
! • MOA: Inhibit Carbonic Anhydrase!
1. Diuretics! !
• increase urinary excretion of Na+ • Effects:!
(natriuresis) and water (aquaresis) = • PCT - short-lived natriuretic effect (NMT 3
diuresis! days); continuous loss of HCO3 -
• site of action: Kidney Tubule! metabolic acidosis!
! • Eyes - decreased intraocular pressure
Parts:! (IOP)!
a. Proximal Convoluted Tubule (PCT)! !
• main site of HCO3- reabsorption! • Uses:!
• reabsorption of Na ions! • first line in the management of open angle
• water permeable! glaucoma!
! • useful as presurgical tx in acute angle
b. Thin Descending Tubule (TDL)! closure glaucoma!
• water permeable! • management of metabolic alkalosis!
! • management of acute mountain sickness!
c. Thick Ascending Limb (TAL)! • management of catamenial seizure
• reabsorption of Na+, K+ and Cl-! (Women - seizure during menstruation)!
• secondary reabsorption of Mg, Ca !
(divalent cations)! • Adverse Effects:!
• water impermeable! • increases risk of metabolic acidosis!
! • Sulfonamide associated AE: rashes/
d. Distal Convoluted Tubule (DCT)! dermatitis (SJS & TEN)!
• reabsorption of Na+, Cl-! • Hematologic: hemolytic anemia, aplastic
• reabsorption of Ca (mediated by PTH)! anemia, neutropenia!
• water impermeable! • Hypersensitivity rxn!
! !
e. Collecting Duct (DT)! • Contraindications:!
• reabsorption of Na+! • px with COPD!
• secretion of K+! • px with chronic liver disease =
! ENCEPHALOPATHY!
! !
! !
15 swelling of optic disc in retina; blurring of vision
46
Mannitol (Aquaretic)! c. Sulfonamide-like Compounds!
• site of action: PCT, TDL! • MOA: Inhibit Na+ Cl- cotransporter inthe
• MOA: creates osmotic16 gradient in water- DCT!
permeable regions of the kidney tubule! !
• Use: management of increased intracranial • Phases of Effects:!
pressure! a. Phase 1: Diuretic effect (2 weeks only)!
• SE: ! b. Phase 2: Vasodilation!
• dehydration! !
• hypovolemia! • Clinical Uses!
• hypernatremia! • first line for hypertension!
! • adjuncts in the management of CHF!
Loop Diuretics / High-ceiling Diuretics! • management of nephrogenic DI (frquent
• site of action: TAL! urination)!
• MOA: inhibit NKCCl in the TAL! • management of nephrolithiasis17!
• Effect: ! !
• decreased serum Na, K, Cl, Ca, Mg! ! There is hypocalcemia in nephrolithiasis,
• Furosemide - vasodilating effect! ! one of the effects of thiazides is
• Examples:! ! hypercalcemia
i. Sulfonamide-like Compounds! !
• Furosemide! • SE:!
• Bumetanide! • electrolyte imbalances (hypo except Ca)!
! • Sulfonamide associated AE!
ii. Sulfonylurea! • Metabolic associated AE (HyperGLU)!
• Torsemide! !
! Potassium-Sparing Diuretics!
iii. Phenoxyacetate! • site of action: Collecting Duct!
• Ethacrynic acid! • Classifications:!
! a. Aldosterone Antagonist!
• Clinical Uses! • Spironolactone, Epteronone!
• adjuncts in the management of pulmonary !
congestion in CHF! b. Epithelial Na+ Channel Blockers
• management of oliguric and anuric ARF! (ENaC)!
• management of anion poisoning! • Amirolide, Triamterone!
! !
• SE/AE:! • Clinical Uses:!
• electrolyte-imbalance (hypo-)! • prevention / tx pf diuretic-induced
• Sulfonamide associated AE:! hypokalemia!
• Ototoxicity: increased risk when • adjuncts in the management of CHF!
combined with aminoglycosides, cisplatin! • management of hyperaldosteronism-
• Metabolic Associated AE:! induced HTN!
• HyperGLU! • Spironolactone: DOC in px with hepatic
• glycemia, lipidemia, uricemia! cirrhosis!
! !
Thiazide Diuretics! • Adverse Effects:!
• Examples:! • Hyperkalemia!
a. Benzothiazides! • Spironolactone:!
• HCTZ, chlorothiazide! • anti-androgen!
! • gynecomastia!
b. Thiazide-like! • decreased libido!
• Indapamide, Metolazone, • hirsutism!
Chlorthalidone! • Triamterene: increased chance of renal
! stone formation!

16 osmosis - movement of water from low to high concentration

17 kidney-stone formation
47
2. Sympathoplegics! ii. Minoxidil!
a. Centrally-acting! • MOA: induce opening of K+
• Alpha-2 Agonists! channel in the vascular/arteriolr
• site of action: Vasomotor Center! smooth muscles!
• Examples:! !
• Clonidine! ! Opening of K+ channels, hyperpolarizes
• Methykdopa (false NT)! ! the cell (overly negative) = relaxation
• Guanfacine! !
• Guanabenz! • Use: most efficacious but
! alternative only for HTN crisis!
b. Peripherally-acting! • SE: Hirsutism, hypertrichosis!
i. Alpha-blockers - “-azosin” “-osin” !
decreases SVR, BP! iii. Diazoxide!
! • MOA: same with minoxidil!
ii. Beta-blockers - “-olols”, decreases • Use: alternative for hypertensive
CO, BP! crisis!
! • SE: HyperGLU (metabolic
iii. Adrenergic Neuronal Blockers! related)!
• alters the physiology in the !
presynapse (storage in vesicles, ! NOTE: Common AE!
exocytosis)! ! 1. All arteriolar vasodilators cause reflex
• Reserpine - inhibits vesicular ! tachycardia!
storage of Dopa (DA)! ! 2. Peripheral edema
• Guanethedine, Guanadrel, !
Bretylium - inhibit release of NE b. Mixed Arteriolar/Venodilator!
via exocytosis! i. Na nitroprusside!
! • MOA: same with hydralazine!
iv. Ganglionic Blockers! • Use: First line in hypertensive
• Nn blockers! emergency!
• Trimethaphan! • note: Na nitroprusside must be
• Hexamethonium! freshly prepared, used within 24
• Mecamylamine! hrs; prone to photodegradation!
! • AE: accumulation of cyanide
3. Vasodilators! (inhibits cytochrome oxidase =
a. Arteriolar Vasodilators! cellular respiration is inhibited)!
i. Hydralazine! • management:!
• MOA: increases levels of Nitric • Cyanide Antidote Kit!
Oxide (endogenous vasodilator)! • amyl nitrate!
! • Na nitrite (NaNO2)!
! When there is increased NO, there will • Na thiosulfate (Na2S2O4)!
! also be an increase in cGMP. NO • Hydroxo / Hydroxycobalamin!
! interactts with guanylate cyclase. GTP is
• Methylene blue (high dose)!
! thus converted to cGMP, which
!
! dephosphorylates MLC-PO4
4. Calcium Channel Blockers (CCBs)!
! (responsible for vasoconstriction) causing
• Site of Action: heart, arterial smooth
! a vasoodilating effect
muscles!
• Uses: ! • MOA: Block L-type Ca-channels!
• management of HTN • Classifications:!
specifically in pregnant wpmen Based on Structure!
with HTN crisis! i. Dihydropyridines (DHPs)!
• adjunct in the management of • “-dipines”!
CHF (with ISDN)! • vasoselective CCBs (arteries)!
• SE: Systemic Lupus • AE: Reflex tachycardia, peripheral
Erythematous! edema!
! !
! !
48
ii. Non-DHPs! • all -prils are prodrugs except:
• Verapamil - cardioselective; greatest Acute ACEi where their parent
depressant effect in the heart amongst all molecules are already activates:!
CCBs! • Capropril!
• Diltiazem - intermediate action; heart • Lisinopril!
and blood vessels! • Enalaprilat (IV)!
• Uses:! !
• alternative management for b. Angiotensin Receptor Blockers
hypertension! (ARBs) / Angiotensin II Antagonists!
• anti-anginals; anti-arrhythmics (Class • prevents the action of AII; blocks the
IV)! binding of AII to its receptor!
! • “-sartan” and Saralasin!
Based on Duration of Action! !
i. Intrinsically Short-Acting! • Adverse Effects:!
• all DHPs except LAL (Lercanidipine, • ACEis:!
Amlodpine, Lacidipine)! • Dry cough: do not shift immediately;
• all non-DHPs! lower the dose or stop therapy
• SE: reflex tachycardia, peripheral edema! temporarily & begin at a lower dose!
! • Angioedema (shift to ARBs)!
ii. Intrinsically Long-Acting! • ACEIs & ARBs!
• LAL (Lecarnidipine, Amlodipine, • hyperkalemia!
Lacidipine)! • interstitial nephritis!
• not associated with reflex tachycardia & • hypotension!
peripheral edema! !
! • Contraindications:!
iii. Modified Long-Acting! • pregnancy (teratogenic) - renal dysgenesis!
• intrinsically short-acting but have been • px with SBP < 100mmHg!
made available as modified release! • hyperkalemic px!
• Adalat GITS - Nifedipine MR! !
• not associated with reflex tachycardia & 6. Renin Inhibitor: Aliskiren!
peripheral edema! • Use: Add on to ACEIs/ARBs!
! • AE: dry cough, rashes, angioedema!
5. Angiotensin Antagonists! !
• Uses:! DRUGS FOR ANGINA PECTORIS!
• 1st Line: ACEIs! • Coronary Artery Disease (CAD) / Coronary
• 2nd Line: ARBs! Heart Disease / Ischemic Heart Disease!
• ACEIs - base treatment in px with CHF! • insufficiency of oxygenated blood reaching
• ACEIs & ARBs - 1st line in the the myocardium!
management of HTN in px with CKD or !
DM; 1st line in the management of • Causes:!
Albuminuria! a. Atherosclerosis (hardening of arterial
! walls)!
a. Angiotensin Converting Enzyme b. Thrombosis (stationary clot)!
Inhibitors (ACEIs)! c. Embolism (mobile clot)!
• prevent formation of Angiotensin II! d. Vasospasm!
! !
! Effects include increasing serum
• Consequences:!
! bradykinin (an autocoid) which induces the
a. Ischemia - low oxygenation of
! release of NO and PGI2 (prostacycline)
myocardium; cells still viable!
! causing vasodilation
b. Infarction - death of myocardial cells!
• Effects:! !
• decrease AII, BV, SVR! !
• inc. bradykinin, decreasing SVR! !
• Examples: “-prils”! !
!
!
49
Angina Pectoris! • management of acute pulmonary
• characterized as chest pain caused by edema!
ischemia or infarction! • alternatives in the management of
• Types / Manifestations:! hypertensive crisis!
a. Acute Coronary Syndrome! • adjunct in the management of CHF
• chest pain lasts for 15-20 minutes! (ISDN with Hydralazine)!
• cannot be relieved by resting or by • management of cyanide poisoning
taking SL nitrates! (amyl nitrite)!
! !
b. Chronic Stable Angina Pectoris / Effort • Examples:!
Angina (CSAP)! a. Very Short-Acting ( < 5-10 minutes)!
• precipitated by stress or by taking • ex. Amyl nitrite (inhalational)!
exercise! !
• lasts for 2-5 minutes! b. Short-Acting (15-20 minutes)!
• can be relieved by resting or by • ex. ISDN (SL), NTG (SL)!
taking SL nitrates (low dose)! c. Intermediate-Acting (5-8 hours)!
• no heightening of severity, duration & • ex. ISDN (PO), NTG (SR PO)!
frequency of chest pain! !
! d. Long-Acting (10-24 hours)!
c. Prinzmetal / Vasospastic / Variant • ex. ISDN (SR PO), NTG
Angina Pectoris! transdermal patch, ISMN (PO)!
• persistent coronary artery vasospasm! • SE:!
! • Hypotension!
• Pathophysiology:! • Drug interaction with PDE5
• Oxygen Supply-Demand Mismatch Inhibitors18 = Fatal Hypotension!
(coronary artery to heart)! • vascular headache / throbbing
• CSAP: increased oxygen demand by the headache!
heart! • tolerance = Monday Disease!
• Prinzmetal: low oxygen supply by the • Amyl Nitrite: Methemoglobinemia!
coronary artery! !
! 2. Beta-Blockers!
• Treatment / Therapeutic Goals:! • 1st line maintenance treatment of CSAP!
• CSAP: lower myocardial oxygen demand • to prevent reflex tachycardia!
(drugs that lower SVR, SV, HR)! !
• Prinzmetal: to increase oxygen supply by 3. Ca-channel Blockers (CCBs)!
the coronary artery (tx: arteriolar a. Non-DHPs (Verapamil & Diltiazem)!
vasodilator)! • alternative for CSAP!
! b. Long-acting DHPs (LAL)!
Drugs Used For Angina:! • alternative for Prinzmetal!
1. Nitrovasodilators / Organic Nitrates! !
• MOA: nitric oxide stores induces the !
formation of cGMP (responsible for !
vasodilation)! !
• Effects:! !
• Low Dose: venodilation (CSAP tx); !
decreases preload, SV, workload and !
therefore decreasing Oxygen demand! !
• High Dose: arteriolar vasodilation !
(increases oxygen supply)! !
• AE: reflex tachycardia (tx: Beta-blockers)! !
! !
• Uses:! !
• management of angina pectoris! !
18 sildenafil, tadalafil, vardenafil (used for ED)
50
 DRUGS FOR HEART FAILURE! • endpoint: increase Ca in the cell (inc.
! contraction)!
Heart Failure! • Uses: adjunct in the management of
• pump / mechanical failure / systolic heart CHF (px with atrial fibrillation)!
failure! • Note:!
• Left-sided: Pulmonary Edema! i. Narrow therapeutic index!
• Right-sided: Peripheral Edema! ii. Toxic Effects enhanced by the
! ff:!
Signs & Symptoms! • hypokalemia!
• dyspnea on exertion (DOB)! • hypomagnesemia!
• Orthopnea - DOB when lying flain bed! • hypercalcemia!
• Paroxysmal Nocturnal Dyspnea! • hypoxia!
• Presence of 3rd heart sound (S3)! • Effects:!
• Edema! i. Mechanical Effect!
• Cardiomegaly! • increase intracellular Ca ions
(inotropism)!
New York Heart Association (NYHA)
Classifications of HF patients !
ii. Autonomic!
Class I no limitation of physical • parasympathetic effect in the
activity atria: Bradycardia!
Class II slight limitation of • M2 activation (increased
physical activity sensitivity to M2)!
• (-) Chronotropy!
Class III marked limitation of • (+) Inotropy!
physical activity !
Class IV at rest, symptoms are iii. Electrical!
• in the ventricles: Tachycardia!
!
experienced
!
• Side Effects!
American College of Cardiology / American • Cardiac: bradycardia in atria;
Heart Association (ACC / AHA) tachycardia in ventricle!
Stage A no HF; high risk • Extracardia: nausea and vomiting
(vomiting is most common); yellow-
Stage B with structural heart green discoloration of vision!
disease; without s/sx !
• Management of Toxicity:!
Stage C with structural heart
disease; with s/sx
• correct all electrolyte imbalances!
• Digoxin Binding Antibodies
Stage D refractory HF (Digibind, Digifab)!
! !
2. Beta Agonists (B1)!
Therapeutic Goals:!
• eg. Dobutamine (B1), Dopamine (B1
1. Increase the force of myocardial
depending on dose)!
contraction with the use of inotropic agents!
• MOA: B1 activation in the heart (inc.
2. Decrease the workload of the heart via:!
cAMP = [+] inotropy)!
• Unloader medications: After & Preload
• Use: !
unloaders (anti-hypertensives)!
! • management of acute heart failure!
• management of CHF with acute
Drugs:!
exacerbation!
A. Inotropic Agents!
1. Digoxin!
!
3. Bipyridines!
• cardiac glycosides (Digitalis
• eg. Inamrinone, Milrinone!
purpurea) white foxglove!
• MOA: Inhibit PDE3 (inactivates the
• MOA: inhibits Na/KATPase Pump (for degradation of cAMP to AMP)!
extrusion of Ca from the
• Use: management of acute heart
myocardiocyte)!
failure & exacerbation of CHF!
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 • SE: Hypersensitivity, Arrhythmia! Drugs:!
! !
B. Unloader Medications! Vaughan-Williams Classification
• First line tx (in combination always)!
! Class I Na-channel Blockers
1. Angiotensin Antagonists (ARBs,
ACEIs)! Class II B-blockers
• decreases preload and afterload Class III K-channel blockers
(arteries)!
! Class IV Ca-channel blockers
2. Diuretics!
• decreases preload (veins, blood
!
volume)! A. Class I!
! 1. Class Ia!
• moderate Na-channel blockers!
3. Vasodilators!
• decreases afterload! • prolong action potential duration!
a. Hydralazine + ISDN! • Double Quarter Pounder!
• HZN (dec. afterload), ISDN (dec. • Disopyramide!
preload)! • Quinidine!
! • Procainamide!
• note: Quinidine causes cinchonism
b. Nesiritide!
(tinnitus, headache, dizziness)!
• Brain Natriuretic Peptide (BNP)
analog! !
2. Class Ib!
• increases cAMP, diuresis!
! • weak Na-channel blocker!
• shorten action potential duration!
c. Bosentan, Tezosentan!
• endothelium antagonists • To Make Love, Please!
(vasoconstrictor)! • Tocainamide!
! • Mexilitine!
• Lidocaine!
4. Beta blockers!
• Carvedilol! • Phenytoin!
• Metoprolol! • note: Lidocaine is the DOC for
digoxin-induced ventricular
• Bisoprolol!
! !
tachycardia!
!
! 3. Class Ic!
• strong Na-channel blockers!
DRUGS FOR ARRHYTHMIA!
! • no effect in the action potential
duration!
Could be:!
• Bradycardia! • More Fries, Papa Enchong!
• Tachycardia! • Moracizine!
! • Flecainide!
• Propafenone!
Therapeutic Goals:!
• Encainide!
1. Block Na channels!
2. Block sympathetic activities! !
3. Prolong effective refractory period (by B. Class II!
• all beta-blockers except Sotalol!
blocking K channels)!
!
4. Block Ca channels!
! !
! !
! !
! !
! !
! !
! !
! !
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C. Class III!
• Amiodarone19, Sotalol, Bretylium,
Ibutilide, Dofetilide!
• Use: 1st line for ventricular tachycardia
(VT)!
• AE:!
• Hepatotoxicity!
• Pulmonary fibrosis!
• Wolff-Chaikoff Effect (initially
hypothyroid, final rxn is
hyperthyroidism)!
!
D. Class IV!
• Verapamil!
• Use: management of paroxysmal
supraventricular tachycardia (SVT)!
• SE: Constipation!
!
E. Miscellaneous Agents!
1. Digoxin!
• for atrial fibrillation!
2. Adenosine!
• management of acute SVT
(paroxysmal)!
• AE: Bronchoconstriction!
!
3. Magnesium Sulfate!
• management of Torsades de Pointes!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
19 Amiodarone - 32% by weight Iodine
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