PHARMACOLOGY

Kenny James P. Merin, RPh, MSc

“
DEFINITION OF TERMS
PHARMACOLOGY
Science that deals with the mechanism of action, uses, and fate
of drugs in animals and humans
PHARMACOKINETICS
What the body does to the drugs
The measurement of plasma drug concentrations following
absorption, distribution, metabolism and exretion
PHARMACODYNAMICS
What the DRUG does to the body
The measurement of responses to drugs and how response relate
to drug dosage or concentration
LIGAND
Any substance that binds to a receptor
AGONIST
Molecules that bind to receptors and initiate changes in cell
function
Full agonist
Initiates high efficacy
Partial agonist
Initiates intermediate efficacy
ANTAGONIST
Molecules that bind to receptor but do not initiate changes in
cell function. They inhibit or block responses caused by agonist

Efficacy is zero
Competitive and reversible antagonist - competes with
agonist for the same receptor site in a reversible manner
Competitive but irreversible - competes with agonist for the
same receptor site but permanently makes the receptor
unavailable to the agonist
Non-competitive antagonist - binds to a different site from the
agonist binding site.
DESENSITIZATION
Pharmacological response to allergens or toxic doses rapidly
decreases when given continuously or repeatedly.
Syn: Tachyphylaxis
TOLERANCE
The pharmacological response of the patient is decreased after
prolonged use
DRUG RESISTANCE
Term used to describe the loss of effectiveness of antimicrobial
or antitumor drugs
PLACEBO
A medical preparation with no specific pharmacologic activity
against the patient’s illness or complaint given solely for its
psychophysiological effects
EC50 / MEDIAN EFFECTIVE DOSE
The concentration that produces 50% of the maximum response.
This is a measure of the potency of an agonist
TD50 / MEDIAN TOXIC DOSE
The dose required to produce a particular toxic effect in 50% of
animals
LD50 / MEDIAN LETHAL DOSE
Dose that effects death to 50% of the population
INTRINSIC ACTIVITY
Ability of a drug to activate a receptor once bound to it
EFFICACY OF A DRUG
Ability of a drug to elicit the pharmacologic response
THERAPEUTIC INDEX
Ratio of the LD over the median effective dose 

50%

(TI = LD /ED )
50 50

The higher the TI, the safer is the drug.

The lower the TI, the greater is the possibility of toxicity
INTRODUCTION
DRUGS:
- articles used in:
1. Diagnosis
2. Mitigation / Treatment
3. Cure
4. Prevention of Disease
Drugs act on specific targets:
Receptors
Ion Channels
Enzymes
Carriers
Transporters
CLASSIFICATION OF DRUGS
1. Functional Modifiers
- alter/ change
a. Pain perception
i. Analgesics
ii. Anesthetics
b. Growth of Blood Vessels “Neurovascularization”
i. Vascular Endothelial Growth Factors (VEGF)
i. Bevacizumab (Avastin)
2. Replenishers
- gives supplement substances that are missing or insufficient
a. Type I DM
i. Insulin
b. Pernicious Anemia
I. Autoimmune disease
causes:
1. Achlorhydria
2. B-12 deficiency - megaloblastic anemia
tx. vitamin B-12 I.M.
3. Diagnostic Agents
- used to confirm / establish diagnosis of disease / condition
a. Edrophonium (Tensilon)
dx for Myasthenia Gravis
b. Dobutamine, Dypiridamole
used for Pharmacologic Stress Testing
heart contractility
4. Chemotherapeutic Agents
- used to kill or inhibit reproduction of cells or nucleic acids
considered as foreign to the body
a. Anti-invectives
b. Tx for cancer (antineoplastics)
 PHARMACODYNAMICS

PHARMACOKINETICS

BODY DRUG
 PRINCIPLES OF
PHARMACOLOGY
PHARMACODYNAMICS

“What the Drug does to the body”

MECHANISM OF DRUG ACTIONS
1. Target Protein-Mediated Mechanism
2. Non Target Protein-Mediated Mechanism
1. TARGET PROTEIN MEDIATED
biological site of action
active ste
binding site
part of cell where drug binds
TYPES OF TARGET PROTEIN
A. Structural Proteins
- make up the cell framework - cytoskeleton
- known as the microtubules/tubulin
ROLES OF MICROTUBULES/TUBULIN
keep organelles in place
cell movement / taxis (inflammatory cells)
axonal transport of neurotransmitters (via vesicles)
separating the “divided/replicated” chromes to each of daughter
cells during mitosis
DRUGS THAT INHIBIT SYNTHESIS FUNCTION OF MICROTUBULES
i. Colchicine
- First line of Tx for Acute Gout
- First line of initial treatment for chronic gout (several weeks)
ii. Griseofulvin
- attached to protein found in the skin “keratin”
- taken with fatty mean to increase absorption
iii. Mitotic Spindle Inhibitors (Antimitotics)
- Vincas
- Vincristine
- Vinblastine VIN!

- Vinorelbine
- Taxols
- Paclitaxel
TiPiD
- Doxetacel
B. Regulatory Proteins
- regulating cell activities / process / functions
i. Channels (Voltage-gated ion Channels)
- activated by the entry of open ion
 1. Voltage gated Na+ Channels

blocked by:
Class I antiarrythmics
Ia - Dispyrimidine, Quinidine, Procainamide Double Quarter Pounder
Ib - Lidocaine, Phenytoin, Tocainide, Mexilitine Lettuce, Pickles, Tomato, Mayonaise
Ic - Encainide, Moricizine, Flecainide, Propafenone, Eat More Fries Please
Local Anesthetics
Some Anticonvulsants
2. Voltage-gated K+ Channels
- inhibited by:
Class III antiarrythmics IS BAD

Ibutlide
Sotalol
Beryllium
Amiodarone
Dofetilide
Insulin Secretagogues
Sulfonylureas, Meglitinides
3. Voltage-gated Ca+ Channels
- blocked by CCBs (DHPs and Non-DHPs)
Divines — Dihydropiridine
Verapamil - Non Dihydropyridine
1. You enter the park gate, the roller coaster looms before you
with a line of people waiting their turn. How long do you have
to wait in line before getting to ride?
 2. Your turn finally comes and now you’re racing and plunging around
the course. What kinds of feelings does the speed bring out in you?
3. At the most exciting point in the course, the roller coaster dives
into a pool of water and you’re drenched by the spray. What do you
shout or scream at this instant?
4. Next you decide to try the merry-go-round. But during your ride,
for some reason the horse you’re riding breaks down and stops
moving. What do you say to the horse?
5. Your ride on the roller coaster was exciting, but it wasn’t all that it
could have been. If you were going to design the perfect roller coaster,
what would the course look like? (Draw a detailed picture of the
course)
 Did you have a good time in the park? In psychological terms,
rhythmical up-and-down motions represent sexual excitement.
So your responses to the five questions actually show your
attitudes toward sex.
1
The time you spend waiting in line reveals how much time you
spend, or would like our partner to spend, on foreplay. Did you
have to stand in line for hours before the main event, or did you
just jump aboard without waiting?
2
Your feelings during the roller-coaster ride reveal how you feel
while making love. Did you think, “This is the best ride I’ve ever
been on!” or was your reaction closer to, “Get me off this thing!
I think I’m gonna throw up!”
3
In Jungian symbolism, water represents the source of life. Your
words at the moment the roller coaster splashed into the pool
show what you might say at the moment of sexual climax. Let’s
hope you didn’t say anything you’ll end up regretting in the
morning.
4
The horse, in psychosexual terms, is a symbol of the masculine
principle. Your words to your broken-down steed reflect what
you might say to yourself or to your partner in situations where
the man failed to rise to the occasion
“It’s all right, don’t worry about it. It’s only a ride.” You have a
truly gentle and forgiving nature.
“I can’t believe this. I want my money back!” You said it, not me.
“Come on you stupid animal, giddyap!” Yikes!
5
Your plan for the ideal roller-coaster course shows your vision of
the perfect sex life. The ups and downs of a roller-coaster ride
are an exact metaphor for the thrills and lulls of lovemaking.
Was it a long, slow ascent followed by a terrifying plunge? A
series of acrobatic loop-the-loop and 360-degree rolls? Or maybe
you drew a course where you spend the whole ride turned
upside down and backward?
ii. Carriers
- Cell membrane proteins with specific binding sites that can
transport molecules across the cell membrane with a change
in their configuration
1. Na+ - K+ ATPase
- inhibited by
Digitalis glycosides

2. H+ - K+ ATPase (Proton Pump)

- blocked by PPIs (Proton Pump Inhibitors) - prazowles
~ Lanzoprazole, Esomeprazole, Omeprazole
*note: Aripiprazole (Abilify) is not a PPI - new gun
antipsychotic for bipolar disorder
iii. Enzymes
Ex.
1. COX2
- inhibited by NSAIDs
2. Kinase II ( ACE)
- inhibited by ACEi
3. MAO (monoamine oxidase)
- inhibited by MAOi
Non Selective MAOi (block MAO-A & MAO-B)
Tranylcypramine T

Isocarboxacid I

Phenelzine P

Selective MAO-A inhibitor

(Reversible Inhibitors of MAO-A [RIMA])
Mabclobenide
Selective MAO-B inhibitor
Selegeline
iv. Receptors
- Functional macromolecular components of cells with
specific stereochemical configuration with which a ligand
interacts usually in a LOCK & KEY method
TYPES OF RECEPTORS
1.Type 1 Receptors
- Ionotropic Receptors
- Ion-channel type or channel linked receptors
- makes use of IONS
- opens only if receptor is activated
- opens/closees ligand-gated ion channels
- location: cell membrane
- action: milliseconds
ex. Nicotinic Receptors, Gaba-A receptor complex, Glutamate
Excitatory NT
2. Type 2 Receptors
- Metabotropic
- G-protein linked receptors
- G-protein coupled receptors
- Metabotropic receptors are the secondary messengers:
CGMP, IP3, DAG, CA3+
-loc: cell membrane
- action: in seconds
3. Type 3 Receptors
- enzyme-linked receptors
- kinase-boinked receptors
ex.
Insulin receptors
Cytokine receptors
Growth Factor receptors
4. Type 4 Receptors
- Gene-transcription linked receptors
- Nuclear Receptors
- Intracellular receptors that regulates gene transcription
- loc: nucleus
- action: in hours
Ex.
Steroid Hormones (Glucocorticoid, Sex Steroids, Vit. D)
Thyroid Hormone Receptors
2. NON TARGET PROTEIN-MEDIATED MECHANISMS
A. Direct Chemical Interaction
i. Neutralization reaction (acid-base reaction)
ii. Chelation Reaction
2. Colligative Mechanism
i. Osmotic Diuretic
3. Counterfeit-Incorporation Mechanism
B. Drug Receptor Interaction
i. Features of Interactions
1. Affinity
- ability to bind to a receptor/ligand activity
2. Intrinsic Activity
- ability to generate a series of biochemical events leading
to an effect
 How do we bring thrills into our lives? Watching movies,
traveling, and playing sports and games of chance. Or maybe a
trip to an amusement park, a world where thrills mingle with
fantasies. Let’s take a trip back to that realm of childhood
excitement and fun.
ii. Classification of Drugs based on Features of Interaction
1. Agonist
- (+) affinity and (+) intrinsic activity
2. Antagonist
- (+) affinity, (-) intrinsic activity
PARTIAL AGONIST
Less than the max or only some of the effects are produced
FULL AGONIST
max effects are produced
iii. Antagonism
- clinically having opposite effects
a. Based on Mechanism of Antagonism
- same receptor
1. Pharmacologic Antagonism
2. Physiologic Antagonism
3. Chemical Antagonism
4. Allosteric Antagonism
b. Based on the Type of Bond Formed with the Receptor
1. Reversible Antagonism
2. Irreversible Antagonism

c. Based on Surmountability of Interaction

1. Competitive Antagonism (Surmountable)
2. Noncompetitive Antagonism (Non-surmountable)
 PRINCIPLES OF
PHARMACOLOGY
PHARMACOKINETICS

“What the BODY does to the Drug”

Transport Processes

1. Passive Transport/Diffusion
2. Carrier Mediated Transport
3. Connective Transport
4. Ion Pair Transport
5. Pinocytosis
LADMER
Liberation
Absorption
Distribution
Metabolism
Excretion
Reabsorption
LIBERATION
- Release of drug from the dosage form / drug delivery system
- highly modifiable
- extended release
- delayed release
ABSORPTION
Physiologic - rate and extend of disappearance of drug from site
of administration

Pharmacokinetic - rate and extent of drug entry into the

systemic circulation

Cmax
tmax
AUC
factors affeting absorption
1. Dose-size administered
2. Surface Area
3. Degree of Perfusion
4. pH of the environment
5. Gastric Emptying Time (GET)
DISTRIBUTION
- process of drug movement from systemic circulation into
different body component
- blood transports drug into the different body compartments

factors:
a. cardiac output
b. regional blood flow
distribution parameters
a. protein binding
b. volume of distribution
METABOLISM
- the objective is to convert drugs / xenobiotics into forms that
are less active/inactive, less toxic/non-toxic, polar/water-
soluble, and easily excreted.

*first pass effect

- initial metabolism of a drug before it reaches the systemic
circulation
Phases of Metabolism
1. Phase I
- functionalization phase
- adding or unmasking of a functional group
- functionalization reactions:
a. oxidation (CYP mediated)
b. reduction
c. Hydrolysis
2. Phase II
- conjugation/synthetic
- addition of polar conjugate
Ex.
i. Glucoronidation
ii. Acetylation
iii. Glutathione conjugation
iv. Glycine conjugation
Enzyme Induction and Inhibition
a. Enzyme induction
- stimulating metabolizing enzyme
b. Enzyme inhibition
- decrease metabolizing activity
EXCRETION
- final loss of drug from the body
- requirement: polar & water soluble
mechanism / routes:
a. Renal
b. Biliary excretion
c. Lungs
d. Mammary
e. Skin, Sweat, Lacrimal, Etc.
The ER physician has ordered that the patient be given
ceftizoxime 2g IV q8h. You notice, upon examining the
patient’s labs, that his serum creatinine is 2.6 mg/dL.
Upon questioning, the patient, 50 years old tells you that
his usual weight is 13 stone. A “stone” is a commonly-
used weight unit in the Commonwealth countries. One
stone equals 14 pounds. He says he is 188cm in height.
Facts and Comparisons ® gives you the following
information about ceftizoxime:

What is the patient’s calculated creatinine clearance?

KOKOLOGY 11 “ABRACADABRA, ALA KAZAM”
Playing cards that dance through the air … rabbits produced
from a silk top hat … a lovely assistant made to disappear in a
puff of smoke. Stage magic is simple deception raised to the
level of entertainment. As you watch the performance, you know
you’re being tricked, but no matter how hard you think about it
or how closely you watch the hands, it seems you can never put
your finger on the secret. But somehow the witty banter and the
sleight of hand make it all fun, and you sit back and enjoy the
display of baffling skill. Perhaps the most important part of the
magician’s act is not in the mastery of the actual techniques or
the preparation of the props, but in the ability to make an
audience willing to believe.
 Wouldn’t it be nice to have that same skill? Well, tonight is
your big chance. Your audience is waiting, and the curtain is
about to rise…
1. You are a stage magician, just setting off on another long tour.
Tonight is opening night, and you are waiting in the wings of the
stage for your act to be announced. How do you feel in the
moments before your show begins?
Part of your act involves calling a member of the audience up on
stage to help you with a trick. Whom do you call to assist you?
Give the name of a person you know.
3. Despite all your years of training and experience, somehow
the trick goes terribly wrong. What do you say to the person you
called up to participate?
 4. You’re back in your dressing room after your act. How do you
feel now that the show has ended?
 Feats of magic are called tricks for a reason. They necessarily
involve making people see things that aren’t really there or miss
realities that are staring them in the face. Essentially, tricks
involve deception and guile. And the way you pictured your own
performance shows how you see yourself when it comes to lying
or deceiving others, especially the people closest to you.
1. Your feelings as you waited to go on tell us how you would
feel when planning (or merely fantasizing about) an illicit affair.
Most people say something like “I hope I don’t mess this up” or
“Wow, I’m really nervous”. But then there are those who seem
to be immune to performance anxiety: “I’m going to go out
there and give them a night to remember!”
2. The person you asked to join you as your helper on stage is
someone you see as simple, naive, and just a little bit gullible. In
short, someone you think is easy to deceive or lie to.
3. The words you said after flubbing your act reveal the types of
excuses you’d make if you got caught cheating. Did you get
flustered and turn red before blurting out, “Sorry about that” Or
did you just try to laugh it off and get on with the show:
“Whoopsy daisy! Well, I guess that goes to show no one is
perfect!” Or are you of the group that tried to pretend it was just
part of the act? That’d be a neat trick if you could really pull it
off.
4. The way you felt after the act was finished is the way you feel
after doing or saying something dishonest.

“That was nerve-racking. What a mess!” That’ll teach you to go

around tricking people.

“That settles it, I’m getting out of this business.” There are plenty of
more satisfying careers for an honest, hardworking type. You’re
probably not cut out for all this smoke and mirrors stuff anyway.

“I’ll get it right next time.” Some people never learn. You may want to
think about getting into politics, law, or used-car sales.

“Actually, I thought the whole experience was kind of stimulating.”

They say that once a fox has had its first chicken, it never forgets the
taste.
I. THE NERVOUS SYSTEM
Central Nervous System
the complex of nerve tissues that controls the activities of the
body. In vertebrates it comprises the brain and spinal cord.
Peripheral Efferent Nervous System
The efferent division sends information from the nervous
system to the organs of the body which then carry out the
appropriate response.
NEUROTRANSMITTERS OF THE BRAIN
THE AUTONOMIC NERVOUS SYSTEM
the part of the nervous system responsible for control of the
bodily functions not consciously directed, such as breathing, the
heartbeat, and digestive processes.
SYMPATHETIC (FIGHT OR FLIGHT)
PARASYMPATHETIC (REST AND DIGEST)
PARASYMPATHETIC (REST AND DIGEST
`
DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM
ANXIOLYTIC DRUGS
An anxiolytic is a medication or other intervention that inhibits
anxiety. This effect is in contrast to anxiogenic agents, which
increase anxiety.
Excitatory neurotransmitters
(opens sodium or calcium channels -> depolarisation -> nerve
impulse )

Inhibitory neurotransmitters (open chloride channels ->

hyperpolarization -> no nerve impulse)
PANIC DISORDER
A panic attack is a sudden episode of intense fear that triggers
severe physical reactions when there is no real danger or
apparent cause. Panic attacks can be very frightening. When
panic attacks occur, you might think you're losing control,
having a heart attack or even dying.
SYMPTOMS
• Sense of impending doom or danger
• Fear of loss of control or death
• Rapid, pounding heart rate
• Sweating
• Trembling or shaking
• Shortness of breath or tightness in your throat
• Chills
• Hot flashes
• Nausea
• Abdominal cramping
• Chest pain
• Headache
• Dizziness, lightheadedness or faintness
• Numbness or tingling sensation
• Feeling of unreality or detachment
CAUSES
It's not known what causes panic attacks or panic disorder, but
these factors may play a role:
Genetics
Major stress
Temperament that is more sensitive to stress or prone to
negative emotions
Certain changes in the way parts of your brain function
COMPLICATIONS
Development of specific phobias, such as fear of driving or
leaving your home
Frequent medical care for health concerns and other medical
conditions
Avoidance of social situations
Problems at work or school
Depression, anxiety disorder and other psychiatric disorders
Increased risk of suicide or suicidal thoughts
Alcohol or other substance misuse
Financial problems
TREATMENT
Selective serotonin reuptake inhibitors (SSRIs).
antidepressants are typically recommended as the first choice of
medications to treat panic attacks. include fluoxetine (Prozac),
paroxetine (Paxil, Pexeva) and sertraline (Zoloft).
Serotonin and norepinephrine reuptake inhibitors (SNRIs).
The SNRI drug called venlafaxine hydrochloride (Effexor XR)
Benzodiazepines. These sedatives are central nervous system
depressants. Benzodiazepines may be habit-forming, causing
mental or physical dependence. alprazolam (Xanax) and
clonazepam (Klonopin).
SOCIAL PHOBIA
It's normal to feel nervous in some social situations. For
example, going on a date or giving a presentation may cause that
feeling of butterflies in your stomach. But in social anxiety
disorder, also called social phobia, everyday interactions cause
significant anxiety, fear, self-consciousness and embarrassment
because you fear being scrutinized or judged by others.
• Fear of situations in which you may be judged
• Worrying about embarrassing or humiliating yourself
• Concern that you'll offend someone
• Intense fear of interacting or talking with strangers
• Fear that others will notice that you look anxious
• Fear of physical symptoms that may cause you
embarrassment, such as blushing, sweating, trembling or
having a shaky voice
• Avoiding doing things or speaking to people out of fear of
embarrassment
• Avoiding situations where you might be the center of attention
• Having anxiety in anticipation of a feared activity or event
• Spending time after a social situation analyzing your
performance and identifying flaws in your interactions
• Expecting the worst possible consequences from a negative
experience during a social situation
Physical symptoms

Physical signs and symptoms can sometimes accompany

social anxiety disorder and may include:
• Fast heartbeat
• Upset stomach or nausea
• Trouble catching your breath
• Dizziness or lightheadedness
• Confusion or feeling "out of body"
• Diarrhea
• Muscle tension
CAUSES
Inherited traits. Anxiety disorders tend to run in families.
However, it isn't entirely clear how much of this may be due to
genetics and how much is due to learned behavior.
Brain structure. A structure in the brain called the amygdala (uh-
MIG-duh-luh) may play a role in controlling the fear response.
People who have an overactive amygdala may have a heightened
fear response, causing increased anxiety in social situations.
Environment. Social anxiety disorder may be a learned behavior.
That is, you may develop the condition after witnessing the
anxious behavior of others. In addition, there may be an
association between social anxiety disorder and parents who are
more controlling or protective of their children.
COMPLICATIONS
• Low self-esteem
• Trouble being assertive
• Negative self-talk
• Hypersensitivity to criticism
• Poor social skills
• Isolation and difficult social relationships
• Low academic and employment achievement
• Substance abuse, such as drinking too much alcohol
• Suicide or suicide attempts
TREATMENT
Selective serotonin reuptake inhibitors (SSRIs) are often the first
type of medication tried for persistent symptoms of social
anxiety. Your doctor may prescribe Paroxetine (Paxil) or
Sertraline (Zoloft).
The serotonin and norepinephrine reuptake inhibitor (SNRI)
venlafaxine (Effexor XR) also may be an option for social anxiety
disorder.
TREATMENT
Other antidepressants. You may have to try several different
antidepressants to find one that's the most effective for you with the
fewest side effects.
Anti-anxiety medications. Benzodiazepines may reduce your level
of anxiety. Although they often work quickly, they can be habit-
forming and sedating, so they're typically prescribed for only short-
term use.
Beta blockers. These medications work by blocking the stimulating
effect of epinephrine (adrenaline). They may reduce heart rate,
blood pressure, pounding of the heart, and shaking voice and limbs.
Because of that, they may work best when used infrequently to
control symptoms for a particular situation, such as giving a speech.
SPECIFIC PHOBIAS
A phobia is an overwhelming and unreasonable fear of an object
or situation that poses little real danger but provokes anxiety
and avoidance. Unlike the brief anxiety most people feel when
they give a speech or take a test, a phobia is long lasting, causes
intense physical and psychological reactions, and can affect your
ability to function normally at work or in social settings.
Phobias are divided into three main categories:

Specific phobias. A specific phobia involves an irrational,

persistent fear of a specific object or situation that's out of
proportion to the actual risk. This includes a fear of situations
(such as airplanes or enclosed spaces); nature (such as
thunderstorms or heights); animals or insects (such as dogs or
spiders); blood, injection or injury (such as knives or medical
procedures); or other phobias (such as loud noises or clowns).
There are many other types of specific phobias. It's not unusual
to experience phobias about more than one object or situation.
➤
 Social phobia. More than just shyness, social phobia involves a
combination of excessive self-consciousness and a fear of public scrutiny
or humiliation in common social situations. In social situations, the
person fears being rejected or negatively evaluated or fears offending
others.
Fear of open spaces (agoraphobia). This is a fear of an actual or
anticipated situation, such as using public transportation, being in open
or enclosed spaces, standing in line or being in a crowd, or being outside
the home alone. The anxiety is caused by fearing no easy means of escape
or help if intense anxiety develops. Most people who have agoraphobia
develop it after having one or more panic attacks, causing them to fear
another attack and avoid the place where it occurred. For some people,
agoraphobia may be so severe that they're unable to leave home.
SYMPTOMS
No matter what type of phobia you have, it's likely to produce the
following reactions:
• A feeling of uncontrollable panic, terror or dread when you're
exposed to the source of your fear
• The feeling that you must do everything possible to avoid
what you fear
• The inability to function normally because of your anxiety
• Physical as well as psychological reactions, including
sweating, rapid heartbeat, difficulty breathing, a feeling of
panic and intense anxiety
• Often, the knowledge that your fears are unreasonable or
exaggerated but feeling powerless to control them
• In some cases, anxiety just thinking about what you fear
• In children, possibly tantrums, clinging or crying
CAUSES
Much is still unknown about the actual cause of phobias.
However, there does appear to be a link between your own
phobias and the phobias of your parents. This could be due to
genetics or learned behavior.
COMPLICATIONS
Social isolation. Avoiding places and things you fear can cause
academic, professional and relationship problems. Children with
these disorders are at risk of academic problems and loneliness,
and they may not develop good social skills.
Depression. Many people with phobias have depression as well
as other anxiety disorders.
Substance abuse. The stress of living with a severe phobia may
lead to substance abuse.
Suicide. Some individuals with specific phobias may be at risk
of suicide.
TREATMENT
Beta blockers. These medications work by blocking the
stimulating effects of adrenaline on your body, such as increased
heart rate, elevated blood pressure, pounding heart, and shaking
voice and limbs that are caused by anxiety. Short-term use of beta
blockers can be effective in decreasing symptoms when taken before
an anticipated event, for example, before a performance for people
who have severe stage fright.
Antidepressants. Antidepressants called selective serotonin
reuptake inhibitors (SSRIs) are commonly used in the treatment of
phobias. These medications act on the chemical serotonin, a
neurotransmitter in your brain that's believed to influence mood. As
an alternative, your doctor may prescribe another type of
antidepressant, depending on your situation.
 Sedatives. Medications called benzodiazepines help you relax
by reducing the amount of anxiety you feel. Sedatives need to be
used with caution because they can be addictive and should be
avoided if you have a history of alcohol or drug dependence.
GENERALISED ANXIETY DISORDER
It's normal to feel anxious from time to time, especially if your
life is stressful. However, excessive, ongoing anxiety and worry
that interfere with day-to-day activities may be a sign of
generalized anxiety disorder.
SYMPTOMS
Generalized anxiety disorder symptoms can vary. They may include:
• Persistent worrying or obsession about small or large
concerns that's out of proportion to the impact of the event
• Inability to set aside or let go of a worry
• Inability to relax, restlessness, and feeling keyed up or on
edge
• Difficulty concentrating, or the feeling that your mind "goes
blank"
• Worrying about excessively worrying
• Distress about making decisions for fear of making the wrong
decision
• Carrying every option in a situation all the way out to its
possible negative conclusion
• Difficulty handling uncertainty or indecisivenes
SYMPTOMS
Physical signs and symptoms may include:

• Fatigue
• Irritability
• Muscle tension or muscle aches
• Trembling, feeling twitchy
• Being easily startled
• Trouble sleeping
• Sweating
• Nausea, diarrhea or irritable bowel syndrome
• Headaches
As with many mental health conditions, the exact cause of
generalized anxiety disorder isn't fully understood, but it may
include genetics as well as other risk factors
COMPLICATIONS
Having generalized anxiety disorder does more than just make you worry.
It can:
• Impair your ability to perform tasks quickly and efficiently because you
have trouble concentrating
• Take your time and focus from other activities
• Sap your energy
• Disturb your sleep

Generalized anxiety disorder can also lead to or worsen other mental and
physical health conditions, such as:
• Depression (which often occurs with generalized anxiety disorder)
• Substance abuse
• Trouble sleeping (insomnia)
• Digestive or bowel problems
• Headaches
• Heart-health issues
TREATMENT
Antidepressants. Antidepressants, including medications in
the selective serotonin reuptake inhibitor (SSRI) and serotonin
norepinephrine reuptake inhibitor (SNRI) classes, are the first-
line medication treatments. Examples of antidepressants used to
treat anxiety disorders include escitalopram (Lexapro),
duloxetine (Cymbalta), venlafaxine (Effexor XR) and paroxetine
(Paxil, Pexeva). Your doctor also may recommend other
antidepressants.
•
 Buspirone. An anti-anxiety medication called buspirone may be
used on an ongoing basis. As with most antidepressants, it
typically takes up to several weeks to become fully effective.
Benzodiazepines. In limited circumstances, your doctor may
prescribe one of these sedatives for relief of anxiety symptoms.
Examples include alprazolam (Niravam, Xanax),
chlordiazepoxide (Librium), diazepam (Valium) and lorazepam
(Ativan). Benzodiazepines are generally used only for relieving
acute anxiety on a short-term basis. Because they can be habit-
forming, these medications aren't a good choice if you've had
problems with alcohol or drug abuse
POST TRAUMATIC STRESS DISORDER
Post-traumatic stress disorder (PTSD) is a mental health
condition that's triggered by a terrifying event — either
experiencing it or witnessing it. Symptoms may include
flashbacks, nightmares and severe anxiety, as well as
uncontrollable thoughts about the event.
SYMPTOMS
Intrusive memories
Symptoms of intrusive memories may include:
• Recurrent, unwanted distressing memories of the traumatic
event
• Reliving the traumatic event as if it were happening again
(flashbacks)
• Upsetting dreams about the traumatic event
• Severe emotional distress or physical reactions to something
that reminds you of the event
Avoidance
Symptoms of avoidance may include:
• Trying to avoid thinking or talking about the traumatic event
• Avoiding places, activities or people that remind you of the
traumatic event
Negative changes in thinking and mood
Symptoms of negative changes in thinking and mood may
include:
• Negative feelings about yourself or other people
• Inability to experience positive emotions
• Feeling emotionally numb
• Lack of interest in activities you once enjoyed
• Hopelessness about the future
• Memory problems, including not remembering important
aspects of the traumatic event
• Difficulty maintaining close relationships
Changes in emotional reactions
Symptoms of changes in emotional reactions (also called arousal
symptoms) may include:
• Irritability, angry outbursts or aggressive behavior
• Always being on guard for danger
• Overwhelming guilt or shame
• Self-destructive behavior, such as drinking too much or driving
too fast
• Trouble concentrating
• Trouble sleeping
• Being easily startled or frightened
CAUSES
• Inherited mental health risks, such as an increased risk of
anxiety and depression
• Life experiences, including the amount and severity of trauma
you've gone through since early childhood
• Inherited aspects of your personality — often called your
temperament
• The way your brain regulates the chemicals and hormones
your body releases in response to stress
COMPLICATIONS
Having PTSD also may increase your risk of other mental health
problems, such as:
• Depression and anxiety
• Issues with drugs or alcohol use
• Eating disorders
• Suicidal thoughts and actions
TREATMENT
Antidepressants. These medications can help symptoms of
depression and anxiety. They can also help improve sleep problems
and concentration. The selective serotonin reuptake inhibitor
(SSRI) medications sertraline (Zoloft) and paroxetine (Paxil).
Anti-anxiety medications. These drugs also can improve feelings
of anxiety and stress for a short time to relieve severe anxiety and
related problems. Because these medications have the potential for
abuse, they are not usually taken long term.
Prazosin. If symptoms include insomnia or recurrent nightmares,
a drug called prazosin (Minipress) may help. Although not
specifically FDA-approved for PTSD treatment, prazosin may
reduce or suppress nightmares in many people with PTSD.
OBSESSIVE-COMPULSIVE DISORDER
Obsessive-compulsive disorder (OCD) is characterized by
unreasonable thoughts and fears (obsessions) that lead you to
do repetitive behaviors (compulsions). It's also possible to have
only obsessions or only compulsions and still have OCD.
SYMPTOMS
Obsessions often have themes to them, such as:
• Fear of contamination or dirt
• Having things orderly and symmetrical
• Aggressive or horrific thoughts about harming yourself or
others
• Unwanted thoughts, including aggression, or sexual or
religious subjects
Examples of obsession signs and symptoms include:
• Fear of being contaminated by shaking hands or by touching
objects others have touched
• Doubts that you've locked the door or turned off the stove
• Intense stress when objects aren't orderly or facing a certain
way
• Images of hurting yourself or someone else
• Thoughts about shouting obscenities or acting inappropriately
• Avoidance of situations that can trigger obsessions, such as
shaking hands
• Distress about unpleasant sexual images repeating in your
mind
As with obsessions, compulsions typically have themes, such as:
• Washing and cleaning
• Counting
• Checking
• Demanding reassurances
• Following a strict routine
• Orderliness
Examples of compulsion signs and symptoms include:
• Hand-washing until your skin becomes raw
• Checking doors repeatedly to make sure they're locked
• Checking the stove repeatedly to make sure it's off
• Counting in certain patterns
• Silently repeating a prayer, word or phrase
• Arranging your canned goods to face the same way
CAUSES
• Biology. OCD may be a result of changes in your body's own
natural chemistry or brain functions. OCD may also have a
genetic component, but specific genes have yet to be
identified.
• Environment. Some environmental factors such as infections
are suggested as a trigger for OCD, but more research is
needed to be sure.
TREATMENT
• Clomipramine (Anafranil)
• Fluvoxamine (Luvox CR)
• Fluoxetine (Prozac)
• Paroxetine (Paxil, Pexeva)
• Sertraline (Zoloft)

However, other antidepressants and psychiatric medications

used for other conditions may be prescribed off label to treat
OCD.
CLASSES OF ANXIOLYTIC DRUGS
SEDATIVE-HYPNOTICS
are drugs which depress or slow down the body's functions.
Often these drugs are referred to as tranquilizers and sleeping
pills or sometimes just as sedatives. Their effects range from
calming down anxious people to promoting sleep.
SEDATIVE HYPNOTICS
Benzodiazepines (most commonly used anxiolytic drug)
Uses
Reduction of anxiety
Sedative-hypnotic; induces sleep
Skeletal muscle relaxant
Seizures: Anticonvulsant
Alcohol withdrawal
Adverse Effects
Drowsiness
Confusion
Amnesia
Respiratory depression/death
Dizziness
Dry Mouth
Constipation
Medication Counselling
do not drive vehicle nor operate machineries
Instruct not to consume alcohol while on medication
have available FLUMAZENIL as antidote for overdose.
Flumazenil is a competitive antagonist


of benzodiazepines at GABA receptor causing reversal of

A

sedation

 LONG-ACTING BENZODIAZEPINES (1-3 DAYS)
Charlie Chaplin Died From Q-Fever

Clonazepam (Rivotril) Anxiolytic, Anticonvulsant, muscle relaxant

Chlordiazepoxide (Librium) Anxiolytic

Diazepam (Valium) Anxiolytic, Anticonvulsant, muscle relaxant

Flurazepam (Dalmane) Hypnotic

Quazepam (Doral) Hypnotic

 INTERMEDIATE-ACTING (10-20 HOURS)
L-A-T-E

Lorazepam (Ativan) Sedative, Anticonvulsant, Muscle Relax.

Alprazolam (Xanax, Xanor) Anxiolytic, Antidepressant

Temazepam (Restoril) Anxiolytic, Hypnotic, Muscle Relaxant

Estazolam (ProSom,Eurodin) Hypnotic, Anxiolytic

 SHORT-ACTING BENZODIAZEPINES (2-8 HOURS)
T-O-M

Triazolam (Halcion) Hypnotic

Oxazepam (Seresta) Anxiolytic
Midazolam (Dormicum) Anxiolytic, Hypnotic, Anticonvulsant,
Used in pre-operative Sedation
KOKOLOGY “IN THE PAGES OF MAGAZINE”
You’ve just bought a copy of a popular weekly magazine and
taken it home to read. How do you go through the features
inside?
1 Read the whole magazine in order from first page to last.
2 Jump straight to the articles that you know will interest you and
read only them.
3 Flip randomly through the pages and read anythings that
seems worthwhile.
4 As long as the format hasn’t been changed, you’d read the
features in the same order as you always do.
1. READ THE WHOLE MAGAZINE IN ORDER.
You’re the type who knows where every penny of your money is
and what it’s being spent on. It’s not that you’re all that
concerned about your budget or financial planning; you just feel
more comfortable when you know exactly how things stand. You
hate the thought of missing something, so you keep all your
accounts in order and know the current balance of your checking
account, including interest, as a matter of course.

2 JUMP STRAIGHT TO THE ARTICLES THAT YOU KNOW WILL INTEREST YOU.

Money burns a whole in your pocket. If you have it, you use it to
buy whatever catches your fancy and think, ‘maybe I’ll start a
savings account next month’, as you spend your last dime. If you
have managed to save something, it’s not unusual for you to
make a trip to the cash machine and make a withdrawal just to
give yourself something to do.
3 FLIP RANDOMLY THROUGH THE PAGES.
You’d say you’re economical. Some would call it stingy. The fact
is, you don’t spend frivolously or waste your resources,
preferring to save it for a rainy day. You’ll never get carried away
with impulse buying or max out your credit cards shopping on
cable TV, but you might want to loosen up on the purse strings
on occasion. After all, money is there to help you live well.
4. SAME ORDER AS YOU ALWAYS DO.
You keep spending according to habit regardless of changes that
take place in your life. If you hit the lottery, it would be hard for
you to stop shopping at discount stores. Alternatively, if you
were facing bankruptcy, you might still insist on designer label
clothes. You can’t be bothered worrying about the vagaries of
fortune, which would make a good idea for you to hook up with
a partner who can, and let him or her handle the finances.
azapirone chemical class.
pharmacology is not related to benzodiazepines or barbiturates,
and so does not carry the risk of physical dependence and
withdrawal symptoms for which those drug classes are known.
causes less psychomotor impairment
BARBITURATES
most likely to produce sleep
non-selective CNS depressant
respiratory depressant
causes sedation
Adverse Drug Effects
tolerance and dependence
increase rish of dependence
enzyme inducer
CNS and respiratory depression
Hallucinations -Epigastric pain Hypersensitivity and Stevens
Jonson syndrome
➤
Medication Counselling
do not drive vehicle nor operate machineries
Instruct not to consume alcohol while on medication 

ULTRA-SHORT ACTING - 30 MINUTES
Thiopental (Trapanal)
Thiamylal (Surital)
SHORT-ACTING 2 HOURS
Hexobarbital
Pentobarbital
INTERMEDIATE-ACTING 3-5 HOURS
Amobarbital
Butabarbital
LONG-ACTING (MORE THAN 6 HOURS)
Barbital
Phenobarbital
CARBAMATES
Meprobamate
was the best-selling minor tranquilizer for a time, but has largely
been replaced by the benzodiazepines due to their wider
therapeutic index (lower risk of toxicity at therapeutically
prescribed doses) and lower incidence of serious side effects.
OTHER SEDATIVES
Zolpidem
Not a benzodiazepine but act on the same site as BZD
Has little or no muscle relaxant and anticonvulsant effects
Has hypnotic actions
Causes minor effects of sleep patterns at recommended
hypnotic dose
Zolpidem
immediate-release forms are Ambien, Intermezzo, Edluar, and
Zolpimist, which are used to help you fall asleep.
The extended-release form of zolpidem is Ambien CR, which has
a first layer that dissolves quickly to help you fall asleep, and a
second layer that dissolves slowly to help you stay asleep.
Chloral Hydrate
metabolised like alcohol, tolerance like bariturates, bedtime
sedative for elderly, “mickey finn” (w/alcohol) - the 1st date rape
drug
“knockout drops”
converted to trichloroethanol (active) 


for preoperative sedation 


Alcohol
CNS effects of alcohol: Produces dose-dependent depression,
produces analgesia, and antipyresis
Mechanism of Action

• Enhances action of GABA at GABA-A receptor 


• inhibits the ability of glutamate to open the cation channel

associated with NMDA 

(N-methyl-D-asparate) subtype of glutamate receptor 


• Disrupt biological membranes through reduction in lipid

viscosity (fluidization) 

other effects of alcohol
vascular: flushed sensation
gi: secretion of saliva and gastric juices
renaL blocks secretion of adh
Consequences of chronic alcoholism
cirrhosis of the liver
tolerance and physical dependence
neurotoxicity
Wenickes-Korsakof ’s syndrome
Hypoglycaemia
Fetal alcohol syndrome
WERNICKES KORSAKKOF’S SYNDROM
Wernicke encephalopathy and Korsakoff syndrome are different
conditions that often occur together. Both are due to brain
damage caused by a lack of vitamin B1.
Lack of vitamin B1 is common in people with alcoholism. It is
also common in persons whose bodies do not absorb food
properly (malabsorption), as sometimes occurs with a chronic
illness or after obesity (bariatric) surgery.
Korsakoff syndrome, or Korsakoff psychosis, tends to develop as
Wernicke symptoms go away. Wernicke encephalopathy causes
brain damage in lower parts of the brain called the thalamus and
hypothalamus. Korsakoff psychosis results from permanent
damage to areas of the brain involved with memory.
ANTIHISTAMINES
H1 receptor antagonist
CNS effects (Drowsiness and sedation) — s/e but are clinically
useful than the peripheral effects
clinically used for allergic reactions, as anti-emetics, and for
sedation
sedative antihistamines are sometimes used as sleeping pills,
particularly for wakeful children
peripheral antimuscarinic actions are always unwanted — dry
mouth, constipation, blurred vision, and urinary retention
DRUG THERAPY FOR NEUROSIS
an accumulation of anxiety and tension leads to emotional
changes and abnormal behaviour
ANTI-ANXIETY AGENTS
Benzodiazepines
Useful in treating anxiety that accompanies some forms of
depression and mania
For panic disorders, ALPRAZOLAM is effective for short term
and long term treatment
DIAZEPAM is preferred for patients with anxiety that may
require treatment for prolonged period of time
5HT1A RECEPTOR AGONIST
Buspirone
BETA BLOCKERS “OLOLS”
Used mainly to reduce physical symptoms of anxiety (tremors,
palpitations, etc.)
No effect on affective component

CNS STIMULANTS
Psychomotor stimulants
Cocaine
binds to the site on dopamine transporter (DAT)
blocks monoamine reuptake into presynaptic terminals
Amphetamines
blocks reuptake
release monoamine oxidase (MAO)
may directly activate catecholamine receptor
Non-Amphetamines
Cocaine
Absorption through mucous membranes (snorting): Cocaine’s
vasoconstrictive property limits its own absorption (20-30%
absorbed).
Peak reached in 30-60 minutes
Inhalation of freebase smoke:
Onset of effect in 8-10 seconds.
6-32% reaching plasma.
Peak plasma levels reached at 5 minutes, persisting for 30 minutes.
Intravenous Administration:
Onset of effect in 30-60 set
Penetrates BBB rapidly, initial brain concentration far exceeds
plasma concentration
Removed slowly from brain
Half-life in plasma = 30-90 minutes
Rapid enzymatic breakdown
Detectable for 12+ hrs after use (metabolites detectable up to 2
weeks after use)
Freely crosses placental barrier
Potentiates synaptic action due to actively blocking the reuptake
of DA, NE & serotonin
Exerts inhibitory effect on postsynaptic dopamine receptors
Blocks the presynaptic transporter protein for DA
Increases levels of DA at the synaptic cleft, creating a euphoric
sensation
Serotonin binding provides additional reinforcement
Low dose is hard to maintain due to increasing tolerance
(progressively higher doses needed)
Appetite repression
See Slide 2: General effects of psychomotor stimulants
(increased BP, HR, body temp etc.)
Low Dose Cocaine

Euphoria, giddiness, boastfulness, self-consciousness (lasting 30

minutes) then mild euphoria, anxiousness (lasting 60-90
minutes)
Then cocaine craving & rebound depression
Eventually, loss of coordination, tremors & seizures
Increased interest in sex & increased sexual dysfunction
High Dose Cocaine

Toxic Paranoid Psychosis – anxiety, sleep deprivation,

hypervigilance, paranoia, suspiciousness
Hyperreactivity, impulsiveness, aggression, homicidal tendencies
Withdrawal can result in hallucinations
Treatment

Obstacles – rewarding nature of cocaine, tendency towards

relapse, presence of other disorders/addictions
Areas of Need – antiwithdrawal agents, anticraving agents
(blocking dopamine receptors), treatment of comorbid
disorders

New types of treatment – ritalin & tricyclic antidepressants

Amphetamines

CNS effects are caused by release of NE and DA from

presynaptic storage sites in the nerve terminals, increasing the
amounts available at the postsynaptic receptor
Pharmacologic Effects

Response intensity and duration varies w/type of drug, dose &

route of administration
Low dose: typical psychomotor stimulation
Moderate dose: tremors, insomnia, agitation, increased
respiration
Continuous high doses: repetitive activity, aggression, delusions,
anorexia
Detectable in urine for 48 hours
Non-Amphetamine
Differ from amphetamines in that they lack the basic
amphetamine nucleus
Have similar effects to amphetamines
Include ephedrine (ma-huang) which is used among athletes as
a stimulant and is found in some OTC weight loss treatments
➤
Sibutramine (Meridia)
Serotonin and norepinephrine reuptake inhibitor
Does not appear to have properties lending it to compulsive
misuse
Causes significant increases in heart rate and blood pressure,
limiting its use
Orlistal (Xenical) can be used as an alternative
➤
Methylphenidate (Ritalin)
Used in treatment of ADHD to calm hyperactivity and improve
attention (prescribed in 90% of cases)
Half-life ≈ 2-4 hours
Variable absorption rates, but generally a rapid onset with short
duration (multiple administrations needed over the course of a
day)
low abuse potential
Stimulants improve behavior and learning in 60-80% of correctly
diagnosed children
10-30% of ADHD individuals are treatment resistant (little to no
response to treatment)
Alternatives: antidepressants like fluoxetine (Prozac), buproprion
(Welbutrin) and buspirone (Buspar)
With antidepressants, rare cases of high cardiac toxicity have
been found
Convulsants and Respiratory Stimulants
Some convulsants were previously used in shock therapy in
psychiatric medicine, as an alternative to electroconvulsive therapy.
A convulsant is a drug which induces convulsions and/or
epileptic seizures, the opposite of an anticonvulsant.
bupropion
tramadol
pethidine
dextropropoxyphene
clomipramine
Psychotomimetic Agents
A drug with psychotomimetic (also known as psychotogenic)
actions mimics the symptoms of psychosis, including delusions
and/or delirium, as opposed to just hallucinations.
Some drugs of the opioid class have psychotomimetic effects.
Pentazocine and butorphanol fall under this opioid class.
[2]

There is evidence that cannabinoids are psychotomimetic,

Methylxanthines
Caffeine, Theophylline, Theobromine
MOA: inhibition of phosphodiesterase thus increase cAMP; b.
increase Ca+ permeability; c. Blockade of the adenosine receptor
Pharmacologic Actions
Decrease fatigue and increase mental awareness, anxiety and
tremors
Has a positive inotropic and chronotropic effects on the heart 


Can induce diuresis 


Stimulates secretions of HCI from the gastric mucosa 


➤
Therapeutic Uses

Caffeine – Include in some OTC analgesic preparations,

particularly in the headache remedies 


Theophylline – For bronchial asthma


Amphetamines
. • CNS effects – Stimulate motor and physical activity; Increase
alertness, decrease fatigue
. • Peripheral actions – Decrease appetite; Increase BP;
Increase in heart rate Therapeutic uses
• Used to treat narcolepsy (Methylphenidate)
• Alleviate behavioral problems and reduce hyperkinesias in
children with attention deficit hyperactivity disorder (ADHD) 

Adverse effects
• Undesirable side effects – Insomnia, irritability, weakness,
dizziness, tremor and hyperactive reflexes
• Chronic use – “amphetamine psychosis”
• Potential for addiction
• Cardiac effects – Cardiac arrhythmias, hypertension
• GI effects – Anorexia, nausea and vomiting, diarrhea
Cocaine
• Potentiates and prolongs CNS and peripheral actions of
catecholamine 


• Produces intense euphoria 


• Used to increase mood and psychomotor activities during the

first few weeks of treatment of 

severely depressed patients 


• Also used as local anesthetic in eye, ear, nose and throat

surgery
Nicotine

• CNS effects – In low doses, it causes arousal and relaxation,

but at high doses, it causes respiratory 

paralysis
• Not currently used therapeutically except in smoking cessation
• Widely abused drug
• Adverse effects – irritability and tremors; Intestinal cramps and
diarrhea; Increased heart rate and BP; 

Increase rate of metabolism of a number of drug
PSYCHOTOMIMETIC AGENTS
Phencyclidine (PCP)
Angel Dust
• Has anticholinergic activity, but produces hypersalivation 


• An analog of Ketamine that produces “dissociative anesthesia”

(insensitivity to pain without loss of 

consciousness) and analgesia 


• Withdrawn from its uses as dissociative anesthetic because of

its hallucinogenic property, and is now replaced by ketamine

KOKOLOGY 15 “IN THE BAG”
All of us lose things. Sometimes we don’t even realize they’re
lost. Think about the last time you lost something: That sense of
frustration as you retraced your steps, scanning the ground,
looking under furniture, and sifting through the trash.
Remember the feeling of desperation as you check your pockets for
the fifth time just to make sure you didn’t miss it? Lost objects
have a way of staying lost, only to turn up months after you’ve
giving up looking and forgotten all about them. Finding things lost
by other people works the same way. You don’t find dropped
wallets in the street or lost purses on the train by consciously
going out to look for them. If you find one, it’s usually just by
stumbling across it while you’re doing something else.
 You’re walking down the street when you come across a closed
black briefcase. There’s no one else around, and when you open
it to check for the owner’s name, out spills a bundle of cash.
What is your first reaction to this sudden windfall?
1. “Hey this must be my lucky day!”
2. “Oh no, what am I’m going to do now?”
3. “I’d better take a night to think this over.”
4. “God must have wanted me to have this.”
Your reaction on finding the bag of money reveals how you
would react if an attractive person suddenly asked you out on a
date.
1. “HEY THIS MUST BE MY LUCKY DAY!”
You have a childlike capacity for joy at your own good fortune. If
more people could express their happiness like you, the world
would be a better place.
 2. “OH NO, WHAT AM I’M GOING TO DO NOW?”
It’s normal to feel a little uncertain at times like these. But in
the end the decision is all up to you. Take your time and think it
over, but don’t spend too long wringing your hands or someone
else might just come along and snatch your good fortune out
from under your nose.
3. “I’D BETTER TAKE A NIGHT TO THINK THIS OVER.”
Big decisions should be made with a clear head after a good
night’s sleep. There’s a lot to be said for your policy of looking
before you leap, but wouldn’t it feel good every once in a while
to cross the street without looking both ways? Sometimes you
need to go with your instincts, even it it means taking some
unacceptable risks. Love and danger go hand in hand.
4. “GOD MUST HAVE WANTED ME TO HAVE THIS.”
Either you don’t take divine intervention very seriously, or you
think of dating as a religious experience.
Lysergic Acid Diethylamide (LSD)
• Interacts with several 5HT receptor subtypes in the brain 


• Low doses: hallucinations with brilliant colors, and mood

alteration 


• High doses; long-lasting psychotic changes 


Tetrahydrocannabinol (THC)
• Main alkaloid in marijuana
• Produces euphoria followed by drowsiness and relaxation;
Impairs short term memory and mental 

activity
• Increase appetite, causes xerostomia, visual hallucinations,
delusions, and enhancement of sensory 

Activity
• MOA is unknown
KOKOLOGY 14 “INTO THE DEPTHS”
Every adventure involves an element of danger—it’s the danger
that makes adventures so exciting and hard to resist. People
willingly spend good money to experience that same thrill
without the physical risk. It’s this fact of human nature that
keeps haunted house attractions and sky-diving schools in
business. The impulse to face risks is in us all. Indeed, the
fascination with danger can prove to be such a powerful lure that
some people will gamble with their own lives to confront a
mystery or explore a new world. We’ve all watched as the
unwitting hero of a horror movie is about to walk through a
darkened doorway and wanted to yell, “Don’t go in there! Are
you crazy?” But what would you do if it were you?
Our next scenario leads us into the dark world, where the line
between simple thrills and actual fear is blurred…
 1. You are in an old, abandoned building where no human has
set foot for years and have discovered a staircase leading
underground. Slowly you make your way down, counting the
steps as you go. One step… two… three… How many steps is it
to the bottom of the stairs?
 2. The underground room is pitch black. Then, from the
darkness you hear the sound of another person. Is the person
weeping softly? Moaning wordlessly? Is it a voice speaking to
you?
3. How do you react on hearing the sound of this other person?
Do you try to search out the source? Is your first instinct to run
up the stairs without looking back? Or are you paralyzed with
fear and frozen where you stand?
4. You hear a person now calling your name and see a figure
descending from the light at the top of the stairs. Who is this
person coming down the stairs?
 Abandoned buildings and underground rooms are highly
symbolic of buried memories and old psychological scars. All of
us have had an experience we’d rather not recall or a heart-break
we thought we’d forgotten. But the memory is not so easily
erased, and the things we hoped to forget linger for longer than
we’d like to admit. Your responses to this situation show how
you deal with painful memories of the past.
1
The number of steps to the bottom of the stairs indicates the
impact of the psychological scars you are bearing. People who
said there were only a few stairs feel little adverse effect from
the past. But those who described a long staircase leading deep
into the earth carry correspondingly deep wounds inside.
2
The sounds you heard out of the darkness reveal how you got through
bad experiences in your past. Those who said they heard weeping have
been comforted by others in times of trouble and recovered with the
help they received. The people who took care of you in their kindness
have helped you become the person you are today. The tears you cried
were not in vain. People who heard wordless moaning went though
hard times in their past alone. The moaning you hear in the dark is
your own buried pain. Perhaps the time has come to open the door and
let the sun shine in. Things won’t look so bleak in the light of day.
Those who heard a voice speaking to them wear their old scars like a
badge of honor, refusing to think of them as wounds. Nietzsche said
“That which does not kill us, makes us stronger.” And you seem to
have taken this philosophy to heart. But be careful not to let this
harden you to the feelings of others
3
Your reaction to the sounds in the darkness shows how you deal
with the painful aspects of your own past. If you went out to
search for the source of the sound, it’s likely you show the same
take-charge attitude in your own life. By facing your problems
head on, you’re bound to discover solutions. Those of you who
ran straight back upstairs without confronting the sounds have a
history of ignoring problems in the hopes that they’ll just go
away. That approach may work sometimes, but don’t be
surprised when the trouble stays around longer that you
anticipated. Sometimes you need to stand and face your fears. If
you were frozen in place with fear, it may be that you have
unresolved conflicts in your own past that continue to haunt you
and keep you from moving ahead with you life.
4
The person who appeared at the top of the stairs calling your
name is someone you feel you can rely on in times a trouble.
The name you gave is the person you believe will comfort you
and help to heal your inner wounds.
DRUG THERAPY FOR PSYCHOTIC DISORDERS
Neuroleptics
Antidepressants
Antigenic
Antipsychotic agents (Neuroleptics)
Typical Neuroleptics
Atypical neuroleptics
Typical (Traditional) Neuroleptics
Phenothiazines
Chlorpromazine (Thorazine), Fluphenazine, Trifluoperazine,
Thiordazine, Perphanazine
Butyrophenones - Haloperidol (Haldol), Droperidol
Thiothixines
Thiothixines, Chloprothixine
Diphenylbutyrylpiperidine
Pimozidine
Dibenzoxepines
Loxapine
Dihydroindolone
Molindone
Atypical Neuroleptics
Dibenzodiazepine - Clozapine (Clozaril), Olanzapine
Sulphide - Benzamide
Risperidone - Bezisoxazole
Sertidole - Phynylindole
Clozapine (Clozaril)
It is mainly used for schizophrenia that does not improve
following the use of other antipsychotic medications
Clozapine is a partial agonist at the 5-HT subunit of the
[43]
1A

serotonin receptor, putatively improving depression, anxiety, and

the negative cognitive symptoms associated with schizophrenia. [44]
Olanzapine (Zyprexa)
binds to 5HT2a receptor
The first-line psychiatric treatment for schizophrenia
Olanzapine is structurally similar to clozapine and quetiapine,
classified as a thienobenzodiazepine.
highest affinity of any second-generation antipsychotic towards
the P-glycoprotein
olanzapine poses a relatively low risk of extrapyramidal side
effects
\
Pharmacologic Actions
Dopamine-receptor blockade: neurological effects
Extrapyramidal syndrome – Occur with chronic use of
antipsychotics
Dystonia
Akinesia
Parkinsons-like syndrome

Akathisia
Tardive dyskinesia
two main kinds of antipsychotic-induced motor disturbances
ACUTE DYSTONIAS (reversible) – Are involuntary movements
(muscle spasm, protruding tongue, torticollis, etc.) and often a
Parkinson-type syndrome
• TARDIVE DYSKINESIA (irreversible) – Consist of involuntary
movements, often of the face and tngue, but also of the trunks
and limbs

*Incidence of extrapyramidal effets is less with “atypical”
antipsychotics
Dopamine-receptor blockage: Endocrine effects
Hyperprolactinemia, Gynecomastia, Galactorrhea, Sexual
dysfunction

Cholinergic Receptor blockade
difficulty micturition, constipation, blurred vision, dry mouth
(xerostomia)
Alpha-adrenoreceptor blockade
failure to ejaculate, orthostatic hypotension, light headedness
Histamine blockade
sedation
Serotonin blockade
hypothermia, hyperthermia
Therapeutic Uses
Treatment of schizophrenia and acute behavioral emergencies

• Adjunct therapy in psychotic depression and mania (Haloperidol is
indicated in highly agitated and manic patients; Sulpiride have specific
antidrepressant action)
• Treatment of Huntington’s chorea (mainly haloperidol) 


• Used in combination with narcotic analgesic for the treatment of chronic

pain with severe anxiety – 

Droperidol and fentanyl citrate 


• Anti-emetic – Phenothiazines are clinically useful, especially promethazine 


• Other clinically Uses of haloperidol: DOC for phencyclidine overdose;

Huntington’s disease; Tourette’s 

Syndrome
Clinical Efficacy of Antipsychotics
• Typical antipsychotics are effective only in 70% of schizophrenic
patients, 30% are classed as “treatment resistant” 


• Typical antipsychotics effectively control the positive symptoms but

ineffectively in relieving negative Symptoms 

• Clozapine overcome the shortcomings of typical antipsychotics,
showing efficacy in “treatment 


ACE LEARNING SPECIALISTS

Page 9
resistant” patient and improving negative, as well as positive symptoms
Other unwanted Effects

• Ocular complications – Corneal deposits (chlorpromazine), retinal deposits

(thioridazine only) 


• Cardiac toxicity – occur with more than 300mg of thioridazine daily 


• Weight gain – Related to 5HT antagonism 


• Idiosyncratic and hypersensitivity reactions 


o Jaundice – occur with older phenothiazines


o Leukemia and agranulocytosis – rare, but potentially fatal
Clozapine produce higher incidence of this reaction, but olanzapine is free of this
disadvantage o Urticarial skin reactions

o Neuroleptic malignant syndrome
DRUG THERAPY FOR MAJOR DEPRESSION
theory of depression
due to a deficiency of NE, 5-HT, and dopamine in the synapses
of the CNS
TRICYCLIC ANTIDEPRESSANTS TCA’S
non selective reuptake inhibitors
Tertiary Amine - Amitriptyline; Imipramine - prototype drug;
Doxepin; Clomipramine; Trimipramine
Secondary Amine - Amoxapine, Maprotiline, Protriptyline,
Deipramine, Nortriptyline
First Generation
Amitryptaline (Elavil), Imipramine (Tofranil), Clomipramine
(Anafranil), Nortriptyline (Pamelor), Desipramine
(Norpramin)
Second Generation Heterocyclics
Bupropion (Wellbutrin), Trazodone, Amoxapine, Maprotiline
Third Generation Heterocyclics
Mitrazapine (Avanza), Venlafaxine (Effexor), Nefazodone
HOW TO REMEMBER?
A Amitriptyline
D Doxepine
I Imipramine
C Clomipramine
ADICT : Pure mixed reuptake inhibitors
T Trimipramine
MaDONE : predominantly NEreuptake inhibitors
Ma Maprteline
D Desimipramine
O Oxaprotiline
N Nortyptyline
A Amoxapine
FIRST GENERATION
PHARMACOLOGIC ACTION

• Elevate mood, improve mental awareness, increase physical

activity, and reduce morbid Preoccupation 


• Onset of mood elevation is slow 


• Do not produce CNS stimulation or mood elevation in normal

individuals
CLINICAL INDICATION
• Mood disorders (in severe major depression) – May require 2
to 8 weeks to become apparent 


• Panic disorders; Generalized anxiety disorder; Post-traumatic

stress disorder 


• Obsessive-compulsive disorder (OCD) - Clomipramine 


• Used to control enuresis in children (Imipramine)

• Pain disorders
COMMON SIDE EFFECTS OF TCAS
Marked autonomic effects including hypotension (orthostatic)
and sinus tachycardia
Excessive sedation
SEROTONIN-SPECIFIC REUPTAKE INHIBITORS (SSRI’S)
Fluoxetine (Prozac) - prototype
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Escitalopram (Lexapro)
Citalopram (Celexa)
PHARMACOLOGIC ACTION
• As effective as the TCA’s in the treatment of depression 


• Fewer sedative, autonomic, and cardiovascular side effects

than TCA’s 


• Flouxetine is a potent inhibitor of hepatic CYP-450 isoenzyme


Clinically uses of SSRI’s: Depression; Effective in treating
Bulimia nervosa and Obsessive-compulsive disorder (OCD);
Also used in Anorexia nervosa; Panic disorders; Pain
associated with diabetic neuropathy; Premenstrual syndrome
MONOAMINE OXIDASE INHIBITORS
Isocarboxazid (Marplan)
Tranylcypromine (Parnate) Have mind amphetamine like stimulant effect

Phenelzineu (Nardil)
PHARMACOLOGIC EFFECT
Require 2 to 4 weeks to produce maximum effects
ATYPICAL ANTIDEPRESSANTS
Trazodone (Desyrel)
Similar structure to alprazolam (xanor)
effective for improving sleep
Inhibits selective reuptake of serotonin
Bupropion (Wellbutrin)
no side effects related to sexual dysfunction
norepinephrine dopamine reuptake inhibitor
ANTIGENIC AGENTS
Lithium
Haloperidol
Anticonvulsant
Valproic Acid
Carbamazepine
LITHIUM (ESKALITH, LITHOBID)
L Leucocytosis
I Insipidus (Diabetic)
T Tremor, Teratogenicity (1st tri)
H Hypothyroidism
I Increased Weight
U Vomiting (substitute V for U) - include Nausea & GI Dist.
M Misc. - ECG Changes, Acne

K - Kidney Damage
CARBAMAZEPINE (TEGRETOL)
• Occasionally used in manic-depressive patients to ameliorate
the symptoms 


• Inhibits uptake and release of NE from synapse but does not

influence GABA uptake
ANTI-EPILEPTIC AGENTS ANTICONVULSANTS
Drugs used in Partial Seizures and generalized Tonic-Clonic
Seizures
Hydantoin Derivatives - Phenytoin, mephenytoin
Barbiturates Derivatives - Mephobarbital, Phenobarbital,
Primidone
➤ Gabapentin
Carbamazepine
➤ Zonisamide
Felbamate
➤ Lamotrigine
Tiagabine
➤ Topiramate
Phenytoin
Vigabatrin
PHENYTOIN (DILANTIN)
• One of the most effective drugs against and generalized tonic-
clonic seizures 


• Reduces hyperexcitability of neurons – Interfering the influx of

excess NA+; Stimulating NA+K+ATPase 

and reestablishes ionic gradient 


• Inhibits the spread of the seizure process – Competing with

the action of calcium
SIDE EFFECTS
Phenytoin Has Given MDs Frustrations
P Peripheral Neuropathy
H Hirsutism
G Gingival Hyperplasia
M Megaloblastic Anemia
D Drug Induced Lupus
S Steven Johnson’s Syndrome
F Fetal Hydantoin Syndrome
CARBAMAZEPINE (TEGRETOL)
Drug of choice for partial seizure
Blocks the NA channels in the brain; Also potentiates the
+

postsynaptic action of GABA

Adverse effects are: Diplopia and ataxia – dose related; Liver
disorders, CV disorder, GI upset, bone marrow depression and
atropine-like reaction

* Oxcarbazepine has a fewer adverse effects and drug interactions
than carbamazepinse
PHENOBARBITAL
Drug of choice for febrile seizures
Potentiate the inhibitory effects of GABA, Also block the
excitatory responses induced by glutamate
Often used with phenytoin in grand mal epilepsy

Primidone – Converted to Phenobarbital; Alternative choice for
adults who have partial generalized seizures
VIGABATRIN (SABRIL)
Indicated particularly for partial seizure 


Irreversibly inhibits GABA aminotransferase (GABA-T), the

enzyme responsible for the degradation of GABA 


Typical toxicities include; Drowsiness, Dizziness and weight gain 


Agitation, confusion and psychosis are less common

(Contraindicated to patients with mental illness)




➤
LAMOTRIGINE (LAMICTAL)
Effective as monotherapy for partial seizures
Active against absence and myoclonic seizures in children
Inactivates Na channels
+

Adverse effects include; Dizziness, Nausea, Headache, Diplopia


FELBAMATE (FELBATOL)
Has weak effects on sodium channels and little effect GABA
Increase plasma concentration of phenytoin and valproic acid
concentration but decrease levels of 

Carbamazepine



GABAPENTIN (NEURONTIN)
Effective as an adjunct against partial and GTC seizures
An analog of GABA, but not acting on GABA receptor, Antiepileptic
effect is poorly understood
Adverse effects: somnolence, dizziness, ataxia, headache and tremor 


➤
TOPIRAMATE (TOPAMAX)
MOA is similar to carbamazepine and phenytoin
Also potentiates inhibitory effects of GABA by acting at a
different receptor from the BZD or 

barbiturate site
Adverse effects: cognitive slowing , parathesias, somnolence,
fatigue, nervousness and confusion 


➤
TIAGABINE (GABITRIL)
MOA: inhibits GABAuptake
Adverse effects include; Dizziness, Nervousness, Tremor,
Depression , Emotional lability 

ZONISAMIDE (ZONEGRAN)
A sulfonamide derivative effective against partial and GTC
seizures
MOA is unknown
Adverse effects include; Drowsiness, Cognitive impairment,
Formation of renal stones 


➤
DRUGS USED IN GENERAL SEIZURES
Succinamides
Ethosuximide (Zarontin)
Methusuximide
Phensuximide
Oxazolidinediones
Trimethadione (Troxidone)
Paramethadione (Paradione)
Propylpentanoic Acid Derivates
Valproic Acid (Depakene)
SUCCINIMIDES
Ethosuximide
particularly effective in absence seizure
MOA: Reduce the T-type Ca currents in thalamic neutrons
+

it lacks the idiosyncratic hepatotoxicity of the alternative anti-

absence drug, valproic acid. [3]

Adverse effects: GI effects, Headache, Dizziness, Blood dyscrasia 


VALPROIC ACID (DEPAKENE)
Inhibits GABA-T in the brain
Very effective against absence seizures and has the ability to
control myoclonic seizure
Also used in atonic attacks; Effective in partial seizure
Adverse effects: GI upset, Drowsiness. Ataxia, liver and blood
disorders, weight gain
Teratogenic effect: Spina bifida
OXAZOLIDINEDIONES
Reduce T-Type Ca currents in thalamic neurons
+

Adverse effects; Sedation , Hemeralopia (A galre effect in which

visual adaptation is impaired), 

Decreased neutropil
OTHER DRUGS USED IN THE MANAGEMENT OF EPILEPSY
Benzodiazepine derivatives
Acetazolamipe
Bromide
 BENZODIAZEPINES
o DIAZEPAM (Valium)– most effective in status epilepticus

o LORAZEPAM (Ativan) – also used in status epilepticus

o CLONAZEPAM (Rivotril) – used in absence seizure, infantile
spasm,
myoclonic seizures and atonic
seizures
o CLORAZEPATE (Tranxene)– adjunct medication in complex partial
seizures

o NITRAZEPAM – used in infantile spasm and myoclonic seizures

o CLOBAZAM
ACETAZOLAMIDE (DIAMOX)
A diuretic that inhibits carbonic anhydrase
Diminish the depolarizing action of bicarbonate ions moving out
of neurons vai GABA receptor ion channel
used for all types of seizures
BROMIDE
First anti epileptic drug
MOA is unknown
Useful in management of epilepsy in patients with porphyria 


Adverse effects include; Skin rashes. Sedation, Behavioral

changes 

KOKOLOGY 16 “CINDERELLA STORY”
The rags-to-riches story of a girl whose dreams come true,
Cinderella is one of the classic fairy tales in world literature. Of
all the memorable scenes in the tale, which stands out most in
your mind?
1. CINDERELLA SUFFERING AT THE HANDS OF HER WICKED STEPMOTHER.
2. CINDERELLA BEING TRANSFORMED INTO A BEAUTIFUL PRINCESS BY HER FAIRY GODMOTHER.
3. CINDERELLA LOSING HER SLIPPER ON THE STEPS TO THE PALACE AS THE CLOCK STRIKES MIDNIGHT.
4. THE SCENE WHERE THE PRINCE FINALLY FINDS HER AND FITS THE GLASS SLIPPER ON HER FOOT.
 Why do you react so strongly to the scene you picked? A closer
look at the elements of each scene tells us your choice is related
to your greatest character weakness or flaw.
1. CINDERELLA SUFFERING AT THE HANDS OF HER WICKED STEPMOTHER.

The thought of poor Cinderella scrubbing the floors while her

stepmother and sisters showered her with abuse evokes strong
feelings of pity. But on the underside of pity lie feelings of
superiority and pride. You remember this scene for the way it
made you feel better than someone. It’s good for you to be able
to look down at others with a tender eye, but be wary of your
tendency to look down on them all the time.
2. CINDERELLA BEING TRANSFORMED INTO A BEAUTIFUL PRINCESS BY HER FAIRY GODMOTHER.

With a wave of her magic wand, her fairy godmother makes

Cinderella into an enchanted princess and changes her world
forever. But here in the real world, things are not easy to do.
Your biggest faults are your blindness to the practical questions
in life and your lack of attention to planning and consequences.
You seem to forget that there are no fairy godmothers waiting to
save you from the problems you create for yourself.
3. CINDERELLA LOSING HER SLIPPER ON THE STEPS TO THE PALACE AS THE CLOCK STRIKES TWELVE.

The scene left a strong impression on you because it played

upon your sense of dependency on others. It’s easy to see
yourself running out at the stroke of midnight, leaving behind
nothing but problems and unanswered questions. In the short
term, relying on others to clean up your messes may seem like
the easy way through life, but one day you’re going to have to
face the music.
4. THE SCENE WHERE THE PRINCE FINALLY FINDS HER AND FITS THE GLASS SLIPPER ON HER FOOT.

Almost everybody loves a happy ending, and you count yourself

among them. And therein lies your problem. You’re too easily
satisfied with the simple, the normal, and the average. All you
expect from life is an average job, an average salary, average
friends, average family, average kids… Work on discovering
more of what makes you unique and original. Remember, you’re
an individual even if you don’t feel like one.
KOKOLOGY “UNDER A CLEAR BLUE SKY”
Imagine a clear blue sky without a cloud in sight. Just thinking
about it should give your spirits a little lift. Now turn your
mind’s eye down to survey the landscape. Which of these scenes
feels most calm and relaxing to you?
1. A WHITE SNOWY PLAIN
2. A BLUE SEASCAPE.
3. A GREEN MOUNTAIN.
4. A FIELD OF YELLOW FLOWERS.
 The color blue has power to soothe the soul. Even a blue image
in the mind can slow the pulse and make you take a deep breath.
Other colors have significance too. The scene you pictured
contrasted against that clear blue sky reveals a hidden talent that
resides in the depths of your untroubled mind.
1. A WHITE SNOWY PLAIN
You are blessed with a special sensitivity that allows you to
comprehend situations at a glance and decipher complex
problems without needing any proof or explanation. You have
what it takes to be a clear-sighted decision maker and even
something of a visionary. Always trust your first intuitions; they
will guide you well.
2. A BLUE SEASCAPE.
You have a natural talent for interpersonal relations. People
respect your ability to communicate with others and the way you
help bring diverse groups together. Just by being around, you
help others work more smoothly and efficiently, making you an
invaluable member of any project or team. When you say “Nice
job, keep up the good work” people know you mean it. So it
means much more to them.
3. A GREEN MOUNTAIN.
Your gift is for expressive communications. You always seem to
be able to find the words to express the way you feel, and people
soon realize it’s exactly how they were feeling too. They say that
joy shared is multiplied while shared grief is divided. You always
seem to help others find the right side of the equation.
4. A FIELD OF YELLOW FLOWERS.
You are a storehouse of knowledge and creativity, bursting with
ideas and almost infinite potential. Keep attuned to the feeling
of others and never stop working on building your dreams, and
there is nothing you cannot achieve.
DRUG THERAPY FOR PARKINSONISM
Drug that increase dopamine levels; Levodopa, Selegiline,
Amantadine

• Dopamine receptor agonist: Bromocriptine, Pergolide,
Pramipexole, Ropinirole • Acetylcholine receptor antagonist:
Benztropine, Trihexyphenidyl, Biperiden
Dopa decarboxylase inhibitor: Cabidopa
COMT inhibitor – Tolcapone, Entacapone 

LEVODOPA (SINEMET)
• Is the metabolic precursor of dopamine 


• Transported into the brain subsequently converted to dopamine in the

basal ganglia 


• It restores the dopamine levels in the extrapyramidal centers –

Decreases the rigidity, tremors and other symptoms 


• Large doses: peripheral side effects (nausea, vomiting, cardiac

arrhythmias, hypotension) 


• It is decarboxylated in the periphery 


o Given in combination with carbidopa (A dopa-decarboxylase inhibitor)


• Adverse effects of levodopa – Nausea and vomiting, Anorexia,
Hallucination, Dyskinesia
WHAT DRUGS SHOULD NOT BE GIVEN WITH LEVODOPA?
• Nonselective MAOI’s – Hypertensive crisis due to excess
dopamine in the periphery 

(Inc. catecholamines) 


• Pyridoxine – Diminishes the effectiveness of Levodopa

because it increase peripheral breakdown of 

the drug 


• Antipyschotics – Oppose levodopa’s effect 


ADVERSE EFFECTS
• Peripheral effects – Anorexia, Nausea and vomiting,
Tachycardia and ventricular extrasystoles, Hypotension,
Mydriasis, Blood dyscracias, + coombs test, Saliva & urine
discoloration


• CNS effects – Visual & auditory hallucinations, Dyskinesia,
Mood changes, Depression and anxiety

Adverse effects: overstimulation of central dopamine receptors

Dyskinesia Hallucination Restlessness Confusion
SELEGILINE (DEPRENYL)
Selectively inhibits MAO-B

o Decrease the metabolism of dopamine by preventing inter-
neuronal degradation o Inhibition of MAO-B slows the
breakdown of dopamine in the striatum
• Adverse effects include; Dyskinesia, Mental and Psychiatric
effect, Nausea
AMANTADINE (SYMMETREL)
• An antiviral agent that enhances the release of dopamine from
surviving nigral neurons 


• Inhibits the reuptake of dopamine at synapses

•Adverseeffectsinclude;Restlessness,Agitationandconfusion,O
rthostatichypotension,Peripheraledema 

DOPAMINE RECEPTOR AGONIST
The main alternatives to levodopa in treating Parkinson’s disease
are the dopamine receptor agonists (dopamine agonists).
These drugs act directly on the dopamine receptors in the brain,
taking the place of the dopamine which the brain cells can no
longer produce.
Dopamine agonists have the advantage of causing fewer long
term motor complications.
BROMOCRIPTINE (PARLODEL)
An ergot derivative that predominantly stimulates the striatal D
2

non-adenyl cyclase-linked dopamine 


Receptors
Adverse effects – Hallucination and Delirium, Nausea and
vomiting, Cardia arrhythmia, Postural hypotension, Worsen
ulcer
PERGOLIDE (PERMAX)
Stimulates popstsynaptic dopamine receptors at both D and
1

D receptor site in the nigrostriatum 


2

Adverse effects are; Anxiety, Confusion, Hallucination,

Dyskinesia 

PRAMIPEXOLE (MIRAPEX)
A non-ergot D – receptor selective agonist
2

Adverse effects; Drowsineness, Hallucination, Insomnia,

Nausea, Orthostatic hypotension
ACETYLCHOLINE RECEPTOR ANTAGONIST
BENZTROPINE (COGENTIN)
• Blocks muscarinic cholinergic receptor in the CNS
o Reduces the excessive cholinergic activity present in the
parkinsonism

• Adverse effects are; Agitation, Nervousness, and Confusion,
Blurred vision, Memory loss,
Hallucination, Difficulty breathing
TRIHEXYPHENIDYL (ARTANE)
• Partially block central cholinergic receptors 


• Helps in restoring the balance of cholinergic and dopamine

activity in the basal ganglia (Classic) Adverse effects of
anticholinergic drugs 


Mydriasis (Blurred vision) Constipation Urinary retention

Tachycardia, Dry mouth and skin
DOPA DECARBOXYLASE INHIBITOR - CARBIDOPA
• It does not cross blood-brain barrier

• Reduces the metabolism of levodopa in the periphery 


• Increase the availability of dopamine to the CNS 


• Decrease the severity of the side effects or periphery formed

dopamine 

COMT INHIBITORS
Entacapone (Comtan) and Tolcapone (Tasmar)
• Used in the treatment of parkinons’s disease as an adjunct to
levodopa/carbidopa therapy 


• Entacapone is a selective and reversible inhibitor of COMT

NARCOTIC ANALGESICS
• Opioids – Refers to all agonist and antagonist with morphine-like
activity

Naturally occurring opioid peptides – Enkephalins, Endorphins,
Dysnorphins Synthetic opioid peptides 


• Heroin
• Morphine related drugs: Morphine (Hydromorphone, Oxymorphone)
• Levorphanol
• Methadone: Propoxyphene
• Meperidine related drugs: Meperidine (Diphenoylate, Loperamde)
• Alphaprodine

• Fentanyl

• Codeine related drugs: Codeine (Hydrocodone, Oxycodone, Tramadol)

• Dextromethorpan

HEROIN
Heroin is an opioid drug that is synthesized from morphine,
from the seed of Asian opium poppy plant.
known as “black tar heroin.”
MORPHINE
It can be used for both acute pain and chronic pain.
used for pain from myocardial infarction and during labour.
It can be given by mouth, by injection into a muscle, by injecting
under the skin, intravenously, into the space around the spinal
cord, or rectally
LEVORPHANOL (LEVO-DROMORON)
Levorphanol acts predominantly as an agonist of the μ-opioid
receptor, but is also an agonist of the δ-opioid, κ-opioid, and
nociceptin receptors, as well as an NMDA receptor antagonist
and a serotonin-norepinephrine reuptake inhibitor
METHADONE (DOLOPHINE)
Levomethadone is a full µ-opioid agonist.
an opioid used to treat pain and as maintenance therapy or to
help with detoxification in people with opioid dependence.
MEPERIDINE (DEMEROL)
pethidine
Like morphine, pethidine exerts its analgesic effects by acting as
an agonist at the μ-opioid receptor
FENTANYL
CODEINE
DEXTROMETORPHAN
Dextromethorphan (DXM or DM) is a drug of the morphinan
class with sedative, dissociative, and stimulant properties (at
higher doses)
It is one of the active ingredients in many over-the-counter cold
and cough medicines
OPIATE AGONISTS
I. Full Agonist – Morphine, Meperidine (1/10x), Methadone (1x),
Fentanyl (80x), Heroin (3-5x),
Hydromorphone (7x)


II. Mixed agonist/antagonist – Pentazocine(1/15x), Nalbuphine

(1x),
Butorphanol (5x)
III. Partial agonist – Codeine (1/12x), Propoxyphene (1/24x),
Oxycodone (2/3x), Hydrocodone,
Buprenorphine (25-50x)
IV. Other opioid agonist – Tramadol

CNS EFFECTS
Analgesia – Reduce both sensory and affective (emotional)
component of pain
Euphoria – A pleasant floating sensation with lessened anxiety
and distress
Sedation; Respiratory depression, Cough suppression; Miosis
Truncal rigidity – An intensification of tone in the trunk muscle
Nausea and vomiting
Temperature – Homeostatic regulation of body temperature
PERIPHERAL EFFECTS
CARDIOVASCULAR SYSTEM – Have no significant direct
effects on the heart; Bradycardia

MEPERIDINE Can result to tachycardia due to its antimuscarinic
action

GI TRACT – Decrease GI motility – constipation

BILIARY TRACT – Contract biliary smooth muscle – biliary colic

RENAL - Depressed, ADH release

UTERUS – May prolong labor


OTHER EFFETS

Neuroendocrine – Stimulate release of ADH, prolactin, and
somatrotopin; Inhibit the release of luteinizing hormone Pruritus;
Modulate the immune system
CLINICAL USES
• Severe pain of coronary, pulmonary and peripheral pain Hepatic
and renal colic 


• Diarrhea Preanesthetic medication Cough suppressant What

physiologic effects of Morphine are not affected by tolerance?
Miosis and Constipation Adverse Effects of Morphine and related
substances

Constrict pupil Causes constipation Respiratory depression

Slows heart rate Dilates blood vessel

Other Adverse Effects of Morphine

• Respiratory depression – Cor pulmonale (pulmonary heart
disease) 


• Elevation of intracranial presence – Head injury

• Withdrawal symptoms – Chills, Diarrhea, Myalgia, Agitation, Anxiety
PECULIAR FEATURES OF SPECIFIC AGENTS
1. METHADONE – used in the treatment of opioid abuse, Tolerance and
dependence develops more slowly

2. FENTANYL

Subgroups: Sufentanil – 5 to 7 more potent than fentanyl; Alfentanil – less
potent but acts more rapidly, shorter duration of action, Remifentanil –
extremely short half-life

3. MEPERIDINE – Has significant antimuscarinic effects, Tachycardia,
dilates pupil

4. CODEINE, OXYCODONE, DIHYDROCODEINE, AND
HRDROCODONE
Less efficacious than morphine (partial agonist); Rarely used alone but in
combination with aspirin,acetaminophen or other drugs
5. ANTIDIARRHEALS – DIPHENOXYLATE – Schedule V; DIFENOXIN
(A metabolite of diphenoxylate, Schedule IV); LOPERAMIDE (Its action is
due peripheral µ-opioid receptor )
6. ANTITUSSIVES – Achieved at does below those necessary
for analgesia

• DEXTROMTHORPHAN – Free of addictive properties; Less
constipating than codeine • CODEINE

• LEVOPROPOXYPHENE – Devoid of opioid effects though can
cause sedation

7. TRAMADOL
• The central analgesic effect is based on; Blockade of the
neuronal reuptake of serotonin; Inhibition of 

NE transporter function; Weak µ-receptor agonist
• Adjunct with pure opioid agonist in the treatment of chronic
neuropathic pain
OPIOID ANTAGONISTS
• Clinically use: Reverse the respiratory depression and coma of
opioid overdose
• Naloxone; Naltrexone




 Kokology 6
“Deep in the Mountains”
The mountain and the sea– nature has a power that
draws us to her. After all, we are all nature’s children,
born into her world and fed on her bounty. No matter
what marvels technology may develop, getting back to
nature lets us feel truly alive. Medical science may
make advances, but the best medicine will always be
nature’s own healing power.

Your next journey will take you back to that green world,
and what better setting for you to rediscover your
natural self?
1. You have to set off to climb a mountain, in search of
a fabulously rare stone. What is your impression of the
mountain as you stand at it’s foot?
2. After a hard search, you still haven’t found the stone,
and now the sun has fallen. What will you do next?
 3. You have finally discovered the stone
you were seeking. What kind of stone is it?
Describe it’s size, weight, and value.
 4. Now it is time to come down from the mountain
and return home. What parting words do you have
for the mountain, and what is its reply?
• The mountain that looms before you represents
your father, or a father figure in your life. In
psychological terms, it is a manifestation of the
archetype of the “wise old man.” The stone you
seek symbolizes the abilities and strengths you
must discover within yourself on your own journey
to adult independence.
 1

• Your impression of the mountain shows the image

you have of your father. Was it difficult and
unforgiving? Gentle and easily conquered? Or did
you have an idealized image of a magnificent peak
that somehow seemed to welcome you and
encourage you in your quest?
 2

• The stone you are searching for represents your as

yet undiscovered talent or strength. Your response
to this question shows whether you will ever realize
that untapped potential. Did you keep searching no
matter what? Did you call it quits for the day but
came back again or did you gave up looking
altogether.
• people who say the’d keep searching for the stone
no matter what tend to show the same persistence
and determination in their own lives, never giving
up even hen efforts seem fruitless

• this who said they’d call it quits for the day but
come back again to continue the search are the
type of people who pace themselves, spreading
their efforts over a long period of time. there're
probably more than a few late bloomers in this
group
• people who gave up looking for the stone
altogether are in danger of never fulfilling their true
potential
 3

• The way you described the stone shows your

feeling of self-worth. How big and heavy was it, and
what did you think of its value?
 4

• Your parting words to the mountain reveal what

you have always wanted, but never been able to
say to your father. The mountain’s reply shows your
idea about his feelings for you.
• you: thanks for everything

• mountain: you take care of yourself

• you: well, it looks life i’m finally through with you

• mountain: you can say that again

• (maybe it’s time you and your father sat down for a
talk!)
 Kokology 5
Picture at an Exhibition

• Every once in a while it’s nice to take break from

your busy schedule and experience the world of art
firsthand. one of us go to concerts or plays, some
take up dance or a musical instrument, others try
their hand at crafts. and of course there’a always a
trip to the museum..
• you are standing in from of a painting at an art
museum, hands clasped behind your back as you
try to take it in. when a total stranger comes up
alongside you and says something to you. which of
the following does the stranger say?
• 1. isn’t that a beautiful picture

• 2. what do you think of this painting

• 3. excuse me, do you have time?

• 4. you know, i happen to be a painter myself

• when a stranger suddenly speakers to you, there’s
always a momentary mix of apprehension and
expectancy. in this imaginary scenario, the words
the stranger spoke actually reflect how you react in
chance encounters and when meeting others. your
answer reveals what kind of impression you make
when meeting someone for the first time
 1

• your friendly and positive nature creates a great

first impression on almost everyone you meeet.
your only concern should be that people may not
take you seriously at first
 2

• you’re the type who likes to feel to the other

person’s permeant before committing yourself to
anything. people can sense that hesistancy, and it
may colour their reactions to you. you wont step on
any toes with your cautious approach, but you may
end up living on other people’s term
 3

• to hald the world you seem like an all right sort, but
to the other half you look just a little strange. you
create a first impression of living life at your own
pace and maintaining an individuality that some
would call eccentric. you don't place much
importance on what others may be thinking or
feeling. for better or worse, therein lies the secret to
you
 4

• on first meeting seomone, you come across as a

little bit nervous and overeager. maybe you're just
trying too hard to be liked. but the harder you try,
the worse an impression you make, don’t worry so
much about making people think you’re great - they
like you better if you just loosen up and relax.
 GENERAL
ANESTHETICS
MECHANISM OF ACTION
➤ increase neuronal threshold for firing
➤ Decrease neuronal activity by hyperpolarzation (Activation of
K+ currents)
GENERAL AESTHETICS
Are CNS depressants which abolish pain by inhibiting the
function of the CNS through an unknown Mechanism
A. General Anesthesia
- loss of consciousness, analgesia, amnesia, skeletal muscle
relaxation
SIGNS AND STAGES OF ANAESTHESIA
STAGE 1 (ANALGESIA) – The cerebral cortex is gradually
inhibited; Euphoria, giddiness, and loss of
consciousness (analgesia, conscious)

STAGE 2 (DELIRIUM AND EXCITEMENT) – Affects the thalamus;
Increase sympathetic tone, increase BP
and heart rate, irregular respirations
STAGE 3 – SURGICAL ANESTHESIA
Plane 1- Sleep, normal BP and respiration

Plane 2 – dilated pupils; loss of corneal reflex
Plane 3 - Skeletal muscle relaxation
Plants 4 - paralysis of the diaphragm

STAGE 4 (MEDULLARY PARALYSIS)
respiratory depression, death
TYPES OF ANESTHETICS
I. INHALATIONAL ANESTHETICS
– VOLATILE LIQUIDS(HALOTHANE, ISOFLURANE, DIETHYL
ETHER);
- GASEOUS – NITROUS OXIDE 


II. INTRAVENOUS ANESTHETICS


1. BARBITURATES – METHOHEXITAL, THIAMYLAL, THIOPENTAL

2. BENZODIAZEPINES – DIAZEPAM, LORAZEPAM, MIDAZOLAM

3. ETOMIDATE

4. OPIOIDS – FENTANYL, MORPHINE

5. DROPERIDOL AND FENTANYL CITRATE (Innovar) –
NEUROLEPTANESTHESIA 6. KETAMINE – DISSOCIATIVE
ANESTHETICS

7. PROPOFOL
HALOTHANE
- 1st halogenated volatile anesthetic
- for children, non hepatotoxic, pleasant odor
- low MAC (0.75%)
- hepatotoxicity, arrhythmia
- may cause uterine relaxation
ENFLURANE - MAC.1.7%
ISOFLURANE - MAC 1.4%
DESFLURANE - MAC 2.0%
SEVOFLURANE
Ae
- cardiovascular depression -> hypotension
- arrythmia due to sensitization of heart to catecholamines
- hepatitis (halothane)
- nephrotoxicity (enflurane)
- malignant hyperthermia (succinylcholine)
-
DISADVANTAGE
- reduces myocardial contractility and causes hypotension
- sensitive myocardium to effects of catecholamines
- hepatotoxicity = hectic necrosis
- malignant hyperthermia (tx. Dantrolene- to counteract muscle
rigidity)
NITROUS OXIDE
- least potent
- laughing gas
- renal surgery (30% NO + 70% 02)
- used with other anesthetic to increase their uptake and
analgesic activity - high MAX 100%
se: post-op nausea and vomiting, oxidizes cobalt in b12->
megaloblastic anemia fetal abnormalities, diffusion, hypoxia
PHYSIOCIOLOGAL EFFECTS OF GENERAL ANESTHETICS
CNS EFFECTS
All nervous tissues are depressed; Voluntary (motor) and involuntary
(automatic) systems are 

Inhibited
Respiratory function is depressed
Some cause pituitary secretion of ADH resulting to post operative urinary
retention
CARDIOVASCULAR EFFECTS –
Myocardium and BP are depressed; Increase heart rate due to vagal Inhibition
RESPIRATORY SYSTEM
Inhaled anesthetics irritate the mucosal lining of the respiratory tract
Increased mucous secretion, coughing and spasm of the larynx SKELETAL
MUSCLES
Causes relaxation due to depression of pyramidal system and spinal reflexes
Some causes relaxation by inhibiting the neuromuscular function
GI TRACT- Nausea and vomiting (occurs during recovery);
Decrease intestinal motility (post operative constipation) 


LIVER – Halothane (high risk), Enflurance and chloroform cause

liver toxicity
INTRAVENOUS ANESTHETICS AND PRE-ANESTHETIC AGENTS
- rapid induction of anesthesia; maintained with inhalation agent
1. thiopental (pentothal, pentobrim)
- ultra-short acting barbituraes; rapid onset (20s) and short
acting (5-10 mins)
- used to induce sedation
2. benzodiazepines
- midazolam
- used for sedation and reduce anxiety
3. Opioids
- fentanyl, morphine
- analgesic
- fentanyl + droperdiol (innovar) - neuroleptanesthesia
(analgesia + amnesia)
3. Propofol (Diprivan, Fresofol)
- for rapid onset, short duration hyponosis
- s/e : pain in injection site, hypotension
ENFLURANE
- less likely to cause tachyarrythmias with epinephrine
- less cardiotoxic

Disadvantage:
- seizures - spike and wake activity; muscle twitching
ISOFLURANE
- induction less than 10 minutes
- preferred anesthetic in neurosurgery
KETAMINE
• dissociative anesthesia
- px remains conscious but has marked catatonic, analgesia,
amnesia
- Produces dissociative anesthesia ( patient appears awake but
is unconscious and does not feel pain)
- bronchodilator
- se: nightmares, HTN, increased ICP
- produces emergence phenomenon
- disorientation, excitation, hallucination, drug recovery (tx.
benzodiazepine)
MOA: blockage of NMDA receptor (excitatory NT)
ULTRASHORT ACTING BARBITURATE (THIOPENTAL)
- used in induction/premedication for anesthesia
BENZODIAZEPINE (MIDAZOLAM)
-premedication
advantage: can cause anterograde amnesia
PROPOFOL
- milk white (1% emulsion)
- rapid recovery and induction antiemetic
- use: indice and maintain GA fast!
- minimal to produce emergence phenomenon
LOCAL ANESTHESIA
moa: blocks sodium channels in nerves
- provides analgesia without the loss of consciousness
Administration:
- topic, injected into nerves, epidural, or subarachnoid
1. Esters
a. Cocaine
— local vasoconstrictor
— not useful clinically
— addictive
— abuse potential
b. Procaine
— 1st synthetic local anesthetic
— limited use
— low potent, slow onset, short duration of action
— used as infiltration anesthetic
2. Amides
- lidocaine
- mepivacaine
- bupivacaine
- prilocaine
- etidocaine
- ropivacaine
- levobupivacaine
- articaine
a. Lidocaine
— most widely used
— anesthetic and antiarrythmic
— combined with epinephrine to limit absorption
c. Bupivacaine (local block)
— longer need of anesthesia
— producing prolonged anesthesia
— cardiotoxic
— causes hypotension and arrhythmia
d. Mepivacaine (regional block)
— intermediate acting
— toxic to neonate
— high therapeutic index in adults compared to lidocaine
AUTONOMIC NERVOUS
SYSTEM
DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM
SYMPATHETIC DRUGS
• A. SYMPATHETICS/ADRENERGICS


1. Direct Sympathomimetics
2. Indirect Sympathomimetics and Mixed Agents

• B. SYMPATHOLYTICS/ADRENERGIC BLOCKERS/
ANTIADRENERGICS

1. Centrally acting antiadrenergics
2. Peripheral presynaptic antiadrenergics
3. Peripheral postsynaptic antiadrenergic – a. α-blockers b. β-
blockers

PARASYMPATHETIC DRUGS
A. PARASYMPATHETICS/CHOLINOMIMETICS

1. Direct cholinergic agonist
2. Indirect cholinergic agents - Choliinesterase Inhibitor

B. PARASYMPATHOLYTICS/CHOLINERGIC ANTAGONIST

1. Muscarinic antagonist/ Antimuscarinic
2.Ganglionic blockers
3. Neuromuscular blockers
BIOSYNTHESIS OF CATECHOLAMINES
Loc: sympathetic - post ganglionic fiber
adrenal medulla - where NT are synthesized
1. Biosynthesis of catecholamines
a. active uptake of Tyrosine (precursor)
aa. into pre synapse (the one who synthesizes)
b. formation of DOPA (dihydroxyphentlamine

TYROSINE ———————————- > DOPA

Tyrosine hydroxylase

x by Metyrosine
c. Formation of 1st catecholamine

DOPA ———————————> DOPAMINE

Dopa decarboxylase

d. Rapid storage / uptake of Dopamine (or any

catecholamine) into presynaptic vesicles

- rationale: Dopamine (and other catecholamines) is

rapidly destroyed by Monoamine oxidase (MAO)

x by Reseprine (not a MAOi— targets storage, not the enzyme)

 e. Formation of the major NT of the sympathetic
postganglionic fiber
Norepinephrine
- intravesicular synthesis

DOPAMINE ——————-———> NOREPINEPHRINE

Dopamine B-hydroxylase

f. Extra step occurring only in adrenal medulla

NOREPINEPHRINE ————————-> EPINEPHRINE

PENMT
Phenyl-ethanolamine N-methyl transferase
g. release of NE into the cleft
- exocytotic
- can be stimulated by:
> amphetamine (metamphetamine)
> ephedrine, angiotensin II
> Tyramine
if given with MAOs = hypertensive crisis

x by Guanethedine, Guanadrel
FATE OF NE IN THE CLEFT
1. binds to post synaptic receptors
2. Metabolism by MAO and COMT (Catechol-o-methyl transfe)
3. major mechanism of loss of NE from the cleft -> reuptake
- accounts 70% of catecholamine loss from cleft
 RECEPTOR, LOCATION, RESPONSE
RECEPTOR LOCATION RESPONSE
A. alpha smooth muscles Contraction
i. alpha 1 (Gq linked) -vascular s.m. -vasoconstricrtion
-prostatic s.m. -contration (urinary ret.)
-radial muscles -contraction (pupilodilat)
-Pilomotor s.m. -hair erection
ii. alpha 2(Gi linked) Presynaptic in the CNS Decrease in the CNS
(vasomotor area) leading to central effects:
- sedation
- depression

Preganglionic Peripheral: vasodialtion

Post-synaptic in blood Peripheral effects:
vessels (Gq linked) - vasoconstriction
 RECEPTOR LOCATION RESPONSE
B. Beta Heart Intoropism
i. Beta 1 (Gs linked) ( strength of contraction)
Chronotropism( HR)
Dromotropism ( HR)
( rate of conduction - AV)

Juxtaglomerular (kidney) renin release

ii. beta 2(Gs linked) smooth muscles
-bronchial s.m. - bronchodilatiom
-uterine s.m. - Uterine relaxation
-vascular s.m. - vasodilation
skeletal muscles
-neuromuscular end plate - contraction (tremors)
-in skeletal muscles - increase intracellular
(tissues) movement of K+
iii. Beta 3 Adipose tissue lipolysis (breakdown body
fats)
 RECEPTOR LOCATION RESPONSE
C. Dopamine
i. D1 renal and shplanchnic Vasodilation
blood vessels kidneys diuresus

ii. D2 (D2-D4) CNS - modulating motor activity

- Perception, behavior
modulation

GIT (peripheral) - inhibits peristalsis

 SYMPATHOMI
METIC DRUGS
(ADRENERGIC
AGONISTS)
Postsynaptic Alpha1 Receptor on Vascular Smooth Muscle
Activation of the receptor results to vasoconstriction
Presynaptic Alpha2 Receptors
Alpha2 receptors also exist presynaptically associated with nerve
terminals Activation of these receptors inhibits the release of NE
NE acts at presynaptic alpha2 recpetors to inhibit its own
release.
Effect of Beta1 Receptor Activation on the Heart
Increase the force of myocardial contraction; Increase the rate of
contraction
Excess stimulation leads to arrythmias

Effects of Beta2 Receptor Activation on Smooth Muscle
Leads to vascular and nonvascular smooth muscle relaxation
Drugs that activates the beta2 receptor can be used to treat as
asthma (by relaxing airway smooth muscle ) and premature
labor (by relaxing uterine smooth muscle).
SYMPATHOMIMETICS ACTING AT BETA RECEPTOR SYSTEM
Dopamine and Dobutamine
Used in Congestive heart failure and cardiogenic shock
Activate the myocardial beta1 receptor and thus increase the
force of contraction of the failing heart
These drugs are reserved for use in the acute management of
the heart failure
SELECTIVE BETA2 AGONIST
Bronchodilation and decrease in airway resistance 


Relaxation of Vascular and nonvascular smooth muscle

USES OF SELECTIVE BETA2 AGONIST

Airway dysfunction; bronchial asthma, chronic bronchitis,
emphysema Resistance
Premature labor

DIRECT SYMPATHOMIMETICS
NE, Epinephrine and Doapmine are endogenous sympathetic
agonist 


Binds to α1, α2, β1, or β2 adrenergic receptors where they “turn

on” second messengers
DIRECT SYMPATHOMIMETICS
I. Catetcholamines – Epinephrine, Norepinephrine, Isoproterenol,
Dobutamine, Dopamine
Metabolized by COMT and MAO: Short duration of action
Clinically used to treat anaphylaxis, cardiac arrest, heart failure
and shock

II. Non-catechomines – Longer half-lives

Phenylephrine & Methoxamine – Marked as nasal and
ophthalmic decongestants
Metaproterenol, Albuterol, Bitolterol, Terbutaline, Isoetharine,
Salmeterol, Salbutamol – bronchodilators
Ritodrine – Uterine relaxant
I. NON SELECTIVE DIRECT ACTING ADRENERGIC AGONISTS
Receptor affinity: B > a

low doses preferential stim. on B

high doses - additional stim. on a
examples:
i. Epinephrine = adrenaline
uses:
- 1st line cardiac stimulant (given during ACLS)
- 1st line in tx of anaphylaxis or anaphylactic shock
- can be given as a local vasoconstrictor
ii. Norepinephrine (Levophed)
Uses:
- 1st line treatment of septic shock
- alte. mx of acute heart failure and carcinogenic shock
 iii. Dopamine (IV infusion)

DOSE/RATE EFFECT
1-3 mcg/kg/min renal vasodilation (d1)
2-5 mcg/kg/min inotropic (b1)
5 mcg/kg/min vasoconstriction (a1)

uses:
- alte.mx of shock states (septic, cardiogenic)
- useful and becomes 1st line if the px with shock has renal
dysfunction or damage
II. SELECTIVE DIRECT ACTING ADRENERGIC AGONISTS
i. B non-selective agonists
- stimulate b1 = b2
Ex: synthetic catecholamines (isoproterenol)
use: alternative inotropic agent
ii. b1 selective agonist
Ex. Dobutamine (IV)
use: 1st line mgt of cartdiogenic shock, acute HF)
iii. b2 selective agonist
ex.
Terbutaline, salbutamol (1st line reliever meds)
Mgt of bronchial asthma
Formaterol, salmeferol

Ritodine Tocolytics
Isosuxprine

s/e: tremors, tachycardia, palpitations, hypokalemia

terbutaline - useful in px with symptomatic bradycardia

iv. alpha 1 adrenergic agonists
effect: vasoconstriction
examples: pehnlephrine, prophylhexedine, methoxamine, oxymetazoline,
xylometazoline, tetrahydralozine
clinical use: nasal decongestants, local vasocontrictions to minimize
absorption of local anesthetic and mgt of hypotension

s/e: systemic administration

i. exacerbate or worsen htn
ii. induce hypertensive crisis if given with MAOs
iii. urinary retention with BPH
iv. tolerance if used more than 5 days (decongestants)
rhinitis medicamentosa
- rebound congestion
- develop if used more than 3 days
KOKOLOGY 18 “UNTAMED”
When you see a tiger or leopard at the zoo, you can’t help
feeling it looks a little tame, as though something in its wild
nature has been lost. Even huge creatures like elephants or
grizzly bears seem diminished when they’re locked up in a cage.
That may be the reason safari parks have become so popular.
The impact of seeing wild animals is so much greater when you
can watch them in their natural state, and the thrill is that much
more when only a thin car window stands between you and a
hungry lion.
You are on a safari park tour, following the road through the
open savanna. A short distance from the trail, you see a lion and
lioness feeding, hungrily tearing at and devouring hunks of raw
meat. What are you thinking as you watch this scene of untamed
savagery?
A Safari tour allows you to observe dangerous wildlife from a
safe and protected distance, and the lions feeding represent a
scene of natural forces unleashed. Your reaction to the scenario
shows how you reacted (or would react) on seeing an adult
video for the first time. What was your response?
“Wow! Look at them go! Hey, I’m getting a little hungry too.” That
doesn’t take much interpretation, does it?

“I don’t want to watch that– it’s disgusting.” Nobody said it was

going to be pretty.

“I’m scared.” It’s natural to be a little bit frightened, but you’re

safe as long as you stay on this side of the glass.

“Oh, give the poor things some privacy.” You’re truly a decent
person, but are you sure you don’t want to watch just a little bit
longer?
v. Alpha 2 adrenergic agonists
- common s/e: sedation and depression
- peripheral vasodilation - used for htn
Ex.
a. clonidine (catapress)
Stimulate post synaptic alpha 2 in blood vessels -> vasoconstriction
dual effect:
- initial and transient
Stimulates presynaptic alpha 2 in the CNS -> vasodilation
- final and long effect
clinical use - alternative mx of HTN spec: HTN crisis and HTN
in px on chronic dialysis
additional s/e:
- abrupt withdrawal causes REBOUND HYPERTENSION
- can occur in just 1-2 missed doses
- mgt is to:
1. reinstate clonidiene
2. give labetolol
3. if in HTN crisis - give Na Nitroprusside
b. Methyldopa
- alpha-methyl-dopa (prodrug) —> crosses BBB

Alpha-methylDOPA (aldomet)

Dopa decarboxylase
Alpha-methyldopamine

Dopamine B-hydroxylase

Alpha-methylnorepinephrine (alpha2 agonist)

Active, false neurotransmitter
clinical use: alternative mx of HTN, useful in HTN in pregnancy
vi. D1 agonist
ex. Fenoldopam
effect: vasodilator
use: alternative in mx of HTN emergencies
INDIRECT ACTING AGONISTS
Release neurotransmitters from presynaptic nerve terminals to
produce sympathomimetic effect
Amphetamine and Methamphetamine
Useful in narcolepsy, hyperkinetic syndrome of children,
attention deficit hyperactivity disorder (ADHD)
i. Reuptake inhibitors
(TCAs, cocaine, NRI)
ii. Releases
(stimulate exocytosis)
- amphetamine - ephedrine
MIXED SYMPATHOMIMETICS
Displace NE from presynaptic terminals and bind to adrenergic
receptors
Ephedrine – clinically used to treat narcolepsy 


Mephentermine & Metaraminol – Treatment of hypotension 


Phenylpropanolamine – Decongestant in oral OTC drugs

ephedrine “ma huang”
-direct agonist to alpha 1, beta 1, and beta 2
- indirect agonist: stimulates the release of E

- used as nasal decongestant by direct application to nasal

mucosa
- IV bolus - mx of acute hypotension

s/e: worsen HTN, induce HTN crisis, risk of addiciton

Phenylpropanolimine
- increased incidence of hemorrhagic stroke among young
women
- increases BP
- brain is having a hard time regulating the BP and compensates
by increasing intracanial pressure
SYMPATHOLYTICS / ADRENERGIC BLOCKERS
MECHANISM
Decreasing the sympathetic outflow from the brain 


Suppressing NE release from presynaptic neurons 


Blocking post-synaptic adrenergic receptors

PRESYNAPTIC ADRENERGIC BLOCKERS
Clonidine, Guanabenz, and α – methyldopa (Centrally acting
antiadrenergics)
Guanethidine, Guanadrel, Bretylium & Reserpine (Peripheral
Presynaptic anti-adrenergics)
These drugs stimulate alpha2 receptors to decrease
sympathetic outflow to the heart and blood vessel
The decrease in sympathetic tone results in a decrease I
peripheral vascular resistance Clonidine and guanabenz are
active drugs
Methyldopa is a prodrug which must first be converted to α-
methylnorepinephrine
Used clinically to treat hypertension (Bretylium – Arrhythmias)
Can cause orthostatic hypotension and rebound hypertension
NONSELECTIVE ALPHA BLOCKER
1. Irreversible
- phenoxybenzamine

2. reversible
- phentolamine

Used clinically in pheochromocytoma; Side effect: Postural

hypotension
SELECTIVE ALPHA 1 - ANTAGONIST
Prazosin and Prazosin analogs (terazosin, doxazosin, trimazosin)

Effects
Relaxes arterial and venous smooth muscle as well as nonvascular
smooth muscle.
Decreases peripheral vascular resistance and venous return.
Decrease systemic arterial blood pressure without a significant
increase in heart rate.
USES – Hypertension; Benign prostatic hypertrophy
SIDE EFFECT – Orthostatic hypotension
SELECTIVE ALPHA 2 ANTAGONISTS
1. Yohimbine (Tolazoline)
2. Rawwolfscine
COMMON
- orthostatic hypotension
- first dose phenomenon seen in..

- orthostatic hypotension 1. the first dose

2. sudden increase of the dose
- syncope
3. concurrent use with other antiHTN

Remedies:
- give doses at night time
- start low, go slow principle
- avoid concurrent use with other antiTHN
BETA ADRENERGIC RECEPTOR BLOCKERS
These drugs are competitive antagonist of the beta adrenergic
receptors 


Beta blockers are either selective for the beta receptor or

1

nonselective beta and beta anatagonist

1 2 

BETA BLOCKERS
PROPRANOLOL is the prototype beta blocker as well as the prototype
of a nonselective beta blocker 


Blocks myocardial beta receptors which is a major site of therapeutic

1

actions
Cardiovascular effects:
a. Decreases force and rate of myocardial contraction
b. Decreases rennin secretion
c. Decreases blood pressure
Blocks beta receptors
2



Cardiovascular Uses: Hypertension; Ischemic heart disease;
Supraventricular tachyarrhythmias

Major disadvantage of nonselective beta blockers – they will block
beta2 receptors associated with airway or vascular smooth muscle
Side effects – Sedation, fatigue; Exacerbation of peripheral
vascular disease, airway dysfunction Atenolol is the prototype
selective beta1 receptor beta blocker
Endocrine effects of Beta blockers
Non-selective beta blockers are contraindicated in diabetic patients 


Selective beta1 blockers should be used with caution in patients

with diabetes 

• In addition all beta blockers mask the tachycardia associated
with hypoglycemia
SUMMARY OF BETA RECEPTOR BLOCKERS
Nonselective α1 β1 β2 blockers – Labetalol –Used in
hypertension Nonselective β1 β2 blockers
Propanolol – Used in hypertension, Glaucoma, Migraine,
Hyperthyroidism, Angina pectoris, Myocardial infraction
Timolol – For glaucoma and hypertension
Pindolol – For hypertension


Β1 specific – Metoprolol, Atenolol, Acebutolol – For hypertension


Adverse effects commonly observed with beta blockers


Hypotension Bradycardia Fatigue, Drowsiness
Brochoconstriction and sexual dysfunction – commonly observed
with propranolol
Classification
1. based on selectivity
a. non selective BB
-non BEAM
b. selective b1 blocker
B isoprolol, betaxolol
E smolol
A tenolol, Acebutolol
M etoprolol
2. Based on the presence of intrinsic sympathomimetic activity
(mixed agonist - antagonist = [partial agonist]
C arteolol
L abetolol
less associated with htn or tachycardia when withrawn
A cebutolol
P indolol
3. based on membrane stabilizing activity

P indolol, Propranolol
A acebutolol
cannot be given as optic drops for glaucoma
L abetolol
M etoprolol
4. based on mixed alpha-beta blocking effects

Carvedilol
Labetolol
clinical uses of beta blockers:
a. first line mx of hypertension in px with prior MI
b. 1st line in the management of chronic stable angina
c. Antiarrythmics (preferred BB: propranolol, esmolol,
acebutolol)
e. prophylaxis against migraine
f. mx of glaucoma
g. Control of sx of hyperthyroidism
h. mx of familial tremors or stage fright, social phobia
cautions/se/contraindications
a. BB can mask early hypoglycemic symptoms (sympathetic:
tachycardia and sweating)
b. bradycardia and heartblock
- preexisting bradycardia or heartblockl
- elderly patients (>65yo)
- concurrently using non-DHD (verapamil, diltiazem)
c. Worsen sx of intermittent claudication bec. of dec. Blood flow
d. metabolic se —> dylipidemia
e. Rebound hypertension when abruptly withdrawn (taper
10-14days)
f. reduce excercise tolerance (blockade of b2 of vascular muscles
that supply exercising muscles)
g. Exacerbate CHF (do not give to unstable CHF)
CHOLINERGIC AGENTS (PARASYMPATHETIC DRUGS)
I. CHOLINOMIMETICS /CHOLINERGIC AGONIST
II. ANTICHOLINERGICS

2. biosynthesis of Ach
1. Active uptake of choline into pre synapse
2. formation of Ach
choline +acetyl COA

choline acyl transferase

Acetylcholine
3. storage of Ach into the synaptic cleft
4. Release of Ach into cleft
2. Fate of Ach
1. stimulate receptors (binds to receptors)
2. can be metabolized by acetylcholinesterase
DIRECT VS INDIRECT-ACTING CHOLINOMIMETICS
A direct-acting cholinomimetic drug produces its
pharmacological effect by receptor activation
An indirect-acting drug inhibits acetylcholinesterase, thereby
increasing endogenous acetylcholine levels, resulting in
increased cholinergic response.
CHOLINERGIC AGONISTS
Acetylcholine - miosis in cataract surgery 


Choline derivatives
Carbachol – Used in glaucoma, miosis for surgery
Methacholine – for diagnosis of bronchial airway hyperactivity
Bethanecol – induce evacuation of non-obstructed bladder 


Alkaloids- Arecoline, Pilocarpine – For glaucoma, xerostomia,

Muscarine, Nicotine – smoking cessation aid
a. direct acting cholinergic agonists
i. choline esters
Acetylcholine
Betahenicol
Methacholine
Carbachol
ii. cholinergic alkaloids
pilocarpine
muscarine
nicotine
Labeline
KOKOLOGY 22 “PLANTING THE SEEDS”
The human spirit loves a challenge. This desire to overcome
may be the secret to our success as a species. Every human
science was born through hard study and failed experiments;
and every human personality is the product of an innate drive to
create something unique from one’s raw individual experience.
The need to be challenged is so strong in us that we sometimes
make things more difficult that they need to be, just so we can
rise to the occasion and overcome the obstacles we have
ourselves created.
How many of those 100 seeds sprout? (Give a number from 0 to
100.)
 The number you gave as an answer correlates to your self-
confidence level. In this story, the scientist stands for feelings of
confidence and even pride. On the other hand, the hostile desert
sands represent a difficult challenge or test and therefore elicit
feelings of doubt and uncertainty. People who answered with
higher numbers felt greater affinity with the scientist and have
high confidence levels. Those who answered with lower
numbers felt the challenge was too great and have
correspondingly lower self-confidence.
 99-100. It’s an understatement to say you’re self-confident; maybe a
better word would be “vain.” Sure, it’s important to believe in
yourself, but you tend to dismiss the challenges of the rest of the
world. Don’t forget that one of the truest signs of strength is
accepting one’s own weaknesses.
81-98. You radiate confidence in yourself and your own capabilities,
but somehow it doesn’t come across arrogance. Those around you
generally feel it as a sense of cool certainty, making you a natural
leader wherever you go
61-80. Maybe you’re best described as a cautious optimist, hoping for
the best but always prepared for the worst. That realistic philosophy
keeps you grounded when others might lose their heads in the clouds.
 41-60. Your self confidence is in the average range-neither too
cocky nor too unsure. Maybe you’re still finding out what it is
you’re best at, or maybe you just have a healthy respect for the
difficulties that stand before you. Believe in yourself and the
world will follow suit.
21-40. While you don’t doubt yourself entirely, you tend to
overestimate the challenges confronting you. You may excuse
this tendency as a simple resignation to the facts, but your
pessimistic outlook affects the way other people see you. The
only way for you to inspire confidence in others is first to have it
in yourself.
 1-20. It’s one thing to be humble, but you need to focus on
developing a better sense of your own value. There’s nothing
wrong with believing you can achieve great things, and with a
little hard work you can. The only thing holding back is you.
0. What looks like an utter lack of confidence is actually a sign
of perfectionistic pride. You can’t tolerate the thought of being
proven wrong or even making a mistake, so you pretend that
everything is too difficult for you. If you don’t learn to face those
fears, you may fool the world into thinking you’re just a ne'er-
do-well, but you’ll always know that you never even tried.
b. indirect acting cholinomimetics
moa: inhibit ACHE enzyme
- anticholinesterases
i. short acting
Edrophonium (tensilon)
ii. intermediate to long acting (2 - <24h)
Organocarbamates
Carbamylesters
iii. very long acting (days to weeks)
Malathion
Parathion

- if duration is less than 24-40 hours, then it is potentially

reversible, beyond is irreversible
- >24hours aging of organophosphate bond is impossible to
break
clinical uses:
a. diagnosis and mx of MG
b. Glaucoma
c. mx of NM blockers toxicity
d. mx of atropine poisoning
e. Non-obstructive ileus
f. mx of urinary retention in BPH
CHOLINESTERASE INHIBITORS
EDROPHONIUM (Tensilon) – Competitive antagonist
CARBAMATES – Compete with Ach for the active site of the
enzyme

• Physostigmine, Demecarium, Neostigmine, Ambenomium,
Pyridostigmine
ORGANOPHOSPHATES

• Have very high affinity for the active site of the enzyme

• Echothiopate – For glaucoma, Parathion, Malathion, - Pesticide
Cholinesterase inhibitors are used to treat glaucoma and
Myasthenia gravis
Some adverse effects observed with cholinergic drugs

Diarrhea Diaphoresis Miosis Nausea Urinary urgency
 You are an eminent scientist who has been working to develop a
new species of plant. You have spent years in your laboratory
experimenting, and now your efforts have begun to show
results. As the ultimate test of the hardiness of your creation,
you plant 100 seeds of the new strain in an inhospitable desert
location.
PARASYMPATHOLYTICS/CHOLINERGIC ANTAGONISTS
a. Antimuscarinics -> antocholinergics (atropine-like)
b. Antinicotinics
i. neuromuscular blockers
ii. ganglionic blockers
a. Antimuscarinics
Atropine is the prototype agent
Actions are dose dependent
Decreased salivary and bronchial secretions
Pupil dilation and tachycardia
Decreases GI motility
Decrease sweating
Inhibition of voiding
Decreased gastric secretions
Muscarinic Antagonists

ALKALOIDS – Atropine, Scopolamine, Homatropine 



SYNTHETIC-TERTIARY COMPOUNDS

Dicyclomine Oxybutynin, Flavoxate, Tolterodine Trihexyphenidyl,
Biperiden, Benztropine



SYNTHETIC_QUATERNARY COMPOUNDS

Propantheline Methscopolamine

Mepenzolate Methantheline



TRICYCLIC BENZODIAZEPINE – Pirenzepine
effects:

m1 block (git) - decrease gastric secretion

m2 block (heart) - tachycardia and increase rate of conduction
across the AV Node (Vagolytic)
m3 block (eyes) - relaxation of ciliary muscles = mydriasis
CNS effects:
-agitation, confusion, seizures
-acute psychotic reaction
“mad as a hatter”
—> cycloplegia (loss of accommodation / near vision)
“blind as a bat”

contraindication: narrow-angle glaucoma —> acute angle closure

glaucoma
-bronchi: bronchodilation
- git: constipation
- urinary bladder - urinary retention (constrict)
- exocrine gland - decrease secretion
“dry as a bone”
decreased sweat gland - thermoregulatory sweating
- hyperthermia (fatal in children)
“hot as hell or hot as a hare:”

cutaneous vasodilation
- flushing or redness “atropine flush”
“red as a beet”
CLINICAL USES

Preanesthesia medication to prevent secretions

Prevent Motion sickness

For irritable bowel syndrome

Adjunct treatment for Parkinsonism

Relieve bladder spasm, enuresis and diarrhoea
For peptic ulcer

Mydriasis and cycloplegia

Antispasmodic

SIDE EFFECTS

Classic anticholinergic/antimuscarinic side effects: Dry mouth,
constipation, and tachycardia Severe antimuscarinic effects
 Restlessness; headache, rapid and weak pulse, blurred
vision, hallucinations, ataxia, “burning” skin and possibly coma 


 Some antipsychotics, antihistamines, antidepressants, and

opioids have anticholinergic effects
Other antimuscarinics
1. CNS acting
a. Scopolamine
- sedative (induce dream-less sleep)
use: antimotion sickness
twilight sleep : scopolamine + morphine
b. Bipereden (akineton), benztropin(cogentin)
- mx of Parkinsonism and extrapyramidal symptoms
2. Eyes
- mydriatic cycloplegia
ex. atropine - optic drop effect lasts for 72 hours
- Itomatropine
- Cyclopentolate
used in eye examinations
- Tropicamide

mydriatics: given to allow examination of the retina

Cycloplegics: to treat eye pain due to inflammation or infection on
the iris or the ciliary muscle.
3. Bronchi
- bronchodilators
- ipratropium, oxytropium, triotropium
- ipratropium + salbutamol - combivent/duavent
4. GIT + urinary bladder
- pure m1 blocker (telenzipine, pirenzepine)
- use in mx of acid peptic disease
- m3 blockers
Hyoscine-n-butylbromide (buscopan)
Dicycloverine, methscopolamine
Antispasmodics, abdominal spasmsa, hyper motility disorders, urinary
incont.
ANTINICOTINICS
NEUROMUSCULAR BLOCKERS
Depolarizing Neuromuscular Blockers 


Non depolarizing Neuromuscular Blockers 


NON-DEPOLARISING NEUROMUSCULAR BLOCKERS
Vecuronium
D-Tubocurarine
Pipecuronium
Atracuriom
Metocurine
Doxacurium (with minimum cardiovascular effect)
Cisatracurium
Mivacurium
Pancurium
Rocuronium
Nondepolarizing
Tubocurarine from Curare (Strychnos sp.) used as arrow poison in
South America

- Pancuronium, Atracurium, Vecuronium
S/E: histamine release!anaphylactoid reaction
Antidote: Neostigmine
S/E: malignant hyperthermia (fever, muscle rigidity); Muscle pain
and myositis → rhabdomyolysis→ acute renal failure and
hyperkalemia

Antidote: Dantrolene
block Ca release!↓ muscle contraction
MECHANISM OF ACTION
Competes with Ach at the nicotinic receptors at the
neuromuscular junction
o No muscle contraction (fasciculations)

o Blockade is overcome by high concentration of agonist (Ach)
DEPOLARISING NEUROMUSCULAR BLOCKERS MECHANISM OF ACTION
PHASE I
 Agonist binds to the receptor causing depolarizing of the
membrane
 Will result to initial discharge causing fasciculations followed by
flaccid paralysis
PHASE II
Slow dissociation of the agonist
Agonist remains bound to the receptor
Membrane repolarizes but receptor is desensitized to the effect
of Ach 

SUCCINYLCHOLINE
Duration of action is extremely short it is rapidly degraded by
plasma cholinesterase 


Order of paralysis: Fasciculations in the chest and abdomen;

Neck, arms and legs, Facial, pharynx, larynx; respiratory muscles
Uses: Ideal for intubation , adjunct to anesthesia and mechanical
ventilation
Side effects: Increase IOP, Dysrhythmias, Post-op muscle pain,
May produce occasionally malignant hyperthermia (high body
temp., acidosis and 


electrolyte imbalance), Prolonged paralysis

OTHER DEPOLARISING AGENTS
Decamethonium – Too long duration of action 


Suxamethonium – Action is shorter than decamethonium since it

is rapidly metabolized by cholinesterase
THERAPEUTIC USES OF NEUROMUSCULAR BLOCKERS
To facilitate endotracheal intubation
In electroconvulsive therapy
To reduce muscle spasm in tetanus
To produce apnea
To relieve laryngeal spasm Adjunct to anesthesia
To relieve laryngeal spasm
Adjunct to anaesthesia
SIDE EFFECTS/ADVERSE EFFECTS
Skin wheals, bronchospasm and transient hypotension 


Flushing, tachycardia, bradycardia 


Paralysis of the respiratory muscle – reversed by cholinesterase

Inhibitor 


➤
SPASMOLYTIC AGENTS
CNS ACTING – Baclofen, Carisopodol, Chlorphenesin.
Metaxalone. Mephenesin, Diazepam, Orphenadrine,
Methocarbamol, Cyclobenzaprine BACLOFEN – Selective
GABAB agonist
DIRECT ACTING – Dantrolene

o Decrease Ca2 release from the sarcoplasmic reticulum in
skeletal muscle

o Interfere with excitation-contraction coupling in the muscle
fiber

o Used in the treatment of spastic diseases and manage
symptoms of malignant hyperthermia (Rare, life-threatening
condition with
muscle rigidity, autonomic lability, and seizures, due to
uncontrolled release of Ca2+ release from the reticulum)
CARDIOVASCULAR
SYSTEM
THE CARDIOVASCULAR SYSTEM
permits blood to circulate and transport nutrients (such as
amino acids and electrolytes), oxygen, carbon dioxide,
hormones, and blood cells to and from the cells in the body
provide nourishment and help in fighting diseases
stabilize temperature and pH
maintain homeostasis.
THE HEART
THE BLOOD
THE BLOOD VESSELS
ARTERIES AND ARTERIOLES
BLOOD PRESSURE
DETERMINANTS OF BLOOD PRESSURE
CARDIAC OUTPUT (CO)
Volume of blood pumped out by the heart in 1 minute
approximately 2.2 – 3.5 L / min / m BSA

2

determined by Stroke Volume (SV) and Heart Rate (HR)

STROKE VOLUME (SV)
Volume of blood pumped out by the heart in every contraction

determined by:



Inotropic activity –strength of cardiac contraction 

Venous return – cardiac preload; amount of blood delivered to
the heart from the veins; affected by the tone of the veins
HEART RATE (HR)
speed of heart contraction
chronotropism
FLUID CONTENT OF THE BLOOD
TOTAL PERIPHERAL RESISTANCE (TPR)
resistance or pressure encountered by the heart as it
pumps out blood into the peripheral circulation (cardiac
afterload)determined by the arterioles
MECHANISM OF BP REGULATION
Baroreceptors Reflex Arch Mechanism
aka: Postural Reflex Mechanism

moment-to-moment BP regulation


Baroreceptor – a type of sensory nerve ending found in the walls

of the atria of the heart, the vena cava, the aortic arch, and the
carotid sinus that is stimulated by changes in pressure
KOKOLOGY 23 “THE STOLEN BERRIES”
Everyone likes a nice person and most of us try to be good in our
own lives. Why is it, then that there are so few people in the
world who are good all the time? As hard as you may try, there
are always those rotten days of moments and weakness where it
just feels better to be bad. Whether that takes the form of driving
too fast on the highway, cheating on a test, or “liberating” a box
of pens from the office, we’ve all done things we can’t be proud
of or justify. The key to becoming a truly good person is in
accpeting the bad parts of your own personality and admitting
that you’re not perfect, not in trying to act like a saint while the
devil on your shoulder whispers in your ear. We all succumb to
temptation sometimes. But in the next scenario you might just
get caught…
 1. On a stroll through the countryside, you come across a field
of delicious-looking strawberries. Your stomach starts to rumble,
and there’s no one else around. Only a fence stands between you
and a free lunch. How high is that fence?
 2. You sneak into the garden and begin to help yourself to the
fruit. How many berries did you eat?
 3. Suddenly the farmer whose berries you’re stealing appears
out of nowhere and starts yelling at you. What do you say in
your own defense?
 4. After all is said and done, how did the berries taste? And
looking back, how did you feel after your berry-stealing
adventure was over? 
 Strawberries -seductively juicy and red - are common symbol of
sexual attraction and desire. The way you envisioned this
scenario helps us to understand your attitude toward forbidden
romance and stolen love.
 1. The height of the fence you imagined around the field is a
measure of your own level of self-control and resistance to
sexual temptation. The higher the fence, the greater your own
defenses. People who imagined a total enclosure exercise
admirable restraint. Those of you who said it was only a string
tied around some be at about knee height run a higher than
average risk of getting burned by the flames of love.
 2. The number of berries you said you would steal is the
number of people you can believe yourself in love (or lust) with
at any given time. If you said you’d quit after eating just one,
you’re likely to be faithful in your own love life as well (or at
least a devoted serial monogamist). Those of you who got onto
double digits may need to think seriously about applying the
brakes to your libido. Nobody can keep that pace up forever.
 3. The excuses you made to the farmer represent the way you’d defend
yourself if you got caught having an affair. What was your excuse?
“I’m so sorry. I promise I’ll never do it again” Sometimes a full
confession and a promise to behave is the best way to get yourself off
the hook.
“They looked so good, I just couldn’t help myself ” Well actually you
did help yourself – to somebody else’s berries. But honesty is the best
policy. After all, it worked for George Washington, didn’t it? If you
keep it up, maybe someday you could be president too
“Hey those berries were great! Do you have if I have a couple more?”
Farmers have shotguns. Spouses have lawyers. Fortunately you still
have a chance to reconsider your choice of words.
4. The way you described the experience and the taste of the
berries gives an indication of how you imagine yourself feeling
when looking back on a past affair.
“Actually, they didn’t taste good as they looked. The whole thing
wasn’t even worth the effort” All too true for most affairs. Chalk
it up to experience and put it behind you.
“So sweet! So juicy and delicious! I’ve never tasted anything like
it!” Uh, let’s just say you’re addicted to love.
“The berries were nothing special, but all in all it kind of fun”
Statistically speaking, you’re in the high-risk group for repeat
offenders.
HYPERTENSION
Persistent or recurrent elevation of BP defined as having a:

Systolic reading > 140 mmHg

Diastolic reading > 90 mmHg

BP > 140/90 

most common cardiovascular disorder
SYSTOLE
The period during which the ventricles are contracting
DIASTOLE
The period during which the ventricles are relaxed and filling
with blood
HYPERTENSION
Essential (Primary, Idiopathic)
Unknown ethology
> 90% of HTNsive cases

Secondary

identifiable causes

Most common cause: CKD
Others:

Pheochromocytoma, Cushing’s syndrome, hyperthyroidim, 1o
aldosteronism
Drugs

Corticosteroids, estrogens, NSAIDs, amphetamines, cyclosporine
Hypertensive Crisis (BP ≥180/120)
rare but life-threatening situation
HTN emergency
IV nitroprusside, NTG, nicardipine. Felodepam, labetalol,
hyrdralazine
HTN urgency
Oral captopril, clonidine, labetalol
DOC: Na nitroprusside
➤
COMPLICATION
Main cause of death Cerebrovascular diseases Cardiovascular
events Renal failure
DIURETICS
CARBONIC ANHYDRASE INHIBITORS
MOA: inhibit carbonic anhydrase (the enzyme that catalyzes the
reaction of CO and H O leading to H and HCO ) that can lead to
2 2
+
3
-

the spillage of Na causing diuresis.

+

Carbonic Anhydrase Inhibitors


Brinzolamide

Acetazolamide

Dorzolamide

Metabolic acidosis
↓Na, ↓K

Others:

bone marrow depression (sulfonamide-like toxicity) allergic
reactions (SJS)

Uses

Glaucoma

Mountain sickness (high altitude sickness)
LOOP DIURETICS
aka: High Ceiling Diuretics
MOA: inhibit the Cl-Na-K-cotransporter Furosemide

Torsemide

Bumetanide

Ethacrynic acid
Side-Effects
↓Ca, ↓HCO3, ↓Na, ↓K
Ototoxicity
Others

Hypovolemia

Sulfonamide allergy
Uses
300/250 emergency
Pulmonary edema
px who cannot tolerate thiazides (or ineffective) Renally
impaired
DI: NSAIDs
THIAZIDE DIURETICS
MOA: inhibit Na-Cl-cotransporter
Chlorothiazide
Hydrochlorothiazide
Indapamide
Chlorthalidone
Maintenance drugs for HTN
first-line drug for uncomplicated hypertension as recommended by
JNC 7
effective initial therapy together with beta-blockers also used for
Nephrogenic Diabetes Insipidus
↓K, ↓Na
↑uricemia, ↑glycemia, ↑lipidemia
Sulfonamide allergy
DI: NSAIDs
moa: inhibits NA+CL- transporters at the distal convoluted
tubule for 2 weeks
effects: 2 phases
phase 1: diuretic effects - 2 weeks
“diuretic breaking phenomenon”
phase 2: venodilation
- seen where your thiazides are given beyond 2 weeks - there is
improvement of vascular compliance / distensibility =
vasodilation
Se: electrolyte imbalance
- hypokalemia
- hyponatermia

remedy:
gibe at very low doses
hctz: not more than 25mg/dl
POTASSIUM-SPARING DIURETICS
MOA: inh Na reabsorption, K secretion and H secretion
+ + +

Spironolactone
Eplerenone
Amiloride
Triamterene
Uses
K wasting w/ diuretics
↓K, concomitant meds (cardiac glycosides)
Aldosteronism (Conn’s syndrome)

Side-Effect
Hyperkalemia (w/ K supplementation & ACEi) Metabolic
acidosis
Gynecomastia
Sterility
impotence
often combined with thiazides Amiloride, Spirinolactone,
Triamterene

Precautions
Avoid in px with acute renal failure; use with caution px with
impaired renal function
THIAZIDE & LOOP DIURETICS
Clinically Uses of Thiazide and Loop Diuretics
Thiazide diuretics – HTN, Mild heart failure, Chronic calcium
stone formation, Nephrogenic diabetes 

insipidus
Loop diuretics – CHF, Cirrhosis, Nephrotic syndrome 


➤
Moa: inhibit the Na+K+ 2cl- cotrasporter at the thick limb of
the loop of henle
furosemide can induce peripheral vasodilation
use: tx of CHF, mgt of pulmonary congestion
mx of hyperkalemia
mx of hypercalcemia
se: dose-related electrolyte imbalance
- hyponatremiua
Mx. NaCl supplement
- hypokalemia
mx of K+ sparing diuretics
Adverse Effects of Furosemide
Not directly related to diuretic property – Hyperuricemia,
Ototoxicity
Attributable to diuretic property – Metabolic alkalosis,
Hypokalemia, Hypocalcemia, Hypovolemia, Hypotension,
Hypomagnesemia
Adverse effects of Chlorthiazide
Not directly related to diuretic property – Hyperuricemia,
Hyperglycemia, Hyperlipidemia 


Attributable to diuretic property - Metabolic alkalosis, Hypokalemia,

Hypocalcemia, Hypovolemia, Hypotension, Hypomagnesemia
Adverse effects of Spironolactone
Attributable to diuretic property – Metabolic acidosis,
Hyperkalemia
Not directly related to diuretic property – Menstrual disorders,
Impotence/gynecomastia, Loss of libido, Hirsutism 

Clinically uses and Toxicities of other Diuretics - CAIs
Clinical uses – Glaucoma, Altitude sickness, Reduce metabolic
alkalosis
ADRs – GI upsets, Paresthesias, Hepatic encephalopathy,
Cross-allergic with other sulfonamides Osmotic Diuretics
Clinical uses – Protect the kidney from solute overload caused
by crush injury or chemotherapy; Acute glaucoma
ADRs – headache, GI upset, Hypotension, Mild hyponatremia
followed by hypernatremia ADH Antagonist 

Lithium
ADRs – Iatrogenic nephrogenic diabetes insipidus
Demeclocycline
Clinical use – Prevent dangerous hyponatremia in syndrome of
inappropriate antidiuretic hormone secretion (SIADH)
ADRs – Iatrogenic nephrogenic diabetes insipidus; Disorders of
developing bones and teeth; Rash; GI upset; Hepatic
dysfunction
OSMOTIC DIURETICS
MOA: increase the osmotic pressure at the proximal convoluted
tubule and Loop of Henle preventing
water reabsorption
Sorbitol
Urea
Mannitol

Uses
Forced diuresis (Li toxicity)
reduce intracranial pressure

Side-Effects
Hypovolemia
Pulmonary edema
MOA: creates an osmotic gradient at the tubule thus preventing
water reabsorption at the h20 permeable regions of renal tubule
Uses: mx of cerebral edema or increased ICP
se: dehydration, hypovolemic hyponatremia, pulmonary edema
OTHER DIURETICS
Carbonic anhydrase Inhibitor – Acetazolamide, Dorzolamide
Osmotic diuretic – Mannitol, Urea, Isosorbide
Xanthine diuretic – Caffeine, Theobromine, Theophyline
ADH antagonist – Demeclocyline, Lithium
Mercurial diuretic – Mercaptomerin
Acidifying salts – Ammonium chloride 


➤
 CENTRALLY
ACTING
SYMPATHOPL
EGICS
CENTRALLY ACTING SYMPATHOPLEGICS
MOA: act primarily within the CNS on alpha-2 receptors to
decrease sympathetic outflow to the CVS
Clonidine
Methyldopa
Guanfacine
Guanabenz

Clonidine
effective in patients with renal impairment

methyldopa (aldomet)
Side-Effect
transient increase in BP
sedation/depression
rebound hypertension on abrupt withdrawal
METHYLDOPA
Reduce TPR with little effect on CO and blood flow to vital
organs (such as kidneys)
effective for patients with renal impairment
used in the management of HTN in pregnancy (pre- eclampsia,
eclampsia)

Side-Effect
Sedation, depression
hepatotoxicity (at doses >2g / day)
(+) Coomb’s Test
PERIPHERALLY
-ACTING
SYMPATHOPLE
GICS
Trimethaphan
Reserpine
Fuanethidine
Guanadrel
TRIMETHAPHAN
Ganglionic receptor blocker
given via IV infusion
used in hypertensive emergencies caused by pulmonary edema
or aortic aneurism when other agents cannot be used
RESERPINE
Plant alkaloid
inhibits catecholamine (NE, Epi, Dopamine, Serotonin) storage
Impairs sympathetic function because of decreased release of
Norepinephrine (NE)
GUANETHEDINE, GUANADREL
Inhibit the response of the adrenergic nerve to stimulation or to
indirectly-acting sympathetic amines blocks the release of stored
Norepinephrine

SE:

orthostatic hypotension

impaired male sexual function
 ALPHA 1
BLOCKERS
ALPHA 1 BLOCKERS
(-zosin)
MOA: inhibit the alpha-1 receptors, resulting to vasodilation of
arteries and veins



Prazosin

Doxazosin

Alfazosin

Terazosin

Alternative drugs for the management of HTN esp among
patients with BPH
First-Dose Phenomenon:

orthostatic hypotension syncope
remedy: take the drug at bedtime, slow increase in dose
 BETA-
BLOCKERS
BETA-BLOCKERS
Used for the initial therapy of HTN; effective for patients with
rapid resting HR or concomitant IHD
MOA
Block stimulation of renin secretion Decrease contractility
decrease CO Decrease sympathetic output centrally
Reduction in HR
reduced CO
SE/Precautions/Contraindications:
can mask hypoglycemia
CI to patients with bronchospastic disease: COPD,
Bronchial Asthma
rebound tachycardia
HTN
easy fatigability exercise intolerance
severe bradycardia and heartblock (seen esp with concomitant
use of verapamil and diltiazem)
Selective
B – Betaxolol
B – Bisoprolol

E – Esmolol

A – Acebutolol

A – Atenolol

M – Metoprolol 

Mixed alpha and beta blocking effect
L – Labetalol
C – Carvedilol
VASODILATO
RS
VASODILATORS
directly relax the peripheral vascular smooth muscles inc HR &
renin rel should be given w/ diuretics & b- blockers

common
SE

reflex tachycardia, peripheral edema

common CI:

as single agents, should be avoided in patients w/ IHD
1. Arteriolar vasodilators
ex. Hydralazine, Minoxidil, Diazoxide

moa (minoxidil)
- stimulate or open up more outward conducting K+ channels
→ hyperpolarization → relaxation/dilation of arteriolar vascular
smooth muscle
Minoxidil
-most effective arteriolar vasodilator
- uses: adjust in mx of HTNsive crisis and hair growth stimulate
se: hypertrichosis and hirsutism
HYDRALAZINE
use:
- management of HTN in pregnancy
- mx of HTNsive crisis
- given with ISDN for CHF
SE: drug induced SLE
DIAZOXIDE
Used in the emergency treatment of hypertensive crisis as
alternative
SODIUM NITROPRUSSIDE
Mixed arterial and venous dilators
Metabolized in the body to NO also called EDRF
1 line drug for almost all types of HTNsive emergencies
st

Caution: use freshly prepared solutions or admixtures protect

from light
SE: thiocyanate or cyanide toxicity, acute psychosis, severe
hypotension, coma, death
Moa

Na Nitroprusside
↓
NO (Nitric Oxide) = EDRF
↓
stimulates guanylyl cyclase

⤼
GTP CGMP
(vasodilation)
 CALCIUM
CHANNEL
BLOCKERS
MECHANISM OF ACTION
MOA

Inhibit influx of Ca through the slow channels in vascular
smooth muscle and cause relaxation
DIHYDROPYRIDINE (DHP)
block Ca channels in the blood vessels

Nifedipine, Nicardipine, Felodipine, Amlodipine


SE: dizziness, headache, reflex tachycardia

(dipines)
Nifedipine
Nimodipine
Amlodipine
moa:
Inhibit the L-type Ca2+ channels primarily in arteriolar vascular
smooth muscle

effect: arteriolar vasodilation

se: reflect tachycardia, peripheral edema
NON-DIHYDROPYRIDINE (NON-DHP)
block Ca channels both in the heart and blood vessels Verapamil
– heart > blood vessels

Diltiazem – heart = blood vessels

SE: bradycardia, AV block, heart failure, constipation

Verapamil
Diltiazaem
moa:

inhibit L-Type ca2+ channels in the arteriolar vascular smooth

muscles of the heart
effects: arteriolar vasodilation
Se: bradycardia, peripheral edema
- intrinsically short acting
Nifedipine
Nicardipine
Verapamil
Diltiazem

- instrinsically long acting

Amlodipine (once a day)
- modified long acting (instrimsically short acting but are
formulated as modified release
Felodipine ER or XR
Nifedipine GITS
Verapamil SR
Diltiazem SR
uses:
- alternative drugs in HTN (2nd line)
- anti anginals: non-DHP CCBs, long acting CCBs (diltiazem)
- anti-arrhythmic: non-DHP CCbs (Verapamil)
- Nimodipine: cerebral vasodilator (after subarachnoid bleed)
contraindications: CHF, HR <60, age >65, px on BB tx.

se:
- peripheral edema: mechanism → capillary congestion (arterial
dilation and no vein dilation)
tx. give drugs w/ ventilating effects
ACEi or AIIRBS
- non DHP: bradycardia and heart block
- short acting: reflex tachycardia
ANGIOTENSIN
CONVERTING
ENZYMES
INHIBITOR
ANGIOTENSIN ANTAGONISTS
I. Angiotensin II-Receptor Blockers – sartans, Losartan, valsartan

II. Angiotensin-converting Enzyme Inhibitors (more effective)
Captopril,Alacepril, Perindropril, Zofenopril
Enalapril, Benazepril
Quinapril, Trandolapril
Lisinopril, Cilazapril
Ramipril, Fosinopril
MOA: inhibit ACE, thereby preventing the conversion of
angiotensin I into the active form angiotensin II Short-acting

Captopril

Long-acting

Enalapril

Lisinopril

Perindopril

Ramipril

Imidapril


SE:

idiosyncratic dry cough (~20% )
CLINICAL USES
ACEI’s – Mild to moderate hypertension; CHF, Diabetes mellitus
ARBs – In patients who cannot tolerate ACEIs


- 1st line of treatment in mx of HTN especially among DM,

chronic kidney disease, and CHF
- 1st line component in combination tx in CHF
- 1st line in mx of albuminuria

AIIRBS are given as alternative when ACE cannot be given

ADVERSE EFFECTS
Hemophilia Headache Fever

Allergy Orthostatic hypotension Cough

Renal damage in nondiabetic renal vascular disease

Severe renal damage in the fetus Hyperkalemia

-idiosyncratic dry cough (bradykinin, seen 25% higher in asian)

Remedy: ↓ dose
stop ACE-I temporarily and restart at a lower dose
if no response and cough is intolerable, shift to AIIRBs
- angioedema
➔ shift to AIIRBs

s/e shared with AIIRBs

- hyperkalemia
interstitial nephritis
Hypotension
→ give ACE-I only if SBP >100mmHg
→ give test doses and slow titrate up dose
CI
- ACE-I: angioedema (↑ bradykinin) [shift to AIIRBs]
ANGIOTENSIN
II RECEPTOR
BLOCKER
AIIRBs
-sartans
Losartan
Valsartan
Irbesartan
Candesartan
direct inhibitors of angiotensin II receptors no vasoconstriction
Losartan, Valdesartan, Candesartan, Irbesartan clinical
use:same as ACE Inhibitors
SE: ↑K, renal insuff; CI: pregnancy

Advantage over ACE inhibitors: less associated with dry cough
 RENIN
INHIBITORS
Aliskerin (Tekturna)
use: additional tx with ACE-I for HTN

moa: binds to the Angiotensinogen-binding site in renin thus

preventing conversion of Angiotensinogen to A-I

se: dry cough, angioedema, rashes

 Kokology 8
“Blue Coat, Yellow Coat”

• Gathering in the town square for the lighting of the

Christmas tree gives people a chance to come
together as a community and celebrate the end of
another year. It’s a time of nostalgia and a chance
for new memories to be born. People are in the
holiday spirit, strangers act like friends, and a
sense of peace is all around.
• The night is cold, and you have come with a group
of friends and acquaintances to watch the lighting
of the tree. In the group of people with you one
person is wearing a yellow coat and another
person is in blue. Who are the people wearing the
blue and yellow coats? (Give the names of people
you know.)
• In psychology, bright colors such as yellow are
associated with warm and positive feelings, while
cool colors like blue are linked with cold, negative
emotions. It may surprise even you, but the person
you named as wearing the yellow coat is someone
you like or who makes you feel happy, while
something about the person in the blue coat leaves
you cold.
CONGESTIVE
HEART
FAILURE
Heart Failure

inability of the heart to pump sufficient amount of blood and
meet the metabolic needs of the body Compensatory Mechanism


Myocardial Hypertrophy

increase in the number of contractile elements in myocardial
cells as a means of increasing their myocardial performance

Weakened heart (poorly contracting)

Dyspnea - exertion DOB or SOB
Orthopnea - SOB when lying flat on bed
Paroxysmal nocturnal dyspnea (SOB that awakens px asleep)
Functional Calassficiation of CHF
I - Dyspnea only when performing activities beyond ordinary
II - Dyspnea when performing ordinary/regular activities
III - Dyspnea when performing less than ordinary activities
IV - Dyspnea or s/sx of HF even at rest
Preload
Afterload
FRANK-STARLING MECHANISM
Intrinsic ability of the heart to adapt to changing volumes of
inflowing blood

1. INOTROPIC
↑ strength of cardiac contraction
a. Digitalis glycosides
ex/ Digoxin (Lanoxin)
CARDIAC GLYCOSIDES
MOA:

inhibits the Na-K-ATPase pump inc intra Na leading to
accumulation of intracellular Ca2+
Use

Pxs w/ atrial fibrillation


effects:
mechanical - ↑ strength of contraction
electrical.- ↓ rate of conducting across the AV node (-dromotropism =
vagonotic_ —> bradycardia


automaticity increased —> arrhythmia
 Sinoatrial Node (SA)
↓
Atrioventricular node
↓
Bundle of HIS
↓
Purkinje Fiber
↓
P-Wave
↓
Atrial depolarisation
(QRS - ventricular, T - ventricular repolarization)
DIGITOXIN (D.PUPUREA - FOXGLOVE)
Pharmacokinetics

>90% Bioavailable

half-life: 168 hours

>90% protein bound

excreted in the bile

More lipophilic

narrow therapeutic index serum digoxin levels should be < 1ng/

mL
Cardiac Glycosides
have narrow therapeutic indices
toxicity can be enhanced by:
hypokalemia (most common)
hypomagnesemia

hypercalcemia
Toxicity
Cardiac Manifestations:

arrhythmias (ventricular tachycardia)

cardiac death


Extra-cardiac Manifestations

GI disturbances (nausea & vomiting)

visual disturbances (blurred vision, alteration of color
perception, haloes on dark objects)
Management of Toxicity
Give potassium supplement
Give digitalis antibodies (FAB fragments) for arrhythmias,
Give lidocaine or amiodarone
BETA 1 AGONISTS
Dopamine, Dobutamine
(low dose: enuresis, high dose: inotropic)


MOA: increase intracellular cAMP, which results in the

activation of protein kinase, that leads to an increase in
intracellular calcium


use: mx of acute heart failure or in acute exacerbation of CHF

Dopamine
Low dose

1-3 ug/kg/min

Renal D1
Mod dose

3-10 ug/kg/min

Inotropic β1
High dose

>10ug/kg/min
Vasoconstrictor at α1

β1 & β2 agonist w/ some α1 agonist effect Inotropic w/o
changing the HR
Use: acute heart failure management
PHOSPHODIESTERASE INHIBITORS
inodilators


MOA: inhibits the enzyme phosphodiesterase (PDE-III) which
hydrolyses cAMP , thereby prolonging the action of protein
kinase = increasing cAMP


Bipyridines

Amrinone

Milrinone

use: mgt of acute heart failure or acute exacerbaten of CHF

UNLOADERS - DIURETICS
↓ Cardiac workload (preload)
Preload unloaders


Spironolactone

Loop diuretics
Thiazide diuretics


Particularly useful in peripheral edema

UNLOADERS - ACE-I & ARBS
preload and afterload unloaders vasodilating effect


Captopril, Enalapril

first line of therapy for CHD

decrease preload and after load


 ACE-I MAX ALLOWABLE

CAPTOPRIL 150-200 MG/DL

ENELAPRIL & LISINOPRIL 20-40 MG/DL

ENALAPRIL DOSE SBP

2.5 MG 130

5.0 MG 120

7.5 MG 110

10 MG 105

12.5 MG 95
UNLOADERS - BETA BLOCKERS
mixed α1 & β

Prolong px life

vasodilating effect


Metoprolol, Bisoprolol, Carvedilol, Metorpolol

proven to decrease mortality and morbidity in stable CHF; never
give to unstable CHF

used for STABLE CHF

(+) response to conventional CHF
tx regimen given for atleast 2-3weeks
give bB on very low doses

Metoprolol - 2.5mg - 10 mg OD
UNLOADERS - VASODILATORS
arterial dilators: inc CO venous dilators: preload reducer, dec
pulmonary congestion

Hydralazine + ISDN
↓ ↓
↓ afterload ↓ preload
hydrazine - decrease after load
ISDN - decrease preload
H-BNP ANALOGUE
human brain natriuretic peptide
ex. Nesiritde (Natrecor) - recombinant DNA

effect: Vasodilator (IV infusion)

Use: adjunctive tx in acute HF or acute exacerbation

DYSLIPIDEMIA
Hypercholesterolemia (↑LDL, ↓HDL) Hypertriglyceridemia
(↑TG, ↑VLDL, chylomicrons) Diagnosis: fasting lipid profile

LDL, HDL, TG

Liver

Converts cholesterol to bile salts

Blood
ATHEROSCLEROSIS
Condition associated with cholesterol deposition in vascular
smooth muscles (arthroma) with consequent narrowing of the
lumen of the affected blood vessels
Could lead to...

CAD

Cerebrovascular disease Aortic disease
Renal artery disease Atherosclerosis
Major Risk factors

Age males: > 45; females: > 55

Smoking

DM is CHD risk equivalent

HPN

Obesity

Family history of CHD

Low HDL (<40mg/dL)


Minor Risk Factors


Chronic infection

Sedentary lifestyle

Modifiable Risk Factors

By therapy

By lifestyle change
HMG-COA REDUCTASE INHIBITORS
statins
Most potent


MOA: inhibit the enzyme HMG-CoA reductase, thereby

inhibiting the first step in cholesterol synthesis first-line drugs
for dyslipidemia

Short-acting

simvastatin

lovastatin

fluvastatin


Long-acting

atorvastatin

rosuvastatin

Long-acting statins can be given any time of the day.
SE:

hepatotoxicity

myositis
rhabdomyolysis (muscle wasting)
NICOTINIC ACID
unknown MOA; blocks lipolysis in adipose↓free f. acid

used in the management of hypertriglyceridemia
SE: flushing (due to percutaneous vasodilation), myositis,
itching, hepa, ↑glucose, ↑uric
BILE ACID SEQUESTRATES
aka: Bile Acid – Binding Resins

MOA: Inhibit reabsorption of bile acid

since liver must maintain a certain amount of bile, it will
synthesize bile from endogenous cholesterol when bile levels go
down

Bile Acid Sequesterants

Cholestyramine

Colestipol

Colsevelam

 SE:

Constipation, bloating, flatulence

impaired absorption of certain drugs (fat sol vitamins) Decrease
BA of acidic drugs (warfarin, nicotinic acid, paracetamol, etc)

may increase incidence / risk of biliary stone formation
FABRIC ACID DERIVATIVES
MOA: stimulate lipoprotein lipase which decreases triglycerides

first-line drug in hypertriglyceridemia

Gemfibrozil

Fenofibrate

Clofibrate (withdrawn)

Fibric Acid Derivatives

 SE:

myositis

rhabdomyolysis

increase risk of bile stone formation

hepatobiliary cancer (Clofibrate)

GI disturbances
PROTOCOL
MOA: anti-oxidant


SE:

increase risk of arrhythmia produces fetid odor
EZETIMIBE
MOA: interferes w/ absorption of cholesterol in intestines

Adjunct w/ statins


SE: GI upset
Coronary Artery Diseases (CAD) or

Ischemic Heart Diseases (IHD) Coronary Artery Diseases
Lack of oxygen & decreased or no blood flow to the heart due to
coronary artery narrowing/obstruction
 KOKOLOGY 2
The Blue Bird
• One day, a blue bird suddenly flies through a
window into your room and is trapped. Something
about this lost bird attracts you, and you decide to
keep t. But to your surprise, the next day the bird
has changed colour from blue to yellow! This very
special bird changes colour again overnight - on
the morning of the third day it is bright red, and on
the fourth it turns completely black. What colour is
the bird when you wake up on the fifth day?
• 1. the bird doesn’t change colour; it stays black

• 2. the bird turns back to its original blue

• 3. the bird turns white

• 4. the bird turns golden coloured

• the bird that flew into your room seemed like a
symbol of good fortune, but suddenly, it changed
colour, making you worry that happiness would not
last. Your reaction to this situation shows how you
respond to difficulties and uncertainty in real life…
 1
• Those who said the bird sats black have a
pessimistic outlook.

• Do you tend to believe that once a situation goes

bad, it never really returns to normal? maybe you
need to try thinking, if this is as bad as it gets, it
can’t get any worse. Remember, there;s no rain
that doesn’t end and no night so dark that there’s
no dawn the next day.
 2
• Those who said the bird turns blue again are
practical optimists.

• You believe that life is a mix of good and bad and

that it doesn’t pay to fight against the reality. You
accept adversity calmly and let things run their
course without undue stress or worry. This
outlook lets you ride out the waves of adversity
without being swept away.
 3
• Those who said the bird turns white are cool and
decisive under pressure.

• You don’t waste time on fretting and indecision,

even when a crisis develops. If a situation gets
too bad you feel it’s better to cut losses and look
for another route to your goal rather than getting
bogged in needless grief. This proactive
approach means that things seem to just
naturally go your way.
 4
• Those who said the bird turns golden can be
described as fearless.

• You don’t know the meaning of pressure. To you,

every crisis is an opportunity. You might be
compared with Napoleon, who said.. “…
impossible: the word is not French.” But be
careful not to let your boundless confidence get
the best of you. It’s a very fine line between
fearless and fooldhardy.
CORONARY
ARTERY
DISEASE
ANGINA PECTORIS
Episodic, reversible oxygen insufficiency

severe chest pains generally radiating to the left shoulder and
down the inner side of the arm

usually precipitated by physical exertion or emotional stress
MYOCARDIAL ISCHEMICA
Deprivation of oxygen to a portion of the myocardium
(reversible)
MYOCARDIAL INFARCTION
Severe, prolonged deprivation of oxygen to a portion of the
myocardium that leads to myocardial tissue necrosis
Risks Factors

Smoking

Hypertension

Diabetes Mellitus

Males >45 yo; Females >55 yo Dyslipidemia
Obesity

Family history of CAD

Others:

sedentary lifestyle, hx of chronic inflammation Etiology
Etiology

Decreased blood flow

Atherosclerosis – most common cause

Coronary artery spasm – sustained contraction of 1 or more coronary
arteries Prinzmetal’s angina or MI Traumatic injury – that interferes with
blood flow in the heart

Embolic events – can abruptly restrict oxygen supply Increased oxygen
demand

Exertion and emotional stress sympathetic stimulation increase HR



Reduced blood oxygenation

Reduced O -carrying capacity (anemia)

2

Angina Pectoris

chest pain

a symptom of myocardial ischemia in the absence of an infaction
ANGINA PECTORIS
Types:
Stable exertional Angina
aka: Classical Angina

develops on exertion and lasts for < 5 min

relieved with rest or drugs

mechanism: imbalance oxygen supply
possible: (+) fixed obstruction to blood flow across arteries
Unstable Angina

can be experienced at rest, or with increasing severity for the last
1-2 months or a new chest pain for < 1 month

Resembles MI

mechanism: thrombosis

Angina Pectoris

Types:

Angina Decubitus

nocturnal angina

occurs in recumbent position

Prinzmetal Angina

aka: Variant Angina

precipitated by coronary artery spasm

Drugs for Angina Pectoris

Nitrates

 MOA: metabolized into NO inc cGMP smooth muscle
relaxation vasodilation

examples

amyl nitrite

nitroglycerin

isosorbide dinitrate (ISDN)

isosorbide mononitrate (ISMN)

 SE:

Postural hypotension, reflex tachycardia, throbbing headache,
tolerance 8-12hrs nitrate free interval
Anti-anginals
- underlying disease is CAD
manifestations of CAD
1. Acute Coronary Syndrome (ACS)
- chest pain lasting for >20 mins relieved by rest or SL nitrates
- 3 forms:
1. STEMI- ST elevation AMI
2. NSTEMI - non ST elevation AMI
3. UAP - Unstable Angina Pectoris
UAP (negative for cardiac biomarkers)
3 types:
1. Rest angina - chest pain at rest
2. Crescendo Angina - increasing severity, duration, or frequency
for the last 2 months
3. New Onset Angina - 1st episode of chest pain
summary of mgt:

NSTEMI, UAP STEMI

↓
Reperfusion strategies:
fibrinolytic, emergency angioplasty
↓
Anticoagulants
2. Chronic Stable Angina Pectoris (CSAP)
- chest pain lasting for 2-5 minutes, precipitated by physical
stress or emotional stress and relieved with rest or sublingual
nitrates
- no change in severity, duration, and frequency of chest pain for
the last 1-2 months

3. Prinzmetal’s or Variant or Vasospastoc angina

mechanism: Coronary Artery Vasoconstriction
Management:
1. ↑ blood flow - ↑ oxygen supply
- interventional: angioplasty (PTCA), bypass grafting (CABG)
- pharmacologic: coronary vasodilators (applicable for
Prinzmetal’s)
2. ↓ oxygen demand
- ↓ sv, ↓ SVR, ↓ HR
A. Nitrovasodilators
Moa

Na Nitroprusside
↓
NO (Nitric Oxide) = EDRF
↓
stimulates guanylyl cyclase
GTP CGMP
⤼ (vasodilation)
effect:

peripheral venodilation
↓
↓venous return / preload
↓
↓ SV = pain relief

High dose: arteriolar and coronary artery vasodilation

- short acting (10-30 mins) SL
SL nitrates:
ISDN
IV NITRATES:
NTG
- intermediate acting (5-8 hours)
ISDN IV
ISDN
NTG Inf.
NTG SR
- LONG ACTING (10 - 24 HOURS)
ISDN SR
ISMN PO
TD patches
clinical uses:
- 1st line in the mx of angina pectoris
→ SL or inhaled or IV infusion
- mx of pulmonary edema
- alternative in mx of HTNsive crisis
→ IV infusion
- Amyl nitrite inhalation - initial mx of cyanide poisoning
Se:
- hypotension
- use only if SBP >90
- avoid use w/in 24 hours of use of PDE-5 (sildenafil)
-throbbing migraine like headache “monday disease”
- due to artery dilation

Tolerance develops when serum nitrate levels are sustained

overtime (depletion of SH sulfahydryl)
- Amylnitrite - methemoglobinemia
tx. methylene blue (low dose too ↑ dose causes methemoglobinemia)
remedies for tolerance:
-use only on a PRN basis
provide SH sources (captorpil, NAC, glutathione)
- maintain TD patches x 10 hours only
-observe free nitrate interval → 10-14 hours w/p nitrates
BETA BLOCKERS
DOC for stable angina, CSAP (Maintenance tx)
MOA:

↓HR & contractility ↓O2 demand reduce arterial BP
- reduction of heart rate with increased diastolic filling time
- improve coronary perfusion and improved O2 supply
- ↓ myocardial contractility and arterial pressure, reducing O2 demand
CCBS
MOA

Inhibits Ca influx into vascular smooth & heart muscles
↑blood flow
↑O2 supply prevent and reverse coronary spasm

dilates peripheral arterioles
↓contractility
↓TPR
↓O2 demand

Indications


Stable angina not controlled by nitrates & beta blockers; pxs

who could not take beta blockers


DOC for Prinzmetal’s angina (with or without nitrates)

DOC of angina at rest

MORPHINE
Unstable angina with no CI; IV doses given after 3 sublingual
nitroglycerin tabs have failed to relieve pain
ASPIRIN
Indefinite in px with stable or unstable angina
HEPARIN, ENOXAPARIN, DALTEPARIN
Together with aspirin hospitalized px with unstable angina
until resolved
MYOCARDIAL
INFARCTION
Myocardial Infarction (MI)

Results from prolonged myocardial ischemia, precipitated in
most cases by an occlusive coronary thrombus at the site of a
pre-existing atherosclerotic plaque
Cellular ischemia Tissue injury
Tissue necrosis
persistent, severe chest pain or pressure “crushing”,
“squeezing” or heavy “an elephant sitting on the chest”

 Signs and Symptoms of MI

Compared to angina

Pain persists longer

Not relieved by rest or nitroglycerin

Sense of impending doom, sweating, nausea, vomiting, difficulty
in breathing; some px fainting and sudden death

Extreme anxiety, restlessness, ashen pallor

 Some px:

Mild or indigestion-like pain, manifest in worsening CHF, loss of
consciousness, acute confusion, dyspnea, sudden drop in BP,
lethal arrhythmia Virchow’s triad of thrombus formation:

Venous stasis

Illness, surgery, paralysis, obesity

Vascular injury

Surgery, trauma, atherosclerosis

Hypercoagulable states

Malignancy, antiphospholipid abnormalities, estrogen
MORPHINE
MOA

causes venous pooling and reduces preload, cardiac workload,
and oxygen consumption
IV until pain is relieved

Indication

DOC for MI pain and anxiety

Precautions

can produce orthostatic hypotension and fainting monitor for
hypotension & signs of resp depression
OXYGEN
for patients who have chest pain and who may be ischemic

improve oxygenation of myocardium
THROMBOLYTIC AGENTS
MOA:

Lysis of thrombus clot

The following are given IV within 12 h to restore normal blood
flow in an acute MI:
Recombinant t-PA (recombinant tissue-type plasminogen
activator alteplase)

STREPTOKINASE
Anisoylated plasminogen streptokinase activator complex
(APSAC)
Reteplase
Tenecteplase
 Post thrombolysis adjunctive therapy

Aspirin

prevents platelet aggregation; shown to reduce post- infarct
mortality

also: dipyridamole, ticlopidine, clopidogrel
HEPARIN
prevent re-occlusion once a coronary artery has been opened

not used with streptokinase increased risk of hemorrhage
WARFARIN
reduce mortality, prevent recurrent MI
BETA BLOCKERS
if administered early reduce ischemia, reduce potential zone of
infarction, decrease oxygen demands, preserve left ventricular
function, decrease cardiac workload
ACE INHIBITORS
improve exercise capacity and reduce mortality in px with CHF;
aid in the prevention of progressive ventricular remodelling
STATINS
reduced mortality due to MI when used by px to aggressively
lower cholesterol

Post thrombolysis adjunctive therapy
LIDOCAINE
used for px who develop ventricular arrhythmia
CCBS
decrease incidence of reinfarction in px with non-Q- wave
infarcts; not for acute mgt.
 DRUGS FOR
COAGULATION
DISORDERS
STIMULI FOR THROMBOSIS
➤ endothelial injury
➤ foreign body in the blood
➤ venous blood stasis
➤ hyper coagulability
- thrombus : clot formation
- emboli : traveling clot
EVENTS IN CLOT FORMATION
vascular events
cellular and protein events
CELLULAR AND PROTEIN EVENTS IN THROMBOSIS
1. Platelet migration and aggregation
2. Coagulation cascade
PLATELET MIGRATION AND AGGREGATION
factors regulating platelet event
pro aggregate
TXA
ADP
5-ht
anit-aggregant
PGI
PGE1 endothelial products

CAMP
receptors involved in platelet aggregation
Glycoprotein IIG, IIA - pro aggregants
important in binding platelet to another platelet
requires fibrinogen
Glycoprotein IA, IB
platelet adhesion to endothelium (Ib)
involved in attaching platelets to the endothelial space
end product : haemostats
white thrombus, platelet plug
unstable and temporary clot
common pathway
fibrin
deposits onto the platelet plug and glues the platelets together
attaches other cells to deposit onto platelet plug
red thrombus - 2’ to homeostasis
stable blood clot — permanent
it takes 6-12 hours from the time of injury for blood clot to
become stable
thrombus: clot formation
emboli - travelling clot
 Drugs for Coagulation Disorders Clotting Mechanism

inciting event: epithelial vascular injury followed by:
migration of platelets to the site of injury platelet aggregation

aka: primary hemostasis

white thrombus
platelet plug

unstable clot

deposition of fibrin over the plug attachment of other blood cells
aka: secondary hemostasis

red thrombus

stable clot
Thrombus
clot that adheres to a blood vessel wall

Embolus
detached thrombus
FIBRINOLYTIC AGENTS / THROMBOLYTICS
MOA

catalyse activation of plasminogen to plasmin

mgt of severe pulmonary embolism

heart attack, acute MI

 SE: hemorrhage

Ex

Streptokinase – destroy fibrin that is either bound to clots or is
in the unbound form

Tissue plasminogen activator – binds to fibrin bound to a clot

Anistreplase (APSAC)

Urokinase – from the kidneys
DRUGS
1. antithrombotics
anticoagulants
antiplatelets
finbrinolytics
2. prothrombotics
vitamin k
e-aminocaproic acid
➤ e-aminocaproic acid
ANTICOAGULANTS
MOA: prevents clot formation

Site of action

synthesis of or directly against clotting factors (II, IIa) Types:

Parenteral

Hirudin, Heparin

Oral

Dicumarol, Warfarin
parenteral
heparin
hirudin, lepirudin, argatroban, bivaluridin
oral
warfarin
dicumarol
DIRECT THROMBIN (PARENTERAL)
HIRUDIN & LEPIRUDIN
obtained from medicinal leeches (Hirudo medicinalis) Direct
thrombin inhibitors

used in the management of HIT
recombinant
use: mx of thrombosis associated with HIT (Heparin Induced
Thrombocytopenia)
s/e: bleeding
BIVALIRUDIN, ARGATROBAN
given to precent thrombosis PTCA (Post transluminal coronary
angioplasty)
bivalirudin can be used for mgt of HIT
INDIRECT THROMBIN INHIBITOR
HEPARIN (SULFATED GAG)
Regular or Unfractionated heparin
HMW 5000-30,000
forms an active complex with antithrombin III which in turn
inactivates thrombin (IIa); Ixa, Xa, Xia

SQ/IV
onset: 6 hours from given dose
dosing and monitoring of effect
IV infusion (bolus, infusion)
Acute Coronary syndrome
bolus dose: 50 iu/k BW, inf rate: 12.5 iv/kgbw/hr
pulmonary thromboembolism
bolus dose: 80 iu/k/bw, inf rate: 19 iu/k/bw/hr
monitor of effect: APTT 96 hours until goal
goal: APTT delay of 46-70 (60-85s)
Subcutaneousdose: 5000 iu bid to 1500 iu OD
monitoring: usually not necessary
HEPARIN
Clinical use

mgt of MI or unstable angina

tx & prev. of PE & DVT

Pregnancy

SE:

hemorrhage (monitor aPTT) 1.5-2.5x control Allergy, Thrombocytopenia

osteoporosis

CI

Hypersensitivity

Active bleeding

Thrombocytopenia

Severe HPN

Active TB
LOW MQ HEPARIN
Inactivates IIa and Xa


Enoxaparin, fraxiparin, dalteparin, tinzaparin

SQ (prefilled syringes)

Longer half life

Less bleeding

uses:
when initiating anticoagulant therapy (if px is to be maintained
with warfarin)
for prevention and tx of pulmonary embolism
mgt of DVT (deep vein thrombosis
mgt of actor coronary syndrome
when anticoagulation is necessary in pregnancy (warfarin is
teratogenic)
APAS (Antiphospholipid Antibody syndrome)
contraindications
hypersensitivity
active bleeding (menstruation is not included!)
thrombocytopenic px
severe HTN - blood vessels on brain
active tuberculosis (hemoptosis
side effect
bleeding/cerebral haemorrhage
tx: protamine sulfate
heparin induced thrombocytopenia (HIT)
tx: stop heparin, use direct thrombin inhibitors
osteoporosis - prolonged used
alopecia
WARFARIN (COUMADIN)
SOA: liver

MOA: inhibits vit. k epoxide reductase enzyme (VKDR)
necessary to convert inactive Vit. K
blocks carboxylation of IX,X, VII,II (1972)

ONSET: 8 – 12 hrs maximum after 1 to 3days Clinical use

Chronic anticoagulation (DVT prophylaxis, cardiac thrombus,
prosthetic heart valves)


first oral anticoagulant

SE:

Haemorrhage
Hemorrhagic dse of the newborn Teratogenic: abnormal bone
formation Cutaneous necrosis

Purple toe syndrome
Alopecia, urticaria,dermatitis


Monitor PT and INR

PT goal: 60-85 [<60: underdose; >85: overdose] Goal for INR = 2-3

With prosthetic heart valves INR goal = 3-4 Antidote: Vit K

earlier consumption of anticlotting factors, thus within the first
week of warfarin use — procoagulant
s/e : cutaneous necrosis (within first therapy)
remedy: co-administration of heparin in the first 5 days

purple toe syndrome

more than 3 weeks of therapy
due to the cholesterol embolisation
dosing and monitoring
asians esp filipinos : 1-2.5/day
caucasians : 5-10 mg / dau PD

lab parameter:
prothrombin time
INR
ANTI PLATELET AGGREGATES
ANTI PLATELET DRUGS
Thromboxane Synthesis Inhibitors

Irreversibly acetylates COX- inhibition of TXA2 synthesis, lasts
for 8 – 10 days
1st line antiplatlet for primary and secondary prevention of
thrombolytic events
secondary prevention of vascular events
ASPIRIN
primary prophylaxis for MI
secondary prophylaxis for MI and stroke SE: GI ulcer, bleeding
THIENOPYRIDINES
ticopenide (ticlid)
dose: 250 mg BID
onset of full effect: 11 days from the start f tx
offset of effect: 1 week from the last dose
use: substitute to aspirin (TIA) transient ischemic attack or
stroke
s/e
neutropenia (agranulocytosis
requires weekly WBC monitoring for first three months
thrombocytopenia
CLOPIDOGREL (PLAVIX)
dose: 75 mg Od
advantage: not associated with neutropenia a
effect: clopidogrel < aspirin
PHOSPHODIESTERASE INHIBITORS
1. Dypiridamole (persantine)


inhibits adenosine uptake and CGM phosphodiesterase activity

given together with antiplatelet; ineffective when alone Inc
cAMP vasodilation

Inh adenosine reuptake dec platelet aggregation
SE: coronary steal phenomenon
effective only if given in combination with other anti platelet
primary prophylaxis for thromboembolism in prosthetic heart
valves
2. CILOSTAZOL (PLETAAL)
VASODILATOR
PRIMARY FOR INTERMITTENT CLAUDICATION
(REYNAUDS)
GLYCOPROTEIN IIB/IIA INHIBITORS
For px undergoing percutaneous intervention (angioplasty)

SE: bleeding

Abciximab

Eptifibatide

Tirofiban
PROCOAGULANT DRUGS
Mgt of bleeding disorders

Vitamin K

K1 – phytonadione (in plants, useful clinically)

K2 – menaquinone (intestinal bacteria)

K3 – menadione (synthetic)

used for Vit. K deficiency; hemorrhagic disorders in newborns
AMINOCAPROIC ACID
prevents activation of plasminogen
TRANEXAMIC ACID (HEMOSTAN)
Analogue

used to decrease risk of post surgery & post dental bleeding
GLYCOPROTEIN IIB/IIA INHIBITORS
ABCIXIMAB
EPTIFIBATIDE
TIROFIBAN

used to prevent thrombosis post PTCA

ARRHYTHMIA
 Refers to any change from the normal sequence of electrical
impulses, causing abnormal heart rhythms Can cause heart to
pump less effectively
TYPES OF ARRHYTHMIA
Supraventicular arrhythmia

Atrial fibrillation

Paroxysmal supraventricular tachycardia

Ventricular arrhythmia

Ventricular tachycardia & torsades de pointes Ventricuar
fibrillarion

CARDIAC CONDUCTION SYSTEM
Sinoatrial node

Pacemaker of the heart

60 – 100 beats/min

Location: posterior wall of the right atrium near the entrance of
the superior vena cava


Atrioventricular node

Location: posterior septal wall of the right atrium immediately
behind the tricuspid valve

Connects the atrial and ventricular conduction systems

Bundle of His (AV bundle)

Delayed transmission

Delays in transmission provide mechanical advantage atria
complete ejection of blood before initiating ventricular
contraction
Purkinje system
Supplies the ventricles

Has large fibers that allow for rapid conduction and almost
simultaneous excitation of the entire left and right ventricles
Rapid rate of ejection is necessary for the swift and efficient
ejection of blood from the heart 

MYOCARDIAL ACTION POTENTIAL
Resting Membrane Potential

membrane is relatively permeable to K+



charges of opposite polarity become aligned along the membrane 


(+) outside (-) inside 

DEPOLARISATION
Cell membrane suddenly becomes selectively permeable to
current-carrying ions such as Na 

+

Na enters cell sharp rise of intracellular potential to positivity

+

while K migrate outside

+
DEPOLARISATION
re-establishment of the resting potential

slower process; increased permeability to K K ions move
+ +

outward removes (+) charges inside the cell

The Na-K pump helps to preserve the intracellular negativity by
moving 3 Na ions out of the cell in exchange for 2 K ions.
+ +
MYOCARDIAL ACTION POTENTIAL
Phase 0:Rapid Depolarization
Phase 1:Early Rapid Repolarization
Phase 2: Plateau Phase of Repolarization
Phase 3: Final Rapid Repolarization
Phase 4: Slow Depolarization
Electrocardiography (ECG)

A recording of the electrical activity of the heart during
depolarization-repolarization

P wave

SA node and atrial depolarization

QRS complex

Ventricular depolarization

T wave

Ventricular repolarization
CAUSES OF ARRHYTHMIA Abnormal automaticity

Effect of drug

Abnormalities in impulse conduction Normal ECG Pattern
ECG Patterns of Arrhythmias
ANTI-ARRYTHMIC AGENTS
CLASS 1A

Slows phase 0 depolarization Prolong action potential
Slow conduction


SE

Cinchonism (HA, vertigo, tinnitus) Torsades de pointes

Anti muscarinic
 CLASS 1B

Shortens phase 3 repolarization Decrease duration of action
potential SE

Convulsion

Allergy 

agranulocytosis
CLASS 1C

Markedly slow phase 0 depolarization SE

Pro arrhythmic
CLASS II

Suppresses phase 4 depolarization
 CLASS III

Prolongs phase 3 repolarization

SE

Amiodarone: hypothyroidism, corneal deposit, pulmonary
fibrosis

Sotalol: torsades, bradycardia, asthma Brettylium: arrhythmia,
hypotension

Ibutilide & Dofetilide: torsades
epinephrine

Procainamide

can cause SLE (Systemic Lupus Erythematosus) Quinidine

drug interaction with digoxin

can increase serum levels of digoxin by at least 2x
 Lidocaine

anesthetic

DOC for digitalis-induced arrhythmias

Propafenone

for acute atrial fibrillation

Amiodarone

iodine-containing molecule

first-line treatment for almost all types of Ventricular Tachycardia
and Atrial Fibrillation

Verapamil

alternative for acute SVT (Supraventricular Tachycardia)

Adenosine

first-line drug for acute SVT
 CLASS IV

Slows phase 4 spontaneous depolarization Shorten action
potential

SE: hypotension
Miscellaneous Agents Adenosine

MgSO 4


Atrial flutter
Class 1 – quinidine Class II - propranolol Class IV – verapam
OTHERS
digoxin Atrial fibrillation
1- quinidine

2- propranolol

3- amniodarone

4 – anticoagulant

AV –nodal reentry

Propranolol

Verapamil

Digoxin

Acute supraventricular tachycardia Verapamil

adenosine

Acute ventricular tachycardia Lidocaine

Sotalol

Amniodarone

Ventricular fibrillation

Lidocaine

Bretylium

Amnidarone
AUTOCOIDS, ANTI-
INFLAMMATORY,
ANALGESICS
Autocoids
“autos” and “akos”
- difference from hormones:
- produced by cells
– local release and action is limited to specific site
– ex, histamines, serotonin, prostaglandins, bradykinin,
kalidin
a. Histamine
b. Setononin
c. Eicosanoids
d. Kinins (Bradykinin)
Autocoids: Chemical Classification
- amines: histamine, 5HT
- small peptides: kinins
- large peptides: interleukin
- lipids: eicosanoids
- Angiotensin
Angiotensin
- vasoconstrictor
- derived from angiotensinogen
- important in RAAS
A. Histamine

L- histidine
↓ decarboxylase
Histamine
Effects of Histamine
i. H1
- vascular smooth muscle: vasodilation
- extravascular smooth muscle
- bronchi: bronchioconstriction
ii. H2
- parietal cells of the stomach
- basal gastric acid secretion
RECEPTORS LOCATION EFFECT

Vascular Smooth Muscle


Extravascular Smooth Muscle
 1. Bronchoconstriction

1. Bronchi
 2. Itch and Pain, Flare

H1
2. Sensory Nerve Endings
 3. Localized Swelling and
3. Endothelial Cells (inner most edema
lining of blood vessels)

H2 Brain CNS Stimulation

Basal Gastric Acid

Parietal Cells
Secretion

Presynaptic (Brain, Mesenteric,

H3 Regulatory
Plexus)
Histamine 1 Antagonist
a. Physiologic - epinephrine
b. Pharmacologic - antihistamine H1 & H2

A. H1 Antihistamine
- general use: anti allergy medication
> allergic rhinitis
> allergic dermatitis
> histamine assoc. reactions
classifications:
1st generation - sedating
2nd generation - less/non sedating

1st gen is most useful for the mx of allergic rhinitis and

prevention of allergic reactions.
se: powerful sedation, anticholinergic effects
1. Ethenolamine
ex. Diphenhydramine
- most sedating
- powerful anticholinergic

2. Ehylenedramines
- pyrilamine, tripelemamine
3. piperazine
ex. Hydroxyzine
Meclizine (antomotion sickness

4. Alkylanines
- Brompheneramine, Chlorpheneramine
- useful components of cold tablets
5. Phenothiazine
ex. Promethazine (Phenargan)
- adjunct to anesthesia

6. Piperidine
ex. Cyproheptiline
- mx of serotonin syndrome
ii. 2nd Generation
1. Piperazines: Ceterizines, Levoceterizine
- less sedating
2. Piperidine: Loratadine, Desloratadine, Fexofenadine
- non-sedating
- allowed for pilots
'
b. H2 antihistamines = h2 blockers
ex. Cimetidine, Ranitidine, Famotidine, Nizatidine
- alternative tx for acid peptic disease
- during chronic use, must be given at bedtime

se: cimetidine
- enzyme inhibition
- anti-adronergic
- gynecomastia
- sterility, infertility, loss of libido
B. Serotonin = 5-hydroxytryptamine (5HT)
Effects:
- CNS/Central
– mood regulation n
- temperature and blood pressure regulation
- appettite, pain perception, vomiitting
- Peripheral
- vasoconstriction
- platelet aggregation
- peristalsis
RECEPTOR LOCATION EFFECT

Inhibit release of 5HT in the

5HT1A Presynaptic in CNS
brain

Vascular Smooth
5HT1B/1D Vasoconstriction
Muscle (Peripheral)

blood vessels:
Smooth Muscle
5HT2A vasoconstriction
(Peripheral)
uterus: uterine conractiojn
Chemoreceptor Trigger
5HT3 Vomitting Center
Zone

5HT4 GIT Peristalsis

3. Drugs acting on 5HT Receptors
a. 5HT1A (Partial Agonist)
- Buspirone (Buspar)
- dec. 5HT CNS levels
- used for mx of anxiety
b. 5HT1B/1D (Full Agonist)
- Triptans
- Sumatriptan, Naratriptan, Zolmotriptan
- mx of acute migraine headache
- se: worsen HTN, induce angina pectoris in CHD
c. 5HT2A Agents
- full agonist: Ergonovine, Ergotamine
- Antagonist: Methyseigide
- mx of migraine - ergonavine, ergotamine
- prophylaxis for migraine - Methyseigide

Se: agonist: worsen htn

All:
retroperitonial fibrosis
“st: anthony’s fire”
- digital necrosis, hyperthermia
d. 5HT3 antagonist = “setrons”
- Ondansetron, Granisetron
- antiemetics
- mx or prevention of cancer chemo induced emesis

e. 5HT4 agonist
- tegaserod
- mx of irritable bowel syndrome
EICOSANOIDS
effectsL
a. Blood vessels
-vasoconstriction: TXA2, PGF2a
- vasodilation: PGI2, PGEseries
b. Git
-cytoprotection - produce mucus and HCO3 at the gastric mucosa
- PGEseries
c. Bronchi
- bronchoconstriction - PGF2a, TXA2, LTC4, LTD4
- bronchodilation - PGI2, PGEseries
d. platelets
- aggregation (thrombossis) - TXA2
- inhibit aggregation (antithrombotic) - PGI2, PGR
(Endothelium products)
e. Uterus
- contraction PGF2a
- dysmenorrhea PGEa

f. eyes
↓ Intraocular Pressure - PGF2a, PGE series
ANALOGUES/DERIVATICES OF PG
a. Epoprosterol
- PGI analogue
- vasodilator
- mx of symptoms of pulmonaryy hypretension
b. Alprostodil
- PGEi analogue
- vasodilation
- mx of dysfunction
c. Misoprostol
- PGE analogue
- cytoprotection
d. Dinoprostone
- PGE2 analogue
- abortafacient
e. Latanoprost
- PHF2a analogue
- mx of glaucoma
DRUGS FOR RHEUMATOID DISORDERS AND RELATED DISEASES
Common hematologic disorders:

1. Rheumatoid Arthritis
2. Osteoarthritis
3. SLE
4. Alkylosing spondylitis
DRUGS
1. NDAIDS
2. DMARDS
3. GLUCOCORTICOIDS
4. MX OF GOUT
5. ANALGESICS
NSAIDS
- inhibits cyclooxygensae
types:
a. COX 1
b. COX 2
1. Non-selective cox inhibitors
- common s/e: ulcer
a. aspirin and the salicylate
3-2-4g/d: anti-inflam
<600mg/d: analgesic
MOA: peripherally inhibits COX, centrally inhibits prostaglandin
synthesis in response to interleukins
- irreversible acetylation of the XOC of platelets leading to decrease of
the synthesis and release of TXA2. this can last for as long as 7 days
- stop aspirin atleast 1 week before any surgery
a/e
1. GIT intolerance
- dyspepsia, epigastric pain w/o ulceration
(take with food)
- gi ulceration/gastritis
- identity risk factors
> old age > chronic/critical ilness
> high doses > steroid use
> multiple nsaids
2. CNS effects - salicylate poisoning
Salicylism, hyperventilation, respiratory alkalosis - low
metabolic acidoses, hyperthermia, fever - moderate
Hypoprthrombinemia - severe
respiratory failure and renal failure - fatal
3. Uric acid
Hyperuricemia (<2g/g)
Urisuria (4g/d)
ci for patients with gout
4. reversible decrease in GFR
- renal failure
5. hypersensitivity
- said induced BA
6. Reye’s syndrome
-hepatic failure and encephalopathy seen among children with
recent or current viral infection given with ASA
OTHER SALICYLATES
- locally acting
— topicalL methylsalicylate
— difulnisal - antipyretic, analgesic, anti inflame.
DMARDS/SAARDS
Drugs used for rheumatic disorders that does not respond to
NSAIDs
Slow the course of disease and may induce remission
3-4 months
IMMUNOSUPPRESSANTS
1. Methotrexate
– 1st line DMARDs

– MOA: dihydrofolate reductase inhibitor

– SE:hepatotoxicity, mucosal irritation, and nausea

– Dose:7-10 mg once/week – Leucovorin/Folinic Acid
2. Azathioprine

– Hepatotoxic
– Hematotoxic
– infertility
3. Cyclophosphamide
– Toxic immunosuppressant

– Reserved for life-threatening RA – SE: Hemorrhagic cystitis, Sterility
4. Chlorambucil and Cyclosporine
– Refractory RA, Life-threatening RA
ANTIMALARIALS
1. Chloroquine
2. Hydroxycholoroquine

• Slow the progression of bone lesions

• SE:Exacerbate dermatitis produced by gold preparations,
retinopathy
➤
GOLD PREPARATIONS
Auronofin (PO), Aurothioglucose (IM), Aurothiomalate (IM)
MOA: taken up by macrophages and suppresses phagocytosis
and lysosomal enzyme activity
SE: dermatitis of the skin or mucous membranes, allergic
reaction, Glossitis
Penicillamine
Used as an antidote of heavy metal poisoning
MOA: alters immune response
SE: dysgeusia, Good Pasture’s syndrome 

NEWER DMARDS
Tumor Necrosis Factor and Interleukin Inhibitors
Leflunomide – monotherapy for RA
inhibits pyrimidine synthesis
hepatotoxic, alopecia
Etanercept – monotherapy or adjunct to methotrexate
binds to TNF-a and -b
immunosuppression, upper resp. infxn.
Infliximab – approved when in combination with MTX
binds to TNF-a
immunosuppression
Anakinra – monotherapy or in conjuction with MTX
IL-1 receptor antagonist
immunosuppressants
HYPERURICEMIA
a condition characterized by high serum levels of uric acid due to
overproduction or impaired renal clearance (> 7mg/dl)
GOUT/GOUTY ARTHRITIS
A disease characterized by sudden attacks of urate- crystal induced arthritis, at
night or early in the morning
“big toe”
Tophi
45-50 years old
Signs and symptoms
Painful joint swelling characterized by redness, warmth and redness
Trigger factors:
Joint trauma, Alcohol, Diuretics, Chemotherapy,
Eating foods high in purins
DIAGNOSTIC CRITERIA
Presence of monosodium urate crystals in the synovial fluid of
the affected joints
High serum level of uric acid, leukocytosis
Dramatic therapeutic response to colchicine
DRUGS FOR GOUT
Colchicine—drug of choice for an acute gout attack
MOA: impairs leukocyte migration to inflamed areas and
disrupts urate deposition
Allopurinol
MOA: inhibit xanthine oxidase
Probenecid and Sulfinpyrazone
MOA: increase uric acid secretion in the proximal tubules
NSAIDs: Indomethacin, Sulindac, COX-2 inhibitors, Naproxen,
Ibuprofen
Glucocorticoids—oral prednisone
NON STEROIDAL ANTI-INFLAMMATORY DRUGS
Salicylates – Aspirin, Salicylic acid, Salsalate, Diflunisal
• Propionic acids – Ibuprofen, Naproxen, Ketoprofen,
Fenoprofen
• Oxicams: Piroxycam
• Indoleacetic acid – Indomethacin, Sulindac, Tolmetin,
Ketorolac, Etodolac
• Pyrazolones – Phenylbutazone, Oxyphenbutazone
• Fenamates – Mefenamic acid, Meclofenamic acid
CLASSIFICATION AND PROTOTYPES OF NSAIDS'S
• Irreversible, nonselective COX inhibitors 


• Aspirin – Prototype of salicylates


Reversible, nonselective COX inhibitors – Ibuprofen, Naproxen,
Indomethacin – have greater anti-inflammatory Effectiveness ;
Ketorolac – has greater analgesic effectiveness

Selective COX-2 inhibitors – Celecoxib, Rofecoxib, Valdecoxib
MECHANISM OF ACTION
Inhibition of COX enzyme thus inhibiting PGs synthesis
COX INHIBITORS
COX-1

Irreversible inhibitor – aspirin

Relatively selective – tolmetin, indomethacin, sulindac, piroxicam
Less selective – ibuprofen, paracetamol

COX-2

Selective – nimuselide, celecoxib, rofecoxib
 Equipotent COX-1 and COX-2 


 Naproxen Diclofenac Flurbiprofen Nabumetone

Other clinical Uses of NSAIDS
Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis, Acute
gout Barter’s syndrome – defect in renal tubular magnesium
reabsorption
Indomethacin

Induce (facilitates) closure of patient ductus arteriosus
Indomethacin
SIDE EFFECTS OF ASPIRIN
Coagulation disorders

Gastric intolerance (epigastric distress, ulceration, and
hemorrhage) – resulted from inhibiton of
prostaglandins that normally stimulate production of the
protective mucus of the stomach and
intestine (PGE2 and PGF2α ) and inhibition of gastric acid
secretion (PGI2)

Hypersensitivity reactions (urticaria or brochoconsriction) –
resulted from increased synthesis of
leukotrienes (especially associated with nasal polyps)

Fewer – which results in energy being wasted as heat due to
uncouple oxidative phosphrylation
Cyclooxygenase
It is the enzyme that converts arachidonic acid into endoperoxide
precursors of prostaglandis 2 isoforms of cyclooxygenase
COX-1 – is primarily expressed in noninflammtory cells and
involved in cell-cell signating and tissue homeostasis
COX-2

Is expressed in activated inflammatory cells such as
lymphocytes, polymorphonuclear cells,
and primary inflammatory cells such as cytokines (e.g.,
interleukins, tumor necrosis factor Is responsible for the
production of prostanoid mediators of inflammatio
COX inhibitors

COX-1

Irreversible inhibitor – aspirin

Relatively selective – tolmetin, indomethacin, sulindac, piroxicam
Less selective – ibuprofen, paracetamol
COX-2

Selective – nimuselide, celecoxib, rofecoxib
 Equipotent COX-1 and COX-2 


 Naproxen Diclofenac Flurbiprofen Nabumetone 


Other clinical Uses of NSAIDS

° Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis,

Acute gout
° Barter’s syndrome – defect in renal tubular magnesium
reabsorption
° Indomethacin

Induce (facilitates) closure of patient ductus arteriosus
° Indomethacin
SIDE EFFECTS OF ASPIRIN
Coagulation disorders


Gastric intolerance (epigastric distress, ulceration, and

hemorrhage) – resulted from inhibiton of prostaglandins that
normally stimulate production of the protective mucus of the
stomach and intestine (PGE2 and PGF2α ) and inhibition of
gastric acid secretion (PGI2)


Hypersensitivity reactions (urticaria or brochoconsriction) –

resulted from increased synthesis of leukotrienes (especially
associated with nasal polyps)
Fewer – which results in energy being wasted as heat due to
uncouple oxidative phosphrylation
OTHER SIDE EFFECTS OF ASPIRIN
Renal toxicity – resulted from inhibition of PGE2 and PGI2 which
are responsible for maintaining renal blood flow
Hepatotoxicity 


Reye’s syndrome – characterized by rapid liver degeneration and

encephalitis in children Salicylism
Respiratory paralysis – resulted from uncouple oxidative
phosphorylation, which leads to elevated CO2 and increased
respiration that may result in central respiratory paralysis and
acidosis
SIDE EFFECTS OF OTHER NSAIDS
Phenylbutazone – causes aplastic anemia and agranulocytosis


Ketorolac – used should be restricted to 72 h because of the risk

of GI and renal damage with longer Administration


Indomethacin – may cause serious hematologic reactions

COMPARISON OF NSAIDS
Indoleacetic acids – not used to lower fever 


Indomethacin – more potent than ASA but inferior at doses tolerated

by rheumatoid arthritic patients 


Sulindac – prodrug, less potent than indomethacin 


Piroxicam – half-life is 50 hours, given once daily

Phenylbutazone – powerful anti-inflammatory but weak analgesic and
antipyretic activities
Diclofenac – approved for long-term use in the TX of rheumanoid
arthritis, osteoarthritis and 

ankylosing spondilitis; more potent than indomethacin or naproxen
ADVANTAGE AND DISADVANTAGE OF COX2-INHIBITORS
Reduced risk of GI effects, including gastric ulcers and serious
gastrointestinal bleeding 


 Lack antiplatelet effects at conventional doses and are

therefore, not cardioprotective 


 Not recommended for renal dysfunction because is

constitutively active in the kidney 


 Celecoxib may cause hypersensitivity reaction in the patients

who aer allergic to other sulfonamides
CLINICALLY MANIFESTATION OF SALICYLISM
Mild – Tinnitus, Vertigo, Respiratory depression


Severe – Coma, Metabolic acidosis, Delirium, Hallucinations,

Respiratory and renal depression 

TREATMENT FOR SALICYSIM
° Maintaining respiration and circulation 


° Minimizing drug absorption (via gastric

lavage) 


° Maximizing elimination (alkalinizing the

urine) 

COMMON DRUG INTERACTIONS OF NSAIDS
Antacids – Reduced rate of aspirin absorption 


 Herapin or oral antiacoagulants – hemorrhage 


 Probenecid and sulfinpyrazone – decreased urate excretion 


 Increased plasma concentration leading to prolonged half-

lives, therapeutic effects, and toxicity of Bilirubin, Phenytoin,
Naproxen , Thiopental, 

Thyroxine

CONTRAINDICATION OF ASPIRIN
Pregnancy,
Peptic ulcer,
hemophilia,
Children with fever caused by viral 


illnesses
CLINICAL USES OF ACETAMINOPHEN (PARACETAMOL)
Clinically uses: analgesic, antipyretic (in Peptic ulcer disease,
Hemophilia and children with viral nfections)
SIDE EFFECTS OF ACETAMINOPHEN
° important side effect: hepatic necrosis

o Toxic doses surpass the liver’s supply of glutathione that may
normally binds and inactivates dangerous metabolites of
acetaminophen –N-acetyl-parabenzoquinoneimina

° Antidote: acetylcysteine (Contains sulfhydryl group to
glutathione)
NAPQI (N-acetyl-p-benzoquinone imine)
NEW THERAPY FOR GOUT - FEBUXOSTAT
MOA: The therapeutic effect of febuxostat is achieved via the lowering of serum uric
acid. The primary mechanism of action of febuxostat evaluated in trials was the
inhibition of xanthine oxidase, evidenced by the increase in serum and urine
xanthine concentrations, decrease in serum and urine uric acid levels, and lack of
significant reduction in total purine synthesis.

• In the majority of patients with gout, the mainstay of treatment for decreasing
serum uric acid concentrations has been with inhibitors of xanthine oxidase
(XO), such as allopurinol (Zyloprim; Aloprim) and febuxostat (Uloric) along with
changes in diet and lifestyle, to achieve a target serum uric acid level of < 6 mg/
dL. 
• Allopurinol is a purine analogue that is subject to being metabolized by many
enzymes involved in purine and pyrimidine synthesis metabolism, whereas
febuxostat is not a purine analogue.
• Allopurinol and its metabolites inhibit not only XO, but can also inhibit purine
nucleoside phosphorylase (PNP) in purine metabolism and orotidine-5'-
monophosphate decarboxylase (OMPDC), which are needed in the synthesis of
pyrimidines that will eventually be used for both RNA and DNA synthesis.
• Febuxostat is only an inhibitor of XO and does not influence the activity of other
enzymes involved in purine or pyrimidine synthesis or metabolism.
KOKOLOGY 24 “CAUGHT IN THE RAIN”
Not everything in life is predictable. We’re always getting hit by
surprises, emergencies, and unforeseen disasters without any
chance to prepare ourselves mentally. Surprises of any kind can
be stress– an unexpected proposal just as much as a sudden
breakup. There are too many things we can’t predict or control;
that’s one of the reasons we all tend to develop habits and
patterns to live by.
 You are walking outside when a hard rain suddenly begins to
fall. Even if you run full speed, you’re still about five minutes
from your destination. Which of the following best describes
your choice of action?
 1. I’d find an awning or tree to stand under and wait for the rain
to stop.
2. I don’t know how long it’s going to keep raining, so I’d run to
where I’m going as fast as I could.
3. I’d see if there was anybody around with an umbrella I could
share or a store where I could buy one.
4. I always have a folding umbrella in my bag when I go out, so
I’d just use that.
 How did you respond to the sudden downpour? The rainstorm
represents unforeseeable and uncontrollable forms in life.
 Specifically, your answer shows how you tend to react when a
fight breaks out between you and a loved one or friend.
1.  "I’D FIND AN AWNING OR TREE TO STAND UNDER AND WAIT FOR THE RAIN TO STOP.“

You’re the type who waits for the other side in a fight to cool off
before trying to settle your differences. You prefer to let them
rant and rave until they run out of steam, then presents your
case calmly and objectively. Some would say this is the
intelligent approach, others would say it’s just sneaky.
2.  "I DON’T KNOW HOW LONG IT’S GOING TO KEEP RAINING SO I’D RUN TO WHERE I’M GOING AS FAST AS I COULD”

  You don’t care about the end result of a fight so much as

getting to speak your mind. You’re sure right, and there’s no
sense in arguing the point. The concept of give-and-take doesn’t
figure into your tactics. If they get angry, you get angrier. If they
start to yell, you scream. This doesn’t make you much fun to
argue with, but at least it’s easy to tell where you stand on an
issue.
3.  "I’D SEE IF THERE WAS ANYBODY AROUND WITH AN UMBRELLA I COULD SHARE OR A STORE WHERE I COULD BUY ONE"

You don’t like conflicts and confrontations, so you try to

smooth things over and calm the other person down whenever a
fight breaks out. Unfortunately, sometimes that only makes
things worse. It may be important for you to make a stand and
weather the storm every once in a while.
4. “I ALWAYS HAVE A FOLDABLE UMBRELLA IN MY BAG WHEN I GO OUT SO I’D JUST USE THAT”

You think you have an answer for every accusation, a

justification for every fault. To you, an argument may be a
chance to hone your skills and debate, but to others you seem
slippery, frustrating, and insincere. But of course, you probably
have a good explanation for that, too.
 Kokology 3
A Night of Symphony
• There’s something magical about a night at the
symphony — a sense of expectation and pure
pleasure. Imagine being able to take a place on
that stage among the other musicians, a once-in-a-
lifetime chance to perform at your very best.

• if you could join the orchestra, what instrument

would you see yourself playing?
• a. Violin

• b. String bass

• c. Trumpet

• d. Flute
• Musical Instruments are symbolic of members pf
the opposite sex. The pairing of your and your
instrument shows how you perceive yourself in
making the music of love. The instrument you
chose gives insight into what you think of as your
strongest lovemaking technique
 1
• Violin

• The violin demands sensitive fingerer and a

delicate touch with the bow to draw forth music
from the taut strings. You see yourself as having
the same awareness and skill in locating and
playing upon your partner’s most sensitive
points. There’s a sense of adventure in the way
your hands can create such beautiful music by
running over the same familiar notes
 2
• String bass

• There’s a feeling of power gotten from taking

position behind an enormous bass and making it
call out in a tremendous moan. in love, your skill
rests in the ability to bend your partners to your
will, taking complete control, and driving them
onward to pleasures they never imagined they
could experience. You never ask for permission,
but that dominating character is what yours you
so irresistible.
 3

• Trumpet

• There’s no getting around it - your moth is the

strongest weapon in your arsenal. whether it’s
whispering love talk in your partern’s ear or
exploring them with your lips, you have all the
characteristics of the oral personality.
 4
• Flute

• the flute demands incredible patience fro those

who want to master it. You show that same
patience in the way you wear down partners with
your persistence, determination, and stamina.
Your lovers are often taken off guard when they
thought would be a brief recital quickly develops
into a full concerto in six movements.
GASTROINTESTINAL
MAJOR PARTS
alimentary canal
mouth
pharynx
oesophagus
stomach
small intestine
large intestine
accessory organs
liver
biliary duct system
pancreas
SALIVARY SECRETION
function
1. Alpha-amylase (ptyalin) begins starch digestion
2. Neutralizes oral bacterial acids, maintains dental
health
3. Mucins (glycoproteins) lubricate food
ALIMENTARY CANAL
Pharynx 


! Passageway for food

! subdivided into: nasopharynx, oropharynx, laryngopharynx
Esophagus
! Runs from the pharynx through the diaphragm to the
stomach Stomach
! temporary storage of food
! breaks down food into nutrients
! moves gastric content into the small intestine
! gastrin, hydrochloric acid, pepsinogen, mucus
Small Intestine
! 3 parts: Duodenum, Jejunum, Ileum
! longest
! Major digestive organ
! Almost all chemical digestion and absorption of nutrients occurs in the small intestine 


Large Intestine Parts:

! Cecum
! Appendix
! Colon
! Rectum
! Anal Canal


! eliminates digestive wastes as feces

! No villi
! Numerous goblet cells (mucus production)
ACCESSORY ORGANS
Accessory Organs
Liver
Location: RUQ ‘

Largest solid organ of the body

Many metabolic and regulatory roles
synthesizes plasma proteins, nonessential a.a., & vit. A
stores Vit. K, D, B & iron
12

Removes ammonia from the body fluids converting it to urea for

excretion of urine
secretes bile
Gall bladder
stores bile produced by the liver
releases bile to the duodenum 

Bile
greenish liquid
composed of water, cholesterol, bile salts, and phospholipids
produced by the liver
promotes intestinal absorption of fatty acids, cholesterol, and
other lipids
aids in the excretion of bilirubin from the liver
Pancreas
Soft, pink, triangular gland that extends across the abdomen
from the spleen to the duodenum
Both endocrine & exocrine gland 

PANCREATIC ENZYMES
Alpha-amylase: starch digestion, secreted in active form.
Lipase, phospholipase A, colipase: fat digestion.
Proteases (trypsin, chymotrypsin, elastase, carboxypeptidases):
protein digestion, secreted as proenzymes.
Trypsinogen is converted to active enzyme trypsin by
enterokinase, a duodenal brush-border enzyme. Trypsin then
activates the other proenzymes and can also activate
trypsinogen (positive-feedback loop).
FACTORS AFFECTING GET
REGULATION OF ACID SECRETION
! Gastric acid secretion by parietal cells of the gastric mucosa is
controlled
GI
! The receptor mediated binding of acetylcholine, histamine or gastrin results in
the activation of H+/K+ ATPase proton pump that secretes HCl into the lumen of
the stomach. 

! In contrast, receptor binding of prostaglandins E2 and I2 diminishes gastric
acid production.
! Histamine binding causes activation of adenylyl cyclase, whereas
binding of prostaglandin E2 and I2 inhibits the enzyme.
! Acetylcholine and gastrin act by inducing an increase in intracellular
calcium levels.
! PGE2 and PGF2a—stimulates secretion of protective mucus and
bicarbonate in the stomach and intestine. PGI2—inhibits gastric acid
secretion
COMMON GI
DISORDERS
AND THEIR
TREATMENT
 `
duodenal gastric

Is sometimes associated with:

1. Intake of aspirin or other NSAIDs
2. he incidence of peptic ulcer is two-fold greater in smokers.
Zollinger-Ellison Syndrome
Caused by gastric hypersecretion due to gastrin-secreting islet cell tumor of the
pancreas
Recurrent peptic ulcer or peptic ulcer in aberrant sites (ex. jejunum)
MEN I (Wermer syndrome)
Autosomal dominant disorder characterized by pituitary, thyroid, parathyroid,
adrenal corticol, and pancreatic islet cell adenomas or hyperplasia associated with
hypergastrinemia and peptic ulcer
DRUGS USED TO TREAT PEPTIC ULCER
Antimicrobials
helps heal ulcers and decrease recurrence
two or more antibiotics in combination with other drugs such as PPIs
duration: 2 weeks
PPIs for 6 weeks
Bismuth
Amoxicillin
Clarithromycin
Metronidazole
Tetracycline
Regimen
PPI based
Bismuth based
Proton Pump Inhibitors
more potent and rapidly effective than H -blockers
2

enteric coated preparation

highly protein-bound and metabolized extensively in the liver
administer in the morning before eating
Omeprazole
Lansoprazole (Prevacid)
Rabeprazole (Aciphex)
Pantoprazole (Protonix)
Esomeprazole (Nexium), (Naproxen/Esomeprazole)
Nexium IV
approved for use in infants and children for short-term
treatment of GERD & corrosive esophagitis
s/e
headache
nausea and vomitting
abdominal pain
diarrhoea
H-2 Receptor Blockers
MOA: Inhibits the action of histamine at parietal cell receptor
sites, reducing the volume of hydrogen ion concentration &
gastric acid secretion
used to treat GERD, duodenal ulcer, & erosive esophagitis
famotidine: most potent acid stimulant
Cimetidine (Tagamet) – Oral, IV

" 1 H2 blocker approved, 50% reduction in gastric secretion
st

Ranitidine (zantaC) – Oral, IV, IM


" more potent, 70% reduction in gastric acid secretion

" Ranitidine Bismuth Citrate + Clarithromycin: H. pylori
eradication
Famotidine (pepcid) – Oral, IV 

" most potent, 94% reduction
Nizatidine (axid) – Oral 

" newest H2-receptor blocker 


" Only non-hepatotoxic

s/e: headache & dizziness
ranitidine
hepatotoxicity
bradycardia
Cimetidine
hepatotoxicity
bradycardia
agranulocytosis
aplastic anemia
drug interaction
Cimetidine – enzyme inhibitor

" Phenytoin, theophylline, phenobarbital, lidocaine, warfarin,
diazepam, propranolol.
reduce clearance of propranolol & lidocaine
inhibits excretion of procainamide
absorption is impaired by antacid (Ranitidine)
Mucosal Protective
Coat any injured area in the stomach to prevent further injury from
acid
Cytoprotective agents 



SUCRALFATE
" #nonadsorbable disaccharide containing sucrose & Aluminum
" #equally effective as H2 -blockers
" #MOA:
" #Admin: 1g , 4x a day ( 1 hr before meals & at bedtime)
" #S/E: constipation 



BISMUTH COMPOUNDS
MOA:
Prevents adhesion of H Pylori to mucosa
suppresses its growth
highly effective when combined with PPIs and AB
preparation: bismuth subsalicylate, Colloidal bismuth substrate
s/e: dark stools and tongue
Antacids
MOA:
neutralize gastric acid, inhibit pepsin activity & strengthen
mucosal barrier
equally effective as H blockers
2

heal peptic ulcers and control ulcer pain

AL(OH)3
adsorbs pepsin and removes it from solution at pH>3 


delays GET(constipation) by relaxing small muscles of the

stomach
stimulate mucus secretion 


Hypophosphatemia 

MG(OH3)
keeps pH sufficiently high to keep pepsin adsorbed to it
lessens relaxant effect(diarrhea) 


CaCo3
can cause rebound acidosis that is prolonged and prominent
;

stone formation


NaHCO3
Baking soda
Most potent
Alkalosis
HTN
Fluid retention
antacids
Slow onset, long duration
Fast onset, short duration
Fast onset, long duration
" S/E:
" #Aluminum – constiptation
" #Magnesium – diarrhea
" #Calcium carbonate – constipation, acid rebound, gallstones (rarely)
" #Sodium bicarbonate – alkalosis, C/I in patients with renal failure ,
respiratory & metabolic acidosis 


" D/I:
" #Antacids bind to folate & reduce absorption by inhibiting their
absorption
" #Antacids may destroy enteric-coating of drugs leading to premature
dissolution in the stomach
" #impair absorption of Cimetidine and Ranitidine (give 1 hr apart),
Digoxin, INH, Anticholinergics, Iron products and 

Phenothiazine
Antimuscarinics
MOA:

" Belladonna leaf, Atropine, Propantheline


" used with antacids


" has no use in ulcer healing

" Most effective when taken at night and in large doses. 

 PIRENZEPINE (Gastrozepine), PROPANTHELINE 


MOA: Block M1 receptors on ECL cells (↓histamine secretion)

and M3 receptors on the parietal cells ( ↓H+ secretion)
Clinical Use: Peptic Ulcer
Toxicity: Tachycardia, dry mouth, difficulty focusing eyes


Prostaglandins
MOA: Suppress gastric acid secretion and guards the mucosa
form NSAID-induced ulcers

Misprostol - a prostaglandin (PGE1) analogue with antisecretory
& mucosal protective activity by increasing bicarbonate and
mucus secretions
Indicated for NSAID-induced gastric ulcers
S/E: diarrhea and abdominal pain; inc uterine contraction!
C/I: pregnant, women with child-bearing potential 


➤
GERD
! Gastroesophageal Reflux Disease (GERD)
" retrograde movement of gastric contents from the
stomach into the esophagus
" heartburn, chest pain, belching, regurgitation,etc. 


! Barrett’s esophagus
! Glandular metaplasia—replacement of the
nonkeratinized squamous epithelium with intestinal or
columnar epithelium in the distal esophagus
! Due to chronic acid reflux
! Risk factor for esophageal CA (squamous cell) 

! Tx
! Phase I
! Lifestyle changes
! Antacids
! Low dose H2RA or PPIs 


! Phase II
! High dose H2RAs/PPIs
! Phase III

! surgery

! Lifestyle Changes
! Elevate head of bed
! Dietary changes Constipation 

! Stop Smoking
CONSTIPATION
Decrease in the frequency of fecal elimination and is
characterized by the passage of hard, dry, and sometimes painful
stools.
S/sx: abdominal bloating, headaches, sense of rectal fullness
Treatment
Non pharmacologic
increase fluid and fiber intake
exercise regularly
bowel training to increase regularity
Pharmacologic

" Laxatives 


" #stimulate defecation 


" #should not be taken if nausea, vomiting, or abdominal pain is

present


! Bulk-forming Laxatives

Bulk-forming laxatives
MOA: natural or synthetic polysaccharide that adsorb water to soften
stool and increase bulk, which stimulates peristalsis
slow onset of action (12-24 hrs, 72 hrs) thus preventive
take with 8 oz of water
Natural bulk-forming laxatives
Psyllium (Metamucil, Fiberall, Konsyl-D, Perdium Fiber Granules)
Malt soup extract (Maltsupex)
Synthetic bulk-forming laxatives
Methylcellulose
Polycarbophil (Ca Polycarbophil impair Tetracycline absorption)
Saline and Osmotic Laxatives
MOA:

" stimulates the activity of cholecystokinin-pancreozymin,
which increases the secretion of fluids into the GI tract "
onset of oral : 3-6 hrs ; rectal – 5-30 minutes

" Take with water
" Saline laxatives – sodium & magnesium salts
> should not be used in patients with HPN, CHF, & renal
impairment
" Examples

" Osmotic laxatives
" Glycerin (Fleet Babylax) – rectal burning
" Sodium stearate
" Lactulose (Chronulac, Enulose) – decrease blood ammonia
levels in hepatic encephalopathy
" flatulence & cramping
Taken with fruit juice, milk or water
"
" Sorbitol- nonabsorbable sugar
" Polyethylene glycol (Miralax)
Stimulant Laxatives
MOA: stimulate intestinal motility and increase secretion of
fluid into the bowel
onset of action of oral: 6-10 hrs; rectal: 30-60 minutes
chronic use can lead to cathartic colon(should not be used for
more than 1 week)
S/E: abdominal cramping, electrolyte and fluid deficiencies,
malabsorption and hypokalemia
Emollient Laxatives
MOA: act as anionic surfactants by allowing absorption of water
into stool
slow onset of action: 24-72 hrs 


should not be used with mineral oil because it facilitates

systemic absorption of mineral oil leading to poor bowel
function (long term)
DIARRHOEA
Abnormal increase in the frequency and looseness of stools
happens when some factors impair the ability of the intestines to
absorb water from the stool
 Causes:

1. Infection – virus, bacteria, protozoa

2. Diet-induced ( high fiber, fatty or spicy food, large amounts
caffeine, milk intolerance) 

3. Drug-induced
Treatment

Antidiarrheal may prevent an attack or relieve existing
symptoms
1 .Antimotility/Antiperistaltic


MOA: stimulate u -opioid receptor slowing motility of the small

and large intestines, works similarly to morphine, decreasing the

activity of the myenteric plexus, which decreases the tone of the
longitudinal and circular smooth muscles of the intestinal wall
S/E: abdominal pain, distension, dizziness, drowsiness, dry
mouth


C/I: acute bacterial diarrhea

2. Adsorbent

MOA: adsorb toxins, bacteria, gases & fluids
Kaolin-pectin mixture, polycarbophil, attapulgite
3. Anti-infectives
4. Octreotide
Refractory chronic diarrhea that does not respond to specific
antimicrobial therapy or standard unspecific medication may
present a challenging and serious clinical problem. Octreotide is
a candidate drug for the treatment of these patients as it inhibits
gastrointestinal motility, pancreatic secretion and inhibits
intestinal absorption.

Other GI disorders Pseudomembranous colitis
inflammation of the colon resulting from the use of antibiotics
including (but not limited to) any penicillin-based antibiotic
such as ampicillin, cephalosporins, and clindamycin, causes the
normal bacterial flora of the bowel to be altered.

mild to bloody diarrhea, abdominal pain, fever up to 40.5 °C or
105 °F, a distinctive foul odor to the stool resembling horse
manure
Sulfasalazine

MOA: a combination if sulfapyridine (antibacterial) and
mesalamine (anti-inflammatory). Activated by colonic bacteria
Clinical uses:

treatment of inflammatory bowel disease, including ulcerative
colitis and Crohn's disease.
Toxicity: malaise, nausea, sulfonamide toxicity, reversible
oligospermia
Infliximab

MOA: a monoclonal antibody to TNF-α, a pro-inflammatory
cytokine Continuous lesions.
Clinical uses: Emesis
Complex process Mediated by:
D2 receptors (CTZ)

5HT3 receptors (CTZ and GIT)

Labyrinthine vestibular systems( cholinergic, histamine) Pain
receptors ( GU tract)

Drugs for nausea and vomiting
 Prokinetic agents Metoclopramide
MOA: act through serotonin receptors to ↑Ach release at the
myenteric plexus
↑Esophageal tone
↑gastric and duodenal contractility
Improving transit time(including through the colon) 




MOA: D2 receptor antagonist. ↑Resting tone, contractility, LES
tone, motility.


Clinical use: used to relieve gastrointestinal symptoms such as

abdominal discomfort, bloating, constipation, heart burn,
nausea, and vomiting. 


Toxicity: ↑parkinson effects. Restlessness, drowsiness, fatigue,

depression, nausea, and constipation. 

RESPIRATORY
COUGH
- a physiologic protective reflex
- not a disease
- purpose: clear the respiratory tract of mucus, inhaled irritants
and other foreign debris
- stimulation of cough receptors in the epithelial lining of the
trachea-bronchial tree (mechanoreceptors, chemoreceptors,
cough center)
A. DRUGS FOR COLDS
COLDS:
i. Common colds → viral → rhinovirus, coronavirus, adenovirus
ii. Allergic colds → allergic rhinitis
Drugs for common colds
⇒ nasal decongestants
i. α1 agonists: phenylpropanolamine, phenylephrine
ii. α2 agonists: clonidine, apraclonidine, bromonidine (nasal
spray)
Drugs for Allergic Colds
i. Nasal decongestants (symptom relief)
ii. H1 antihistamines
B. DRUGS FOR COUGH AND MUCUS PRODUCTION
i. Mucolytics
- break disulfide linkages between mucus molecules
ex. NAC
ii. Mucoregulators
-moa: ↑ H2O portion of mucus
ex. Carbocisteine (S-carboxy methylcysteine)
Ambroxol
Bromhexine
iii. Expectorants
moa: stimulate bronchial glands to ↑ h20 portion of mucus
ex. Guifenesin
iv. Antitussives
-cough suppresants
- indication: for cough that are useless, excessive, harmful/
dangerous
a. peripherally acting:
- moa: ↓ sensitivity of peripheral irritant cough receptors
- ex. Butamirate citrate
b. centrally acting
▪ The physiological mechanism of cough is complex, and little is
known about the specific mechanism of action of the opioid
antitussive drugs
▪ The receptors involved appear to be different than those involved
with the other actions of opioids
▪ It is likely that both central & peripheral effects may play a role
- narcotic - codeine
- non narcotic- dextrometorphan
C. DRUGS FOR BRONCHOSPASTIC DISEASES (BA,COPD)
Bronchial Asthma
- Chronic inflammation
- Reversible bronchospasm
- Asymptomatic patients in between episodes of bronchospasm
COPD
- Chronic Inflammation
- Progressive, not completely reversible bronchospasm
- symptomatic patients in between exacerbations
2 forms of COPD:
1. chronic bronchitis “blue bloaters”
2. Emphysema - “pink puffers”
Reliever Meds
- effect an immediate relief on acute bronchospasm
- prn
Controller Meds
- given to ↓ severity/duration/frequency of subsequent attacks/
exacerbations
- given as maintenance
Bronchodilators
a. b2 agonists
- SABA (Short acting b2 agonists
- 1st line relievers in BA
- salbutamol / albuterol / terbutaline
- route of administration
> inhalation (MDI or nebules)
> oral
> SQ (terbutaline)
- LABA (Long acting b2 agonists)
- Salmeterol, Formeterol, Babuterol
- contoller meds in BA and COPD

b. Methylxanthines
- Theophylline, Aminophylline
moa: adenosine antagonism, PDEIII inhibitor
- controller for BA (bedtime dosing = ↓ nocturnal asthma att.)
-alt. Tx for status asthmaticus (iv infusion)
- respiratory stimulant for COPD
se
-CNS stimulation - agitation, confusion, seizures
-CVS: tachycardia, palpitations,

c. Anticholinergis
- Ipratropium Br, Oxytropium, Tiotropium
- preferred bronchodilators in COPD
- minimal se
2. mast cell stabilizers
- Nedocromil Na
- moa: open onward conducting Cl- channels in mast cells to
prevent the release of histamine
- effect seen after atleast 3-4 weeks of rtf
- maintenance for allergic BA and allergic rhinitis
- se: acute bornchospasm (irritant effect of cromones)
- pretreat with SABA
3. Antiinflammatory
a. Leukotriene Modifiers
LOX inhibitors
- Zilueton
Leukotriene Antagonists
- Montelukast (Singulair)
- Zafirlukast (Accolate)
- bronchodilator and anti inflammatory effect
-moa: inhibits bronchoconstriction as competitive receptor agonist or
leukotrienes D2 and E4; receptor occupation and cysteine leukotriene
production has been associated with the pathophysiology of asthma
- use: alternative controller meds in BA
- useful in NSAID induced BA
- se: unmasking of symptoms of Churgg-Strauss Syndrome
(eosinophilic vasculitis)
b. glucocorticoids
- moa: inhibit phospholipase A2 (release of arachidonic acid
from phosphoilipids) (traditional/old)
- inhibit late phase allergic reaction with happens atleast 2-8
hours from onset of allergy central cell: Macrophages
-release two powerful cytokinesL
> major basic protein
> eosinophilic cationic protein
effects:
- more severe bronchospasm
- profuse bronchial secretions
- mucus plugging
* status asthmaticus
- inhibit cytokine release from macrophages
types:
-local or inhaled GCs
ex.
Budesonide
Fluticasone
inhaled MDI
Beclomethasone
Triamcinolide
- used 1st line controllers in BA
se: minimal systemic SE if given at doses <1,000 - 1,200 mcg/d
- oropharyngeal candidiasis (oral thrush)
- prevention: adequate gargling after each use
Oral systemic GCs
Preferred: low potency, short acting
ex. Prednisolone, Prednisolone
Use: given short term (<100) after an acute exacerbation
parenteral systemic GCs
- ex. Hydrocortisone, Methylprednisolone
- use: 1st line in mx of status asthmaticus or severe exacerbation
KOKOLOGY 44
Remember practicing for your driver’s license and all the little things
you had to learn? U-turns, parallel parking, hand signals, and car
lengths… Sure, they’re all important, but that isn’t what driving is
really all about. Driving is about the way you felt after passing those
tests and taking to the road all by yourself for the very first time. It’s
about being able to go where you want, when you want. It’s about
power, freedom, and speed. And the car you drive is an expression of
the way you view the whole driving experience. It tells the world
something about who you are and what you want out of life.

Take a moment to picture your dream car, without giving any thought
to expense or other practical considerations. What kind of car do you
envision yourself in?
1. A high-performance vehicle with all the options.

2. A marvel of design with a sleek and beautiful chassis.

3. A status-symbol ride with a price tag to match.

4. Anything will do as long as it runs.

 People’s taste in cars typically reflects their taste in members of
the opposite sex. The features you want in your dream car reveal
the things you respond to when looking for a partner.
1. A HIGH-PERFORMANCE VEHICLE WITH ALL THE OPTIONS
Ideally you want everything out of your car and your partner,
but that also means you’re willing to appreciate the good points
in everyone. Your wide range of tastes means you might look a
little inconsistent, equally attracted to beauty, kindness,
sophistication, humor, or charm. But that makes it possible for
you to evaluate potential partners on their own strengths, giving
you a basis for comparison before making your final choice.
2. A MARVEL OF DESIGN WITH A SLEEK AND BEAUTIFUL CHASSIS.
There’s little doubt that physical appearance is the key to
winning your heart. It’s not only finding someone whose looks
appeal to that’s important. You also want someone you can show
off to the world. The exaggerated emphasis you place on the
exterior means it’s easy for you end up with a real lemon.
Always check under the hood before you drive anything home.
3. A STATUS-SYMBOL RIDE WITH A PRICE TAG TO MATCH.
Social position and material success are crucial to you, and that
carries over to your choice of partners as well. The right family,
the right school, the right career: for you they all add up to make
the right person. Ambition is not a bad thing in itself, but your
mate might not appreciate being just another rung on the the
ladder to your success.
4. ANYTHING WILL DO AS LONG AS IT RUNS.
You’re happy with just about anyone who meets certain
minimum standards, which makes you open, accepting, and
forgiving. You don’t expect others to fulfill your dreams and
enjoy the same consideration in return. That could be a smooth
road to contentment. But when you think about it, it might
mean others aren’t really expecting much from you, either.
ENDOCRINE
NERVOUS SYSTEM
communicates locally by electrical impulses and NT act within
milliseconds

ENDOCRINE SYSTEM
releases hormones into the blood and carries these chemical
messengers to target cells

seconds to months
A. Hypothalamic-Pituitary
B. Adrenocortical Hormones
C. Thyrod Disorders
D. Diabetes Mellitus
REGULATORY MECHANISM FEEDBACK REGULATION
consistent findings in hyperthyroidism?
increased t4 and t3
decreased TSH

hypothyroidism:
decrease T4, T3
increased TSH
SUMMARY OF THE HORMONES
thyroid
hypothalamic product: TRH (thyrotropic RH)
anterior pituitary: TSH (thryoid stimulating hormone)
thyroid: T4, T3
adrenocorticoid
hypothalamic product: CRH (corticotropic RH)
anterior pituitary: corticotropin = acth (adrenocroticotropic
hormone)
adrenal cortex: cortisol
gonadal
hypothalamic product: GNRH (Gonadotropin RH)
anterior pituitary: gonadortopins
FSH: Follicle Stimulating Hormone
LH: Leutinizing Hormone
Gonads: Oestrogen, progesterone (ovarian)
Growth Hormone
hypothalamic product: GHRH (Growth Hormone RH)
anterior pituitary: Growth Hormone - somatropin
liver: somatropis = insulin like growth factors
ANTERIOR PITUITARY
Adenohypophysis

Synthesis and release of the trophic or stimulating hormones

Synthesis and release of prolactin
POSTERIOR PITUITARY
Neurohypophysis

Storage and release of oxytocin and vasopressin
HYPOTHALAMIC RH
Hypothalamic RH are used for diagnostic purposes Pituitary
hormones are administered

IM

SQ 

intranasally Not PO
GROWTH HORMONE DEFICIENCY
manifestation depends on onset
prepubertal: puberty dwarfism
post pubertal: ↑ cardiovascular mortality

management:
hypothalamic course
GHRH or GH
antipituiry
GH
GROWTH HORMONE PREPARATION
cadaveric gh - somatropin
s/e creutzfeld-jakob disease
recombinant GH - somatrem
s/e glucose intolerant (DM
TREATMENT
GH replacement


Side Effect: Creutzfeldt-Jakob disease


Prions

administering of human growth hormone derived from cadaver
pituitary glands.
PREPARATIONS
Somatrem

therapeutically equivalent drug
Sermorelin

infusion of GHRH used to assess status of GH deficiency
➤
GROWTH HORMONE EXCESS
Growth Hormone EXCESS

A) Prepubertal Effect: pituitary gigantism

B) Post-pubertal (adult) Effect: acromegaly
ACROMEGALY
macrognathia
protrusion of the chin
macroglossia
widening of space between the teeth
frontal bossing/embossed eyebrows
thickened skin

TREATMENT
1. Surgical removal of tumor causing pressure in GH release

2. Somatostatin/Octreotide
general inhibitory hormone
GH
TSH
Insulin
Glucagon
Gastrin
direct vasoconstriction
SOMATOMEDIN
INSULIN LIKE GROWTH FACTORS Polypeptide growth factor

secreted by liver and tissues

Effects

Stimulate incorporation of SO into cartilage Stimulate collagen
4

formation

Increase cell division in the body
SOMATOSTATIN
originally isolated from the hypothalamus, also found in the
neurons throughout the body


Analogue: OCTREOTIDE


USE:

acromegaly caused by hormone-secreting tumors

moa: ↓ GH secretion, secretion of gastin, glucagon, seretin, serotonin

release and pancreatic polypeptide: in acromegaly, octreatide decreases
growth hormone, suppresses LH response to GnRH secretion
ADRENOCORTI
COTROPIC
HORMONE
CORTICOTROPHIN
Sources of ACTH preparations:
a) anterior pituitaries of domestic animals (antibodies can form)

b) synthetic human ACTH preparations= COSYNTROPIN
preferred in the diagnosis of adrenal insufficiency

1. Glucocorticoids
2. Mineralocorticoids
3. Adrenal Sex Steroids
GLUCOCORTICOIDS
- main endogenous GC: cortisol = hydrocortisone

2 regulatory methods:
a. negative feedback
b. circadian rhythm
Circadian Rhythm
1. just before waking up
2. at about to wake up: rising levels of cortisol peaks in about 2
hours
3. declines throughout the day
effects:
1. Physiologic
- metabolism of the primary macromolecules CHOH, CHON,
AND FATS
- generate energy
2. Pharmacologic
- anti-inflammatory
- immunosuppression
Se:
- cushing’s syndrome (moon face, buffalo humo, truncal obesity,
thinning of the skin, easy bruising, poor wound healing
- increased risk of infection
- glucose intolerance
- adrenal suppression (if given >10-14 days)
inhibitory effect

< 10-14 days - ant. pituitary can resume ACTH secretion right
after stopping cortisol or GC
> 10-14 days - when excess cortisol is stopped - acth production
does not resume for a long time

- renal suppression (low ACTH production due to inhibitory

effect)
adrenal crisis = septic shock
- hypotension
- ileus
- abdominal pain

- since without cortisol to cope up with stress, it can lead to coma and
death
- give GC <10d
2. if GC are given >10-14days, do not abrupty stop tx, taper
dose
Glucocorticoids
Short Acting
- Hydrocortisone -pred
Intermediate Acting
- “flu” pred
Long Acting
- Dexamethasone
MINERALOCORTICOID
endogenous: aldosterone
regulation: under RAAS
effects:
- h20 and electrolyte imbalance
- reabsorption of h20, water, HCO3
- secretion K+, H+, Cl-

used for hypoeraldosteronism

ADDISON’S
DISEASE
Primary adrenocortical insufficiency
CUSHING’S
SYNDROME
Pharmacologic doses of glucocorticoids Bilateral hyperplasia of
adrenal glands Cushing’s disease if due to increased ACTH
Adrenocortical Excess
PHEOCHROMO
CYTOMA
GLUCOCORTICOIDS
endogenous
Cortisol
Cortisone
Corticosterone
Glucocorticoids
THERAPEUTIC USES
Allergy
Hematologic disorders
Collagen vascular disease
Inflammation of bones and joints
Skin disease 


➤
GI disease: IBD

Organ Transplant, immunosuppresion Pulmonary disease:
COPD and BA Nephrotic syndrome

Glucocorticoids 

SIDE EFFECTS
Cushing Syndrome
Protein Catabolism
Skin thinning/ easy bruising Impaired wound healing
Inc susceptibility to infection
HPN
Acne

Adrenal suppression Hyperglycemia/glucose intolerance Fat
deposition
Osteoporosis
PUD/ cushing’s ulcer
Psychosis
Cataracts
Glucocorticoids
SPECIAL PRECAUTIONS
DM

PUD

Heart Disease 

HTN CHF Infections
MINERALOCORTICOIDS
Physiologic effects = Pharmacologic effects
Reabsorption: Na, HCO3, Water
Secretion: K, Cl, H
Endogenous: Aldosterone, Desoxycorticosterone Hypernatremia

metabolic alkalosis

Hypervolemia

HTN

Hypokalemia

Hypochloremia

metabolic alkalosis 


➤
1. Metyrapone
• MOA:
• Use: test for adrenocortical function 2. Aminogletethimide
2. Aminogletethimide
• MOA:
Use: eliminate estrogen and androgen production; Breast CA
. 3. Ketoconazole
Use: Cushing Syndrome 


4. Mitotane
• MOA: Use: most commonly used in 

conjunction with pituitary irradiation 

 THYROID
HORMONE
facilitates in the normal growth and maturation by maintaining
the level of metabolism in the tissues that is optimal for their
function

Thyroid hormones are important for:

Growth and development

Body temperature

Energy levels
Steps in thyroid synthesis
1. active uptake of iodide into follicular cells
- local regulation: wolf-chaicoff effect
- any excess iodide can inhibit further uptake of iodide lasting
10-14 days
- beyond 10-14 days however, any excess will be used as
substrate for thyroid hormone synthesis
2. Peroxidase. mediated steps
a. Peroxidation of iodide into iodine
b. Organification of iodine iodinations of the tyrosyl amino acid
residues or thyroglobulin
c. coupling reaction:
MIT + DIT = T3 - TG
DIT + DIT = T4 - TG
3. Proteolysis
T3-TG → T3 + TG
TG - TG → T4 + TG
4. Release of T4 & T3 (ratio 4:1)
5. Peripheral denomination of T4
T4 → T3
Thyroid hormones
-indication: mx of hypothyroidism (replacement therapy)
-forms:
1. L-T4 - levothyroxine
2. L-T3 - levothyronine

- 1st line maintenance therapy: L-T4

- L-T3 given only in the initial management of myxedema coma
ANTITHYROID MEDICATIONS
- mx of hyperthyroidism
1. Inorganic anions
- percholate, thiocyanate
moa: inhibit iodide uptake
use:
Amiodarone—induced hyperthyroidism
2. Thionamides or thioamides
- PTU, methimazole, Carbimazole
moa: inhibit peroxidase enzyme
-peroxidation, organification, coupling mechanism
ANTITHYROID DRUGS
3 Iodides
- SSKI, Lugol’s solution
- moa: wolf-chaickoff effect

use:
- adjunct tx for thyroid storm
- preoperative mx for hyperthyroidism (10-14days before
surgery)
Se:
- iodize
ci: pregnancy (fetal goiter)
4. Radiocontrast dyes
5. Betablockers (propranolol)
6. Dexamethasone
7. Radioactive iodine

moa: emission of B-radiation leading to oxidation and destruction

of follicular cells of thyroid glands

conseq: hypothyroidism
Ci: pregnancy
MYXOEDEMA
COMA
 Thyroid Hormones: deficiency

Myxedema coma

History of poor compliance, or patient is previously undiagnosed

High mortality rate

Decreased consciousness

Seizures

Hypothermia
LEVOTHYROXINE
1.6 ug/kg body weight daily 100-150 ug daily
If elderly, with CAD: start with 12.5-25 ug/day
levothyroxine (200ug)
Liothyronine (25 ug)
Hydrocortisone (50-100 ug/day)
SYNTHETIC LEVOTHYROXINE (T4)
Preparation of choice for replacement and suppression therapy

Stable 

Uniform content

Low cost

Long half-life

Conversion to both T4 and T3
DESICCATED THYROID
Though inexpensive, not recommended Antigenicity

instability

Variable hormone content
LIOTHRYRONINE (T3)
3-4x more active than levothyroxine, but not recommended

Higher cost

Short half-life (24 hours)

Greater potential for carditoxicity
LIOTRIX
A 4:1 combination of synthetic T4 and T3 Expensive
Same disadvantage as levothyronine
GRAVE’S
DISEASE
Thyrotoxic Crisis or thyroid storm Rare, Life-threatening

Fever, delirium, seizures, coma, vomiting, diarrhea, jaundice


Cardiac failure, arrhythmia, hyperthermia Treatment: PTU then
iodide
Precipitating factors: Acute illness Surgery Radioiodine therapy
Hyperthyroid
TREATMENT Antithyroid drugs Pharmacokinetics: Antithyroid
drugs

PROPYLTHIOURACIL (PTU)
Propylthiouracil (PTU) Methimazole Carbimazole
MOA:
PTU-also inhibits peripheral conversion
➤
SIDE EFFECT
pruritic maculopapular rash (most common)

Rash, urticaria, fever, arthralgia (1-5%)

Hepatitis, SLE-like syndrome, agranulocytosis (<1%) hepatitis
(PTU)
obstructive jaundice(methimazole)
ANIONIC INHIBITORS
(Inorganic anions)

K perchlorate Thiocyanate

MOA:

S/E:

Aplastic anemia (KClO ) Nephrotic syndrome
4
IODIDES
KISS

Lugol’s solution

Indications:

Thyrotoxic symptoms improve within 2-7 days. Not used alone

May exacerbate thyrotoxicosis Contraindications:

Chronic use in pregnancy

Cross placenta 

Cause fetal goiter

Lugol’s solution

MOA:

S/E:

hypersensitivity reaction, Iodism Sialodenitis, conjunctivitis,
rhinitis Antithyroid drugs
Advantages:
Simplicity

Inexpensive

Relatively nontoxic

Absence of glandular dysfunction
Disadvantages:
―Escapeǁ from iodide block Aggravation of thyrotoxicosis

Allergic reactions

Delay onset of thioamide therapy Prevent RAI therapy for several
weeks
RADIOCONTRAST DYES
Ipodate Iopanoic Acid MOA:
PROPRANOLOL
Beta-blocker
MOA:

DEXAMETHASONE
RAI (I131)
MOA

Indications:

only isotope used for the treatment of thyrotoxicosis.
Pharmacokinetics:
given as oral solution, I is rapidly absorbed, concentrated in the
thyroid, and incorporated into storage follicle
Advantages:
easy administration

Effectiveness

low expense

absence of pain

Disadvantage:

induction of delayed hypothyroidism Contraindication:
pregnancy, crosses the placenta excreted in breastmilk
PANCREAS
OVERVIEW
The pancreas is a glandular organ in the digestive system and
endocrine system of vertebrates.
producing several important hormones, including insulin,
glucagon, somatostatin, and pancreatic polypeptide
a digestive organ, secreting pancreatic juice containing digestive
enzymes that assist digestion and absorption of nutrients in the
small intestine. These enzymes help to further break down the
carbohydrates, proteins, and lipids in the chyme.
THE PANCREAS IS BOTH AN ENDOCRINE AND EXOCRINE ORGAN
ENDOCRINE: Insulin, glucagon, somatostatin
EXOCRINE: digestive enzymes
INSULIN
4 Main Sites of Action:
1. Glucose transporters to facilitate glucose movement across
cell membranes.
2. Liver to increase storage of glycogen and decrease post-
absorptive catabolism.
3. Muscle to promote protein and glycogen synthesis.
4. Adipose tissue to reduce free fatty acids and promote
triglyceride storage.
DIABETES
MELLITUS
DIAGNOSTIC CRITERIA
Symptoms of DM + RBS > 11.1 mmol/L or (200 mg/dL)
FBS > 7 mmol/L (126 mg/dL)
2 hour plasma glucose > 11.1 mmol/L during an oral glucose
tolerance test

*confirmed by repeat testing on a different day
Type 1 diabetes mellitus: results from the body's failure to
produce sufficient insulin.
Type 2 diabetes mellitus: results from resistance to the insulin,
often initially with normal or increased levels of circulating
insulin.
Gestational diabetes: pregnant women who have never had
diabetes before but who have high blood glucose levels during
pregnancy are said to have gestational diabetes. Gestational
diabetes affects about 4% of all pregnant women. It may precede
development of type 2 (or rarely type 1) diabetes.
Secondary diabetes: accounts for only 1-2% of patients with diabetes mellitus.
Causes include:
Pancreatic disease: cystic fibrosis, chronic pancreatitis, pancreatectomy,
carcinoma of the pancreas.
Endocrine: Cushing's syndrome, acromegaly, thyrotoxicosis,
phaeochromocytoma, glucagonoma.
Drug-induced: thiazide diuretics, corticosteroids, atypical antipsychotics,
antiretroviral protease inhibitors.
Congenital lipodystrophy.
Acanthosis nigricans.
Genetic: Wolfram's syndrome (which is also referred to as DIDMOAD: diabetes
insipidus, diabetes mellitus, optic atrophy and deafness),[2] Friedreich's ataxia,
dystrophia myotonica, haemochromatosis, glycogen storage diseases.
 Some patients with type 2 diabetes require insulin, so the old
terms of insulin-dependent diabetes mellitus (IDDM) for type 1
diabetes and non-insulin-dependent diabetes mellitus (NIDDM)
for type 2 diabetes are inappropriate. Type 2 diabetes is
increasingly diagnosed in children and adolescents and so the
old term maturity-onset diabetes for type 2 diabetes is also
inappropriate.
 INSULIN
THERAPY
FORM
1. Human Insulin (Recombinant)

sources:
1. Animal Insulin - phased out
2. Human Insulin - Recombinant DNA Product
INSULIN PREPARATIONS
Usually injected SQ


Short-acting and ultra-short acting mimic the post- prandial rise

in insulin.
IV for hyperglycemic emergencies and DKA
NPH, long and ultra-long acting—mimic basal insulin
INSULIN THERAPY
Mainstay treatment in:

All type 1 diabetics

Type 2 diabetics not adequately controlled


Insulin injected SQ differs from endogenously secreted insulin in

two ways:


Does not reproduce the rapid rise and fall occurring when
insulin is secreted with ingested food.
Diffuses into systemic circulation instead of being secreted into
portal circulation.
INDICATION
Type 1 diabetics

Type 2 diabetics with OAD failure
INTERMITTENT IR OCCASIONAL USE
Gestational DM

Type 2 DM during 

Acute Infection or Fever

Major Surgery

Acute Mi, stroke, or any coronary event Diabetic Emergencies

Hepatic or renal insufficiency

Insulin Hypoglycemia
Most common complication

Main signs occuring with plasma glucose of 60-80 mg/dL.
Neuroglycopenic
Autonomic hyperactivity
Sympathetic

Parasympathetic
Rapidly relieved by giving glucose
Orange juice or any sugar-containg food or beverage IV 50%
glucose, 20-50 ml over 2-3 min
Insulin has 3 characteristics:
Onset is the length of time before insulin reaches the
bloodstream and begins lowering blood glucose.
Peaktime is the time during which insulin is at maximum
strength in terms of lowering blood glucose.
Duration is how long insulin continues to lower blood glucose.
 Rapid-acting insulin: It starts working approximately 15 minutes after injection
and peaks at approximately 1 hour but continues to work for two to four hours.
This is usually taken before a meal and in addition to a long-acting insulin.
Short-acting insulin: It starts working approximately 30 minutes after injection
and peaks at approximately 2 to 3 hours but will continue to work for three to
six hours. It is usually given before a meal and in addition to a long-acting
insulin.
Intermediate-acting insulin: It starts working approximately 2 to 4 hours after
injection and peaks approximately 4 to 12 hours later and continues to work for
12-18 hours. It is usually taken twice a day and in addition to a rapid- or short-
acting insulin.
Long-acting insulin: It starts working after several hours after injection and
works for approximately 24 hours. If necessary, it is often used in combination
with rapid- or short-acting insulin.
 Premixed insulin can be helpful for people who have trouble drawing up
insulin out of two bottles and reading the correct directions and dosages. It
is also useful for those who have poor eyesight or dexterity and is
convenient for people whose diabetes has been stabilized on this
combination.
In 2015 an inhaled insulin product, Afrezza, became available in the U.S.
Afrezza is a rapid-acting inhaled insulin that is administered at the
beginning of each meal and can be used by adults with type 1 or type 2
diabetes. Afrezza is not a substitute for long-acting insulin. Afrezza must be
used in combination with injectable long-acting insulin in patients with type
1 diabetes and in type 2 patients who use long-acting insulin.
Inhaled insulin begins working within 12 to 15 minutes, peaks by 30
minutes, and is out of your system in 180 minutes. Types: Technosphere
insulin-inhalation system (Afrezza)
insulin secretion:
2 patters:

1. Basal Insulin - secretion of small pulses/bursts q10mins

2. Large Insulin Release - large boluses of insulin q 90-180mins
1. Ultrarapid Acting Insulin
- Modified Insulin
Insulin Lispro
Insulin Aspart
2. Short-acting
Regular Insulin (Semilente) (IV - Only 1)

3. Intermediate Acting
NDH Insulin - Isophane Insiulin (Lente)

4. Long Acting
Insullin Ultralente
Peak-less insulin
- modified insulin
Insulin Glargine
Insulin Levemir

- add myristic acid

- never mix with other insulins
Basal Insulin
Intermediate, Long acting

Demand Insulin
Ultra-rapid, short-acting
- given to control postprandial hyperglycemia
Route of administration
1. SQ - abdomen, inner thigh
2. IV - Regular Insulin

s/e
1. Hypoglycemia - Insulin shOCK
MX:
oral glucose sources (dextrose)
Glucagon 30mg
se
animal insulin
1. Lipoatrophy
2. Lipodystrophy
- due to repeated SQ injections over the same site
ORAL ANTI
DIABETIC
DRUGS
B. Insulin Secretagogues
moa:
inhibit/block the outward K+ conductance in the B cells of the islet of
langerhans
↓
depolarization of B cells
↓
insulin release

i. Sulfonylureas
ii. Meglitinides
SULFONYLUREAS
Most effective for individuals with recent DM onset (<5 years).

Reduce both fasting and post-prandial glucose Should be taken
shortly before meals.

C/I: hepatic and renal failure

MOA:
Stimulate pancreatic release of insulin
Inhibit pancreatic release of glucagons
Increase insulin binding capacity
Decrease hepatic extraction of insulin
1st Generation Sulfonylureas
Chlorpropamide
Longest half-life (60-90 hours)
Has most side effects Avoided in initial treatment
Tolbutamide
Fastest onset of action (30 mins)
Most cardiotoxic
Acetohexamide
Converted to an active metabolite (hydrohexamide)
Tolazamide

- ↓ potent, ↑ se
2 Generation Sulfonylureas Glyburide/

nd

Glybenclamide

Glipizide 

Gliclazide Glimepiride
Side effects:
Hypoglycemia

Blood dyscrasias

Disulfiram-like reactions (with 1 generation agents and Glipizide)

st

Weight gain

- ↑ potent, ↓ se
Se:
- disulferam like SE
- 1st gen & Glipizide
MEGLITINIDES
Repaglinide, Nateglinide

- duration 1-2h
- Used mainly for controlling post-prandial glucose levels.

- Taken shortly before meals

- Can be used for patients allergic to SU

MOA
Increase pancreatic insulin secretion
Short-duration of action: 1- 3 hours
Side effects:
Hypoglycaemia
Weight gain
BIGUANIDES
Euglycemic or antihyperglycemic

Reduce fasting and postprandial glucose


MOA:

Liver: Decrease the amount of glucose made by the liver

Muscles and Fat Tissue: Increase insulin sensitivity of muscles
and adipose tissue
- first line initial tx for T2DM esp in obese
- mx of PCOS (Polycystic Ovarian Syndrome) assoc. with insulin
resistance
- mx of pre-diabetes

Se:
- diarrhea (resolves in chronic use)
- lactic acidosis (most serious)
happens when you’re at risk: dehydration, CHF, liver dse,
chronic renal disease
 Metformin

USE:

for obese patients

Type 2 DM who do not respond to SU alone

Side effects:

GI: anorexia, nausea, vomiting, abdominal discomfort, diarrhea

Lactic acidosis

Megaloblastic Anemia

 C/I:

Renal failure, Radiographic contrast studies, Seriously ill,
acidosis

Cannot readily control the symptoms of DM because of its MOA

Patients fail to respond initially when blood glucose level is high

Better to add a secretagogue

Metformin + SU
 Α-GLUCOSIDASE INHIBITORS
Acarbose, Voglibose, Miglitol

- take at the first bite of the meal

MOA:
Inhibit alpha-glucosidase and prevents the conversion of
disaccharides, dextrins, polysaccharides to the absorbable
monosaccharide form.


Side Effects:

Flatulence, Diarrhea, Abdominal pain Acarbose: maybe hepatotoxic
C/I:

Chronic or intestinal bowel disease
THIAZOLIDINEDIONE (TZD)
Pioglitazone (Actos)
Rosiglitazone (Avandia) - withdrawn due to cardiovascular tox.


MOA:

Insulin sensitizers by stimulating PPARy receptors— increase
skeletal muscle sensitivity
Decrease hepatic gluconeogenesis

Major site of action: adipose tissue

Se: hepatotoxicity, cardiovascular mortality (rosiglitazone)

Incretin Analogues
GLP1 - Glucagon-like peptide 1
- responsible for the normal response to an oral glucose load
oral glucose load:
↑ insulin, ↓ Glucagon
DM PX:
oral glucose load:
↑ insulin, ↑ Glucagon
1. GLP1 Analogues
Exenatide (Byetta) SQ
se: nausea and vomiting, hypoglycemia
Benefit: weight loss

2. DPP IV Antagonists/inhibitors
Sitagliptin (Januvia)
Sitagliptin + Metformin (Janumet) Oral
-benefit: weight loss
- Se: nausea and vomiting
6. Amylin Analogue
Pramlintide
role: co-secreted with insulin and improve response to insulin
use: given only to px on insulin to improve response to tx
route: SQ
se: ↑ risk of hypoglycemia
SODIUM GLUCOSE CO TRANSPORTER 2 INHIBITORS
DAPAGLIFLOZIN, CANAGLIFLOZIN
 NATURAL
METHODS OF
CONTRACEPTI
ON
MENSTRUAL CYCLE
28 days + or - days

Varies from 28-40 days

The time from ovulation to beginning of menses is constant
(14-15 days).
Days 1-5: Menses—thick endometrial lining from the uterus is
sloughed off
Days 6-14: Proliferative stage—stimulated by rising estrogen levels
produced by growing follicles of the ovaries, the endometrium is
repaired, glands are formed in it and the endometrial supply is
increased OVULATION occurs at the end of this stage in
response to LH surge
Days 15-28: Secretory stage

Corpus luteum produces progesterone
PROGESTERONE
Further increases the blood supply of the ovary Causes the
endometrial glands to increase in size and begin secreting
nutrients in the uterine cavity, which will sustain the developing
embryo

If fertilization occurs: embryo will produce a hormone similar to
LH, which will cause the corpus luteum to continue producing
hormones.
If fertilization does not occur, the corpus luteum begins to
degenerate toward the end of this period when LH declines.
Natural method of contraception Fertility awareness methods

Periodic abstinence is also referred to: 

a) Rhythm method

b) Natural family planning 

c) Ovulation detection
➤
TEMPERATURE METHOD
Within 24 hour preceding ovulation, there is a moderate drop in
basal temperature followed by a noticeable rise in body
temperature, usually 24 hours after ovulation
Falling to rising temperature

Abstinence 5 days after onset of menses until 3 days after
transition of temperature
CALENDAR METHOD
Based on 3 assumptions:
Ovulation occurs 14(+ 2) days before the onset of next menses
Sperm remain viable for 2-3 days
Ovum survives for 24 hours



Women tabulate menstrual period for at least 1 year Subtract
18 from shortest cycle

Subtract 11 from longest cycle
CERVICAL MUCUS METHOD OR BILLING’S METHOD
Cervical mucus method or Billing’s method Normal: thick,
creamy white
Ovulation: clear and tenacious (like raw egg white)
Abstinence 3-4 days after peak change
 HORMONAL
CONTRACEPTI
VES
GONADOTROPIN RELEASING HORMONE
Function:
1. controls release of FSH and LH
2. Used in Hypogonadism
ANALOGUES: 

Leuprolide 

Goserelin 

Nafarelin 

Histrelin
These act as inhibitors of GnRH Effective in suppressing gonadal
H
 CLINICAL USE:

prostatic cancer

endometriosis 

precocious puberty
OESTROGEN
Natural, steroidal
Estradiol (E2)—major secretory estrogen
Estrone (E1), Estriol (E3)—formed from estradiol in the liver
or from androstenedione and other androgens in peripheral
tissues
Synthetic, Steroidal
Ethynilestradiol, Mestranol, Quinestrol
Synthetic, Nonsteroidal
DES, Chlorotrianisene, Methallenestrel
EFFECTS:

1. Normal female maturation and development of endometrium

2. Metabolic effects

a. Dec bone resorption, Inc bone formation

b. Inc HDL, Dec LDL

c. Inc biliary cholesterol secretion with dec bile acid secretion.

d. Inc circulating levels of Factors II, VII, IX and X and Dec anti-
thrombin III, Inc plasminogen levels
Therapeutic indications

Oral contraceptives (in combination with progestins) Treatment
of menopausal symptoms

Urogenital atrophy

Psychologic disorder

Acne

Osteoprosis

Prostate CA
 Adverse Responses (dose-dependent):

a. Congenital reproductive tract abnormalities

b. Clear cell vaginal and cervical adenoCA in women exposed to
estrogens in – utero (esp DES)

c. Endometrial CA

d. Post-menopausal bleeding

e. Nausea and Breast tenderness

f. Hyperpigmentation

g. Migraine headache

h. HTN
TAMOXIFEN
Nonsteroidal, competitive partial agonist – inhibitor of
estradiol at estrogen receptors.
Antagonistic effects: blocks binding to receptors in estrogen
receptor – containing neoplasia.
Agonisticeffects:metaboliceffects on bone and lipids 


SIDE EFFECTS: Hot flushes, N&V

PROGESTINS
Natural: Progesterone
Synthetic:
Progesterone derivatives:

Hydroxyprogesterone caproate

Medroxyprogesterone acetate 

Megestrol acetate
Testosterone derivative:

Dimethisterone
19-Nortestosteone derivatives: 

Norethynodrel 

Lynestrenol

Norethindrone and its acetate 

Ethynodiol diacetate

L-norgestrel
13-Ethyl 19-Nortestosterone derivatives—less androgenic
Desogestrel 

Norgestimate 

Gestodone
Effects

↑ lipoprotein lipase activity

↑basal insulin and insulin response to glucose Hepatic
glycogenesis and ketogenesis

Compete with aldosterone (but stimulate aldosterone secretion)

Thermogenic effect (hypothalamus)

Depressant and Hypnotic effects on the brain Alveolobular
development of secretory apparatus of the breast

Endometrial changes
 Adverse Effects

HTN

Reduction of plasma HDL levels in women (of the more
androgenic progestins)
ANTIPROGESTINS
RU 486 (MIFEPROSTONE)
MOA: 

Competitive antagonism of both Progesterone and
glucocorticoid to their receptors (in the presence of an agonist) 

Acts as a weak partial agonist when given alone 


Administration during EARLY pregnancy result in abortion


S/E: Uterine bleeding and incomplete abortion 

+ PGE1 intravaginally or Misoprostol PO = complete abortion
 HORMONAL
CONTRACEPTIVE
S (COMBINATION:
OESTROGEN +
PROGESTIN)
HORMONAL CONTRACEPTIVES
(contain both Estrogen and Progestin)
Providedas21or28daypacks
Estrogen component: Ethinyl estradiol, Mestranol Progestin
component: 19-Nor compounds
Combination Oral Contraceptives 

1. Monophasic 

$ Sameamountofhormonesineach pill taken daily 

2. Biphasic

$ Provide2-3differentpillswith 

varying amounts of active 

3. Triphasic 

$ Ingredientsaretakenatadifferent times during the 21 day
cycle. 

 HORMONAL
CONTRACEPTI
VES
(PROGESTIN
ONLY)
PROGESTIN ONLY CONTRACEPTIVES POST COITAL
Contraceptives 

#Morning-after pills 

#Ethinyl estradiol + Norgestrel, 

Ethinyl Estradiol, Conjugated estrogen, Estrone, DES 

GOSSYPOL
Chemical Contraceptive Gossypol

From cottonseed

Destroys seminiferous tubule 

FERTILITY
DRUGS
ANDROGENS
Testosterone
Methyltestosterone
Danazol
Nandrolone
Endogenous: Testosterone (dose: 8ug/day)— converted by 5 a
reductase to dihydrotestosterone Effects:

Male differentiation

Pubertal changes

Inc skeletal muscle

Inc bone growth

Development of 2° sexual characteristics

USE:

Androgen replacement

Gynecologic disorders (endometrial bleeding) Anabolism

Refractory anemia

Osteoporosis

S/E:

Masculinizing

Na and Water retention

Cholestatic jaundice
AROMATASE
INHIBITORS
Anastrozole

Letrozole

Use: Treatment of advanced breast CA
 ANTI
ANDROGENS
Benign prostatic hyperplasia (BPH) Common in men > 50 years
old
May be due to age-related increase in estradiol with possible
sensitization of the prostate to the growth- promoting effects of
DHT

POSTERIOR
PITUITARY
HORMONES
OXYTOCIN
1. Stimulate uterine contraction 

2. Reinforce labor
3. Promote breastmilk ejection
 ROUTE admnistered:

IV: induce labor

nasal spray: induce milk letdown

MOA: it contracts myoepithelial cells around the mammary
alveoli
ANTIDIURETIC HORMONE
Desmopressin
Analog of vasopressin

preferred because free of pressor effects and longer- acting

Administered intranasally

major use of ADH and Desmopressin: Diabetes insipidus
 BONE
HOMEOSTASIS
Regulation of Calcium Concentration

• The important role that calcium plays in so

many processes dictates that its concentration,
both extracellularly and intracellularly, be
maintained within a very narrow range.
• This is achieved by an elaborate system of
controls
 Calcium and phosphorous
• Calcium is tightly regulated with Phosphorous
in the body.
• Phosphorous is an essential mineral necessary
for ATP, cAMP second messenger systems,
and other roles
 Calcium and bone

• 99% of Calcium is found in the bone. Most is

found in hydroxyapatite crystals. Very little
Ca2+ can be released from the bone– though it
is the major reservoir of Ca2+ in the body.
 Bones
• 99% of the Calcium in our bodies is found in our bones which
serve as a reservoir for Ca++ storage.
• 10% of total adult bone mass turns over each year during
remodeling process
• During growth rate of bone formation exceeds resporption
and skeletal mass increases.
• Linear growth occurs at epiphyseal plates.
• Increase in width occurs at periosteum
• Once adult bone mass is achieved equal rates of formation
and resorption maintain bone mass until age of about 30 years
when rate of resportion begins to exceed formation and bone
mass slowly decreases.
 Bone cell types
• There are three types of bone cells: Osteoblasts are
the differentiated bone forming cells and secrete bone
matrix on which Ca++ and PO precipitate.
• Osteocytes, the mature bone cells are enclosed in
bone matrix.
• Osteoclasts is a large multinucleated cell derived
from monocytes whose function is to resorb bone.
Inorganic bone is composed of hydroxyapatite and
organic matrix is composed primarily of collagen.
 Bone formation

• Active osteoblasts synthesize and extrude

collagen
• Collagen fibrils form arrays of an organic
matrix called the osetoid.
• Calcium phosphate is deposited in the osteoid
and becomes mineralized
• Mineralization is combination of CaP04, OH-,
and H3CO3– hydroxyapatite.
 Mineralization

• Requires adequate Calcium and phosphate

• Dependent on Vitamin D
• Alkaline phosphatase and osteocalcin play
roles in bone formation
• Their plasma levels are indicators of
osteoblast activity.
Control of bone formation and resorption

• Bone resorption of Ca++ by two mechanims:

osteocytic osteolysis is a rapid and transient effect
and osteoclasitc resorption which is slow and
sustained.
• Both are stimulated by PTH. CaPO4 precipitates out
of solution id its solubility is exceeded. The
solubility is defined by the equilibrium equation: Ksp
= [Ca2+]3[PO43-]2.
• In the absence of hormonal regulation plasma Ca++ is
maintained at 6-7 mg/dL by this equilibrium.
 Bone resorption

• Does not merely extract calcium, it destroys

entire matrix of bone and diminishes bone
mass.
• Cell responsible for resorption is the
osteoclast.
 Bone remodeling
• Endocrine signals to resting osteoblasts generate
paracrine signals to osteoclasts and precursors.
• Osteoclasts resorb and area of mineralized bone.
• Local macrophages clean up debris.
• Process reverses when osteoblasts and precursors are
recruited to site and generate new matrix.
• New matrix is minearilzed.
• New bone replaces previously resorbed bone.
Osteoclasts and Ca++ resorption
Hormonal
control of
bones
 Hormonal control of Ca2+
• Three principal hormones regulate Ca++ and three
organs that function in Ca++ homeostasis.
• Parathyroid hormone (PTH), 1,25-dihydroxy
Vitamin D3 (Vitamin D3), and Calcitonin, regulate
Ca++ resorption, reabsorption, absorption and
excretion from the bone, kidney and intestine. In
addition, many other hormones effect bone formation
and resorption.
 Vitamin D

• Vitamin D, after its activation to the hormone

1,25-dihydroxy Vitamin D3 is a principal
regulator of Ca++.
• Vitamin D increases Ca++ absorption from the
intestine and Ca++ resorption from the bone .
 Synthesis of Vitamin D
• Humans acquire vitamin D from two sources.
• Vitamin D is produced in the skin by ultraviolet
radiation and ingested in the diet.
• Vitamin D is not a classic hormone because it is not
produce and secreted by an endocrine “gland.” Nor is
it a true “vitamin” since it can be synthesized de
novo.
• Vitamin D is a true hormone that acts on distant target
cells to evoke responses after binding to high affinity
receptors
 Synthesis of Vitamin D
• Vitamin D3 synthesis occurs in keratinocytes in the
skin.
• 7-dehydrocholesterol is photoconverted to previtamin
D3, then spontaneously converts to vitamin D3.
• Previtamin D3 will become degraded by over
exposure to UV light and thus is not overproduced.
• Also 1,25-dihydroxy-D (the end product of vitamin D
synthesis) feeds back to inhibit its production.
 Synthesis of Vitamin D
• The mitochondrial P450 enzyme 1α-hydroxylase
converts it to 1,25-dihydroxy-D, the most potent
metabolite of Vitamin D.
• The 1α-hydroxylase enzyme is the point of regulation
of D synthesis.
• Feedback regulation by 1,25-dihydroxy D inhibits
this enzyme.
• PTH stimulates 1α-hydroxylase and increases 1,25-
dihydroxy D.
 Vitamin D
• Vitamin D is a lipid soluble hormone that binds to a
typical nuclear receptor, analogous to steroid
hormones.
• Because it is lipid soluble, it travels in the blood
bound to hydroxylated α-globulin.
• There are many target genes for Vitamin D.
 Vitamin D action

• The main action of 1,25-(OH)2-D is to stimulate

absorption of Ca2+ from the intestine.
• 1,25-(OH)2-D induces the production of calcium
binding proteins which sequester Ca2+, buffer high
Ca2+ concentrations that arise during initial
absorption and allow Ca2+ to be absorbed against a
high Ca2+ gradient
Vitamin D promotes intestinal calcium
absorption
• Vitamin D acts via steroid hormone like
receptor to increase transcriptional and
translational activity
• One gene product is calcium-binding protein
(CaBP)
• CaBP facilitates calcium uptake by intestinal
cells
 Vitamin D Actions on Bones

• Another important target for 1,25-(OH)2-D is the

bone.
• Osteoblasts, but not osteoclasts have vitamin D
receptors.
• 1,25-(OH)2-D acts on osteoblasts which produce a
paracrine signal that activates osteoclasts to resorb
Ca++ from the bone matrix.
• 1,25-(OH)2-D also stimulates osteocytic osteolysis.
 Vitamin D and Bones

• Proper bone formation is stimulated by 1,25-

(OH)2-D.
• In its absence, excess osteoid accumulates
from lack of 1,25-(OH)2-D repression of
osteoblastic collagen synthesis.
• Inadequate supply of vitamin D results in
rickets, a disease of bone deformation
 Parathyroid Hormone

• PTH is synthesized and secreted by the

parathyroid gland which lie posterior to the
thyroid glands.
• The blood supply to the parathyroid glands is
from the thyroid arteries.
• The Chief Cells in the parathyroid gland are
the principal site of PTH synthesis.
 Synthesis of PTH

• PTH is translated as a pre-prohormone.

• Cleavage of leader and pro-sequences yield a
biologically active peptide of 84 aa.
• Cleavage of C-terminal end yields a
biologically inactive peptide.
 Regulation of PTH

• The dominant regulator of PTH is plasma

Ca2+.
• Secretion of PTH is inversely related to
[Ca2+].
• Maximum secretion of PTH occurs at plasma
Ca2+ below 3.5 mg/dL.
• At Ca2+ above 5.5 mg/dL, PTH secretion is
maximally inhibited.
Calcium regulates PTH
 Calcium
regulates
PTH
secretion
 PTH action
• The overall action of PTH is to increase plasma Ca++
levels and decrease plasma phosphate levels.
• PTH acts directly on the bones to stimulate Ca++
resorption and kidney to stimulate Ca++ reabsorption
in the distal tubule of the kidney and to inhibit
reabosorptioin of phosphate (thereby stimulating its
excretion).
• PTH also acts indirectly on intestine by stimulating
1,25-(OH)2-D synthesis.
 Calcitonin

• The major stimulus of calcitonin secretion is a

rise in plasma Ca++ levels
• Calcitonin is a physiological antagonist to
PTH with regard to Ca++ homeostasis
 Calcitonin

• The target cell for calcitonin is the osteoclast.

• Calcitonin acts via increased cAMP
concentrations to inhibit osteoclast motility
and cell shape and inactivates them.
• The major effect of calcitonin administration
is a rapid fall in Ca2+ caused by inhibition of
bone resorption.
 Calcitonin
• Role of calcitonin in normal Ca2+ control is not understood
—may be more important in control of bone remodeling.
• Used clinically in treatment of hypercalcelmia and in
certain bone diseases in which sustained reduction of
osteoclastic resorption is therapeutically advantageous.
• Chronic excess of calcitonin does not produce
hypocalcemia and removal of parafollicular cells does not
cause hypercalcemia. PTH and Vitamin D3 regulation
dominate.
• May be more important in regulating bone remodeling than
in Ca2+ homeostasis.
Vitamin D

Produced in the skin from 7 dehydrocholesterol under influence
of UV light

Also found in food

PLANTS: Vitamin D2: ergocalciferol

ANIMALS: Vitamin D3:cholecalciferol 

prohormone
 Calcitriol: 1,25 (OH) vitamin D
2 3


Promotes intestinal absorption of calcium, PO4 25 (OH) vitamin

D:

Increase bone resorption

Increase renal reabsorption of Ca, PO4
SECONDARY
HORMONES
CALCITONIN
Secreted by parafollicular cells of thyroid Regulation of calcium
and bone metabolism Actions:


Inhibits bone resorption ! ↑ serum calcium Increase renal

excretion of filtered phosphate, calcium, sodium (dec. tubular
reabsorption)
Indication

Paget’s disease 

Postmenopausal osteoporosis 

hypercalcemia


Contraindication: hypersensitivity
GLUCOCORTICOID
Antagonizes vitamin D-stimulated intestinal calcium transport

Increase renal Ca excretion

Blocking bone collagen synthesis

Increasing PTH stimulated bone resorption
OESTROGEN
Reduces the bone resorption action of PTH 

Increases 1,25 (OH)2 vit D3 levels Indication
 NON-
HORMONAL
AGENTS
Hypercalcemia secondary to malignancy Osteoporosis
Syndrome of ectopic calcification Paget’s disease
RALOXIFINE
Selective estrogen receptor modulator (SERM) Reduces bone
resorption and decreases bone turnover


Estrogen agonist on bone


Estrogen antagonist on breast and uterine tissue USE:

prevention of osteoporosis
 Kokology 9
“Sweet Memories”
• What is it about reminiscences of childhood that stir
the heart so deeply and make us long to turn back
the clock? Is is that sense of returning to innocence
or just the pleasure of feeling young again? Those
were the days when every toy, doll, and game was
a special kind of treasure. The collector’s mania for
antiques and memorabilia has its roots in these
childhood fascinations and the desire to relive the
past, if only for a short while.
• 1. Inside the candy store, you find rows and rows of
the old familiar candies, chocolate bars, chewing
gums, and sweets from your youth. Some are
stacked in organized shelves, some are loose in
baskets and jars. What candy do you pick first, and
why did you choose it?
• 2. While you’re wandering the store making
selections, you notice that outside a group of
children look as though they’re getting ready to
enter the store. How many children actually come
in?
• 3. You make your purchases and go home with a
bag of candy. But when you open the bag, you see
that the shopkeeper has added some free extra
candies as a special treat for you. How many did
you get?
• 4. You’ve been thinking about giving the candy
you bought as a gift to someone. To whom, if
anyone, would you give it?

•
• The candy theme harkens back to the time in your
life when you could count on an occasional treat
and even expect to be spoiled. This scenario
reveals your expectations of others and your level
of dependence.
 1
• If you thought something like “I’d take the one with
the secret toy surprise in the pack”, you’re likely the
type who responds well to people bearing gifts. If you
said you choose the candy because you remember
how good it tasted or it made you feel nostalgic, you
are hungry for the same attention and affection you
received from your mother as a child. Men, if you
answered this way, you may be looked on as
something of a mama’s boy. If you made your decision
based on external factors, you’re the type of person
who makes judgments based on appearance alone.
 2
• 2. The number of children who entered the store
while you shopped represents the number of
people in your life you need to depend on. Most
people imagine between one and five children.
People who said more than five still have a way to
go before they reach an adult level of
independence. But those who said no children
came in also might need to reconsider the way they
look at the world.
 3

• The number of free treats you got reveals how

much you still depend on your mother. The amount
of special attention the store-keeper showed you is
a measure of attention you actually want from your
mother.
 4

• To whom would you give the candy? The person

you chose is a person you would like to be able to
take care of someday or have become dependent
on you.
CANCER CHEMOTHERAPY
Cancer Chemotherapy - Lecture Outline

1. Targets for cancer chemotherapy

2. Classification of anticancer drugs
3. Cell cycle specificity
4. Drug resistance
5. New approaches
 Introduction

Cancer is an an unregulated proliferation of

cells of which the cardinal features in addition to
growth are invasion and metastasis.

Unlike microbial chemotherapy in which

there are marked differences in chemistry from
the host cells, the cancer cell provides relatively
limited changes from the normal cells and does
not offer clear targets for chemotherapeutic
attack.
 Drugs Approved by the FDA in 2014

Drug Name Generic Mode of Action Indication

Opdivo Nivolumab PD-1 inhibitor Melanoma

Lynparza Olaparib PARP inhibitor Ovarian cancer
Blincyto Blinatumomab CD19 and CD3 ALL
Akinzeo Netupitant/ Nausea in
palonosetron chemotherapy
Keytruda Pembrolizumab PD-1 inhibitor Melanoma
Zydelig Idelalisib PI3K δ inhibitor 3 blood cancers
Beleodaq Belinostat pan-HDAC inhibitor T-cell lymphoma
Zykadia Ceritinib ALK inhibitor NSCLC
Cyramza Ramucirumab VEGFR2 inhibitor Stomach cancer
Types of Therapy Drugs
A. Cytotoxic
- traditional anti-cancer (Vincas)
B. Hormonal Drugs
1. Estrogen Partial Agonist (Tamoxifens)
2. Aromatase Inhibitors (Exemestane)
3. Finsteride-5-α-reductase inh.
4. Flumatide androgen Antagonist
C. Biological Drugs
1. Monoclonal Antibodies -(mab)
a. Trastuzumab (Herceptin)
Mx. of breast cancer
B. Bevacizumab (Avastin)
moa: blocks the vascular endothelial growth factor receptor
(VEGF-R)
2. Tyrosine-Kinase Inhibitors (-tinib)
a. Imatinib (Gleevec)
-most effective tx for chronic myelogenous leukemia
b. Soretinib
mx for renal CA
TREATMENT PRINCIPLES
1. Traditional anti-CA drugs target only cells that are in the cell
cycle (actively dividing)
- CELL CYCLE
G0 Phase

Sometimes the cells in the quiescent and senescent cells are

referred to as post mitotic. The cells which are indivisible
in multicellular eukaryotes generally enter the quiescent G0 state
from G1.

They may remain in the quiescent state for long periods of time.
This state can be for indefinite like in neurons and is very
common in cells that are fully differentiated. Death of the cells in
response to damage of DNA or degradation would make the
progeny of the cells nonviable. Some cells like the cells of liver
and kidney enter the G0 phase semi-permanently.
Interphase

Earlier to to the cell division process, the cell needs to accumulate

nutrients. During the interphase all the preparations are done.

In interphase of a newly formed cell, a series of changes takes place in

the cell and the nucleus, before it is capable of division. This phase is
also known as intermitosis. Earlier this stage was known as resting
stage because no remarkable activiyt realated to cell division takes
place here. Interphase proceeds in a series of three stages, G1,S, and
G2. Division of cell operates in a cycle, hence the interphase of the cycle
is preceded by the previous cycle of M phase and
cytokinesis. Interphase is also called the preparatory phase. In the
interphase stage the division of nucleus and cytosol does not occur. The
cell prepares for division. This is a stage between the end of mitosis and
start of the next phase. Many events occur in this stage and most
significant event that occurs is the replication of genetic material.
G1 Phase

This is the first phase in the interphase. From the end of the
previous M phase till the beginning of the DNA synthesis in the
next cycle is called the G1 phase, here G indicates gap. This
phase is also called growth phase.

In this phase the biosynthetic activities of the cell, which shows a

considerable slow down during the M phase of resumes it
activities at a high rate. In this phase there is a marked
production of proteins by the use of 20 amino acids. Also
enzymes that are required in S phase needed during DNA
replication. The duration of the G1 phase is highly variable, also
among different cells of the same species. The G1 phase is under
the control of the p53 gene.
S phase

The start of the S phase is when the DNA replication

commences. When the phase completes all the chromosomes
have been replicated.

Each chromosome has two sister chromatids. During this phase,

the amount of DNA in the cell is doubled but the ploidy of the cell
remains unchanged. In this phase the synthesis is completed as
soon as possible as the exposed base pairs are sensitive to
external factors like drugs or mutagens.
G2 phase
It is again the gap phase which happens during the gap between
the DNA synthesis and mitosis. During this phase the cell will
continue to grow. The G2 checkpoint mechanism controls to
ensure that the cell is ready to enter the M (mitosis) phase and
divides.

Mitosis or M phase
The M phase consists of karyokinesis - nuclear division. The M
phase is of several distinct phases, known as
Prophase,
Metaphase,
Anaphase,
Telophase,
Cytokinesis.
Fig. 6. Therapeutic targeting of the hallmarks of cancer.
Taken from D. Hanahan and R.A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell 144: 646-674,
2011
CLASSIFICATION BASED ON CELL CYCLE ACTIVITY
a. Phase Specific
i. S phase specific - inhibit DNA synthesis
ex. Antimetabolites (antifolates, purine/pyrimidine analogues)
ii. M-Phase specific (Antimitotic/mitotic spindle inhibitors)
ex. Vincas, Taxols, Estramustine
b. Non-specific
- target calls in any phase of cell cycle
rest: Alkylating, Antibiotics, Anthracyclines, Podophyllumz,
Enzymes, Topoisomerase inhibitors
KINETICS OF TUMOR GROWTH
`
CANCER CELL # CLINICAL FEATURES

9 Subclinical = asymptomatic

<10 (1 billion)
size at diagnosis = 1cm diameter

12
<10 fatal size = 1 kg
`
Cancer growth - gompertzian growth curve
initial growth - logarithmic (rate of growth ↑ with time)
later growth - declining growth rate
bec. ↓ blood supply = becomes dormant
BASIS OF CHEMOTHERAPY REGIMEN
- consistent cycles/sessions of chemotherapy
- intermittent, interval may be for 3-4 weeks
- usually given at 5 - 6 cycles
a. Objectives of chemotherapy
- reduce cancer cells to < 0.01 cell
b. each session/cycle of chemotherapy will reduce cancer cell
number by 99% (3-log kill hypothesis)
Ex.
10 cancer cells = 1,000,000,000
x 0.001 (3-log)
100,000
c. Intermittency (3-4 weeks)
- allows recovery of normal cells
- allows cancer cells in G0 (dormant) to enter cell cycle thus be
susceptible
4. Rescue therapy
- management of toxicities associated with anti cancer drugs
a. Methothrexate poisoning
-leucovorin
b. Hemorrhagic cystitis seen with cyclophosphamide and
ifostamide
- mercaptopurine sulfonate
CLASSIFICATION OF ANTI CANCER DRUGS
Direct DNA Interacting
Indirect DNA Interacting
DIRECT DNA INTERACTING
alkylating agents
moa: intercalate, by forming DNA adducts with DNA
1. - platinum: cisplatin, carboplatin
2. phosphomides: cyclophosphamide, ifotamide, nitrogen
mustard = meclorethanime (chemical warfare agent “agent
orange”
TOXICITIES
alkylating
fosfamides: hemmorhagic cystitis
mech: metabolism to acrolein -> urinary bladder irritant
cisplatin: neurotoxicity
bisulfan: pulmonary fibrosis (irreversible), renal suppression
CYCLOPHOSPHAMIDE (Cytoxan)

1. MECHANISM OF ACTION: Bifunctional alkylating activity, inhibition

of DNA synthesis
2. RESISTANCE: Increased proficiency of DNA repair
3. CELL CYCLE SPECIFICITY: Causes more cytotoxicity during S
phase
4. TOXICITY: Nausea and vomiting, thinning of the hair, cystitis
5. METABOLISM AND EXCRETION: For activity the drug must be
metabolized in the liver to give the metabolites phosphoramide mustard
and acrolein. Excretion is primarily via the kidneys.
anti-tumor antibiotics (-mycin)
moa: alter DNA structure
dactinomycin, mitomycin, bleomycin
moa: topoisomerase inhibitors
inhibit the enzyme topoisomerase II and DNA gyrate
DACTINOMYCIN (Actinomycin D, Cosmagen)
1. CHEMICAL NATURE: An antibiotic from a Streptomyces
species. It contains two cyclic polypeptides which are linked by a
chromophore moiety.
2. MECHANISM OF ACTION: Binds noncovalently to DNA.
Intercalates between adjacent G C base pairs.It inhibits RNA
polymerase more than DNA polymerase
3. RESISTANCE: Decreased ability of cells to take up or retain the
drug.
4. CELL CYCLE SPECIFICITY: Cell cycle stage-nonspecific
5. TOXICITY: Nausea and vomiting, local vesicant,
myelosuppression, redness of skin where radiation has been
given, alopecia
BLEOMYCIN (Blenoxane)

1. CHEMICAL NATURE: Bleomycin sulfate is a mixture of 13

different bleomycin peptides derived from a Streptomyces species
2. MECHANISM OF ACTION: Inhibits DNA synthesis. Binds to
DNA and causes DNA strand breaks
3. RESISTANCE: Increased hydrolase activity, decreased uptake
and increased efflux
4. CELL CYCLE SPECIFICITY: Increased sensitivity in G2
5. TOXICITY: Fever, dermatologic reactions, pulmonary toxicity
and fibrosis, minimal myelosuppression
TOXICITIES
anti tumor
mitomycin: hemolytic uremic syndrome (HUS)
initially seen with coli
leads to adrenal crisis - lack of cortisol
anthracyclines (-rubicin)
doxorubicin
epirubicin
moa: topoisomerase inhibitors
inhibit the enzyme topoisomerase II and DNA gyrate
DAUNORUBICIN (Daunomycin, Rubidomycin)
1. CHEMICAL NATURE: An anthracycline glycoside isolated from a Streptomyces species,
red color
2. MECHANISM OF ACTION: Intercalates between base pairs of DNA and inhibits RNA
synthesis
3. RESISTANCE: Decreased uptake or more rapid removal of the drug
4. CELL CYCLE SPECIFICITY: Cell cycle stage-nonspecific
5. TOXICITY: Nausea and vomiting, Myelosuppression, Cardiomyopathy, Alopecia

DOXORUBICIN ( Adriamycin)
1. CHEMICAL NATURE: Same as Daunorubicin except there is an additional hydroxyl
group
2. MECHANISM OF ACTION: As for Daunomycin
3. RESISTANCE: As for Daunomycin
4. CELL CYCLE SPECIFICITY: Cell cycle stage-nonspecific but greater efficacy in S
5. TOXICITY Similar to daunomycin
6. THERAPEUTIC USE: Acute leukemias, lymphomas, many solid tumors including
sarcomas
TOXICITIES
antracyclines (-rubicin)
cardiotoxicity
podophylum resins (-poside)
teniposide
etoposide
moa: topoisomerase inhibitors
inhibit the enzyme topoisomerase II and DNA gyrate
 ETOPOSIDE (VP-16-213)

1. CHEMICAL NATURE: semi-synthetic alkaloid derived

from podophyllotoxin
2. ACTION: Binds to tubulin but this is not believed to be
important for the therapeutic effect. May stimulate
topoisomerase II to cleave DNA
3. CELL CYCLE SPECIFICITY: Greatest lethality seen in
S and G2 phases
4. TOXICITY: Leukopenia, nausea and vomiting more
common with oral administration, alopecia
campthotecan derivatives (-tecan)
irinotecan
mitoxantrone
moa: topoisomerase inhibitors
inhibit the enzyme topoisomerase II and DNA gyrate
INDIRECT ACTING
antimetabolites
antifolaxe: methotrexate
purine/pyrimidine analogues
5- fluouracil
mercaptopurie
flu cytosine
azacutidine
METHOTREXATE (Amethopterin)
1. MECHANISM OF ACTION: Analog of folic acid which inhibits
dihydrofolate reductase and thereby inhibits one carbon transfers
required for nucleic acid synthesis. Selective rescue of normal cells may
be achieved with leucovorin (citrovorum factor).
2. RESISTANCE:
a. Decreased transport
b. Decreased affinity of target enzyme
c. Gene amplification and increased synthesis of target enzyme
3. CELL CYCLE SPECIFICITY: Kills cells in S phase but also slows
entry of cells into S phase
4. TOXICITY: Myelosuppression, Mucosal ulceration in GI tract, Nausea
5-FLUOROURACIL (5-FU)
1. CHEMICAL NATURE: structural analog of thymine
2. MECHANISM OF ACTION: 5-fluorouracil is metabolized to ribo and
deoxyribonucleoside phosphates. There is inhibition of thymidylate
synthetase by 5-fluoro-2'- deoxyuridine-5'-monophosphate. In addition
there is incorporation of 5-fluorouridine triphosphate into RNA.
3. RESISTANCE: Multiple mechanisms including increased synthesis
or altered affinity of target enzymes, decreased activation and
increased catabolism
4. CELL CYCLE SPECIFICITY: cells are killed throughout the cell cycle
5. TOXICITY: Myelosuppression, Nausea and vomiting, Anorexia,
Alopecia
6. THERAPEUTIC USE: GI tract adenocarcinomas, in combination
protocols for breast cancer, topical application for premalignant
keratoses
7. METABOLISM: Similar to uracil after action of dihydrouracil
dehydrogenase in the liver.
enzyme (-ase)
asparginase
tx of pancreatic cancer
antimitotics
mitotic spindle inhibitors
vincas
vincristine, vinblastine, vinorelbine
Taxols
paclitaxel, docetaxel
estramostine
VINBLASTINE (Velban)
1. CHEMICAL NATURE: Vinblastine sulfate is the salt of a dimeric alkaloid from the plant
Vinca rosea
2. MECHANISM OF ACTION: Binds to tubulin and interferes with spindle assembly in
mitosis
3. RESISTANCE: Decreased cellular uptake or increased efflux
4. CELL CYCLE SPECIFICITY: Mitosis, but at high concentrations inhibits S and G1
5. TOXICITY: Leukopenia, nausea and vomiting

VINCRISTINE (Oncovin)
1. CHEMICAL NATURE: Vincristine sulfate is the salt of a dimeric alkaloid from the plant
Vinca rosea.It differs from Vinblastine in the substitution of an aldehyde for a methyl group.
2. MECHANISM OF ACTION: Binds to tubulin and interferes with spindle assembly in
mitosis
3. RESISTANCE: Decreased cellular uptake or increased efflux
4. CELL CYCLE SPECIFICITY: Mitosis
5. TOXICITY: Numbness and tingling of fingers and toes, hair thinning, minimal
myelosuppression
TOXICITIES
vincas
neurotoxicity - vincristine