PHARMACOLOGY

Dr. Kenny James P. Merin, RPh, ClinPharm, MSc

“
DEFINITION OF TERMS
PHARMACOLOGY
The study of substances that interact with living
systems through chemical processes, especially by
binding to a regulatory molecules and activating or
inhibiting normal body processes.

Moreover, it is also defined as the 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
excretion

ADME
PHARMACODYNAMICS
What the DRUG does to the body
The measurement of responses to drugs and how
response relate to drug dosage or concentration
MEDICAL PHARMACOLOGY
Study of substances used to prevent, diagnose, and treat
disease.
PHARMACOGENOMICS
The relation of the individual’s genetic make up to his or
her response to specific drugs.
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:
Transporters
Receptors
Ion Channels
Carriers
Enzymes
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 site
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)
Dipines — Dihydropiridine
Verapamil - Non Dihydropyridine
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
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-linked 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
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
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. Convective Transport
4. Ion Pair Transport
5. Pinocytosis
1. PASSIVE DIFFUSION
- dominant transport
- slowest
- movement along with concentration
- downhill movement
- non energy requiring
Factors affecting passive diffusion
a. surface area surface area = rate of transport
b. thickness thickness = rate
c. conc. gradient > gradient = rate
d. Diffusion coefficient
- related to particle size
- related to lipophilicity
- particle size = diffusion coefficient
2. CARRIER MEDIATED TRANSPORT
- common features / propoerties:
i. Specificity / selectivity
ii. Subject to inhibition / antagonism / competition
iii. Subject to satiability

2 formsL
i. Active transport
ii. Facilitated transport/diffusion
i. Active transport
- energy requiring
- against the concentration movement
- uphill transport
- fastest route of movement

ii. Facilitated diffusion

- non-energy requiring
- movement is along the concentration gradient
- downhill transport
3. CONVECTIVE TRANSPORT
- movement through water-filled pores (channels)
features:
- transport is limited by size of the pore and charge of the
pore lining
4. ION PAIR TRANSPORT
- mech of movements of large ions
- form a neutral pair with endogenous oppositely charged
ions
5. PINOCYTOSIS
- “cell drinking”
- involves vesicles
- requirement micelle form
- ATP requiring
LADMER
In simple terms:
Liberation is the release of the drug from its dosage form
Absorption is the movement of drug from the site of
administration to the blood circulation
Distribution is the process by which drug diffuses or is
transferred from the intravascular space to extravascular space
Metabolism is the chemical conversion or transformation of
drugs into compounds which are easier to eliminate
Excretion is the elimination of unchanged drug or metabolite
from the body via renal, biliary, or pulmonary processes
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

C max is the maximum concentration and is usually reached

after a few hours
T max is the time taken to reach the maximum concentration
AUC (Area Under the Curve) it reflects the actual body
exposure to drug after administration of a dose of the drug.
Factors affecting ABSORPTION

1. Dose-size administered
2. Surface Area
3. Degree of Perfusion
4. pH of the environment
5. Gastric Emptying Time (GET)
DOSE-SIZE AND SURFACE AREA
Smaller the particle size (by
micronization)

Greater is the effective surface area

more intimate contact between

solid surface and aqueous solvent

higher is the dissolution rate

increase in absorption efficiency

GASTRIC EMPTYING
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
Cardiac Output:
- volume of blood pumped out by heart in one minute
- Slow cardiac output = delayed effect of certain drugs

Regional Blood Flow

- fraction of cardiac output that is delivered to specific
organs/tissues
- Liver = 25% of CO Lungs = 100% of CO
- Kidney = 25% of CO
Tissues and organs with poor regional blood flow:
- bones
- adipose tissues 1% of CO

- mx of osteomyelitis (bacteria) — IV ABX >6 weeks

- mx of pneumonia 7-14 days ABX PO
distribution parameters
a. protein binding
b. volume of distribution
Protein Binding
- binding the drug to blood proteins

FREE DRUG BOUND DRUG

Remains in the
Can be distributed
circulation

Can be metabolised role: reservoir

Proteins involved in protein binding
i. Albumin
-major protein
-structure non-selective
-preferentially binds with acid
ii. Alpha 1 acid glycoprotein
-structure non-selective
-preferentially binds with weak bases
iii. Globulins
- specific proteins in protein binding
- primarily proteins that binds with hormones

b. Volume of distribution
- volume of body fluid necessary to dissolve a given
amount or dose of a drug to a concentration equal to that
of plasma
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
-extensive metabolism of a drug reduces bioavailability of
drug products
EXCEPT

i. Prodrugs
ii. Toxicity
iii. Active drug
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

Enzyme Induction Enzyme Inhibition

Stimulating Metabolizing Enzyme 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.
PROBLEM:
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?

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.
THE NERVOUS SYSTEM
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)
`
DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM
ANXIETY
What about it?
DEFINITION
Anxiety  is a general term for several disorders
that cause nervousness, fear, apprehension, and
worrying.

These disorders affect how we feel and

behave and can cause physical symptoms.
Mild anxiety is vague and unsettling, while
severe anxiety can seriously affect day-to-
day living.
ANXIOLYTIC DRUGS
An anxiolytic is a medication or other intervention that
inhibits anxiety. This effect is in contrast to anxiogenic
agents, which increases anxiety.

EXCITATORY INHIBITORY
NEUROTRANSMITTER NEUROTRANSMITTER

1. Norepinephrine

2. Dopamine
1. Gamma-aminobutyric Acid
3. Acetylcholine
2. Glycine
4. Glutamate

5. Aspartate
EXCITATORY INHIBITORY

Opens Na or Ca
Open Cl channels
channels

Depolarization Hyperpolarization

Nerve Impulse 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.

Panic attacks tend to occur and escalate rapidly

and peak after 10 minutes. However, they may
last for hours.
SYMPTOMS
CAUSES
It's not known what causes panic attacks or panic
disorder, but these factors may play a role:
TESTIMONIES OF PEOPLE WHO HAS P.D.
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
scrutinised or judged by others.
SYMPTOMS
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 behaviour.
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
behaviour. That is, you may develop the condition after
witnessing the anxious behaviour 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
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 risof 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

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
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

Phenelzine (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 

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,Agitationandconf
usion,Orthostatichypotension,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 non-adenyl cyclase-linked dopamine
2 


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 D receptor site in the nigrostriatum 

1 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




 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 - Cholinesterase
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 ———————————-
Tyrosine hydroxylase > DOPA

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

SYMPATHOMIMETIC
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, salmeterol

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
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

1

therapeutic 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
less associated with htn or tachycardia when withrawn
L abetolol
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
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
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
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
2 2
+

HCO ) that can lead to the spillage of Na causing

3
- +

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
SYMPATHOPLEGICS
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
SYMPATHOPLEGICS
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
VASODILATORS
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

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
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.
`
Deprivation of oxygen to a portion of the myocardium
(reversible)
 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 : haemostasis
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
 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
fibrinolytics
2. prothrombotics
vitamin k
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
➤ e-aminocaproic acid
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
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


Ia - Dispyrimidine, Quinidine, Procainamide

SE

Cinchonism (HA, vertigo, tinnitus)
Torsades de pointes

 CLASS 1B

Shortens phase 3 repolarization
Decrease duration of action potential

Ib - Lidocaine, Phenytoin, Tocainide, Mexilitine

SE

Convulsion

Allergy 

agranulocytosis
CLASS 1C

Markedly slow phase 0 depolarization

Ic - Encainide, Moricizine, Flecainide, Propafenone,

SE

Pro arrhythmic
Class I antiarrythmics
Ia - Dispyrimidine, Quinidine, Procainamide
Ib - Lidocaine, Phenytoin, Tocainide, Mexilitine
Ic - Encainide, Moricizine, Flecainide, Propafenone,

Double Quarter Pounder

Lettuce, Pickles, Tomato, Mayonaise
Eat More Fries Please
CLASS II

Suppresses phase 4 depolarization
Class II antiarrythmics
Carvedilol
Propranolol
Esmolol
Timolol
Metoprolol
Atenolol
Bisoprolol
Nebivolol
 CLASS III

Prolongs phase 3 repolarization

SE

Amiodarone: hypothyroidism, corneal deposit,
pulmonary fibrosis

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

Ibutilide & Dofetilide: torsades
Class III antiarrythmics
Ibutlide
Sotalol IS BAD

Beryllium
Amiodarone
Dofetilide
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

NONDHP CCBS
Verapamil
Diltiazem


SE: hypotension
Miscellaneous Agents
Adenosine

MgSO 4


Atrial flutter
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
effects
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 (thrombosis) - 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.
Aspirin
Ibuprofen
Ketoprofen
Flurbipofen
Naproxen
Nabumetone
Etodolac
Ketorolac
Piroxicam
Indomethacin
Sulindac
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
Remember:

N S A I D s o n l y p r ev e n t p a i n a n d
inflammation but it DOES NOT prevent
the destruction of the joint by WBCs
(chemotaxis) in RA

So we give DMARDs
DMARDs

Generally:
▪ MOA: IMMUNOSUPPRESSION
▪ ADR: Px is IMMUNOCOMPROMISED
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
Abatacept
Azathioprine
Cyclophosphamide
Cyclosporine
Chloroquine and Hydrochloroquine
Leflunomide
Methotrexate
Mycophenolate
Sulfasalazine
TNF alpha blockers – Infliximab, Adalimumab,
Etanercept
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
Acute Attack of Gout
COLCHICINE
▪ MOA: inhibit TUBULIN (for WBC migration)
▪ Short duration of action – for ACUTE GOUT
▪ ADR:
▪ DIARRHEA
▪ GI disturbance
▪ HEPATOTOXICITY
▪ NEPHROTOXICITY
▪ ALOPECIA
Drugs that Decrease URIC ACID

Allopurinol
Feboxostat
Probenecid
Sulfapyrazone
Allopurinol

XO inhibitor
Active metabolite: Alloxanthine

PURINE XO Uric Acid

F0r CHRONIC GOUT

Probenecid & Sulfapyrazone

Inhibit reabsorption of uric acid in PCT

They are called URICOSURIC AGENTS

Note: Probenecid and Penicillin

Prolongs the action

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)
Feboxostat

First NON-PURINE Xanthine Oxidase

Inhibitor
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.
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
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
4

collagen 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
ADRENOCORTICOTRO
PIC 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
PHEOCHROMOCYTOMA
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
st

Glipizide)

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 CONTRACEPTION
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
CONTRACEPTIVES
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
CONTRACEPTIVES
(COMBINATION:
OESTROGEN +
PROGESTIN)
HORMONAL CONTRACEPTIVES
(contain both Estrogen and Progestin)
Providedas21or28daypacks
Estrogen component: Ethinyl estradiol, Mestranol
Progestin component: 19-Nor compounds
HORMONAL CONTRACEPTIVES
MOA

Prevents ovulation (release of eggs from the ovaries)

Change the lining of the uterus to prevent pregnancy
Change the mucus at the cervix to prevent sperm from
entering
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
CONTRACEPTIVES
(PROGESTIN ONLY)
PROGESTIN ONLY CONTRACEPTIVES POST COITAL
Contraceptives 

#Morning-after pills 

#Ethinyl estradiol + Norgestrel, 

Ethinyl Estradiol, Conjugated estrogen, Estrone, DES 

MOA
Thickens mucus in the cervix - making it difficult for
sperm to enter the uterus and fertilise an egg
Stop ovulation (40% of women who use progestin-only
pills will continue to ovulate)
Thin linings of the uterus
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
 CANCER
CHEMOTHERAPY
 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.
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
PRINCIPLES OF ONCOLOGY
CANCER CELLS
Carcinogenesis - mechanism of how many cancers occur
is through to be multistage, multifactorial process that
involves both genetic and environmental factorsa.
a. Initiation" first step involves the exposure of
normal cells to a carcinogen, producing genetic damage
to a cell.
b. Promotion"environment becomes altered to allow
preferential growth of mutated cells over normal cells.
The mutated cells become cancerous.

c. Progression"Increased proliferation of cancer cells
allows for invasion into local tissue and metastasis
PRINCIPLES OF ONCOLOGY
Types of cancer

1. BENIGN
- slow growing, resemble normal cells, localized, not
harmful
2. MALIGNANT
- tumors often proliferate more rapidly, have an atypical
appearance, invade and destroy surrounding tissues, and
are harmful if left untreated. Malignant cancers are further
categorized by the location from where the tumor cells
arise.
PRINCIPLES OF ONCOLOGY
a. Solid tumors.
Carcinomas are tumors of epithelial cells. These include
specifi c tissue cancers (e.g., lung, colon, breast). Sarcomas
include tumors of connective tissue such as bone (e.g.,
osteosarcoma) or muscle (e.g., leiomyosarcoma).
b. Hematological malignancies.
Lymphomas are tumors of the lymphatic system and
include Hodgkin and non-Hodgkin lymphomas.
Leukemias are tumors of blood-forming elements &
classified as acute or chronic and myeloid or lymphoid
PRINCIPLES OF ONCOLOGY
Most common cancers are

BREAST CANCER
PROSTATE CANCER
COLORECTAL CANCER

Leading cause of cancer death: LUNG CANCER

PRINCIPLES OF ONCOLOGY
Causes:
Many factors have been implicated in the origin of cancer. Some of
these factors are as follows:
1. Viruses, including Epstein-Barr virus (EBV), hepatitis B virus
(HBV), and human papillomavirus (HPV)

2. Environmental and occupational exposures, such as ionizing and
ultraviolet radiation and exposure to chemicals, including vinyl
chloride, benzene, and asbestos
3. Lifestyle factors, such as high-fat, low-fi ber diets and tobacco and
ethanol use
4. Medications, including alkylating agents and immunosuppressants
5. Genetic factors, including inherited mutations, cancer-causing
genes (oncogenes), and defective tumor-suppressor genes
PRINCIPLES OF ONCOLOGY
Detection and Diagnosis:
1. Warning signs
2. Screening
3. Tumor Markers
4. Tumor Biopsy
5. Imaging Studies
6. Laboratory Tests
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.
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.

Interphase is also called the preparatory 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.
S phase

The start of the S phase is when the DNA

replication commences. When the phase
completes all the chromosomes have been
replicated.
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. M phase: mitotic inhibitors (e.g., vinca alkaloids,
taxanes) b. G1 phase: asparaginase, prednisone
(antineoplastic agent prepration from E.coli containing
the enzyme L-asparagine amidohydrolase
c. S phase: antimetabolites
ex. Antimetabolites (antifolates, purine/pyrimidine
analogues)

d. G2 phase: bleomycin, etoposide


b. Non-specific
- target calls in any phase of cell cycle
rest: Alkylating, Antibiotics, Anthracyclines,
Podophyllumz, Enzymes, Topoisomerase inhibitors
b. Cell Cylce - Non-specific
- effective in all phases, including G0
CARMUSTINE AND LOMUSTINE
RADIATION THERAPY
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
CHEMOTHERAPY
OBJECTIVES OF CHEMOTHERAPY
1. For leukemia and lymphoma, several phases are
necessary
a. Remission induction
b. Consolidation
c. Maintenance
OBJECTIVES OF CHEMOTHERAPY
2. For solid tumors, one or more approaches of
chemotherapy may be used when seeking cure based on
the known utility with other modalities, such as surgery
and radiation.
a. Adjuvant chemotherapy
b. Neoadjuvant chemotherapy
c. Palliative therapy
d. Salvage Chemotherapy
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; forms DNA cross-links resulting to
the inhibition of DNA synthesis and function.

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.
CLINICAL APPLICATIONS
Breast Cancer
Ovarian Cancer
Non-Hodgkin’s Lymphoma
Chronic Lymphocytic Leukemia
Neuroblastoma
ANTIBIOTICS
anti-tumor antibiotics (-mycin)
From streptomyces genus
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
CLINICAL APPLICATION
Ewing’s Sarcosoma
Rhabdomyosarcosoma (Childhood Tumors)
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
CLINICAL APPLICATION
LYMPHOMAS
MYELOMAS
SARCOMAS
BREAST, LUNG, OVARIAN, AND THYROID CANCERS
TOXICITIES
antracyclines (-rubicin)
cardiotoxicity
PLANT ALKALOIDS
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. Inhibits
topoisomerase II resulting in DNA damage.
3. CELL CYCLE SPECIFICITY: Greatest lethality
seen in S and G2 phases
4. TOXICITY: Leukopenia, nausea and vomiting
more common with oral administration, alopecia
CLINICAL APPLICATION
LUNG CANCER
NON-HODGKIN’S LYMPHOMA
GASTRIC CANCER
campthotecan derivatives (-tecan)
irinotecan
mitoxantrone
moa: topoisomerase inhibitors
inhibit the enzyme topoisomerase I and DNA gyrase
resulting in DNA damage
CLINICAL APPLICATION
SMALL CELL LUNG CANCER
OVARIAN CANCER
antimitotics - VINCA ALKALOIDS
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
Taxanes
Paclitaxel

moa: interferes with microtubule function, resulting in

impaired mitosis
CLINICAL APPLICATION
BREAST CANCER
OVARIAN CANCER
LUNG CANCER
GASTROESOPHAGEAL CANCER
PROSTATE CANCER
BLADDER CANCER
HEAD & NECK CANCERS
TOXICITIES
MYELOSUPPRESSION
PERIPHERAL SENSROY NEUROPATHY
INDIRECT DNA INTERACTING
ANTIMETABOLITES
antifolate: methotrexate
purine/pyrimidine analogues
5- fluouracil
mercaptopurie
fluocytosine
azacutidine
METHOTREXATE (Amethopterin)
1. MECHANISM OF ACTION: Analog of folic acid which inhibits
dihydrofolate reductase (DHFR) 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
CLINICAL APPLICATION
BREAST CANCER
HEAD.& NECK CANCER
PRIMARY CNS LYMPHOMA
NON-HODGKIN’S LYMPHOMA
BLADDER CANCER
CHORIOCARCINOMA
5-FLUOROURACIL (5-FU)
1. CHEMICAL NATURE: structural analog of thymine
2. MECHANISM OF ACTION: inhibits thymidylate synthase, and its
metabolites are incorporated into RNA and DNA, all resulting in
inhibition of DNA synthesis and function and in RNA processing.
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.
CLINICAL APPLICATION
GI CANCERS
BREAST CANCERS
HEAD & NECK CANCERS
HEPATOCELLULAR CANCER
ENZYME
enzyme (-ase)
asparginase
tx of pancreatic cancer
Asparaginase is an enzyme that causes the degradation
of the amino acid asparagine to aspartic acid and
ammonia.
Unlike normal cells, tumor cells lack the ability to
synthesize asparagine.
This is a G1 phase–specifi c agent.

MONOCLONAL ANTIBODIES
TYROSINE KINASE INHIBITORS
IMATINIB

MOA: inhibits bcr-abi tyrosine kinase and other receptor

tyrosine kinases

S/E: nausea and vomiting

CLINICAL APPLICATION
CHRONIC MYELOGENOUS LEUKEMIA (CML)
GI STROMAL TUMOR
TOXICITIES
FLUID RETENTION W/ANKLE PERIORBITAL EDEMA
EDEMA
DIARRHEA
MYALGIAS
CONGESTIVE HEART FAILURE
GROWTH FACTOR RECEPTOR INHIBITORS
TRASTUZUMAB (HERCEPTIN)

MOA: inhibits binding of EGF to the HER-2/neu growth

receptor

S/E: nausea and vomiting

CLINICAL APPLICATION
HER-2/neu RECEPTOR POSITIVE BREAST CANCER
(METASTATIC BREAST CANCER)
TOXICITIES
CARDIAC DYNSFUNCTION
VASCULAR ENDOTHELIAL GROWTH FACTOR
(VEGF INHIBITORS)
BEVACIZUMAB

MOA: inhibits binding of VEGF to its receptor, resulting

in inhibition of tumour vascularisation

S/E: nausea and vomiting

CLINICAL APPLICATION
COLORECTAL CANER
BREAST CANCER
NON-SMALL CELL LUNG CANCER
RENAL CANCER
TOXICITIES
ARTERIAL THRMBOEMBOLIC EVENTS
GASTROINTESTINAL PERFORATIONS
WOUND HEALING COMPLICATIONS
PROTEINURIA
HORMONES
HORMONE AGONISTS
PREDNISONE
*most commonly used glucocorticoid in cancer chemo

MOA: may trigger apoptosis

S/E: nausea and vomiting

CLINICAL APPLICATION
HEMATOLOGICAL CANCERS
TOXICITIES
ADRENAL SUPPRESSION
GROWTH INHIBITION
MUSCLE WASTING
OSTEOPOROSIS
SALT RETENTION
GLUCOSE INTOLERANCE
BEHAVIORAL CHANGES
HORMONES
HORMONE ANTGONISTS
TAMOXIGFEN, RALOXIFENE

MOA: estrogen antagonist actions in breast tissue and

CNS; oestrogen agonist effects in liver and bone

S/E: nausea and vomiting

CLINICAL APPLICATION
PREVENTION OR ADJUVENT TX OF HORMONE-
RESPONSIVE BREAST CANCER
TOXICITIES
HOT FLUSHES
THROMBOEMBOLISM
ENDOMETRIAL HYPERPLASIA
ADMINISTRATION
1. Routes of administration vary depending on the agent
and the disease state.
intravenous (IV) administration is most commonly
employed, oral administration of chemotherapy is
becoming increasingly more common.
2. Other administration techniques include oral,
subcutaneous, intrathecal, intra-arterial, intraperitoneal,
intravesical, continuous IV infusion, bolus IV infusion,
and hepatic artery infusion.
ADMINISTRATION
3. Drugs that may be given intrathecally include
methotrexate, cytarabine, and hydrocortisone. Drugs
should not be administered by the intrathecal route
without specific information supporting intrathecal
administration.
Inadvertent administration of vinca alkaloids (e.g.,
vincristine) by the intrathecal route results in ascending
paralysis and death.
4. Products with different formulations, including
liposomal or pegylated agents (e.g., liposomal
doxorubicin, pegfilgrastim), are being used to decrease
frequency of administration and/or reduce toxicities.
RESPONSE TO CHEMOTHERAPY
1. Complete response (CR) indicates disappearance of all
clinical, gross, and microscopic disease.

2. PR indicates a greater than 50% reduction in tumor
size, lasting a reasonable period. Some evidence of
disease remains aft er therapy.
3. Response rate (RR) is defined as CR _ PR.

4. SD indicates tumor that neither grows nor shrinks
signifi cantly (less than 25% change in size).

5. PD or no response aft er therapy is defi ned by a
greater than 25% increase in tumor size or the
appearance of new lesions.
OTHERS
1. Surgery
2. Radiation Therapy
3. Hematopoietic Stem Cell Transplantation
 PHARMACOLOGY
Dr. Kenny James P. Merin, RPh, ClinPharm, MSc