FARMAKOLOGI

UMUM
DAN
TERAPI

DR. HERJANTO KURNIA, M.A.

 FARMAKOLOGI UMUM DAN
TERAPI
Topik Pengajar
Kuliah Farmakologi Umum 1: Pengantar Farmakologi Herjanto Kurnia, dr., M.A

Kuliah Farmakologi Umum 2: Farmakokinetik Herjanto Kurnia, dr., M.A

Kuliah Farmakologi Umum 3: Analgetik

Herjanto Kurnia, dr., M.A
Praktikum Farmakologi Umum 1: Absorpsi dan Ekskresi pada
Manusia Dra. Rosnaeni dan Herjanto Kurnia, dr., M.A
Kuliah Farmakologi Umum 4: Antibiotik
Herjanto Kurnia, dr., M.A
Kuliah Farmakologi Umum 5: Anestesi lokal
Herjanto Kurnia, dr., M.A
Kuliah Farmakologi Umum 6: Penulisan resep Dra. Rosnaeni

Kuliah Farmakologi Terapi 1: Pengantar obat otonom

Herjanto Kurnia, dr., M.A
Praktikum Farmakologi Umum 2: Penulisan Resep Dra. Rosnaeni dan Herjanto Kurnia, dr., M.A

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 FARMAKOLOGI UMUM DAN
TERAPI
Kuliah Farmakologi Terapi 2: Pengaruh obat
Herjanto Kurnia, dr., M.A
otonom pada organ
Kuliah Farmakologi Terapi 3: Obat-obat
Herjanto Kurnia, dr., M.A
antihipertensi
Kuliah Farmakologi Terapi 4: Antibiotik di
Herjanto Kurnia, dr., M.A
bidang kedokteran gigi
Kuliah Farmakologi Terapi 5: P-drug Herjanto Kurnia, dr., M.A
Kuliah Farmakologi Terapi 6: Kortikosteroid Herjanto Kurnia, dr., M.A

Kuliah Farmakologi Terapi 7: Insulin dan OHO Herjanto Kurnia, dr., M.A

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PHARMACOLOGY
BASICS
 Introduction to
PHARMAKOLOGY
FOUNDATIONAL CONCEPTS
Pharmacology:
The effect of
drugs on a body
and the effect
of the body on
drugs.
 Farmakologi

Obat pertama kali yang digunakan berasal dari

tanaman / jamu.
Dianggap kurang memuaskan, mulai melakukan
isolasi zat aktif
Menghasilkan serangkaian zat-zat kimia sebagai obat
Efedrin : Ephedra vulgaris
Atropin : Atropa belladona
Morfin : Papaver somniferum
Digoksin : Digitalis lanata
Reserpin : Rauwolfia serpentina
Vinblastin dan vinkristin : Vinca rosea
 Farmakologi
Adalah ilmu yang mempelajari
pengetahuan obat dengan seluruh
aspeknya, baik sifat kimiawi, fisika,
kegiatan fisiologi, resorpsi dan nasibnya
dalam organisme hidup
Farmakognosi : pengetahuan dan
pengenalan obat yang berasal dari
tanaman, mineral dan hewan. Ekstrak
Ginkoa biloba (penguat daya ingat),
bawang putih (antikolesterol), tingtur
hyperici (antidepresi), ekstrak fever few
(pencegah migrain)
 Farmakologi
Biofarmasi : ilmu yang mempelajari
pengaruh pembuatan sediaan farmasi
terhadap efek terapeutik obat.
Farmaceutical availability (ketersediaan
farmasi) : ukuran waktu yang diperlukan
oleh obat untuk melepaskan diri dari
bentuk sediaannya dan siap untuk proses
absorpsi.
Larutan suspensi emulsi serbuk
kapsul tablet enterik coated long
acting.
 Istilah dalam farmakologi
Biological availability (ketersediaan hayati) : prosentasi obat
yang diresorpsi tubuh dari suatu dosis yang diberikan dan
tersedia untuk melakukan efek terapeutiknya.
Therapeutical equivalent (kesetaraan terapeutik) : syarat yang
harus dipenuhi oleh suatu obat yang meliputi kecepatan
melarut dan jumlah kadar zat yang berkhasiat yang harus
dicapai dalam darah
Bioassay : cara menentukan aktivitas obat dengan
menggunakan hewan percobaan seperti kelinci, tikus, dll.

Farmakokinetik : segala proses yang dilakukan tubuh

terhadap obat berupa absorpsi, distribusi, metabolisme dan
ekskresi.
 Istilah dalam farmakologi
Farmakodinamik : mempelajari kegiatan obat terhadap
organisme hidup terutama cara dan mekanisme kerjanya,
reaksi fisiologi, serta efek terafi yang ditimbulkan.
Toksikologi : pengetahuan tentang efek racun dari obat
terhadap tubuh.
Farmakoterapi : mempelajari penggunaan obat untuk
mengobati penyakit atau gejalanya. Phytoterapi :
menggunakan zat-zat dari tanaman untuk mengobati
penyakit.
Farmakologi klinik : cabang farmakologi yang mempelajari
efek obat pada manusia.
 Penggolongan Obat
Obat farmakodinamis
Obat kemoterapeutis
Obat diagnostik
Obat farmakodinamis, bekerja terhadap host dengan jalan
mempercepat atau memperlambat proses fisiologi atau fungsi
biokimia dalam tubuh, misalnya hormon, diuretika, hipnotika,
obat otonom
Obat kemoterapeutis, dapat membunuh parasit dan kuman di
dalam tubuh host. Hendaknya obat ini memiliki kegiatan
farmakodinamis yang sekecil-kecilnya terhadap host, contoh :
antibiotik, antijamur, obat-obat neoplasma (onkolitik, sitostatik)
 Penggolongan Obat
Obat diagnostik merupakan obat pembantu untuk
melakukan diagnosis (pengenalan penyakit),
misalnya BaSO4 digunakan untuk diagnosis
penyakit saluran pencernaan, Na propanoat dan
asam iod organik untuk saluran empedu
 Menurut Permenkes RI
No. 949/Menkes/Per/VI/2000

1. Obat bebas Penandaan

2. Obat bebas
terbatas
Obat keras
K
3.
4. Obat wajib apotek
5. Obat narkotika
6. Obat psikotropika
 Permenkes RI No.
949/Menkes/Per/VI/2000
Obat Bebas Obat yang dapat Minyak kayu putih,
dijual bebas kepada OBH, OBP,
umum tanpa resep Paracetamol, Vit. C,
dokter B Komplex, dll.

Obat Bebas Obat bebas yang Antihistamin,

pada penjualannya klorokuin, kalii
Terbatas (W :
disertai tanda kloras, suppositoria,
waarschuwing) peringatan. dll.

K
Obat Keras Obat berbahaya jika Adrenalin,
pemakaiannya tidak antibiotika,
(G : Gevaarlijk) berdasarkan resep antihistamin, dll.
dokter.

K
OWA Obat keras yang Linestrenol, antasid,
dapat diserahkan salbutamol,
oleh apoteker tanpa basitrasin krim,
resep dokter. ranitidin, dll.
 Permenkes RI No.
949/Menkes/Per/VI/2000
Narkotika Zat atau obat yang berasal dari Tanm. Papaver
tanaman atau bukan, sintetis atau somniferum,
semisintetis yang dapat kokain, ganja,
menyebabkan penurunan atau heroin, morfin,
perubahan kesadaran, hilangnya opium, kodein, dll.
rasa, mengurangi sampai
menghilangkan rasa nyeri.

K
Psikotropika Zat atau obat baik alamiah Lisergida,
maupun sintetis bukan narkotika psilosibina,
yang berkhasiat psikoaktif melalui amfetamin,
pengaruh selektif pada SSP yang diazepam,
menyebabkan perubahan khas fenobarbital,
pada aktifitas mental dan perilaku. klordiazepoksida,
dll.
 UJI KLINIK
Fase I : pengujian obat untuk pertama kali pada
manusia, yg diteliti : keamanan obat.
Fase II : pengujian obat utk pertama kali pd
sekelompok kecil penderita, tujuan : melihat efek
farmakologik. Bisa dilakukan secara komparatif
dg obat sejenis ataupun plasebo. Jumlah 100-
200 orang
Fase III : Memastikan obat benar2 berkhasiat,
dibandingkan dg plasebo, obat sama tp dosis
beda, obat lain indikasi sama. Min 500 org
Fase IV : Post Marketing Drug Surveillance,
tujuan menentukan pola penggunaan obat di
masy, efektivitas dan keamanannya.
 Introduction to Pharmacology
FOUNDATIONAL CONCEPTS
Drugs interact with the cells and
extracellular components on a
molecular level to produce an effect.
Molecular interactions between the
drug and body determine how, when,
and where the action of the drug will
be terminated.
Pharmacology encompasses the
therapeutic responses and adverse
effects of drugs as well as the
absorption, metabolism, and
excretion of drugs.
 Introduction to Pharmacology
SUBDIVISIONS OF PHARMACOLOGY

Pharmacokinetics:
Factors that affect the
time course of the
drug.
Rate at which drugs begin
to take effect
Duration of the effect
Rate of change at the of
action
 Introduction to Pharmacology
SUBDIVISION OF PHARMACOLOGY

Pharmacodynamics:
The study of the
mechanism of
action of drugs.
Combine with enzymes
Combine with
receptors
 Introduction to Pharmacology
WHAT IS A DRUG

Chemicals used to
treat or prevent
disease
Table sugar?
Vitamins?
Herbal products?
 Introduction to Pharmacology
CLASSIFICATION OF DRUGS

Grouped based on
their chemistry
Categorized by legal
classification
OTC Drugs drugs that do
not require a prescription
Prescription
Controlled substances
 Introduction to Pharmacology
CLASSIFICATION OF DRUGS-OTC

Do not require a
prescription
Contain a lower of drug
per dosage as compared
to prescription drug
Contain multiple active
ingredients in the same
dosage form
 Introduction to Pharmacology
CLASSIFICATION OF DRUGS-PRESCRIPTION

Greater potential for adverse

effects
Require monitoring for interaction
with other drugs
Only used for a restricted time
period
Medical supervision mandated
Prescribed by physician
prescription filled by pharmacist
 Introduction to Pharmacology
CLASSIFICATION OF DRUGS -CONTROLLED SUBSTANCES WHAT SCHEDULE DRUG IS THIS?

Referred to as scheduled drugs

Have abuse potential
More restrictive requirements:
distribution, storage, and record
keeping as compared with
prescription drugs
Schedule I have greatest potential
for abuse Schedule V have lowest
potential for abuse
 Plasma Site of
Dosage Effects
Concen. Action

Pharmacokinetics Pharmacodynamics
 Farmakodinamik
Adalah cabang ilmu yang
mempelajari efek biokimia dan
fisiologi obat serta mekanisme
kerjanya.
Tujuannya meneliti efek utama
obat, interaksi obat, spektrum
efek dan respon yang terjadi.
 Mekanisme Kerja Obat
Timbul karena interaksi obat dengan
reseptor pada sel organisme
Terjadi perubahan biokimiawi dan
fisiologi yg mrp respons khas untuk
obat tersebut
Reseptor merupakan makromolekul
fungsional yang mencakup 2 konsep
penting yaitu agonis dan antagonis
 Reseptor Obat
Komponen penting : protein
(asetilkolinesterase, Na+, K+ ATPase,
tubulin, dll)
 Reseptor Obat
Ikatan obat-reseptor : ikatan ion, hidrogen,
hidrofobik, van der waals, kovalen.
Struktur kimia suatu obat berhubungan
erat dengan afinitasnya thd reseptor
Hubungan dosis dengan intensitas efek
D+R DR + Efek
Intensitas efek obat berbanding lurus
dengan fraksi reseptor yang diduduki
 Reseptor Obat
Dalam menimbulkan efek, obat
tertentu tidak berikatan dengan
reseptor :
- Mengubah sifat cairan tubuh :
antasid, Na bikarbonat dlm
membasakan urin
- Berinteraksi dg ion : CaNa2 EDTA
dlm mengikat Pb2+
- Masuk ke komponen sel
PHARMACODYNAMICS
Definition: The study of
the impact of drugs on the
body
Primary focus are the
mechanisms by which
drugs exert their
therapeutic & adverse
effects
As the dose changes the
type and degree of the
response changes
More receptors will be
occupied
PHARMACODYNAMICS

Therapeutics
The study of the
parameters that determine
the most appropriate
therapy for the patient
 FOUNDATIONAL IS CODEINE DISPENSE IN
CONCEPTS THE SM CLINIC?
Addictive Effect
An effect in which two
substances or actions used
in combination produce a
total effect the same as the
sum of the individual
effects
Synergistic Effect
The use of two or more
drugs that produce a
greater effect of one drug
used alone
Ex. NSAID added to
codeine for pain relief
 FOUNDATIONAL
CONCEPTS
Antagonistic Effect
The use of a second drug
reduces the effect of
another drug
The second drug has an
antagonistic effect
A second drug may bind
to the same receptor as
the first drug, thus
preventing the agonist
response
 FOUNDATIONAL IS THE PLACEBO EFFECT AN
ETHICAL PATIENT TREATMENT IN
CONCEPTS AT?

Placebo Effect
Either a therapeutic or
adverse response that
cannot be attributed to the
pharmacological effect of
the drug
Contains no active
ingredient
35% of the population
responds to a placebo effect
Responses include relief of
fever, headache, anxiety,
nausea, & pain
Effect is not imaginary
 FOUNDATIONAL CAN A PLACEBO BE USED AS
CONCEPTS A DIABETIC TREATMENT?

If a patient is convinced
that pain relief is
imminent upon
administration of an
analgesic, a placebo
effect may bring greater
relief than what would
be expected from the
drug alone
 FOUNDATIONAL
CONCEPTS
Tolerance
A diminished response to
a drug as a result of
continued use
Not all drugs produce
tolerance
When tolerance is
developed for one drug in
a category, a cross
tolerance may developed
for another drug in the
same category
 FOUNDATIONAL
CONCEPTS ENZYME OR RECEPTOR?

2 major mechanisms
that cause
pharmacological
tolerance
Enzyme Induction
The liver produces more
drug-metabolizing
enzymes
Receptor Effects
Responsiveness of the
receptors decreased
 DOSE-RESPONSE
RELATIONSHIP
As the concentration of
the drug increases,
more molecules will
occupy more receptors,
which then produces a
greater response
This is known as the
Does-Response
Principle
 CAFFEINE OR
SINGLE DOSE AMPHETAMINES?
Potency
The dose of a drug
required to produce a
particular effect relative to
the dose of another drug
that acts by a similar
mechanism to produce the
same effect
Caffeine vs
Amphetamines
 MULTIPLE DOSE &
STEADY STATE
When multiple doses of a
drug are administered,
blood concentration
increases beyond that of a
single dose
The body absorbs what it
can and metabolizes or
excretes the excess
The leveling off of the
drug is the steady state
 MAINTENANCE &
LOADING
Maintenance Dose
A dose administered at a
regular dosing interval on
a repetitive basis
Loading Dose
One or more doses that
are higher than the
maintenance dose &
administered at the
beginning of therapy
Achieves the desirable
concentration quicker
PATIENT COMPLIANCE

Refers to the extent to

which the patient is
taking the medication as
prescribed
Reasons for patient non-
compliance
High cost
Forgetting to take meds
Inconvenience
Poor patient education
 THERAPEUTIC DRUG
MONITORING
Measure blood
concentration of the
drug
The range between the
low and high desired
concentration is referred
to as therapeutic range
or therapeutic window
 LIVER & KIDNEY
FUNCTION HUMAN LIVER

The liver and kidney

remove most drugs
from the body
Disease, drug toxicity,
& aging process may
necessitate dosage
adjustment
 TYPES OF DRUG
INTERACTIONS
Receptor Antagonist
2 drugs have an affinity
for the same receptor
One drug displaces the
other and diminishes the
response
Agonist vs Antogonist
 TYPES OF DRUG
INTERACTION
Enzyme Induction
When a drug increases the
metabolizing enzymes for
another drug
Enzyme Inhibition
2 drugs bind on the same
metabolizing enzyme
One drug inhibits the
enzyme for the other
 TYPES OF DRUG
INTERACTIONS
Physiologic
Antagonism
2 drugs given
concurrently oppose each
other
Neither drug effects the
mechanism of action
 TYPES OF DRUG
INTERACTIONS
Physiologic Agonists
2 or more drugs used
concurrently result in an
increase in physiologic
effects
The drugs do not have the
same mechanism of action
 TYPES OF DRUG
INTERACTIONS
Absorption Effects
The use of one drug
inhibits the absorption of
another when given
concurrently
Excretion Effects
One drug increases or
decreases the excretion of
another
 ADVERSE DRUG
REACTIONS
Side Effects
Expected responses based
on the pharmacologic
action of the drug
Allergic Reactions
Exaggerated immune
response to a certain drug
Organ Cytotoxic Effects
Adverse effects on organs
 ADVERSE DRUG
REACTIONS
Idiosyncratic Reactions
Reaction that is particular
to an individual or defined
group of people
Drug-drug Interactions
Interaction of 2 or more
drugs that result in a
disadvantage to a patient
Drug-food Interactions
Interaction of a drug with
food that results in an
adverse patient reaction
 ADVERSE DRUG
REACTIONS
Drug-herb Interactions
Interaction of a drug with
herbal products that
results in an adverse
patient reaction
Drug Use During
Pregnancy
Most drugs cross the
placenta
Thus, posing an adverse
reaction to the child
DEFINITIONS
Pharmacokinetics
The process by which a drug is absorbed,
distributed, metabolized and eliminated by
the body

Pharmacodynamics
The interactions of a drug and the receptors
responsible for its action in the body
 Farmakokinetik
Tempat kerja Depot jaringan
(reseptor)
Bebas Terikat
Terikat Bebas

Sirkulasi
sistemik

Absorpsi Obat bebas Ekskresi

Obat Terikat Metabolit

Biotransformasi
 LOCUS OF ACTION TISSUE
RECEPTORS RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
THE LIFE CYCLE OF A DRUG
(PHARMACOKINETICS)

Absorption
Distribution
Degradation
Excretion
 SLOW ABSORPTION

Orally (swallowed)

through Mucus Membranes

Oral Mucosa (e.g. sublingual)
Nasal Mucosa (e.g. insufflated)

Topical/Transdermal
(through skin)

Rectally (suppository)
FASTER ABSORPTION
Parenterally (injection)
Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC)
Intraperitoneal (IP)

Inhaled (through lungs)

FASTEST ABSORPTION
Directly into brain
Intracerebral (into brain tissue)
Intracerebroventricular (into brain
ventricles)

General Principle: The faster the absorption,

the quicker the onset, the higher the
addictiveness, but the shorter the duration
ABSORPTION: SOLUBILITY
Water-soluble
Ionized (have electrical charge)
Crosses through pores in capillaries, but
not cell membranes

Lipid(fat)-soluble
Non-ionized (no electrical charge)
Crosses pores, cell membranes, blood-
brain-barrier
 ABSORPTION: SOLUBILITY
Dissociation constant or pKa indicates
the pH where 50% of the drug is ionized
(water soluble) and 50% non-ionized (lipid
soluble);
pKeq = pH + log [X]ionized/[X]non-ionized

This affects a drug's solubility,

permeability, binding, and other
characteristics.
(hydroxyl group)

(amine group)
DISTRIBUTION: DEPENDS ON BLOOD FLOW
AND BLOOD BRAIN BARRIER
 Excludes ionized
substances;
Active transport
mechanisms;
Not uniform
leaky
(circumventricular
areas)
 Pharmacokinetic Principles
SITE OF ACTION

A drug must reach its site of action

to have an effect
Intended site is called the
molecular site
Molecular site is where a significant
chemical reaction to produce a
biologic affect takes place
Site of action is either a receptor on
a cell surface or inside a specific
cell or enzyme within a cell
 Pharmacokinetic Principles
CAN WE DETERMINE DURATION OF
ONSET AND DURATION OF ACTION ACTION TIME?

Onset Action: the time it takes to

cause a noticeable biological
response from the drug taken

Duration Action: The length of time

the drug produces an effect
 Pharmacokinetic Principles
HOW LONG DOES IT TAKE BLUE TO REACH
HALF-LIFE & CLEARANCE RATE A HALF-LIFE?

Half-life: the time required for the

amount of drug in the blood to be
reduced to one-half
Metabolism & excretion are the
mechanisms that clear the drug
from the body
Clearance Rate: a measurement of
the time it takes for metabolism &
excretion to be completed
 Pharmacokinetic Principles
HALF-LIFE NAPROXEN OR IBUPROFEN?

Drugs with a longer half-life have a

longer duration of action
Naproxen, a nonsteroidal anti-
inflammatory drug (NSAID) has a
half-life of 14 hours and is
recommended to take twice per
day. Ibuprofen has a half-life of 2
hours and is recommended to be
taken 3 or 4 times per day.
Acutely sprained ankle..
 Pharmacokinetic Principles
DO THESE DRUGS HAVE
BIOAVAILABILITY& BIOEQUIVALENCE BIOEQUIVALENCE?

Bioavailability: amount of drug

available in systemic circulation
(blood)
Reduced if capsule incompletely
dissolves in GI tract or drug is
inactivated by intestinal enzymes

Bioequivalence: the amount and

rate of drug entering the general
circulation for 2 or more similar
formulations of the same drug
 Pharmacokinetic Principles
LOW OR HIGH VOLUME OF
VOLUME OF DISTRIBUTION DISTRIBUTION?
V of D: the space in the body that is
available to the drug
The more extensive the distribution, the
larger the volume of distribution
Larger volume of distribution drugs:
distribute into adipose tissue, bind to
muscle, or bind to plasma protein
Body size effects V of D, binding of drug to
plasma increases V of D

Drugs with a high V of D have less

drug available for blood circulation,
thus less drug is available for the site
of action
 Pharmacokinetic Principles
SOLUBILITY OF DRUGS GI TRACT
Determines how quickly a drug is
dissolved in the GI tract
More water soluble the drug, the more
readily it will dissolve in the GI Tract
More lipid soluble the drug, the more
readily the drug will cross membranes
to move form the GI tract into the
blood
Water soluble drugs excreted by the
kidneys faster
Lipid soluble penetrate the CNS more
readily
 Pharmacokinetic Principles
3 MAIN MECHANISMS FOR TRANSPORT
OF DRUGS

Passive Diffusion
Active Transport
Facilitated
Diffusion
 Pharmacokinetic Principles
PASSIVE DIFFUSION

The drug penetrates the

cellular membrane due to the
solubility of the drug in the
membrane
Lipid soluble drugs diffuse
more quickly
Drugs move from areas of
higher concentration to lower
from inside or outside the
cell
 Pharmacokinetic Principles
ACTIVE TRANSPORT

Active transport mechanisms have

a protein with a binding site to
which the compound being
transported attaches
The advantage of AT is selectivity of
compounds for the cell membrane
Plays an important role for the
transport of some drugs into the
urine or bile
 Pharmacokinetic Principles
FACILITATED DIFFUSION

Combines the characteristics of

passive diffusion and active
transport
Requires a carrier protein
Selectivity and system saturation is
possible
A high-to-low concentration
gradient must be present for net
diffusion to occur
 Pharmacokinetic Principles
ROUTES OF DRUG ADMINISTRATION WHICH TYPE OF DRUG ADMIN IS THIS?
Oral
Most common

Sublingual & buccal

Placed under the tongue or against the cheek

Rectal
Advantageous for unconscious, vomiting, or young
patients

Parenteral
Intravenous, intramuscular, or subcutaneous

Topical
Skin, eyes, nose, throat, ears

Inhalation
Lungs
 Pharmacokinetic Principles
PURPOSE OF INACTIVE INGREDIENTS

Binds drugs together

Increasing the bulk of the
tablet
Controlled-release
Tablet survival to GI tract
Enhancing physical
appeal of drug
 Pharmacokinetic Principles
METABOLISM (BIOTRANSFORMATION) WHERE IS KIDNEY METABOLISM?

The chemical alteration of the drug

by one or more enzymes in the
body
The liver is primary
biotransformation site
Kidney, intestinal cells, lungs, &
brain are secondary
Metabolism makes the drug water
soluble which is important for
excretion
 Pharmacokinetic Principles
ARE THE KIDNEYS LOCATED MORE
DRUG EXCRETION ANTERIOR OR POSTERIOR?
Removal of drugs from the body
Kidney and bile primary routes for
excretion
Secondary routes: sweat, saliva, and
lungs
BILLARY EXCRETION
drugs pass through the liver into the
bile and eventually to the small
intestines
Excreted in the feces or reabsorbed
into the blood
 Pharmacokinetic Principles
IS STOMACH EMPTYING INCREASED OR
POTENTIAL EFFECTS OF EXERCISE DECREASED?

Light exercise decreases stomach

emptying
Strenuous exercise increases
stomach emptying
Oral absorption is decreased by
exercise due to decreased blood
flow
Exercise increases the duration of
action by drugs cleared by the
kidney
 Pharmacokinetic Principles
INCREASED OR DECREASED VOLUME OF
POTENTIAL EFFECT OF EXERCISE DISTRIBUTION?
Exercise increases the duration of
action for drugs that are
inactivated by the liver
An exception to this is protein bound
NSAIDs
Sweating decreases the volume of
distribution, increasing drugs at the
site of action
Long-term exercise may increase
metabolism and excretion rates of
pharmaceuticals
 Pharmacokinetic Principles
WILL THIS HAVE A PROMINENT EFFECT ON
POTENTIAL EFFECT OF EXERCISE PHARMACEUTICALS?

Intensive exercise
for long duration
has the most
prominent
impact on
pharmaceuticals
BIOAVAILABILITY
The fraction of an administered dose of drug that reaches the
blood stream.
What determines bioavailability?
Physical properties of the drug (hydrophobicity, pKa, solubility)
The drug formulation (immediate release, delayed release, etc.)
If the drug is administered in a fed or fasted state
Gastric emptying rate
Circadian differences
Interactions with other drugs
Age
Diet
Gender
Disease state
 DEPOT BINDING
(ACCUMULATION IN FATTY TISSUE)
Drugs bind to depot sites or silent receptors
(fat, muscle, organs, bones, etc)

Depot binding reduces bioavailability, slows

elimination, can increase drug detection window

Depot-bound drugs can be released during

sudden weight loss may account for flashback
experiences?
 Degradation & Excretion
Liver
Enzymes(cytochrome P-450)
transform drugs into more
water-soluble metabolites
Repeated drug exposure
increases efficiency tolerance

Kidneys
Traps water-soluble (ionized)
compounds for elimination via
urine (primarily), feces, air, sweat
 EXCRETION: OTHER ROUTES
Lungs
alcohol breath
Breast milk
acidic ---> ion traps alkaloids
alcohol: same concentration as blood
antibiotics
Also bile, skin, saliva ~~
METABOLISM AND ELIMINATION (CONT.)
Half-lives and Kinetics
Half-life:
Plasma half-life: Time it takes for plasma
concentration of a drug to drop to 50% of initial
level.
Whole body half-life: Time it takes to eliminate half
of the body content of a drug.
Factors affecting half-life
age
renal excretion
liver metabolism
protein binding
First order kinetics
A constant fraction of drug is eliminated per unit of time.

When drug concentration is high, rate of disappearance

is high.
Zero order kinetics

Rate of elimination is constant.

Rate of elimination is independent of drug

concentration.

Constant amount eliminated per unit of

time.

Example: Alcohol
COMPARISON
First Order Elimination Zero Order Elimination
[drug] decreases [drug] decreases linearly
exponentially w/ time with time
Rate of elimination is Rate of elimination is
proportional to [drug] constant
Plot of log [drug] or ln[drug] Rate of elimination is
vs. time are linear independent of [drug]
t 1/2 is constant regardless No true t 1/2
of [drug]
 DRUG EFFECTIVENESS
Dose-response (DR) curve
Depicts the relation between
drug dose and magnitude of
drug effect
Drugs can have more than
one effect
Drugs vary in effectiveness
Different sites of action
Different affinities for
receptors
The effectiveness of a drug
is considered relative to its
safety (therapeutic index)
ED50 = effective dose in 50% of population

100

% subjects 50
ED50

0
0 X
DRUG DOSE
 Therapeutic Index
Effective dose (ED50) = dose at which 50% population shows response
Lethal dose (LD50) =dose at which 50% population dies
TI = LD50/ED50, an indication of safety of a drug (higher is better)

ED50 LD50
 Potency
Relative strength of response for a given dose
Effective concentration (EC50) is the concentration of an agonist needed to
elicit half of the maximum biological response of the agonist
The potency of an agonist is inversely related to its EC50 value
D-R curve shifts left with greater potency
Efficacy
Maximum possible effect relative
to other agents
Indicated by peak of D-R curve
Full agonist = 100% efficacy
Partial agonist = 50% efficacy
Antagonist = 0% efficacy
Inverse agonist = -100% efficacy
Comparisons C
HI
B

Average
Response
Magnitude

LO
0 X
DRUG DOSE
 Tolerance
(desensitization)
Decreased response to same
dose with repeated (constant)
exposure
or more drug needed to achieve
same effect
Right-ward shift of D-R curve
Sometimes occurs in an acute
dose (e.g. alcohol)
Can develop across drugs (cross-
tolerance)
Caused by compensatory
mechanisms that oppose the
effects of the drug
 Sensitization
Increased response to same dose
with repeated (binge-like)
exposure
or less drug needed to achieve
same effect
Left-ward shift in D-R curve
Sometimes occurs in an acute
dose (e.g. amphetamine)
Can develop across drugs (cross-
sensitization)

It is possible to develop tolerance to some side effects AND sensitization

to other side effects of the same drug
 Mechanisms of Tolerance and Sensitization
Pharmacokinetic
changes in drug availability at site of
action (decreased bioavailability)
Decreased absorption
Increased binding to depot sites
Pharmacodynamic
changes in drug-receptor interaction
G-protein uncoupling
Down regulation of receptors
 Other Mechanisms of
Tolerance and Sensitization
Psychological
As the user becomes familiar with the drugs effects, s/he
learns tricks to hide or counteract the effects.
Set (expectations) and setting (environment)
Motivational
Habituation
Classical and instrumental conditioning (automatic physiological
change in response to cues)

Metabolic
The user is able to break down and/or excrete the drug more
quickly due to repeated exposure.
Increased excretion
DRUG-DRUG INTERACTIONS
Pharmacokinetic and pharmacodynamic
With pharmacokinetic drug interactions, one drug
affects the absorption, distribution, metabolism, or
excretion of another.
With pharmacodynamic drug interactions, two drugs
have interactive effects in the brain.
Either type of drug interaction can result in adverse
effects in some individuals.
In terms of efficacy, there can be several types of
interactions between medications: cumulative, additive,
synergistic, and antagonistic.
Cumulative Effects

Hi

Drug B
Response

Drug A
Lo
Time
The condition in which repeated administration of a drug may produce effects
that are more pronounced than those produced by the first dose.
Additive Effects
Hi

A+B
Response
A B

Lo
Time
The effect of two chemicals is equal to the sum of the effect of the two
chemicals taken separately, eg., aspirin and motrin.
Synergistic Effects
A+B
Hi

Response
A B

Lo
Time

The effect of two chemicals taken together is greater than the sum of their
separate effect at the same doses, e.g., alcohol and other drugs
Antagonistic Effects
Hi

A+B

Response
A B

Lo
Time

The effect of two chemicals taken together is less than the sum of their separate
effect at the same doses
 Pharmacodynamics
Receptor
target/site of drug action (e.g. genetically-coded proteins
embedded in neural membrane)

Lock and key or induced-fit models

drug acts as key, receptor as lock, combination yields response
dynamic and flexible interaction
 Pharmacodynamics (cont.)
Affinity
propensity of a drug to bind with
a receptor

Selectivity
specific affinity for certain
receptors (vs. others)
AGONISM AND ANTAGONISM

Agonists facilitate receptor

response

Antagonists inhibit receptor

response

(direct ant/agonists)
MODES OF ACTION
Agonism Antagonism
A compound that does the A compound inhibits
job of a natural substance.
an enzyme from
Does not effect the rate of an
doing its job.
enzyme catalyzed reaction.
Up/down regulation Slows down an
enzymatically
Tolerance/sensitivity at the catalyzed reaction.
cellular level may be due to a
change in # of receptors
(without the appropriate
subunit) due to changes in
stimulation
AGONISTS/ANTAGONISTS
Full A single drug can bind to a single
receptor and cause a mix of effects
(agonist, partial agonist, inverse agonist,
Partial antagonist)

Functional Selectivity Hypothesis:

Direct/Competitive Conformational change induced by a
ligand-receptor interaction may cause
differential functional activation
Indirect/Noncompetitive
depending on the G-protein and other
proteins associated with the target
Inverse receptor
 Important implications of
drug-receptor interaction
drugs can potentially alter rate of any bodily/brain
function

drugs cannot impart entirely new functions to cells

drugs do not create effects, only modify ongoing

ones

drugs can allow for effects outside of normal

physiological range