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Introduction to

Pharmacology

Wawaimuli Arozal MD,PhD

Department of Pharmacology
FMUI

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INTRODUCTION

Pharmacology : science about drug


Drug : any substance that effect a living cell
Poison : any substance that damage a living cell
Difference between drug and poison : !! only the dose

Pharmacodynamics : effect of substance/drug to


living cell
- mechanism of action & effect on organ system

Pharmakokinetics : effect of living cell to


substance/ drug
- absorption, distribution, metabolism & excretion
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Introduction
Clinical Pharmacology : Study of drug in man
Experimental Pharmacology : Study of drug
in living organisms
Pharmacoepidemiology: study of drug in the
society
Pharmacoeconomic : study about cost of
drug therapy
vs. Pharmacy a science of producing,
compounding, distributing and preparing
drug for patients
the expert are : Pharmacist
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Pharmacokinetics
= fate of drugs in the body
= effects of the body on drugs

4 processes : ADME
- Absorption (A)
- Distribution (D)
- Metabolism (M)
Elimination
- Excretion (E)
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Mechanism of drug action
3 level :
on the whole human body : stamina
quality of life
on a system : cardiovascular, nervous system
On tissue: myocardium, liver
on cells and its organel :
membranes
macromolecules

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3 types of functional cell in the body
1. Muscle contraction, relaxation
2. A gland secretion
secretion
3. Nerve impuls
impuls

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A.Drug binding to receptors
Receptors :
Specific site of cell that bind drug
selectively. The drug is the ligand
A receptor is a macromolecul

Ligand a small molecule that bind to a big


molecule
Ligand receptor binding change of :
conformation of the macromolecules
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A drug's action is affected by the quantity
of drug that reaches the receptor and the
degree of attraction (affinity) between it
and its receptor on the cell's surface.
Once bound to their receptor, drugs vary
in their ability to produce an effect (intrinsic
activity). Drugs vary in their affinity and
intrinsic activity.

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DRUG EFFECT

Ligand Binding to the receptor


conformational changes
Initiate a cascade of even resulting in:

Drug effect
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Biological consequences of binding

Drug binding & Biological effect

2 aspect of drug action :

potency & efficacy

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Potency and Efficacy
A drug's effects can be evaluated in terms of
strength (potency) or effectiveness (efficacy).
Potency refers to the amount of drug (usually
expressed in milligrams) needed to produce an
effect, such as relief of pain or reduction of blood
pressure.
For instance, if 5 milligrams of drug A relieves
pain as effectively as 10 milligrams of drug B,
drug A is twice as potent as drug B.

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Efficacy refers to the potential maximum therapeutic
response that a drug can produce.
For example, the diuretic furosemide Trade Names
LASIX eliminates much more salt and water through
urine than does the diuretic chlorothiazide Trade Names
DIURIL
Thus, furosemide has greater efficacy than
chlorothiazide
However, greater potency or efficacy does not
necessarily mean that one drug is preferable to another.
When judging the relative merits of drugs for a person,
doctors consider many factors, such as side effects,
potential toxicity, duration of effect (which determines the
number of doses needed each day), and cost.
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Agonist and Antagonist
Many drug act through endogenous
receptors such as:
* receptors of the autonomic nervous
system
* hormones receptors or other
endogenous substance

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Drugs that activate receptors (agonists) must
have both great affinity and intrinsic activity:
They must bind effectively to their receptors, and
the drug bound to its receptor (drug-receptor
complex) must be capable of producing an effect
in the targeted area.
In contrast, drugs that block receptors
(antagonists) must bind effectively but have
little or no intrinsic activity, because their
function is to prevent an agonist from interacting
with its receptors

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Agonist and Antagonist
Agonist : mimic the endogenous substance by
producing the same conformational change

same biologic response

Antagonist binding

conformational change

biological effect by
interfering/negating endogenous NT

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In between : partial agonist

partial biological response

Example :
Buprenorphine is a partial agonist of opioid
receptor
low doses : mild analgesics effect
high doses: - fail to yield a stronger effect
- antagonize the effect of
morphine discourage abuse
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Neurohumoral transmission
Many drugs act by influencing steps in
neurotransmission
A system transmitting impuls from neuron
to neuron or neuron to effector

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Site and mech. of action on
neurotransmission

Steps in Neurohumoral Transmission (NHT) :


1. synthesis
2. storage and release
3. binding NT to receptors
4. Termination of effect

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Mechanism of action of drug on
neurotransmission
1. Interfering or promoting synthesis of NT :
Dopamin in the brain : Levodopa

2. Interfering storage and release


a) depleting Dopamine, Norephinephrine storage:
reserpine
b) Dopamine release : amphetamin
c) Blocking release Acetylcholine in myoneural
junction:
Toxin botulinum : < spastic contraction in stroke
patients
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Mechanism of action of drug
on neurotransmission

3. Binding to receptor
a) Stimulating receptor of:
- Acetylcholine: Acetylcholine, Bethanecol
- Norepinephrine: Epinephrine
- D2 : Bromocriptine (dopaminergic)
- Opiod : morphine, heroine

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Mechanism of action of drug
on neurotransmission

b) Blocking receptor :
- D2 : Phenothiazine
- muscarinic: atropine
- 5-HT2 : Atypical antipsychotic :
Olanzapine
- Opioid : Naloxone
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Mechanism of action of drug
on neurotransmission

c) facilitating binding of neurotransmitter to receptor :


- Benzodiazepine : GABA receptor :
* anti anxiety: diazepam
* anti convulsant : clonazepam
* muscular relaxation: baclofen

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Mechanism of action of drug
on neurotransmission
4. Interfering with termination of
neurotransmission :
a) Inhibit asetilcholinesterase :
Rivastigmin
Donepezil
b) Inhibit MAO-B :
Selegiline, dopamine in C.striatum
c) Inhibit COMT :
Entacapone, dopamine in C.striatum
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Mechanism of action of drug
on neurotransmission

d) Block transporter : Inhibit uptake of NT


NT in synapse
NE : amitriptylline
D : cocaine
5-HT : fluoxetine
(selective serotonin reuptake
inhibitor)

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Mechanism of action of drug
on neurotransmission
e. Inhibit metabolism:
In the peripheral , dopa-decarboxylase
converted levodopa to dopamin ,less
levodopa enter the brain
Dopa-decarboxylase Inhibitor preserve
Levodopa more enter the brain increasing
its therapeutic effect

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Non receptor binding

- Bind to small molecules: antacids bind HCl


Cholestyramine: bind cholesterol and bile
acids
manitol, glycerol: Osmotic pressure
- Anestethics: Disolving into axonal membrane
or permeability of the membrane

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- Antimetabolite: incorporated into
metabolic pathway: antivirus, anticancer
termed counterfeit incorporation mechanisms

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TRANSMITTERS
Transmitter:
Endogenous substance synthesize in neuron,
transmit signal through synaptic cleft
neurotransmission

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TRANSMITTERS
- acetylcholine (Ach):cholinergic neuron
- epinephrine(E), norepinephrine(NE), and
dopamin (DA): adrenergic neuron
- Serotonin : serotonergic neuron
- Histamin: histaminergic neuron
- GABA (gamma amino butyric acid): gabaergic
neuron
- Glutamate: glutaminergic neuron

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CNS Neurotransmitter
GABA
Enzymes
Synthesis : glutamic acid decarboxylase
Degradation : GABA-transaminase
Receptors : GABA A
GABAB
Drug acting on GABA system
GABAA : Benzodiazepin, Barbiturates
GABAB : Baclofen

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CNS Neurotransmitter
ACETYLCHOLINE
Enzymes
Synthesis : Choline-acetyl transferase
Degradation : Acetylcholinesterase
Receptors : - Muscarinic
- Nicotinic
Drug acting on this system
* Inhibit acetylcholinesterase :
- organophosphate pestiside, Rivastigmin,
Donepezil
* Blocking muscarinic receptor : trihexyphenidyl 44
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CNS Neurotransmitter
SEROTONIN
Enzymes
- Synthesis : Tryptophan
Hydroxylase
- Degradation : monoamine oxidase
aldehyde dehydrogenase
A
- Peneal body : serotonin N.acetyl serotonin
B
Melatonin

A : 5 HT-N-acetylase
B : 5-hydrxy indole O-methyltransferase
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CNS Neurotransmitter
SEROTONIN
Receptor : 5HT1, 5HT2 Drec, 5HT3
numerous subtype
Transporter : 5HT-transporter DAT
(dopamin transporter)
Drug acting on 5HT system
Agonist : 5HT1D : sumatriptan
Antagonist : 5HT2A : Ketanserin (not selective)
5HT2D : Metergolin
5HT3 : Ondansetron
5HT2A > D2 : Clozapin
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CNS Neurotransmitter
DOPAMINE
Enzyme :
Synthesis : tyroxine hydroxylase
dopa decarboxylase
Degradation : - MAOB > MAOA
- COMT (Catechol Oxy Methyl-
Transferase)
Receptor :
D1-like : D1, D5 : Gs-coupled activation AC
cAMP
D2-like : D2, D3, D4 : Gi-coupled inhibition of AC
cAMP
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CNS Neurotransmitter
DOPAMINE
Transporter : Dopamin transporter (DAT)
5HT-transporter
Drug acting on Dopaminergic system
- synthesis D in the brain : Levodopa
- agonist : Bromocriptine
Pergoline
- antagonist : D2 : Phenothiazine
D2, D3, D4 : atypical antipsychotic :
olanzapin
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Drugs of Abuse
Drug abuse: the use of an illicit drug or
the excessive or nonmedical use of a licit
drug

Addiction: compulsive drug-using


behavior in which the person uses of drug
for personal satisfaction, often in the face
of known risks to health; formerly termed
psychological dependence
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Abstinence syndrome/withdrawal syndrome:
a term used to describe the signs and symptoms
that occur on withdrawal of drug in a dependent
person
Dependence: a state characterized by signs and
symptoms, frequently the opposite of those
caused by a drug, when it is withdrawn from
chronic use or when the dose is abruptly lowered
(physiological dependence)
Tolerance: a decrease response to a drug,
necessitating larger dose to achieve the same
effect
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Sign/symptom
1. Tolerance
2. Withdrawal
3. Persistent desire or unsuccessful attempt to
reduce drug use
4. Use in larger amount than intended
5. Reduction an important social, occupational
or recreational activities because of drug
use
6. Considerable time spent obtaining the
substance
7. Continued used despite health, social or
economic problem
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Amphetamines
Effect: inhibit transporter of CNS amines
including dopamine, norepinephrine, and
serotonin thus enhancing their actions
Cause a feeling of euphoria and self
confidence that contribute to the rapid
development of addiction
Dextroamphetamine, metamphetamine
Congeners: MDA. MDMA (ectassy)
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The mechanism of action of
cocaine
Cocaine modifies the action of dopamine in the brain.
The dopamine rich areas of the brain are the ventral
tegmental area, the nucleus accumbens and the
caudate nucleus these areas are collectively known
as the brains reward pathway.
Cocaine binds to dopamine re-uptake transporters on
the pre-synaptic membranes of dopaminergic
neurones. This binding inhibits the removal of
dopamine from the synaptic cleft and its subsequent
degradation by monoamine oxidase in the nerve
terminal.
Dopamine remains in the synaptic cleft
and is free to bind to its receptors on the
post synaptic membrane, producing
further nerve impulses. This increased
activation of the dopaminergic reward
pathway leads to the feelings of euphoria
and the high associated with cocaine
use.

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The mechanism of action of heroin at the delta () and
kappa () opiate receptors

Heroin modifies the action of dopamine in the nucleus


accumbens and the ventral tegmental area of the brain
these areas form part of the brains reward pathway.

Once crossing the blood-brain barrier, heroin is


converted to morphine, which acts as an agonist at the
delta and kappa opioid receptors subtypes.
-This binding inhibits the release of GABA from the nerve
terminal, reducing the inhibitory effect of GABA on
dopaminergic neurones.
-The increased activation of dopaminergic neurones and
the release of dopamine into the synaptic cleft results in
activation of the post-synaptic membrane.pathway.
REFERENCES
Basic and clinical pharmacology, BG
Katzung, 11th edition; 2009; chapter:
1. Chapter 1: Introduction: pp 1-14
2. Chapter 2: Drug Receptor and
Pharmacodynamic: pp15-36
3. Chapter 21: Introduction to the
Pharmacology of CNS drugs: pp 357-370

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