Pharmacology Lab 3a - 3f - 4

PHARMACOLOGY LAB
3A-3F
POST LAB DISCUSSION
ROUTE OF ADMINISTRATION
• BIOAVAILABILITY - the amount of drug that reaches the systemic
circulation after administration.
Factors that modify absorption:
1. Absorption regardless of the site is dependent on DRUG SOLUBILITY
2. CONCENTRATION OF THE DRUG influences rate of absorption
3. BLOOD CIRCULATION at the site of absorption
4. AREA OF THE ABSORBING SURFACE to which the drug is exposed
I. ENTERAL
• ORAL
• Advantage:
• Convenience in administration
• Disadvantage:
• Some drugs that are destroyed by
digestive enzymes and gastric pH may not
be administered by this route
• Irregularity of absorption
I. ENTERAL
• ORAL
• Disadvantage:
FIRST PASS METABOLISM
• The decrease in bioavailability seen after oral
administration.
• The structures of the GIT (esophagus, stomach,
intestines) are drained by veins that drain into
the PORTAL VEIN that brings blood into the
liver.
• Exposure of an orally administered drug to the
enzymes of the hepatocytes may metabolize
the a significant amount of drug and make it
inactive, or hydrophilic that the drug is readily
excreted.
I. ENTERAL
• SUBLINGUAL/ BUCCAL
• This route bypasses the
hepatic circulation (LESS FIRST
PASS EFFECT, GREATER
BIOAVAILABILITY)
• Venous drainage from the
mouth is to the superior vena
cava, which protects highly
soluble drugs from rapid
hepatic first-pass metabolism
UPPER PART is
drained by the
ROUTE OF ADMINISTRATION INFERIOR
MESENTERIC
VEIN  PORTAL
VEIN (liver) 
I. ENTERAL SYSTEMIC
CIRCULATION;
RECTAL FIRST PASS
EFFECT
• Convenient for patients who are
unconscious or patients with LOWER PART is
intractable vomiting. drained by the
INTERNAL
• Bioavailability less predictable ILIAC VEIN 
INFERIOR
• Approximately 50% of the drug that VENA CAVA 
SYSTEMIC
is absorbed from the rectum (lower CIRCULATION;
vault) will bypass the liver, thus THE LIVER IS
BYPASSED – no
reducing the hepatic first-pass effect. first pass
effect
II. PARENTERAL
• INTRAVENOUS
• bioavailability is rapid and complete (100% F)
• INTRAMUSCULAR
• Drugs in aqueous solution are absorbed rapidly
after IM injection depending on
• rate of blood flow to the injection site
• fat versus muscular composition of the site
• The rate of absorption following injection of an
aqueous preparation into the deltoid or vastus
lateralis is faster than when the injection is made
into the gluteus maximus.
• The rate is particularly slower for females after
injection into the gluteus maximus.
II. PARENTERAL
• SUBCUTANEOUS
• Injection of a drug into a subcutaneous site can
be used only for drugs that are not irritating to
tissue; otherwise, severe pain, necrosis, and
tissue sloughing may occur.
• The rate of absorption is sufficiently constant and
slow to provide a prolonged effect.
• INTRATHECAL
• The blood–brain barrier and the blood–
cerebrospinal fluid (CSF) barrier often preclude
or slow the entrance of drugs into the CNS.
• Drug is injected directly into the spinal
subarachnoid space.
• Meningitis and brain tumors
II. PARENTERAL
• INTRA-ARTERIAL
• The drug is injected directly into an artery to
localize its effect on a particular organ or
tissue.
• INTRAPERITONEAL
• The peritoneal cavity offers a large absorbing
surface for which drugs enter the circulation
through the veins in the intestinal/ mesenteric
vessels eventually leading into the portal vein
then into the systemic circulation.
• INTRAOSSEOUS
• Through the bone
III. OTHERS
• INHALATIONAL
• Gaseous and volatile drugs may be inhaled and
absorbed through the pulmonary epithelium and
mucous membranes of the respiratory tract.
• The lung’s surface area is large (~140m2)
• First-pass metabolism is avoided.
• TOPICAL
• Through keratinized/ non-keratinized skin or mucosa
• Factors affecting topical absorption
• Surface of the human skin is hairy
• Patches may not adhere on the surface if the skin is sweaty
because of high atmospheric temperature.
• ONSET OF ACTION – time (point) at which the drug begins working
• LATENCY PERIOD – the length of time (duration) needed for the drug
to exert its effect.
• DURATION OF ACTION – length of time during which the
therapeutic effect is observed.
• SUMMARY
CHEMICAL STRUCTURES
STRUCTURE ACTIVITY RELATIONSHIP
• The affinity of a drug for its receptor and its intrinsic activity are
intimately related to chemical structure
• Relative minor modifications in drug molecule may result in major
changes in pharmacologic properties (pharmacodynamic and/or
pharmacokinetic)
CHEMICAL STRUCTURES
BENZODIAZEPINES
• Sedative-hypnotic
• Enhance the action of GABA
(i.e. opening of the chloride
channel) by INCREASING THE
FREQUENCY OF CHLORIDE
CHANNEL OPENING.
CHEMICAL STRUCTURES
BENZODIAZEPINES
• The benzodiazepines will not
exert their effect on the
absence of GABA.
• Therapeutic uses
• Treatment of anxiety disorders
• Muscular relaxation
• Treatment of seizure disorders
• Treatment of sleep disorders
• Pre-anesthetic agent
R1
N
CHEMICAL STRUCTURES R7
R2
R6 + R3
• 5-Aryl-1,4-benzodiazepine nucleus N
R5
R4
R1
N R2
R7
CHEMICAL STRUCTURES
R6 + R3
N
Diazepam (Valium) R5
R4
• It is very lipophilic and is thus rapidly and
completely absorbed. CH3
• Maximum peak blood concentration
occurs in 2 hours and elimination is slow, Cl N O
with a half-life of about 46 hours.
N
R1
N R2
R7
CHEMICAL STRUCTURES
R6 + R3
N
Diazepam (Valium) R5
R4
• Is a long acting benzodiazepine.
• Removal of the methyl group leads to the CH3
formation of DESMETHYLDIAZEPAM
which is an active metabolite (capable of N O
producing a therapeutic effect). Cl
• Desmethyldiazepam, when further
metabolized, is converted to OXAZEPAM
which is also active. The formation of the N
active metabolites are responsible for the
long duration of diazepam.
CHEMICAL STRUCTURES
R1
N R2
CHEMICAL STRUCTURES R7
R6 + R3
Midazolam (Dormicum) N
R5
• Short acting sedative– R4
hypnotic and as an induction N
anesthetic because of its CH3
short half-life for the same N
reason
N HCl
F Cl
CHEMICAL STRUCTURES
BARBITURATES
• extensively as sedative–hypnotic
drugs.
• characteristic CNS effects mainly by
binding to an allosteric recognition
site on GABAA receptors that
positively modulates the effect of
the GABAA receptor—GABA binding.
• by binding to the barbiturate
modulatory site, it can also increase
chloride ion flux without GABA
attaching to its receptor site on
GABAA. This has been termed a
GABA mimetic effect.
CHEMICAL STRUCTURES • is a long-acting sedative and
O hypnotic.
BARBITURATES • It is also a valuable anticonvulsant,
especially in generalized tonic–clonic
• Phenobarbital NH and partial seizures.
H3C • Metabolism to the p-hydroxylphenyl
O N O compound followed by
H glucuronidation accounts for about
90% of a dose.
N
CHEMICAL STRUCTURES N
CH3
• SUMMARY
N HCl
F Cl
CH3
N O
Cl
N
ENZYME INDUCTION
METABOLISM/ BIOTRANSFORMATION
• The metabolism of drugs and other xenobiotics into more hydrophilic
metabolites is essential for their elimination from the body.
• Drug metabolism or biotransformation reactions are classified as either

• PHASE 1 (functionalization/redox reactions)
• PHASE 2 (biosynthetic (conjugation) reactions)
ENZYME INDUCTION
METABOLISM/
BIOTRANSFORMATION
• Drug metabolism or
biotransformation
reactions are classified as
either
• PHASE 1
(functionalization/redox
reactions)
• PHASE 2 (biosynthetic
(conjugation) reactions)
ENZYME INDUCTION
• PHASE 1
• makes the drug more polar/ionized (water soluble) by unmasking a
functional group
• hydroxylation, reduction, oxidation
• enzyme involved:
• NADPH-CYTOCHROME P450 REDUCTASE
• CYTOCHROME P450 (terminal oxidase)
• *found in the smooth endoplasmic reticulum of the liver
• ** CYP3A4 accounts for the metabolism of over 50% of the prescription
drugs metabolized in the liver
ENZYME INDUCTION
• PHASE 2
• Makes a drug more polar by conjugating with an endogenous
substance
• enzyme involved: TRANSFERASES (UGTs – most common)
• Conjugate formation involves high-energy intermediates and specific
transfer enzymes.
• glucuronidation, acetylation, and sulfation reactions
• Phase II reactions are relatively faster than P450-catalyzed reactions,
thus effectively accelerating drug biotransformation.
ENZYME INDUCTION
*ENZYME INDUCTION
• Occurs when a drug binds to the metabolizing enzyme and promotes
enzyme activity
• Example: Drug A is metabolized by Enzyme X. Drug B (the inducer)
binds to enzyme X. The activity of enzyme X is increased, the
concentration of Drug A in the system becomes DECREASED.
• Many drugs are known to be inducers of CYP450 enzymes.
• These drugs promotes increased rate of metabolism of substrate
metabolized by CYP.
ENZYME INDUCTION
• Examples
ENZYME INHIBITOR
• Occurs when a drug binds to the metabolizing enzyme and inhibits its
activity. This leads to decreased metabolism of the enzyme
substrate.
ENZYME INHIBITOR
• Another example of enzyme inhibition is the effect of DISULFIRAM on
Ethanol detoxification.
AGONISM
AGONIST – a drug that binds to and activates a receptor (Ra)
• Full agonist – a drug that binds to and activates the receptor (Ra) to the
MAXIMUM EXTENT
• Partial agonist – a drug that binds to activates the receptor (Ra) to a
LESSER EXTENT even when the dose is increased.
• Inverse agonist – a drug that has a higher affinity for the inactive
receptor (Ri), therefore reducing the receptor’s constitutive activity
OPPOSITE OF THE EFFECTS PRODUCED BY THE CONVENTIONAL
AGONIST.
ANTAGONISM
ANTAGONIST – a drug that binds to a receptor but does not cause activation
• Antagonism may be categorized as
1. COMPETITIVE
• The antagonist competes with the agonist;
• Surmountable; high concentration of agonist may overcome the
antagonism
2. NON-COMPETITIVE
• IRREVERSIBLE
• Non-surmountable; usually seen when the antagonist is capable of binding with the
receptor COVALENTLY; the receptor remains unavailable for the activation of an
agonist
• ALLOSTERIC
• The antagonist binds to a site (allosteric site) in the receptor other than the binding
site for the agonist.
• The occupancy of the allosteric site by the antagonist deactivates the receptor NO
EFFECT SEEN
ANTAGONISM
Other classification of antagonism:
1. CHEMICAL ANTAGONISM
• Occurs when the antagonist binds to the agonist and causes
conformational change in the agonist’s chemical structure
• Eg. PROTAMINE and HEPARIN; TETRACYCLINE and CALCIUM
2. PHYSIOLOGIC ANTAGONIST
• Occurs when two systems opposing each other become activated
• Agonist A activates one physiologic system (X) and then another
agonist (agonist B) activates another physiologic system (Y), and
systems X and Y oppose each other
• Eg. Epinephrine (Sympathetic autonomic nervous system) and Acetylcholine
(Parasympathetic autonomic nervous system)
ANTAGONISM
COMPETITIVE ANTAGONISM
• ANTAGONISM is simply summarized by this equation: 1 + 1 = 0,
where the combination of two drugs results in the cancellation of the
effect of the other.
COMPETITIVE ANTAGONISM
• MORPHINE SULFATE – an opioid (mu) receptor
agonist. Opioid analgesic
• NALOXONE HCl – pure antagonist,
surmountably blocks opioid receptors; has no
effects in narcotic-free individuals; used for the
treatment of opioid agonist agonist overdosage.
SYNERGISM
• ADDITION – the response elicited by the combined drugs is equal to
the combined response of the individual drugs. i.e. 1 +1 = 2
• POTENTIATION - a drug which has no therapeutic effect enhances the

effect of a drug, i.e. 1 +0 = 2;
• example: potentiation of the CNS depressant effects of benzodiazepine by
alcohol.
• SYNERGISM - the response elicited by the combined drugs is greater

than the combined response of the individual drugs i.e., 1 + 1 = 3
SYNERGISM
SYNERGISM
EXPT 4: DRUGS AFFECTING THE CNS
Central Nervous System Brain and spinal cord
Nervous System
Neurons located ouside the
brain and spinal cord
Peripheral Nervous System
Nerves enter and leave the CNS

(cranial nerve and spinal nerve)
NEURONAL ACTIVATION
• The neuron as a cell is responsive to
changes in ion concentration in the cellular
environment.
• The membrane potential is maintained by
the balance between cations and anions.
• regulated either by voltage control (voltage-
gated channels) or by neurotransmitter
activation (ligand-gated channel)
• The resting state is maintained by the
regulated efflux of POTASSIUM.
NEURONAL ACTIVATION
• The ACTION POTENTIAL is produced
when the cell membrane charge
becomes more positive
(DEPOLARIZATION) due to Na+ entry.
• After depolarization, when the Na
channels close, potassium channels
open and K+ goes out of the cell.
• This now leads to membrane
REPOLARIZATION and the resting
membrane potential is restored.
NEUROTRANSMITTERS
• Chemical substances produced and
released by a neuron
• Carry information from one neuron to
another
• Neurotransmission in the CNS is
similar to the neurotransmission
observed in the autonomic nervous
system (ANS), but utilizes chemicals
and peptides in addition to the
neurotransmitters Ach and NE.
NEUROTRANSMITTERS IN THE CNS
1. GLUTAMATE
• major excitatory neurotransmitter
• derived from glucose
• The receptor (e.g. AMPA, NMDA and kainate receptors) for
glutamate is ionotropic and is coupled to a SODIUM CHANNEL.
Activation of this receptor leads to DEPOLARIZATION OF THE (post
synaptic) NEURON EXCITATION or ACTIVATION
2. GLYCINE
• Inhibitory
• Restricted to the spinal cord and brainstem
• Glycine receptors are pentameric which are selectively permeable to
Cl-
• Blocked by strychnine
3. GAMMA AMINOBUTYRIC ACID (GABA)
• major inhibitory neurotransmitter in
the brain
• derived from glutamate
• The receptor (e.g. GABAA) for glutamate
is ionotropic and is coupled to a
CHLORIDE CHANNEL. Activation of this
receptor leads to
REPOLARIZATION/HYPERPOLARIZATION
OF THE (post synaptic) NEURON 
INHIBITION
4. ACETYLCHOLINE (Ach)
• Derived from choline and acetyl coA
Receptors:
• MUSCARINIC RECEPTORS (m1-m5)
• Metabotropic (G-protein coupled)
• NICOTINIC RECEPTORS (Ng or Nn)
• Ionotropic (sodium channel coupled)
5. CATECHOLAMINES
• NOREPINEPHRINE (NE)
• Derived from TYROSINE
• Receptors:
• α1, α2, β1, β2 adrenergic receptors
• sympathetic neurotransmitter
• DOPAMINE (DA)
• Synthesized from DOPA degraded by monoamine
oxidase A (MAO A) in the brain and MAO B
outside the CNS and catechol-Omethyl
transferase (COMT)
• D1 and D2 receptors in the brain blocked by
antipsychotic drugs
• Generally exerts a slow inhibitory action in the
CNS neurons
5. CATECHOLAMINES
• SEROTONIN (5HT)
• Synthesized by hydroxylation and
decarboxylation of tryptophan
• Released by inhibitory neurons 5-
HT1, 5HT2
• increases intestinal motility,
bronchodilates and modulates
vasodilation - LSD is an agonist
CNS Depressants
• Prototype is alcohol
Primary chemical classes:

1. Benzodiazepines
2. Barbiturates
CNS Depressants
According to USE
1. Sedatives (Anxiolytic): relax, calm or tranquilize, relieve
anxiety
2. Hypnotics: induce sleep
3. Anesthetics: loss of sensation
4. Opioid Analgesics: relief from pain – morphine, codeine
5. Antipsychotic or Neuroleptics: modify mood, used to treat
psychoses, were called major tranquilizers – phenothiazines
(chlorpromazine, thioridazine), butyrophenones
(haloperidol), clozapine, olanzapine, risperidone
CNS Depressants
According to USE
6. Antidepressants – MAOIs (phenelzine), TCAs – SNRI
(amitriptyline, imipramine, clomipramine), SSRIs (fluoxetine,
citaprolam, paroxetine), 2nd and 3rd gen. antidepressants
(amoxapine, mirtazapine, trazodone)
7. Anti-Parkinson’s – bromocriptine, pergolide, selegiline,
enatacapone
8. Antiepileptics (AEDs) – carbamazepine, phenytoin,
gabapentin, topiramate
General Anesthetics
1. Inhalational (Volatile)
e.g. isoflurane, sevoflurane, diethyl ether, nitrous oxide
2. Intravenous (Non-volatile)
e.g. propofol, ketamine
General Anesthetics
Mechanism of Action:
1. Activates on the GABA-A receptor-chloride channel  opening of the
chloride channel  hyperpolarization  difficulty in stimulation by
excitatory neurotransmitters
2. Antagonism on the N-methyl-D-aspartate (NMDA) receptor for the
excitatory neurotransmitter, glutamic acid (e.g. ketamine and nitrous
oxide)
3. Activation of potassium channel  hyperpolarization
4. Decrease the duration of opening of nicotinic receptor-activated cation
channel  decreases the effects of acetylcholine
5. Acts on glycine receptor
General Anesthetics
Stages of Anesthesia
1. Stage 1 Analgesia
• conscious but drowsy
• no response to painful stimuli
• later part, amnesia is produced
2. Stage 2 Excitement
• delirious & may vocalize but is definitely amnesic
• irregular respiration
• retching & vomiting may occur if stimulated
• dangerous state
General Anesthetics
Stages of Anesthesia
3. Stage 3 Surgical Anesthesia
• respiration is regular but shallow
• No movement
4. Stage 4 Medullary Paralysis
• vasomotor and respiratory support ceases
• death occurs in a few minutes
CNS STIMULANTS
Strychnine
• alkaloid found from the seeds of the Indian tree
• poison for vermins
• MOA: blocks postjunctional glycine inhibition at the receptor in the CNS
& spinal cord
• Causes violent extensor spasm (voluntary muscles), seizures, CNS
excitation
• Effects: Rhisus sardonicus
• Tx: diazepam to prevent seizures
• Similar to C. tetani
CNS STIMULANTS
Categories:
1. Category 1 Convulsants & Respiratory Stimulants
Doxapram, nikethamide, leptazol, strychnine
2. Category 2 Psychomotor Stimulants
Amphetamine, caffeine, cocaine
3. Category 3 Psychomimetic drugs
LSD (Lysergic Acid Diethylamide), phencyclidine, cannabinoids (THC)
CNS STIMULANTS
Categories:
Amphetamines and Methylphenidate
• CNS stimulant, anorectic, sympathomimetic actions
• MOA
• indirect acting dopaminergic & noradrenergic agonist
• release biogenic amines (norepinephrine, dopamine, serotonin) from storage
vesicles
• Can be attenuated by dopamine antagonist (chlorpromazine, haloperidol)
CNS STIMULANTS
Categories:
• Indication
• ADHD (attention deficit hyperactivity disorder, narcolepsy)
• Adjunct therapy for obesity  anorexiant effect
• Adverse effect
• Increase arousal and wakefulness, mood alteration,
• Increase confidence, ability to concentrate, euphoria, increased motor activity,
anorexia, insomnia
• Prolonged exposure can cause “amphetamine psychosis”
CNS STIMULANTS
Categories:
• Tolerance/Dependence
• Very addictive and often abused
• Overdose treatment:
• acidify urine
• Give chlorpromazine to treat CNS symptoms
• Alpha-receptor blocker to lower BP
CNS STIMULANTS
Categories:
• Drug interaction
• MAO inhibitors: hypertensive crisis, CNS overstimulation
• Barbiturates: superadditive mood elevation
• Tricyclic antidepressants: potentiate CNS stimulation, inhibit metabolism of
amphetamine
CNS STIMULANTS
Categories:
Methylated xanthines
• caffeine (1,3,6-trimethylxanthine), theophylline (1,3-dimethylxanthine,
theobromine (1,6-dimethylxanthine)
CNS STIMULANTS
Categories:
• MOA
• Inhibits phosphodiesterase thus increases cAMP, increasing Ca permeability at
sarcoplasmic reticulum
• Adenosine receptor antagonist
• Indication
• Included in some OTC analgesic in headache remedies – caffeine
• Bronchial asthma - theophylline
CNS STIMULANTS
Categories:
• Adverse effect
• Insomnia, restlessness, anxiety neurosis, nausea, tachycardia, diuresis
• Withdrawal may cause headache, anxiety and muscle tension
• Inhibit metabolism of oral contraceptives and cimetidine
CNS STIMULANTS
Categories:
Selective Serotonin Reuptake Inhibitors (SSRI)
• fluoxetine (Prozac), sertraline (Zoloft), escitaprolam (Lexapro)
• MOA
• Blocks serotonin reuptake  increase serotonin levels
CNS STIMULANTS
Categories:
Selective Serotonin Reuptake Inhibitors (SSRI)
• Indication
• Clinical depression, anxiety disorders, obsessive compulsive disorders (OCD)
• Adverse effect
• Nausea, headache, insomnia, diarrhea, impotence, decrease appetite
• Life threatening reaction possible with MAO inhibitors
CNS STIMULANTS
Categories:
Monoamine Oxidase Inhibitors
• tranylcypromine (Parnate), phenelzine, selegiline
• MOA
• Blocks metabolism of biogenic amines (epinephrine, serotonin, dopamine)
• Indication
• Depression, narcolepsy, phobic/anxiety states,Parkinson’s disease
CNS STIMULANTS
Categories:
Monoamine Oxidase Inhibitors
• Adverse effects
• Hepatotoxicity, excessive CNS stimulation, orthostatic hypotension, agitation,
convulsions, altered BP, hallucinations
• Low likelihood of abuse
• Potentiate the effects of sympathomimetics
CNS STIMULANTS
Categories:
Cocaine
• alkaloid form the leaves of Erythroxylon coca
• MOA:
• blocks reuptake of norepinephrine, serotonin and dopamine
• Effects include acute increase in arterial pressure, tachycardia and ventricular
arrhythmias
CNS STIMULANTS
Categories:
Cocaine
• Adverse effects
• loss of appetite, insomnia, hyperactive
• Increase risks of intracranial hemorrhage, myocardial infarctions,
generalized/partial seizures
• High addiction potential together with amphetamines
• Overdose can lead to hyperthermia, coma or death
CNS STIMULANTS
Categories:
MDMA (Ecstasy)
• methylenedioxymethamphetamine
• main effect is to foster feelings of intimacy and empathy without impairing
intellectual capacities
• MOA
• release of biogenic amines from vesicles with preference for serotonin
• Toxic effects:
• hyperthermia, dehydration, seizures, neurotoxicity with repeated administration
due to depleted serotonin, serotonin syndrome (autonomic hyperactivity, mental
status change)

Pharmacology Lab 3a - 3f - 4

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PHARMACOLOGY LAB

• Drug metabolism or biotransformation reactions are classified as either

• POTENTIATION - a drug which has no therapeutic effect enhances the

• SYNERGISM - the response elicited by the combined drugs is greater

Central Nervous System Brain and spinal cord

Peripheral Nervous System

Nerves enter and leave the CNS

Primary chemical classes:

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