EXPERIMENT 3, 4 AND 10

EXPERIMENT NO. 3 (Factors Modifying Drug Action)

A. Routes of •BIOAVAILABILITY - the amount of drug that reaches the systemic circulation after administration.
Administration Factors that modify absorption:
1. Absorption regardless of the site is dependent on DRUG SOLUBILITY
Biopharmaceutics Classification System of Solubility
BCS CLASS 1 high solubility, high permeability
BCS CLASS 2 low solubility, high permeability
BCS CLASS 3 high solubility, low permeability
BCS CLASS 4 low solubility, high permeability

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

Different Routes of Administration

I. Enteral
A. Oral
B. Sublingual/Buccal
C. Rectal
II. Parenteral
A. IV B. IM
C. SQ D. Intrathecal
E. Intra-arterial F. IP
G. Intraosseous
III. Other Routes of Administration
A. Inhalational
B. Topical
Notes to consider:
I. Onset of Action
II. Latency Period
III. Duration of Action
B. Chemical STRUCTURE ACTIVITY RELATIONSHIP
Structure •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
(pharmacodynamics and/or pharmacokinetic)

Example:

A. BENZODIAZEPINES (e.g Diazepam,

Midazolam)
•Sedative-hypnotic
•Enhance the action of GABA (i.e. opening
of the chloride channel) by INCREASING
THE FREQUENCY OF CHLORIDE CHANNEL
OPENING. (GABA is the most common and
major inhibitory neurotransmitter (NT) in the
brain and it exerts its rapid inhibitory action mostly through GABA receptors. It is a ligand-gated chloride
ion channel. Upon activation, Cl influx is increased and the membrane becomes hyperpolarized, resulting
in neuronal inhibition)

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

C. Enzyme bjective of metabolism: Convert drugs into: Inactive, Polar/Water Soluble (Ionized form), Non toxic and
Induction/ easily excreted metabolites.
Inhibition Main Site of Metabolism: LIVER

Drug metabolism classification:

I. Phase I
Functionalization/Redox reactions
Goal: Add/Unmask the functional groups
Dominant Phase: Oxidation Reactions
Others: Hydroxylation and reduction
Enzyme Involve: (1) NADPH-Cytochrome P450 reductase
(2) Cytochrome P450 (Terminal Oxidase)
Found in the SMOOTH ENDOPLASMIC RETICULUM of the LIVER.
 **CYP3A4 major metabolizer of drugs in the liver.
II. Phase II
Makes a drug more polar by conjugating with endogenous substance.
Enzyme Involved: TRANSFERASES (Most common)
Others: Glucoronidation, Acetylation and sulfation reactions
**Phase II reactions are relatively faster than P450-catalyzed reactions, thus effectively
accelerating drug biotransformation.

ENZYME INDUCTION: Occurs when a drug binds to the metabolizing enzyme and promotes enzyme activity.
(Stimulation of the enzyme activity→increased metabolism)
Drug-Drug Interaction involving enzyme induction
Ripampficin + Disopyramide (Reduced disopyramide level)

ENZYME INHIBITION-Occurs when a drug binds to the metabolizing enzyme and inhibits its activity. This leads
to decreased metabolism of the enzyme substrate

D. Drug I. AGONIST- A drug that binds to and activates a receptor.

Receptor A. Full Agonist-a drug that binds to and activates the receptor to the MAXIMUM EXTENT
Interaction B. Partial Agonist-A drug that binds to and activates the receptor to a LESSER EXTENT even when
the dose is increased.
C. Inverse Agonist- A drug that has a higher affinity for the INACTIVE RECEPTOR, therefore reducing
the receptor’s constitutive activity.
II. ANTAGONIST- A drug that binds to a receptor but does not cause activation
A. Based on the Mechanism of Action
i. Functional Antagonism (Physiologic antagonism)
Occurs when two systems opposing each other becomes activated. (Eg. Epinephroine
and Acetylcholine/Histamine.
ii. Receptor Antagonism (Pharmacological Antagonism) “Blockers”
Occurs when two chemicals that binds to the same receptor produce less of an
… effect/opposing effects, when given together that the addition of the separate effect.
*Naloxone-respiratory depressive effects of morphine and other morphine-like
narcotics by competitive binding to the same receptor site.
**Tamoxifen- to lower the breask cancer risk among women at high risk for thos
estrogen-related cancer. Tamoxifen competitively blocks estradiol from binding to
its receptor site. Treatment of organophosphate.
***Atropine- Insceticide poisoning which involves blocking the receptor (cholinergic
receptor) for the excess of acetylcholine that accumulates by poisoning of the
cholinesterase by the organophosphate
iii. Chemical Antagonism (Inactivation)
Chemical reaction between two compounds that produces a less toxic effect
Iv. Dispositional Antagonism-occurs when the dispositions altered so that the concentration
and/or duration of the chemical at the target organ are diminished.
Eg. (1) Prevention of absorption of toxicant by ipecac or charcoal
(2) Increased excretion of a chemical by administration of an osmotic diuretic or
alteration of the pH of the urine.
(3) Warfarin toxicity- administering a drug that increases the activity of the
metabolizing enzymes (enzyme inducer: phenobarbital) will decrease its toxicity.
(4) Organophosphate Poisoning (Eg. Parathion) Inhibiting its biotransformation by an
inhibitor of microsomal enzyme activity (Piperonyl butoxide) will decrease its
activity.
B. Based on the type of Interaction.
i. Reversible Antagonism- Temporary (<24 hours)
ii. Irreversible Antagonism- Permanent (>24 Hours)
C. Based on the Surmountability of Interaction
i. Competitive antagonism (Surmountable)
The antagonist competes with the agonist, surmountable; high concentration of agonist
may overcome the antagonism.
ii. Non-Competitive Antagonism
* Irreversible- (Non-surmountable) usually when 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 that the
bonding site for the agonist. The occupancy of the allosteric site by the antagonist
deactivates the receptor hence NO EFFECT SEEN.
D. Competitive antagonism- simply summarized by equation 1+1=0, combination of two drugs
. results in cancellation of the effect of the other

•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.
 •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

EXPERIMENT No. 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)

A. 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.
•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.

B. Neurotransmitters involved in CNS

•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.
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 à
. 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 à 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
•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

C. DRUGS AFFECTING CNS

>CNS DEPRESSANTS
** Prototype is Alcohol
I. Primary Chemical Classes
i. Benzodiazepines
ii. Barbiturates
II. According to Use
i. Sedative (Anxiolytic): Relax, calm or tranquilize, and relieve anxiety.
ii. Hypnotics- induce sleep
iii. Anesthetics- loss of sensation
iv. Opiods Analgesic- relief from pain (Morphine and Codeine)
v. Antipsychotic or Neuroleptics-modify mood; used to treat psychoses, were called major tranquilizers
(1) Phenothiazine (Chlorpromazine and Thioridazine) (2) Butyrophenone (Haloperidol) (3) Clozapine,
Olanzapine and Risperidone.
vi. Antidepressants- Examples: MAOI’s (Phenelzine), TCA’s-SNRI(Amitryptyline, Imipramine, Clomipramine), SSRI’s
.. (Fluoxetine, Citlopram, Paroxetine) and 2nd and 3rd Gen Atidepressants (Amoxapine, Mirtazapine and
Trazodone)
vii. Antiparkinsons- Bromocriptine, Pergolide, Selegiline and Entacapone.
viii. Antiepileptics (AED’s) Carbamazepine, Phenytoin, Gabapentin and Topiramate
III. General Anesthetics
i. Inhalational (Volatile) eg. Isofluranr, Sevoflurane, diethyl ether and Nitrous oxide.
ii. Intravenous (non-volatile) eg. Propofol, Ketamine
MOA: (1) Activation of the GABA-a Receptor chloride channel
(2) Antagonism on the NMDA receptor
(3) Activation of potassium channel
(4) Decrease the duration of opening of nicotinic receptor.
(5) Action on glycine receptor.
STAGES of ANESTHESIA.
(Stage 1) ANALGESIA Conscious but drowsy|No response to painful stimuli | later part, amnesia is
produced.
(Stage 2) EXCITEMENT- Delirious and may vocalize but is definitely amnesic | Irregular respiration |
Retching and Vomiting may occur if stimulated | Dangerous Stage
(Stage 3) SURGICAL ANETHESIA –Respiration is regular but slow | No Movement
(Stage 4) MEDULLARY PARALYSIS – Vasomotor and respiratory support ceases | Death may occur
in few minutes
>CNS STIMULANT
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)

I. STRYCHNINE-
–Alkaloid from Strychnos nux vomica which is a vermin poison
MOA: Blocks postjunctional glycine inhibition at the receptor in the CNS and Spinal Cord
Causes violent extensor spasm (voluntary muscle), Seizures and CNS excitation
Effects: Rhisus sardonicus
Treatment: DIAZEPAM to prevent Seizures
II. AMPHETAMINES AND METHYLPHENIDATE
-CNS Stimulant, anorectic, sympathomimetic actions
MOA: (1) Indirect acting dopaminergic and noradrenergic agonist
(2) Release biogenic amine (NE, DOPAMINE and SEROTONIN) from storage vesicles
(3) Can be attenuated by dopamine antagonist (Chlorpromazine and Haloperidol)
INDICATION (1) For treatment of ADHD and Narcolepsy (2) Adjunct therapy for obesity
ADVERSE EFFECTS: (1) Increase arousal and wakefulness, mood alteration
(2) Increased confidence, ability to concentrate, Euphoria, Increased Motor Activity, Anorexia and
Insomnia
(3) Prolonged exposure may cause “Amphetamine Psychosis”
TOLERANCE and DEPENDENCE (1) Very addictive and often abused
OVERDOSE TREATMENT: (1) Acidify the urine, (2) Give chlorpromazine to treat CNS Symptoms and (3) Alpha-receptor
blockers to lower the BP
DRUG INTERACTION:
(1) MAO Inhibitors: Effects: Hypersensitive crisis, CNS Overstimulation
(2) Barbiturates: Super additive mood elevation
(3) TCA: Potentiate CNS Stimulation, inhibit metabolism of amphetamine.

III. METHYLATED XANTHINES

i. Caffeine (1,3,7-Trimethylxanthine)
ii. Theophylline (1,3-Dimethylxanthine)
iii. Theobromine (3,7-Dimethylxanthine)
MOA: (1) Inhibits phosphodiesterase thus increase cAMP, Increasing Ca permeability ate sarcoplasmic reticulum
(2) Adenosine receptor antagonist
INDICATION: (1) Included in some OTC analgesic drug in headache remedies (Caffeine)
(2) Bronchial Asthma- Theophylline
ADVERSE EFFECTS; Insomnia, Restlessness, anxiety, Neurosis, Nausea, Tachycardia and Diuresis
TOLERANCE: Withdrawal may cause headache, Anxiety and Muscle Tension
DRUG INTERACTION: Inhibit metabolism of oral contraceptives and Cimetidine

IV. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)

INCLUDES: Fluoxetine, Sertraline and Escitalopram
MOA: Blocks serotonin reuptake thus increasing serotonin levels.
INDICATION: Clinical Depression, Anxiety disorder, OCD
ADVERSE EFFECTS: Nausea, Headache, Insomnia, Diarrhea, impotence and decrease appetite
DRUG INTERACTION: MAOI’s: Life threatening

V. MONOAMINE OXIDASE INHIBITORS (MAO)

INCLUDES: Tranylcypromine, Phenelzine and Slegiline
MOA: Blocks metabolism of Biogenic Amine (EPINEPHRINE, SEROTONIN and DOPAMINE)
INDICATION: Depression, Narcolepsy, Phobic/Anxiety stress and Parkinson Disease
ADVERSE EFFECTS: Hepatotoxicity, Excessive CNS Stimulation, Orthostatic Hypotension, Agitation, Convulsion,
Altered BP and Hallucinations
TOLERANCE/DEPENDENCE: Low likelihood of abuse
DRUG INTERACTION: Potentiate the effects of sympathomimetics

VI. COCAINE
Alkaloid from the leaves of Erythroxylon coca
MOA: Blocks reuptake or NE, Serotonin and Dopamine resulting to Increase arterial pressure, Tachycardia and
Ventricular Arrhythmias.
ADVERSE EFFECTS: (1) Loss of appetite, Insomnia and Hyperactivity. (2) Increased risk of intracranial hemorrhage, MI
and generalized/partial seizures (3) High addiction potential together with amphetamines (4) Overdose can
lead to hyperthermia, coma and death
DRUG INTERACTION: MAOI’s: Life threatening

VII. METHYLENEDIOXYMETHAMPHETAMINE (MDMA) (ECSTASY)

Main effect is to foster feeling of intimacy and empathy without impairing intellectual capacities
MOA: Release biogenic amine from vesicles with preference for serotonin.
TOXIC EFFECTS: Hyperthermia, Dehydration, Seizures and Neurotoxicity (With repeated administration may lead to
serotonin syndrome-autonomic hyperactivity, mental status change

GASTROINTESTINAL DRUGS
• Cholinergic antagonist
Atropine
• MOA: competes with Ach at the muscarinic receptors causing blockade of cholinergic effects
 resulting to DECREASE GI MOTILITY
• Reversible (Surmountable)
• Indirectly acting cholinergic agonist (Acetylcholinesterase inhibitor)
Neostigmine • MOA: Carbamate esters by binding with acetylcholinesterase resulting to Increase Acetylcholine
at the synaptic cleft increasing the cholinergic effect resulting to INCREASE GI MOTILITY.
Dicyclomine, • Inhibit Muscarinic cholinergic receptors
Hyoscyamine • USES: Antispasmodics
(N-Hyoscine-
butyl bromide
• OPIOD AGONIST
• (Loperamide and Diphenoxylate)
• MOA: Inhibition of presynaptic cholinergic nerves
• USES: Treatment of Diarrhea
• Kaoiin and Pectin (Kopectate)
• Kaolin (Hydrated Magnesium Silicate or Attapulgite) + Pectin (Indigestible Carbohydrate
derived from apples.
ANTIDIARRHEAL • MOA: Adsorbent of bacteria, toxins and fluid decreasing the stool liquidity.
AGENTS • USES: Antidiarrheal
• BILE SALT BINDING RESINS
• Example: Cholestyramine and Colestipol)
• MOA: Adsorbs bile salt (which cause secretory diarrhea and C. difficile toxin
• USES: Treatment of diarrhea caused by C. difficile and bile salts
• SOMATOSTATIN, OCTREOTIDE
• MOA: Regulatory peptide slows the GI motility and intestinal fluid secretion
• USES: Effective for diarrhea due to vagotomy, short bowel syndrome
AGENTS THAT • Antacids
REDUCE • H2-Receptor Blocker
GASTRIC • Proton Pump Inhibitor
ACIDITY
MUCOSAL • Sucralfate
PROTECTIVE • Prostaglandin analog
AGENTS
LAXATIVES • Bulk
• Osmotic
• Stool Softener
• Cathartic
Clinical Techniques for Evaluating Cholinergic Blocking Agents
•Pathophysiologic Considerations
•Anticholinergic drugs inhibit the neuronic or vagal mechanism of gastric secretion.
•The more effective agents decrease both volume and acidity of gastric secretions.
•Anticholinergic drugs also block vagal stimulation of smooth muscle and depress GI motility.
•Pharmacologic Considerations
•Acetylcholine is the mediator of nerve impulses at the ganglionic synapses of both subdivisions of the ANS
and of impulses from the post ganglionic parasympathetic fibers to the effector organ.
•The classic parasympathetic depressant, atropine, lacks sensitive action, so that blockade of the peripheral
effects of Ach includes not only the GIT but also the sphincter muscle of the iris, ciliary muscle of the lens, and
salivary gland.