*DRUG RECEPTOR INTERACTIONS (WEEK 1)

Receptors​ are:
● Protein molecules that respond to endogenous chemical signals and produce an effect
which can be via neurotransmitters, hormones or an inflammatory mediator
● Target molecules that combines with a drug molecule to elicit specific effect (lock & key
model) which can be an Agonist or an Antagonist
They should be able to bind to a drug with relatively high affinity and transduce a signal thereby
producing a biological effect (can be produced at very low concs.)

Chemical Basis for Drug Receptor Interactions

1. Electrostatic Interactions
2. Hydrophobic Interactions
3. Covalent Bonds
4. Stereospecific Interactions
Drug effects depends on:
● [Drug] at receptor i.e. dose
● Pharmacokinetics of drugs i.e. ADME (Absorption, Distribution, Metabolism, Elimination)

➔ Affinity- refers to the ability of a drug to bind to the receptor and is based on chemical
interaction.
➔ Efficacy- refers to the ability of a drug to activate a receptor and elicit a response after it
is bound. Max effects a drug can produce regardless of the dose.
➔ Potency- [Drug] required to produce a given effect. High [Drug] = Low potency.
➔ Selectivity- Ability of a drug to preferentially produce biological effects. Relates to
structural specificity of drug binding to receptors. Higher the dose= increased chance of
losing selectivity.
➔ Specificity- Specific drug action/ mechanism of actions; shows a high degree of binding
site specificity.

Dose- Response Curve

● EC50- [Drug] required to produce 50% of drug effect. Refers to the potency of the drug.
Agonist
● A drug that binds and activates a receptor
● Agonist potency depends on affinity & efficacy
● Drugs with high potency generally have a high affinity for receptors and occupy a
significant proportion of receptors even at low concs.
Antagonist
● A drug that binds without causing receptor activation - zero efficacy
● Occupies site to prevent agonist from binding, but generates no stimuli
● Competitive Antagonism (Reversible), Competitive Antagonism (Irreversible), Non
competitive.

COMPETITIVE ANTAGONISM- REVERSIBLE

● Competitive- Agonist and antagonist are competing so an increase in [agonist] will
displace antagonist and restore receptors occupancy by agonist.

➔ Dose ratio: The ratio by

which the [agonist] has to be
increased to restore a given level
of response i.e. how much agonist
needs to be increased- indicates
that the curve shifts only to right
without the suppression of Emax.
COMPETITIVE ANTAGONISM- IRREVERSIBLE
● Antagonists bind to the same site on the receptor as the agonist but dissociates slowly or
not at all from the receptors.
● Bind covalently at receptor site
● At high [irreversible antagonist], depression of maximum occurs; downward shift of
Emax.
● At low [irreversible antagonist] a parallel shift of log concentration- response occurs
without a decrease in Emax.

Other Mechanisms of Drug Antagonism

01. Chemical Antagonism- occurs due to chemical reactions between one drug and the
other drug that leads to reduce in response
02. Pharmacokinetic Antagonism- when one drug affects the ADME of another drug,
accelerates the metabolism or elimination of another
03. Physiological Antagonism- the interaction of two drugs producing opposing physiological
effects that tend to cancel out each other.
04. Pharmacologic Antagonism- the antagonist which inhibits the downstream signaling
pathway as induced by the agonist.

Repeated Exposure of Ligands to Receptors

● Tachyphylaxis- Reduction in number of receptors due to continuous exposure to
agonists. Develops over a few minutes.
● Desensitization- Decrease in responsiveness to the drug.
○ Change in receptor​- agonist induced change in receptor conformation (Ex-
receptor phosphorylation- inability of receptors to be responsive to ligand)
 ○ Loss of receptors​- internalization of receptors into endocytic vesicles.
➔ Heterologous Desensitization- One agonist can desensitize other receptors, effects are
generally weak and short lasting.
➔ Homologous Desensitization- Agonists only affect receptors they activate, effects are
profound and long lasting.
◆ Involves receptors internalization(endocytosis)
◆ This desensitization is typically reversible after removal of agonist or an increase
in the level of neurotransmitter.

Therapeutic Index (T.I) fo therapeutic explanation

● Drugs:
○ Therapeutic Effects
○ Toxic Side Effects - dose dependent TD50
○ Lethal Effects - dose dependent LD50
*PHARMACOKINETICS OF DRUG ACTION (WEEK 2)

Highly perfused organs (central Less perfused organs (peripheral

compartment) compartment)

Heart, lungs, liver, kidneys Fat tissue, muscle tissue and cerebrospinal
fluid
Two compartment model Q.

Why is the slope so steep for the distribution phase of the Cp vs t curve?

Once a drug enters the body, elimination begins. After an i.v. bolus injection to the central
compartment, there is distribution into the peripheral compartment and elimination from the
central compartment. Thus, the concentration decreases rapidly at first. Distribution into the
peripheral compartment continues until the free concentration in the central compartment
(plasma) is equal to the free concentration in the peripheral compartment (tissue), i.e. there is a
net flow of drug out of the plasma (along the concentration gradient) until steady-state is
reached. In this situation, steady-state is not maintained and is only momentary. After
steady-state, a concentration gradient is again created - this time in the opposite direction - by
the continual elimination of drug from the central compartment. In response to this, drug begins
to flow back into the central compartment where it is eliminated. Thus, in the β-phase, the
concentration of drug in the peripheral compartment is greater than that in the central
compartment. The concentrations in both compartments decrease proportionally as elimination
from the plasma continues. This may be viewed as a "pseudo steady-state": the body wants to
reach an equilibrium between the amount of drug in each compartment (Xc and Xp for central
and peripheral) but cannot due to elimination (k10).

Two Compartment Model

*ADVERSE DRUG REACTIONS (WEEK 4)

Type A- Common. Related to dose: Overdose, Alteration of drug.

Type B- Idiosyncratic. Not common, not predictable & not related to pharmacological actions
Type C- Related to long term drug therapies
Type D- Reactions found to be apparent only after some time of treatment
Type E- Occurs when drug treatment is suddenly terminated

TYPE OF HYPERSENSITIVITY REACTIONS

Type I Involves IgE and release of histamines from mast cells and basophils.
Ex: anaphylaxis

Type II Involves IgG & IgM which binds to cell surface antigens and leads to
cellular destruction. Ex: hemolytic anemia

Type III Antigen- antibody complex formed which is not cleared by the immune
system on time leading to an inflammatory response with leukocytes
arriving at the site of inflammation

Type IV Involving T helper cells which are activated by antigen presenting

reactions. When antigen is presented again later, memory T helper cells
will activate macrophages and cause an inflammatory response.
*AUTONOMIC NERVOUS SYSTEM- PART 1 (WEEK 5)
 Sympathetic
● Close to spinal cord
● Long postganglionic fibres
● Lots of postganglionic branching so
that multiple organs can be mobilized
at once.
● NE/ Ach released
● Thoracolumbar spinal nerves
Parasympathetic
● Close to target organs
● Short postganglionic fibres
● Little postganglionic branching
● Acetylcholine released
● Cranial (e.g. vagus) and sacral spinal
nerves
 ● Both sympathetic and parasympathetic divisions are functioning together at any given
time but one may be acting dominantly.
Sympathetic Response
● “Fight & Flight”- helps to prepare our
bodies during dangerous situations which
is vital for survival
● Physiological changes:
○ Increased heart rate
○ “Tunnel vision”- narrowing of
vision to focus on danger point
○ Increase blood flow to muscles
○ Increase accuracy in hearing
○ Increase production of adrenaline
which increases blood sugar
levels and fatty acids- for extra
energy on cellular level
Parasympathetic Response
● “Rest & Digest”- Important to rest after a
meal, providing the body a chance to
digest foods
● Physiological changes:
○ Slowing heart rate
○ Slowing our breathing
○ Salivation
○ Digestion- release of digestive
enzymes
○ Elimination- release of waste,
toxins & other harmful substances
○ Lacrimation
 ● Preganglionic fibres of SANS & PNS secrete acetylcholine- cholinergic fibres
● Postganglionic fibres of PANS secrete acetylcholine- cholinergic fibres
● Postganglionic fibres of SANS secrete norepinephrine- adrenergic fibres

01. Action potential reaches the nerve terminal

02. Voltage cates Ca2+ channels open up
03. Influx of Ca2+
04. Trigger the release of neurotransmitter into synaptic cleft
05. Neurotransmitter binds to postsynaptic receptors
06. Neurotransmitter broke down in cleft

Action Potential
➔ When a neurotransmitter binds to a neuron it leads to an opening of sodium ion
channels that can cause an increase in intracellular Na+ concentration (-70 mV Resting
Membrane Potential)
➔ As the Na+ increases the excitatory effect leads to a rise in the RMP whereby it reaches
the Threshold Potential. When it reaches the TP voltage gated Na+ channels open
causing depolarization.
*AUTONOMIC NERVOUS SYSTEM - PART 2 (WEEK 5)

01. Synthesis
02. Storage
03. Release
04. Response (receptor activation)
05. Termination of action

Cholinergic Neurotransmission
● The 5th step involves degradation of the neurotransmitter in the synaptic gap and the 6th
step is the recycling of choline

01. Synthesis of acetylcholine

○ Choline is transported from extracellular fluid into the cytoplasm of the cholinergic
neuron by an energy- dependent carrier system that cotransports sodium
○ Choline → Acetylcholine = catalysed by Choline acetyltransferase + Acetyl CoA
(derived from mitochondria)
02. Storage of acetylcholine in vesicles
○ Acetylcholine is packaged into presynaptic vesicles by an active transport
process coupled to the efflux of protons.
○ Contains not only acetylcholine but also ATP (co- transmitted) & proteoglycan
03. Release of acetylcholine
○ Action potential triggers Ca2+ influx causing release of neurotransmitters via
exocytosis.
○ Can be blocked by Botulinum toxin
04. Binding to the receptors
○ Leads to a biologic response within the cell, such as the initiation of a nerve
impulse in a postganglionic fibre or activation of specific enzymes in effector cells
as mediated by second- messenger molecules.
05. Degradation of Acetylcholine
○ Acetylcholine → choline + acetate = cleaved by acetylcholinesterase
06. Recycling of Choline
○ Choline may be recaptured by a sodium- coupled high affinity uptake system that
transports the molecule back into the neuron, where it is acetylated into
acetylcholine that is stored until released by a subsequent action potential

Neuromodulation- Neurotransmitters can modulate their own release or the release of other
neurotransmitters.
A drug might:
01. Increase leakage of neurotransmitter from vesicle to cytoplasm exposing it to enzyme
breakdown
02. Increase transmitter release into cleft
03. Block transmitter release
04. Inhibit transmitter synthesis
05. Block cleft enzymes that metabolize transmitter
06. Bind to receptor on postsynaptic membrane to block (antagonist) or mimic (agonist)
transmitter action
07. Inhibit or stimulate second- messenger activity within postsynaptic cell
Adrenergic Neurotransmission

01. Synthesis of Norepinephrine

○ Tyrosine is transported by a Na+ linked carrier into the axoplasm of the
adrenergic neuron
○ Tyrosine → Dihydroxyphenylalanine (DOPA) = hydroxylated by thyroxine
hydroxylase (rate limiting step)
○ DOPA → Dopamine = carboxylated by dopa decarboxylase in the cytoplasm of
the presynaptic neuron
02. Storage of Norepinephrine
○ Dopamine is then transported into synaptic vesicles by an amine transporter
system that is also involved in the reuptake of preformed norepinephrine.
○ Dopamine → Norepinephrine = dopamine β- monooxygenase.
○ In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of
which are stored in chromaffin cells.
03. Release of Norepinephrine
○ Action potential triggers Ca2+ influx causing release of neurotransmitters via
exocytosis.
04. Binding to receptor
○ Adrenergic receptors ​use both cAMP second messenger system and the
phosphatidylinositol cycle​, to transduce the signal into an effect.
05. Removal of Norepinephrine
○ Metabolized to O- methylated derivatives by catechol O-methyltransferases in the
synaptic space- postsynaptic cell membrane- associated
○ Recaptured by an uptake system that pumps the norepinephrine back into the
neuron (Uptake 1)
○ Diffuse out of the synaptic space and enter the general circulation and undergo
reuptake by extraneuronal tissue like the liver (Uptake 2). The NE taken in will be
hydrolysed by monoamine oxidase.
■ Uptake by the neuronal membrane involves a sodium/ potassium
activated ATPase that can be inhibited by tricyclic antidepressants.
*DRUGS TARGETING CHOLINERGIC NEUROTRANSMISSION (WEEK 6)
● Sites of autonomic drug action: CNS, Ganglia, Postganglionic nerve terminals, effector
cell receptors (selectively), Mechanism of transmitter synthesis, storage, release,
termination of action
● Ex: Cholinomimetic & Cholinesterase- inhibiting agents

DIRECT ACTING CHOLINOMIMETICS: CHOLINESTERS

● 3 main properties:
a. Susceptible to cholinesterase
b. Muscarinic action
c. Nicotinic action
● Ach has no therapeutic factors because of its half life and non- selective action
INDIRECT ACTING CHOLINOMIMETICS
● Inhibit acetylcholinesterase
● Distributed to the CNS and more toxic than polar quaternary carbamates
● Organophosphates are well absorbed from all body sites so are dangerous to humans
and highly effective as insecticides

Cholinoceptor Blocking Drugs- Anticholinergics

● Drugs that oppose the action of acetylcholine
 ○ Antimuscarinic drugs-​ Postganglionic nerve endings (parasympathetic) (Ex:
atropine- related drugs). Act on brain (M1), Heart (M2) and glandular, gastric
parietal cells and smooth muscle cells (M3)
○ Antinicotinic drugs-​ ganglion & neuromuscular blocking drugs

ANTIMUSCARINIC DRUGS/ MUSCARINIC ANTAGONISTS

● Competitive antagonists to muscarinic receptors
● Ammonium compounds & are sufficiently lipid soluble to be readily absorbed
from gut or conjunctival sac and, importantly, to penetrate BBB.

01. Ganglionic Stimulant

○ Drug that stimulates nicotinic neural (Nn) receptors to increase ANS activity.
○ Stimulate both parasympathetic & sympathetic ganglion neurons
○ Sympathetic- vasoconstriction, tachycardia & hypertension
○ Parasympathetic- increased gut motility, increased salivary & bronchial secretion
02. Ganglionic Blocker
○ Drug that blocks the nicotinic neural (Nn) receptors and reduces the activity of
the ANS
○ Interfere with Ach synthesis & release; Ex: Botulinum toxin- inhibit the release of
Ach
○ Prolonged depolarization

Neuromuscular Blocking Drugs

● Presynaptically inhibit Ach synthesis or release (Ex: Botulinum toxin)
● Postsynaptically inhibit neuromuscular transmission (Neuromuscular Blocking Drug)
● Acetylcholinesterases
*DRUGS TARGETING ADRENERGIC NEUROTRANSMISSION (WEEK 6)

Major effects mediated by adrenoreceptors

● ⍺1 mediated: Mydriasis (pupil dilation), vasoconstriction, contraction of bladder
● ⍺2 mediated: decrease release of NE
● 𝛽1 mediated: increase in heart contractility
● 𝛽2 mediated: bronchodilation, vasodilation, glycolysis, gluconeogenesis, relax smooth
muscle
● 𝛽3 mediated: ipolysis, skeletal muscle thermogenesis
*DRUG ABUSE (WEEK 6)

Factors that increase the risk of addiction

01. Genetic factors
02. Early use
03. Method of Administration- Smoking or injecting can increase its addictive potential

Drugs working in the brain leads to development of addiction

● Marijuana and heroin mimic the effects of natural neurotransmitters

● Fools the receptors and allows drug to attach and activate neurons
● They don’t activate neurons in the same way as natural neurotransmitters and they lead
to abnormal messages being transmitted through the network
● Drugs such as cocaine stimulate neurons to release abnormally large amounts of natural
neurotransmitter or prevents the normal recycling of these brain chemicals
● Greatly amplified message, ultimately disrupting communication channels

What happens to brain if keep taking drugs

● The brain adjusts the overwhelming surges of dopamine by producing less dopamine or
reducing the number of receptors that can receive the signals
● Dopamine impact on the reward circuit of someone who abuses drugs can become
abnormally low and that person's ability to experience pleasure is reduced.
● The person will often take larger amounts of the drug to produce the familiar dopamine
high- tolerance
*DRUGS AFFECTING CNS (WEEK 7)

Stages of Anaesthesia
● I- Analgesia
● II- Excitation
● III- Surgical anesthesia
● IV- Medullary depression (Overdose)