Introduction to Pharmacology

Introduction to Pharmacology

• Receptors:
  • Proteins with binding sites that are specific for ligands.
  • Ligand binding leads to a cellular response.
  • The strength of the drug-receptor interaction is called affinity.
• Signal Molecules:
  • Hormones, neurotransmitters, and other signalling molecules in the blood can reach a large number of cells.
  • However, not all cells respond to circulating chemicals.
  • Specificity is provided by receptors, which are only present in specific cells.
• The Receptor Concept:
  • Chemicals produce their effects by combining with specific receptor sites in cells.
  • The response is a function of the number of occupied receptors.
  • The lock and key hypothesis describes chemical specificity.

Receptor Locations

• Receptors can be found in different locations within the cell:
  • Plasma membrane: Receptors for most water soluble ligands.
  • Cytoplasm: Receptors for small, lipid soluble ligands.
  • Nucleus: Receptors for steroid hormones.

Four Types of Receptors

• Ion channels
  • Receptors that are directly linked to an ion channel.
  • Ligand binding opens the channel, allowing ions to flow across the membrane.
• Enzyme-linked receptors:
  • Receptors that are linked to an enzyme.
  • Ligand binding activates the enzyme, which catalyzes a biochemical reaction.
• G-protein coupled receptors (GPCRs):
  • Largest family of cell surface receptors.
  • Ligand binding activates a G protein, which in turn activates other downstream signaling molecules and pathways.
• Nuclear receptors:
  • Located in the nucleus of the cell.
  • Bind to DNA and regulate gene expression.

Transmitters

• Neurotransmitters
  • Chemical messengers that are released from presynaptic neurons and bind to receptors on postsynaptic neurons or effector cells.
  • Examples: acetylcholine, dopamine, serotonin, glutamate, GABA.
• Hormones
  • Chemical messengers that are released from endocrine glands and travel through the bloodstream to target cells.
  • Examples: insulin, glucagon, cortisol, thyroid hormone.
• Autocoids:
  • Local signalling molecules that act on nearby cells.
  • Examples: histamine, prostaglandins, leukotrienes.
• Neuropeptides:
  • Short chains of amino acids used as neurotransmitters and hormones.
  • Examples: endorphins, enkephalins, substance P.
• Neuromodulators:
  • Substances that alter neuronal activity without directly causing an action potential.
  • Examples: norepinephrine, dopamine, serotonin.
• Cytokines:
  • Signaling molecules that regulate cell growth, differentiation, and inflammation.
  • Examples: interleukins, interferons.

Neurotransmitter Release

• Exocytosis: The process by which vesicles in the presynaptic neuron fuse with the cell membrane and release their contents into the synaptic cleft.
• Calcium (Ca++) influx: Ca++ influx into the presynaptic terminal triggers exocytosis.
• Diffusion: The neurotransmitter travels through the synaptic cleft.
• Binding to post-synaptic receptors: Neurotransmitters bind to receptors on the postsynaptic neuron or effector cell.
• Termination of transmission: Neurotransmitters are removed by reuptake into the presynaptic neuron, enzymatic degradation, or diffusion away from the synapse.
• Synapse: The junction between two neurons.

Neurotransmitter Recovery and Degradation

• Neurotransmitters are removed from the synaptic cleft by:
  • Diffusion: Movement away from the synapse.
  • Reuptake: Neurotransmitter is transported back into the presynaptic neuron.
  • Enzymatic degradation: Breakdown of the neurotransmitter by enzymes.

Major Neurotransmitters

• Acetylcholine (ACh): Involved in muscle contraction, memory, and learning.
• Monoamines:
  • Norepinephrine (NE): Involved in fight-or-flight response, arousal, and attention.
  • Dopamine (DA): Involved in reward, motivation, movement, and mood.
  • Serotonin (5-HT): Involved in mood, sleep, appetite, and aggression.
• Amino acids:
  • Glutamate (GLU): Major excitatory neurotransmitter in the CNS.
  • Gamma-aminobutyric acid (GABA): Major inhibitory neurotransmitter in the CNS.
• Neuropeptides:
  • Endorphins: Involved in pain perception and mood.

Hormone vs. Neurotransmitter

• Neurotransmitters:
  • Local communication: Act on nearby neurons or effector cells.
  • Fast acting: Effects often occur in milliseconds.
• Hormones:
  • Long-distance communication: Travel through the bloodstream to target cells.
  • Slower acting: Effects often occur in minutes, hours, or days.

Adrenaline vs. Noradrenaline

• Adrenaline (epinephrine): A hormone released by the adrenal glands.
• Noradrenaline (norepinephrine): A neurotransmitter in the brain and sympathetic nervous system.
• Both adrenaline and noradrenaline contribute to the fight-or-flight response by increasing heart rate, blood pressure, and glucose release.

Receptor Subtypes

• Cholinoceptors: Bind acetylcholine.
  • Nicotinic receptors: Found in skeletal muscle and the CNS.
  • Muscarinic receptors: Found in smooth muscle, heart, and glands.
• Adrenoceptors: Bind norepinephrine and epinephrine.
  • Alpha receptors: Mediate vasoconstriction and other effects.
  • Beta receptors: Mediate bronchodilation, increased heart rate, and other effects.
• Histamine receptors: Bind histamine.
  • H1 receptors: Involved in allergic reactions, inflammation, and itching.
  • H2 receptors: Involved in gastric acid secretion.
• Dopamine receptors: Bind dopamine.
• Serotonin receptors: Bind serotonin.
• Insulin receptors: Bind insulin.
• Steroid receptors: Bind steroid hormones.

Acetylcholine Receptors

• Nicotinic receptors:
  • Ligand-gated ion channels.
  • Permeable to Na+ ions.
  • Excitatory.
• Muscarinic receptors:
  • G-protein coupled receptors.
  • Five subtypes (M1-M5).
  • M1, M3, and M5 are excitatory.
  • M2 and M4 are inhibitory.

Nicotinic Receptor Structure

• Pentameric (consists of 5 subunits):
  • Each subunit has four transmembrane regions.
  • Subunit variations lead to different nicotinic receptors in muscles and neurons.

Glutamate Receptors

• The primary excitatory neurotransmitter in the brain:
  • Ionotropic: Directly linked to ion channels (AMPA, NMDA, kainate).
  • Metabotropic: G-protein coupled receptors.

GABA Receptors

• The major inhibitory neurotransmitter in the CNS:
  • GABAA: Ligand-gated ion channel (chloride channel).
  • GABAB: G-protein coupled receptor, ultimately inhibiting voltage gated Ca++ channels and opening K+ channels.

G-Protein Coupled Receptors

• A very large family of receptors:
  • Involved in many signaling pathways, including visual, olfactory, and hormonal signaling.
  • Examples: muscarinic, alpha/beta adrenoceptors.
• G proteins: A family of proteins that bind guanine nucleotides (GTP and GDP).
  • Inactive: G protein bound to GDP.
  • Active: G protein bound to GTP.

G Protein-Dependent Signal Transduction

• Active G protein: Interact with ion channels or enzymes.
  • Ion Channels: Open or close channels, altering ion flow across the membrane.
  • Enzymes: Activate or inhibit enzymes, leading to the production of second messengers.

Second Messengers

• Intermediary molecules that relay signals from the activated receptor to downstream targets.
• Examples: cyclic AMP (cAMP), cyclic GMP (cGMP), diacylglycerol (DAG), inositol triphosphate (IP3), and calcium (Ca++).

Ligands Acting on Receptors

• Agonist: A ligand that binds to a receptor and activates it, producing a cellular response.
• Antagonist: A ligand that binds to a receptor and blocks its activity, preventing the agonist from activating the receptor.

Drug Actions

• Most drugs act by interacting with specific proteins on cell membranes:
  • Receptors: Drugs bind to receptors and mimic or block the action of natural ligands.
  • Enzymes: Drugs can inhibit enzyme activity by binding to the active site or by altering the enzyme’s conformation.
  • Transport systems: Drugs can block transporter proteins that move molecules across cell membranes.
  • Ion channels: Drugs can block or modulate ion channels by binding to specific sites on the channel.
  • Microbes: Drugs can target specific proteins or processes in invading organisms.
• Non-specific drug actions: Drugs can also have effects that are not mediated by specific receptors or enzymes, such as by altering the physical properties of cells or tissues.

Types of Drug Action

• Transport systems (5%): Inhibitor drugs block or interfere with transporter proteins.
• Enzymes (15%): Drugs can inhibit enzyme activity, preventing the production of a specific molecule or product.
• Microbes (40%): Medications target specific proteins or processes in microbes, inhibiting their growth or survival.
• Cellular receptors (40%): Drugs can activate, block, or modulate receptor activity.
• Others (less than 1%): Include drugs that act on DNA or other cellular processes.
• Genetic transplants (0.00000000001%): A highly specialized and experimental approach.

Explore the fundamentals of pharmacology, focusing on receptors and their role in cellular responses. Understand how ligands interact with specific receptors and the concept of affinity in drug-receptor relationships. This quiz will help you grasp the significance of signal molecules and receptor locations in pharmacological processes.