Pharmacodynamics: How Drugs Affect the Body

• Pharmacodynamics describes the effects of drugs on the body, altering physical and chemical environments.
• Drugs primarily act on receptors, specific cellular components, accounting for 90% of drug actions.
• Receptors are usually transmembrane or cytosolic proteins like enzymes, transporters, or ion channels, but can also be lipids or nucleic acids.
• Drugs that bypass receptors take effect through physical or chemical processes.

Physical Processes

• Surface tension changes, such as mineral oil reducing stool tension.
• Lubrication, provided by mineral oil or artificial tears.
• Adsorption, where substances like activated charcoal bind toxins, preventing cell absorption.

Chemical Processes

• Neutralization, like antacids counteracting gastric acid.
• pH alteration
• Changes in the volume, composition, or balance of body fluids, such as with electrolytes or IV saline.
• The lock and key model dictates that a drug's shape must precisely fit a target's structure to activate or block it.
• Drug-target interactions are specific and based on physical shape, requiring drugs to have an affinity for their receptors.
• Affinity is the force of attraction between a receptor and a drug; receptors have high affinity, while drugs may have low affinity.
• Drugs with low affinity bind weakly, detach easily, and need higher doses.
• High-affinity drugs bind strongly and are effective at lower doses.
• Receptors with high affinity tightly bind available drugs.
• Selectivity is the degree to which a drug acts on a specific target compared to other sites.
• Agonism occurs when a drug binds to a receptor and causes a pharmacological response.
• Antagonism is when a drug binds to a receptor without producing a pharmacological response, blocking agonists instead.
• The effect intensity of an antagonist relates to the concentration of the agonist present.
• Binding in both agonism and antagonism can be reversible or irreversible.

Dose-Response Curve

• Illustrates the relationship between drug dose and response intensity.
• Determines the minimum effective drug amount and the maximum possible response, which is limited by receptor availability.

Efficacy

• Measures the largest effect a drug can produce.
• Very high maximal efficacy is not always the most desirable trait.

Potency

• Represents the minimum amount of a drug required to achieve a specific effect.
• Potency is about the dosage needed and indicates nothing about maximal efficacy.
• Therapeutic Drug Monitoring (TDM) measures drug levels in blood or urine to ensure safe and effective concentrations.
• It is important for drugs with a narrow therapeutic range.
• Sampling measures maximum (Cmax) and minimum (Cmin) drug concentrations.
• Cmax is the maximum drug concentration, typically 1-2 hours post-administration, and helps understand absorption and peak effect.
• Cmin is the lowest drug level, measured right before or 1 hour before the next dose. TDM provides insights into patient compliance, drug interactions, and necessary dosing adjustments.
• Drug classes often monitored include analgesics, antimicrobials, anticonvulsants, chemotherapeutics, bronchodilators, cardiovascular, and immunosuppressant drugs.

Nervous System

• Central nervous system (CNS) comprising the brain and spinal cord.
• Peripheral nervous system (PNS) includes all nerves outside the CNS, connecting it to the rest of the body.

PNS Subdivisions

• Somatic nervous system (SNS) controls voluntary movements by connecting the CNS to muscles.
• Autonomic nervous system (ANS) regulates involuntary functions.
• The ANS efferent arm splits into the sympathetic and parasympathetic branches.
• Sympathetic nervous system (SNS) prepares the body for stress or emergencies; increases focus; fight or flight.
• Parasympathetic nervous system (PNS) helps the body relax and conserve energy; rest and digest.
• Synaptic transmission involves neuron activation.
• Depolarization is a signal that changes the membrane potential, making the neuron more positively charged due to influx of positively charged sodium ions.
• Depolarization triggers action potentials.
• Neurons synthesize and store neurotransmitters like acetylcholine (ACh) in synaptic vesicles within axon terminals.
• Release of neurotransmitters happens when an action potential reaches the axon terminal, triggering ACh release into the synaptic cleft.
• Neurotransmitters bind to Receptor by crossing the synaptic cleft to bind to receptors on the postsynaptic membrane, activating a receptor.
• Activating a target neuron or tissue triggers various effects.
• The ANS consists of chains of two neurons, preganglionic and postganglionic.

Ganglia

• Collections of nerve cell bodies outside the CNS, serving as relay stations for nerve signal transmission between neurons.
• Parasympathetic neurons originate in the craniosacral region, with localized effects due to short postganglionic neurons and no hormones.
• Cranial nerves III, VII, IX, and X are parasympathetic.
• Sacral nerves S2-S4 supply pelvic organs.
• Sympathetic neurons originate in the thoracolumbar region (T1-L2), with diffused body effects by long postganglionic neurons and adrenal hormones.
• Paravertebral ganglia lie along the vertebral column, while prevertebral ganglia are deeper in the body core.

Sympathetic System

• Eyes: Mydriasis (pupil dilation) through radial sphincter muscle contraction.
• Heart: Increased rate and force.
• Lungs: Bronchi dilatation.
• Adrenal Glands: Release of adrenaline and noradrenaline into the bloodstream.
• Brain: Increased focus and vigilance.
• Blood Vessels: Constriction in skin/GI system, dilation in muscles/heart.
• Sex Organs: Ejaculation (males), vaginal contractions (more broadly)
• Urinary System: Detrusor muscle relaxation, internal sphincter contraction.
• Digestive System: Reduced gastric/intestinal secretions and motility.
• Liver/Adipose Tissue: Glycogenolysis and lipolysis.
• Sweat Glands: Diaphoresis (sweating).
• Coagulation: Increased to minimize bleeding.

Parasympathetic System

• Eyes: Miosis (pupil constriction) through iris sphincter muscle contraction, near vision focus through ciliary muscle contraction.
• Heart: Reduced rate, slightly reduced force of atrial contraction.
• Lungs: Bronchoconstriction, increased secretions.
• Stomach/Intestines: Stimulated secretions and motility.
• Sex Organs: Erection, tissue filling with blood.
• Urinary System: Bladder contraction; opening (relaxation)
• Blood vessels: No effect.
• The parasympathetic system has long preganglionic and short postganglionic neurons.
• The sympathetic system has short preganglionic and long postganglionic neurons.

Neurotransmitters (ANS)

• Parasympathetic: Release ACh → ACh, uses muscarinic cholinergic receptors.
• Sympathetic: Release ACh → NE, uses adrenergic receptors (Alpha or Beta).
• Adrenal Medulla Exception: Release ACh → Epi, Uses adrenergic receptors (Alpha or Beta).
• Sweat Gland Exception: Release ACh → ACh, Uses muscarinic cholinergic receptors.
• Somatic: One neuron (no ganglion), ACh to nicotinic cholinergic receptors on muscles for voluntary movement.
• Noradrenaline synthesis involves tyrosine, DOPA, dopamine, and noradrenaline.

Steps of Noradrenaline Synthesis

• NE synthesis.
• NE storage in vesicles.
• Release into the gap.
• Action on adrenergic receptors.
• NE reuptake into the presynaptic neuron.
• Repackaging and storage.
• OR, breakdown by enzymes like MOA (inside neuron) and COMT (outside neuron).
• Degradation of products are VMA and MOPEG, which are found in urine.
• Synthesis inhibitor such as alpha-methyl tyrosine or alpha-methyl DOPA leads to less NA.
• Reserpine decreases NE storage.
• Guanethidine decreases NE release.
• Dobutamine stimulates beta 1 adrenergic receptors
• Metoprolol blocks beta 1 adrenergic receptors. Cocaine and tricyclic antidepressants inhibit NE reuptake, while Pargyline inhibits MOA to increase stored NA.
• ChAT catalyzes acetyl-CoA + choline to produce acetylcholine and CoA.
• After synthesis, ACh is stored in vesicles and released into the gap upon stimulation.
• ACh then acts on nicotinic or muscarinic receptors.
• The enzyme AChE breaks ACh down into choline + acetate.
• Finally, choline is reuptaken and stored, while acetate diffuses away.

ACh Neurotransmission

• Vesamicol inhibits ACh storage, Botulinum toxin inhibits ACh release; Latrotoxin increases ACh release which depletes ACh.
• Muscarine stimulates muscarinic cholinergic receptors.
• Atropine blocks muscarinic cholinergic receptors.
• Neostigmine inhibits enzymatic breakdown, and Hemicholinium inhibits choline reuptake.

Receptor Types

• Sympathetic Nervous System
• NE: Acts on Smooth muscle (Alpha and Beta Receptors)
• ACh: Acts on Glands (Muscarinic Receptors)
• Epi: Acts on Adrenal Medulla (N Receptors)
• Parasympathetic Nervous System
• ACh: Acts on Muscarinic receptors
• Somatic System
• ACh: Acts on Nicotinic receptors

Adrenergic Receptors (Sympathetic)

• Alpha 1
• Blood vessels: Cause Vasoconstriction
• Internal urinary sphincter: Cause Contraction
• Penis: Cause Ejaculation
• Piloerector muscles (hair): Cause Contraction
• Salivary glands: Cause Thick viscous secretions (instead of water from para)
• Eye (radial muscle): Cause Contraction (mydriasis; dilation)
• Alpha 2
• Presynaptic: Cause Inhibition of NA release: negative feedback
• Pancreas: Cause Decreased insulin secretion
• Gastrointestinal tract: Cause Decreased secretions
• Beta 1
• Heart: Cause Increased heart rate, increased force of contraction, increased conduction velocity
• Kidney: Cause Increased blood pressure (due to release of renin)
• Beta 2
• Lungs, Uterus, Bladder (detrusor): Cause Relaxation
• Blood vessels (muscles, coronaries): Cause Dilatation
• Liver: Cause Glycogenolysis (body breaks down glycogen into glucose) and gluconeogenesis (synthesizes glucose from non-carbohydrate precursors)
• Gastrointestinal tract: Cause Decreased motility (relaxation)
• Skeletal muscles: Cause Increased uptake of K+
• Beta 3
• Adipose tissue: Cause Lipolysis (body breaks down stored fat into fatty acids and glycerol) ACh → N (somatic)
• ACh → N → ACh → M (sweat)
• ACh → N → Epi → a or ẞ (sympathetic) Acetylcholine (ACh): Non-selective
• Can bind to two subtypes of receptors, both of which are named cholinergic receptors:

Nicotinic (N) Cholinergic Receptors

• Relative Selective
• Nicotinic Receptor Subtypes:
• Nicotinic Neuronal (Nn) - Sympathetic and parasympathetic postganglionic ganglions. - Adrenal glands (medulla) - Adrenaline and noradrenaline (4:1 ratio) released as hormones in the bloodstream.
• Nicotinic Muscular (Nm)
• Skeletal muscles
• Skeletal muscle depolarization and contraction.
• Overstimulation leads to paralysis.

Muscarinic (M) cholinergic receptors

• M1, M4, M5: Brain
• Variety of effects according to neuronal pathway that is implicated
• M2
• Heart muscle - Decreased heart rate, decreased force of contraction (atria)
• M3: Smooth muscle*, glands: (salivary, lacrimal, bronchial, Gl), stimulation of parasympathetic effects.
• Eyes: Iris sphincter, ciliary muscle
• Contraction (miosis, accommodation)
• Sweat glands **(sympathetic system)
• Diaphoresis

Cholinergic Drugs

• Cholinomimetics Act like ACh
• First act on ACh Receptors:
• Nicotinic
• Neuronal Nicotinic receptor agonist
• Skeletal muscle nicotinic receptor agonists
• Muscarinic
• Muscarinic Receptor Agonists
• 2. Indirect Acting: (↑↑ Ach Levels*)
• Inhibtors of acetylocholinergic AChe Cholinesterase Inhibitors
• Cholinolytics Acts to block ACh related effects
• Nicotinic Neuronal Nicotinic Receptor antagonists (Antonomic Ganglia Antagonist)
• Sk MUscle Nicotinic receptor antongist
• Muscarinic 2. Cholinergic Receptor Agonist*

Cholinometrics (direct)

• Neuronal Agents A(N(N))
• Nicotine
• Result: Increased release of noradrenaline and acetylcholine that act on target tissues

Muscarinic Agents

• AKA parasympathomimetics
• Stimulation of Muscarinic Receptors: para + sweet glands
• Stimulates targets of parasympathetic symptoms + glands (sympathetic) Decreased heart rate, constriction of lung bronchi, miosis; any other parasympathetic are effects can be:
• SLUDGE Salivation Lacrimation (tears) Urination Diaphoresis GI Motility Diaruhea Emesis

Adverse Effects

• Overstimulation can effect Paraympathetic targets
• Bethamechol * Treats Urinary Retention and intestinal paraylysis
• Pilocarpine : Used to treat glaucoma in hopes of reducing Intraocular pressure -Carbachol (Zemostomia Dry Mouth)

Example of muscarinic agents

• Arecoline, Acetulcholine , Muscarine
• Muscarine Agents Found in Poisonous Mushrooms*
• Toxicity = S.L.U.G.E( Agent found in poisonous mushrooms: Amanita muscaria Inocybe and Clitocybe)
• Treatment if Ingested is muscarine* Antagonists

Cholinomimetrics is (Indirect) Achetulcholinesterase (AchE Inhibitors

• Reversible Inhibitors (Neostigmine ,Neutral
• Phusostigmine
• Edrophonium Mechanisms of inaction - temporarily inactivate ACH
• Increased ACH effects increased at masculinic and neruomuscular (N(N)) chollinergic receptor

Excessive stimulation of masculinic + Neurmm receptors

• Clinical Users
• Myasthenia Gravis paralysis introduced

The most common symptom is inactivations and lack of muscle. The goal would be to make an improvement if effects are increased. 4. Cholinergic Criss The consequence of an myasthenia gravis treatment when agents NE increase levels -Can lead to block.

Reuptake and Cholinergic Blocking Agents and Inhibitors

Alpha 1 agonist: Phenylephrine Alpha 2 adrenergic agonists: Clonidine. Beta 1 adrenergic agonist: Doubutamine. Beta 2 adrenergic agonist: Salbutamol. Beta 3 agonist: Mirabegron helps reduce urinary in continence Mixed acting sympathomimetic: Ephedrine, Pseudoephedrine, amphetamine. Acidification of urine is used to treat Amphetamine. weak based toxin . This is why its useful with base toxins (remains charged as 1 bit) Treatment of Beta and NE. Also Result in 11 sympathetic levels of noradrenaline. Alpha 1 Antagonists: Prazosin, Terazosin, Doxazosin. Used for high blood pressure Alpha 2 Anatagonist: Tachycardia and hypoglycemia

Reversible (generally) blockade of adrenergic receptors 3. Alpha 1 Anatagonists 4. Alpha 2 Anatagonist (Yolimbine) Non Selective Alpha Antagonist .Phentolanmine can treat noradrenaline - secreting tumours that form

-Beta receptors are Angina, used for anxiety in hypertension, heart failure, and high blood pressure

Antimicrobial drug class

Is when A Inhibits the metabolic path - B inhibits the cell. C inhibits protein. D inhibits acids Folate antognists like those found in Sulfonamide . The structure has some chemical structures found in diuretics , diuretics-Hydroclorotide ,Insulin drugs such as glyburide and anti-inflammatories. There are two types of reactions

• Hypersensitivy
• Good news Trimehtoprime This is useful with downstream infections. Stevens Johnson Sydrome * Very risky / toxic. -8 weeks , skin rashes are typical in months
• • drugs contain Sulunaminds, anti seizure mediators and certain ns aids