Medchem EXAM 3

Adverse Drug Events

• ADEs are injuries resulting from medical intervention related to a drug

• Include allergic reactions, side effects, adverse drug reactions, overmedication, and medication errors

• Adverse drug reactions (ADRs) fall into ADEs, and are characterized by harms directly caused by a drug at normal doses

• Drug classes that are common causes of ADEs include anticoagulants (bleeding), diabetes agents (hypoglycemia), opioids (overdoses)

• ADRs can be Type A: on-target (side effects) or Type B: off-target (unpredictable)

Hypersensitivity Reactions

• Occur when the immune system responds abnormally to an antigen and can be harmful

• Type I- Immediate/anaphylaxis

• Type II- Cytotoxic reaction

• Type III- Immune complex reaction

• Type IV- Delayed reaction

• Certain drug functional groups can form covalent bonds to macromolecules and cause hypersensitivity reactions: ring strained B-lactams, epoxides, a,B-unsaturated carbonyls, aromatic amines, sulfhydryl groups

Mutagenicity

• Mutagenesis- the ability of chemicals to cause changes to DNA (mutations) that are transmitted during cell division; can be germline (mutations to sperm and egg, heritable) or somatic (mutations in all other cell types, nonheritable)

• Nitrogen Mustards- cytotoxic nonspecific DNA alkylating agents

• Base analogs- structural mimics of DNA bases, can be incorporated into DNA synthesis and cause mutations

• Polycyclic aromatic hydrocarbons- molecules formed by the incomplete combustion of organic matter; carcinogenic and mutagenic, found in tobacco smoke, car exhaust, some foods, etc.

Teratogenesis

• Teratogenesis- the creation of a deformed organism

• Teratogens- Drugs/chemicals/infections that cause birth defects

• Drug example: Thalidomide- marketed in Europe and thought to help with morning sickness, turned out to cause birth defects. Not FDA approved in US until 1988 after it was shown to be safe/effective in treating leprosy

• NON EXAM drug example: isotretinoin (Accutane)

Nervous System

• Consists of Central Nervous System (CNS) and Peripheral Nervous System (PNS)

• CNS- consists of brain and spinal cord; conducts the direct function of all tissues; protected by the Blood Brain Barrier (BBB), an endothelial barrier of blood vessels that prevents solutes in the blood from crossing into the CNS

• PNS- consists of all of the nerves outside of the CNS; split into somatic (voluntary) and autonomic (involuntary)

• Sensory (afferent) nerves- carry impulses from outside to the CNS (bring in)

• Motor (efferent) nerves, carry impulses from CNS outward (carry out)

Drug Entry to CNS through BBB

• Hard for drugs to cross BBB

• Can bypass BBB by direct administration into CNS (intrathecal, intranasal, etc)

• Can cross BBB by fitting into the Rule of Five (have appropriate size, lipophilicity, charge, and number of H bond donors/acceptors OR by utilizing existing transcellular pathways

• Solutes can cross a weakened BBB due to developmental challenges, hypertension, exposure to radiation/infection, head trauma, etc.

PNS Breakdown

• Somatic (voluntary)- perceives senses and controls skeletal muscle

• Autonomic (involuntary)- controls functions of smooth muscle and glands, maintains homeostasis, split into sympathetic and parasympathetic

• Sympathetic- “fight or flight” 

• Parasympathetic- “rest and digest”, adjusts internal environment (blood pressure, heart rate, temperature control, digestion) 

Neuronal Conduction

• Neurons (nerve cells) communicate with each other by producing action potentials, electrical signals that travel along the neuron’s axon and are transmitted to target tissues

• When an action potential reaches the axon terminal of a neuron, it stimulates the release of a chemical neurotransmitter. These neurotransmitters then diffuse across the synaptic cleft between two neurons and interact with the other neuron’s postsynaptic receptors

• Some substances released due to action potentials end up in the bloodstream, acting as neurohormones

Cholinergic System

• Cholinergic System- Budding branch of the autonomic nervous system that utilizes acetylcholine to play roles in regulating autonomic nervous system functions, such as muscle contraction, digestion, and memory

• Acetylcholine- a type of neurotransmitter released in the neuromuscular junction between a motor neuron and a muscle fiber, causing the muscle to contract. It is also involved in the retrieval of memories and in regulating certain autonomic nervous system functions

• Removed by Acetylcholinesterase (AChE), which hydrolyzes acetylcholine and terminates its activity

• The cholinergic system has two major receptor classes: muscarinic (binds muscarine) and nicotinic (binds nicotine)

• Electrostatic interactions within acetylcholine itself can result in two different conformations, one that can interact with muscarinic receptors and one that can interact with nicotinic receptors

Cholinergic Drugs Overview

• Cholinergic drugs act by mimicking the effect of acetylcholine

• Direct cholinergic agents- activate muscarinic and nicotinic receptors

• Indirect cholinergic agents- block AChE

• Cholinergic antagonists (anticholinergics)- reduce responses and effects associated with cholinergic system stimulation by blocking acetylcholine

Diseases Caused by ACh Defects

• Alzheimers- reduction of ACh levels due to depletion of neurons that synthesize/use it

• Myastenia gravis- immune system attacks/destroys ACh

• Lambert-Eaton syndrome- antibodies decrease the release of ACh

• Some snake venom- blocks ACh receptors

• Some spider venom- huge release of ACh

Agents Affecting ACh Synthesis/Release

• Hemicholinium chloride- toxic, inhibits ACh synthesis by blocking choline transport systems

• Botulinum toxin (Botox)- neurotoxin that inhibits ACh release

• Guanidine- Increases ACh release, can treat Lambert-Eaton syndrome

Muscarinic Receptors

• GPCRs located in the CNS

• Binds muscarine, a compound derived from the amanita muscaria mushroom that can activate cholinergic receptors, toxic due to this (mycetism)

Nicotinic Receptors

• Ligand-gated ion channels located in ganglia and neuromuscular junctions, as well as other sites like the brain

ACh Structure Activity Relationship (SAR)

• Acyl group- increasing size increases antagonistic effects

• Ether group- substitutions on the a or B carbon of this group has a variety of effects on nicotinic and muscarinic activity

• Amine group- portion needed for agonistic action, increasing the size of the alkyl sidechains will turn it into an antagonist

Direct Acting Cholinergic Drugs

• Michol-E (acetylcholine)- suspension used in eye surgery 

• Provocholine (methacholine chloride)- used to diagnose asthma

• Miostat (carbachol)- eyedrop used to induce miosis for surgery and reduce intraocular pressure

• Duvoid (bethanechol)- treats acute, functional, postpartum and postoperative urinary retention

• Salagen (pilocarpine)- also induces miosis and reduces intraocular pressure in glaucoma

• Evoxac (cevimeline)- treats dry mouth associated with Sjorgen’s syndrome

Muscarinic Blockers Overview

• Anticholinergics that specifically block muscarinic receptors, acting as competitive antagonists

• Primarily work to treat symptoms of cholinergic crisis (salivation, lacrimation, urination, defecation)

• The epimerization of (-)-hyosycamine to atropine is used in a lot of antimuscarinic drugs

Muscarinic Receptor Antagonist Drugs

• Atropen (atropine)- poisoning remedy

• Scopolamine- transdermal patch that treats motion sickness

• Donnatal- gastrointestinal antispasmodic

• Equipin (homatropine bromide)- dilates pupil, treats uveal tract inflammation, cough suppressant 

• Pamine (methscopolamine bromide)- treats peptic ulcer disease

• Buscopan (butylscopolamine)- treats menstrual and other abdominal cramps

• Atrovent (ipratropium bromide)- treats symptoms related to COPD

• Spiriva (tiotropium)- long acting once-daily treatment for COPD

• Incruse Ellipta (umeclidium)- maintenance treatment for COPD

• Duaklir (aclidinium bromide)- long-acting COPD treatment

• Cogentin (benztropine mesylate)- treats Parkinson’s

• Benadryl (diphenhydramine)- antihistamine

• Ditropan (oxybutynin chloride)- treats overactive bladder (OAB)

• Vesicare (solfenacin succinate)- treats OAB

• Detrol (tolterodine tartrate)- treats OAB

• Enablex (darifenacin hydrobromide)- treats OAB

• Myrbetriq (mirabegron)- first adrenergic B3 agonist to be approved to treat OAB

• Cobenfy- mixture of agonist/antagonist that treats schizophrenia