Pharmacology Lecture Notes Flashcards

Flashcards of key vocabulary and concepts from Pharmacology Lecture Notes

Drug Approval Process: Clinical Trials

FDA estimates 8-9 years to bring a drug to market from first animal testing to final approved product.

Preclinical Testing

Animal testing is the first step in the drug approval process.

Investigational New Drug Application (IND)

Outlines what is proposed for human testing in clinical trials.

Phase I Clinical Trial

Typically involves 20-80 people.

Phase II Clinical Trial

Involves tens to hundreds of people.

Phase III Clinical Trial

Involves hundreds to thousands ( less than 3000) of people.

Phase I Clinical Trial Emphasis

Safety is prioritized in this phase, using healthy volunteers to test for side effects and sometimes pharmacokinetics.

Phase II Clinical Trial Emphasis

Effectiveness is tested in people with the disease, often including a placebo group.

Phase III Clinical Trial Details

Usually compared to placebo, may test dosages, provides more info on safety/effectiveness, and may test different populations.

Clinical Trial Limitations

Populations in clinical trials are often healthier than real-world populations, and some side effects may be missed.

Generics Production

Can be produced/marketed once the patent life has expired.

Strategies to Delay Generics

Paying generic manufacturers to delay entry, patent infringement suits, and product hopping.

Product Hopping

Changing a drug's concentration, dosing frequency, or tablet amount serially.

Stress Components

Stressful experience, processing, perception, adaptation.

Physiological Symptoms of Stress

Increased muscle tension, restlessness, impaired concentration, sleep disturbances, irritability.

Sympathetic Autonomic Nervous System Activation

Fight-or-flight response, anxiety.

Anabolic Steroid Cycling

Patterns are 6 to 12 weeks long, with periods of abstinence in between.

Reasons for Steroid Cycling

Minimizes tolerance, reduces side effects, maximizes performance at an event, may help avoid detection of a banned substance.

Steroid Pyramiding

Gradually increasing the steroid dose until the midpoint of the cycle and then gradually decreasing.

Metabolic Tolerance

Increase in P450 liver microsomal enzymes that metabolize the alcohol.

Cross-tolerance

Smokers are able to break down caffeine faster due to upregulation of cytochrome P450 in the livers.

Pharmacodynamic Tolerance

Neurons adapt to the continued presence of drugs by making compensatory changes in cell function.

Common Mechanism of Addictive Drugs

All addictive drugs increase dopamine levels in the nucleus accumbens.

Dopamine and Glutamate Co-incident Activation

Mediates association learning that leads to reward-seeking behavior.

Dopamine Release

Serves as prediction-error signal. Signifies a reward that has not been predicted.

Addictive Drugs and Dopamine

Differ from natural rewards because they always cause dopamine release, so the brain interprets this signal as 'better than expected', maximizing drug-seeking.

Relapse Triggers

Small dose (drug priming), stress, environmental cues previously paired with the drug.

Methamphetamine Pharmacokinetics

Peak plasma concentrations at 3-6 hours (oral). Half-life ~12h. IV or smoked gives an initial rush followed by euphoria.

Dopamine Cycle Components

Synthesized from DOPA. Vesicular transporter VMAT2 Blocking this reduces dopamine levels. Dopamine transporter (DAT): clears dopamine from the synapse. Monoamine oxidase (MAO): metabolizes stray monoamine neurotransmitters in presynaptic terminals.

Amphetamine Mechanisms of Action

Causes several transporters for neurotransmitters to reverse -> release neurotransmitters (Dopamine, serotonin and norepinephrine) into synapse Also blocks MAO, so more dopamine available for packaging into vesicles.

GHB Low Dose Effects

Alcohol-like experience such as mild euphoria, relaxation, social disinhibition.

GHB Higher Dose Effects

Lethargy, ataxia, slurring of speech, dizziness, nausea, vomiting. Overdosing is dangerous: Respiration depressed à risk of loss of consciousness/coma, Potential for seizures.

GHB Receptor Target

Likely some action through GABAB, tendency to inhibit signaling in neurons GABAB knockout mice have high affinity GHB binding sites but don’t respond to GHB treatment Most effects of GHB are blocked by GABAB antagonists.

Inhalants Effects on CNS

Enhance function of inhibitory GABAA receptors and inhibit activity of excitatory NMDA glutamate and nicotinic cholinergic receptors.

Lisdexamfetamine (Vyvanse) Mechanism

Increases monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) in the synaptic cleft by inhibiting re-uptake, MAO, and disrupting vesicular release.

Ghrelin

Produced in the stomach and increases appetite (orexigenic).

Anandamide

Produced in neurons in the hypothalamus and increases appetite (orexigenic).

Insulin

Produced in the pancreas and promotes satiety (anorexigenic), glycogen and lipid storage.

Leptin

Produced by adipocytes and promotes satiety (anorexigenic)long term.

CCK (cholecystokinin)

Produced in the small intestine, induces early satiety (anorexigenic), and promotes release of digestive enzymes from pancreas/gallbladder/stomach.

PYY (peptide tyrosine tyrosine)

Produced in the ileum and colon and promotes satiety (anorexigenic).

Vagal Mechanism of Satiety

The afferent signals in the vagus conveyed to the brain that function to limit meal size information from stretch receptors in the stomach wall & sensors in the portal blood vessels

Vagal afferents

Minimum electrical current required to trigger an action potential , in vagal afferents of high-fat fed (HFF) mice was almost twice the amount required for low-fat fed (LFF) mice - high-fat diet leads to reduced membrane excitability of vagal afferent neurons

VMH lesions

Bilateral lesions placed in the region of the ventro medial hypothalamus (VMH) increase appetite, resulting in marked hyperphagia.

VLH lesions

Bilateral lesions of the ventro lateral hypothalamus (VLH) produced an anorexic condition. Animals failed to feed and experienced wasting.

Leptin function

Leptin regulates the amount of fat stored in the body. Leptin is reduced by sleep deprivation.

Leptin and Insulin

Infused directly into brain ventricles of insulin-deficient diabetic animals normalizes blood glucose levels despite persistent, severe insulin deficiency

GLUT-1

Location: Erythrocytes, blood–brain barrier. Comments: Low level of basal glucose uptake required to sustain cellular respiration

GLUT-2

Location: Beta cells, renal tubular cells, liver, intestinal epithelial cells. Comments:

GLUT-3

Location: Neurons and placenta. Comments:

GLUT-4

Location: Striated muscle and adipose tissue. Comments: ONLY insulin-regulated GLUT: It is responsible for insulin mediated glucose uptake.

Westernization and Gut Microbiome

Shift from high-fiber to low-fiber diet leads to reduced diversity in gut microbiome across generations, with decreasing recovery potential on return to high-fiber diet.

Infusions (Herbal Remedies)

Hot water extracts of herbs.

Tinctures (Herbal Remedies)

Alcoholic (100%) extracts of herbs.

Elixirs (Herbal Remedies)

Alcoholic extract of herbs, ethanol percentage of 12-38%.

Syrups (Herbal Remedies)

Extracts of herbs with syrup or honey.

Factors Affecting Active Ingredient Concentration in Herbal Remedies

Geographic location, UV exposure, plant competition, time of harvest, ripeness, enhancer use, harvesting method, storage/shipment conditions, shelf life.

Metabolism of Cocaine

Butyrylcholinesteraseè hydrolysis; Liver cholinesterases; Liver cytochrome P450 3A4 Inhibited by grapefruit juice substrates include acetaminophen, codeine, cyclosporin, diazepam, erythromycin, and chloroquine.

Cocaine and Alcohol Interaction

Using cocaine with alcohol or after drinking alcohol can lead to up to a 30% increase in cocaine levels in the blood.

Cocaine Half-Life

1 hour in plasma.

Neurotransmitters: Cocaine and Catecholamines

Adrenaline, Noradrenaline, Dopamine - Heart rate , Blood pressure, Contractility, Coronary spasm+vasoconstriction, Platelet adherence/ thrombus, O₂ demand supply, _Na transport

Cocaine: Physiological effects

SERT11 Serotonin receptor, Dopamine receptor, NAT Adrenoreceptors

Cocaine - Common Adverse Effect of Cocaine use in Pregnancy

restricts blood flow to the uterus, cause fetal hypoxia. Uterine contractions, CNS infarction, Heart defects.

Cocaine Binds to ..

dopamine (DA) re-uptake transporters on the pre-synaptic membranes of dopaminergic neurons

Consequence of Cocaine binding

This binding inhibits the removal of DA from the synaptic cleft and its subsequent degradation by monoamine oxidase in the nerve terminal

Cocaine effects on synaptic DA

DA remains in the synaptic cleft and is free to bind to its receptors on the post synaptic membrane, producing further nerve impulses

Cocaine - Neuroinflammation

NOT ALWAYS A NEGATIVE THING: Play a positive role under normal low-level or transient activation. Strong, or chronic activation associated with damaging effects

Synaptic pruning

Adolescence - critical period for brain development, Reorganization of synapses by Microglia +

Traumatic Brain Injury (TBI)

HEAD TRAUMA - TEMPORARY or PERMANENT BRAIN DYSFUNCTION

Lyme Disease Causative Agent

Borrelia burgdorferi (Bacterial infection)

Naegleria fowleri

Brain-eating amoeba; Treatment: Antifungal drug amphotericin B

Multiple Sclerosis (MS) - Mechanism

Demyelinization - Anoctamin 2 - Protein in myelin; MS is considered an autoimmune disease Presence of T cells that recognize oligodendrocyte myelin-specific antigensMS causes are unknown, but several factors contribute to development of the disease

Multiple Sclerosis (MS) Treatment

Disease-modifying treatments reduce frequency and severity of relapses and accumulation of lesions: Increases suppressor T-cell function.

Copaxone (glatiramer acetate)

Synthetic protein with random combination of four amino acids that are found in myelin - May work by acting as a decoy target for immune system

SMA is a genetic disorder Mutation

in the survival motor neuron gene 1 (SMN1) causes SMA; survival motor neuron gene 2 (SMN2) plays a secondary role in symptom severity

Who is at risk of SMA

In people with SMA, both copies of their SMN1 gene are either missing or mutated

SPINRAZA (NUSINERSEN)

antisense oligonucleotides only for 5q spinal muscular atrophy; targets the SMN2 gene and enables it to produce more functional, full-length SMN protein

RISDIPLAM - Action

a small molecule drug that targets the ‘back up’ survival motor neuron 2 (SMN2) gene to produce more SMN protein only used to treat 5q variant spinal muscular atrophy (5q SMA)

ZOLGENSMA™ (ONASEMNOGENE ABEPARVOVEC)

gene therapy that delivers a working copy of the SMN1 gene to motor neurons made from parts of a virus called AAV9 (adeno-associated virus 9)

Amyotrophic lateral sclerosis (ALS)

a degenerative disorder with principally motor symptoms; Death from respiratory failure is generally within 5-7 years

ALS: SOD1 gene

SOD1 serves as antioxidant

ALS: C9ORF72 gene

An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat is a common genetic cause of ALS

Riluzole (Rilutek)

Only one drug is FDA approved for ALS is a presynaptic inhibitor of glutamate release; blocks Na channels à reduces action potentials

Edaravone

Edaravone stroke ALS -slightly slower progression

TUBEROUS SCLEROSIS COMPLEX (TSC)

Rare multisystem autosomal dominant genetic disease that causes non- cancerous tumors to grow.

TSC1

Hamartin -

TSC2

Tuberin -

mTOR inhibitors

selective for the mTORC1 protein complex

Huntington’s disease

symptoms is uncontrolled movement; also causes: decline in thinking and reasoning skills (memory, concentration, judgment and ability to plan and organize)

Huntington Disease: neuropathology

Degeneration in much of the brain → striatum - Key player in motor control

Tetrabenazine - Function

Blocks VMAT2 (vesicular transporter). Prevents uptake of catecholamines into vesicles. Monoamine levels are reduced because they are not packaged into protective vesicles.

Huntington Disease causes

aggregates delay axonal transport

AMT-130

reduce the production of both normal and mutated huntingtin protein by targeting the HTT gene’s messenger RNA (mRNA); adeno-associated virus serotype 5 (AAV5) to deliver microRNA AMT-130

Rabies Transmission

Transmitted via bites or “inhalation” of the virus Symptoms develop within 1 week – 1 year Retrograde travel from site to Brain “universally” fatal

Rabies symptoms

slight or partial paralysis Hydrophobia (larynx) anxiety insomnia Confusion agitation abnormal behavior paranoia terror hallucinations delirium Coma Death

Herpes Simplex Virus (HSV)

There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2); positive status is associated with cognitive deficits, bipolar and Alzheimer's

Parkinsons Disease stages

Stage 1: Develop mild symptoms; Stage 2: Symptoms such as tremors and stiffness begin to worsen; Stage 3: Movement begins , loss of balance; Stage 4: Symptoms are severe; Stage 5: Walking or standing may be impossible

Bradykinesia

Slowness of movement also results in small handwriting, decreased speaking volume, and monotonous speech

Lewy bodies

consist of α-synuclein and other proteins

Alzheimer - Aβ

formed by the sequential cleavage of amyloid precursor protein (APP) by ẞ-secretase and y-secretase ;accumulation; hyperphosphorylation (Neuronal cytoskeleton)