MT1 Flashcards
Define (medical) pharmacology and toxicology
Pramacolgoy: The study of stubstances that interact with living systems through chemical processes
Medical pharamcology: The study of substances used to prevent, diagnose, and treat disease
Toxicology: A branch of pharmacology that studies undesireable effects of chemicals on living systems and ecosystems.
When/where was pharmacology made, and how is it different from pharmacology today?
Found in 2500 BC records in China, Greece, Egypt, and India as there are lists of beneficical or toxic effects of remedies, but efficacy was unknown.
- They were reliant on theorization rather than observation and experimentation beginning in Roman times.
What is pharmacogenomics and its techniques?
The relation of an individual’s genetic makeup to his or her response to specific drugs; what are the side effects of a drug to an individual.
Individuals have different genetic makeup and could inherit diseases.
Genetic techniques: gene therapy, knockout mice
Role of academics and industries in pharmaceutical industry.
Academic institutions discover ‘new’ drug compound for a new drug target.
Industries develop new drugs as they are expensive to produce.
What is a drug and how can it operate?
A drug is any substance/ligand that brings a change in biological function through chemical actions
- Agonist: Activator of a biochemical pathway; mimic endogenous signaling which conformationally changes the receptor
- Inverse agonist: stabilize receptors in an inactive form; closes a receptor that is open/leaky
- Antagonist: inhibitor of a biological pathway (block endogenous signaling)
– Competitive: Binds to same site as natural ligand
– Noncompetitive: Binds to different site as natural ligand and causes a conformation change at the receptor site
– Irreversible: covalent modifaction of receptor
Considerations for drug making.
Drugs must have appropriate: size, electrical charge, shape, and atomic composition with its target receptor. Size varies from 100-1000 MW and exists in organic and inorganic compounds.
Drugs must be able to reach receptor (be able to pass blood brain barrier) and be inactivated/excreted.
Ways to administer drug
Fastest effect
Intravenous (blood vessel)
Intramuscular (muscle) <- painful but large volumes
subcutaneous (under skin) <- painful and small volumes
Inhalation <- often rapid onset
Oral <- Convenient but first-pass effect is significant
Parenteral Rectal <- Less first-pass effect than oral
Transdermal (through skin) <- Very slow absorption
Slowest effect
Types of drug-receptor bonds.
Drug molecuels interact with receptors via chemical bonds/forces
Covalent: very strong bond (usually nonreversible and uncommon)
Electrostatic: Common (charged ionic molecuels, hydrogen bonding, dipole)
Hydrophobic: Weak (highly lipid-soluble molecules)
How can drug action be terminated?
- Dissociation of drug from receptor
— Instant termination of effect as it is a primary channel
— Slow termination of effect as it sends secondary messenger - Destruction of receptor (drug is covalently bonded)
- Desensitization mechanisms
What factors do the receptor control?
Receptors determine the quantitative relations between dose/concentration of drug and effect (# of receptors = limitor of effect)
Receptors are responsible for selectivity of drug action
Receptors mediate the actions of agonists and antagonists
Which drug receptors are mainly targeted?
- G-protein coupled receptor as it mediates natural chemical signals and activates cellular responses
- Enzymes
- Transport proteins
- Strucutral proteins
What is the concentration-effect curve and its equation?
- Curve that describes the effect of a drug due to its concentration.
- Response increment diminishes as dose increases due to the limited amount of receptors
Equation
effect = (Emax*[drug])/([drug]+[drug = 50% of E)
Emax = maximum effect
What is the difference between potency and efficacy?
Potency: Concentration of drug required to achieve a pharmacological response (compared to other drugs). These comparisons are usually made with EC50 (concentration of drug for individual at 50% effectivness) or ED50 (Dose of drug for population at 50% effectivness).
Define alkylating agents
- Binding DNA by creating covalent bonds -> cross-link DNA -> prevent unwinding of DNA -> decrease protein synthesis
- Example: Cyclophosphamide
- oncology
Define epipodophyllotoxins
- inhibit topoisomerase II, enzyme responsible for DNA breaks, thereby inhibiting DNA synthesis
- Example: Etooposide
- Oncology
Define taxanes
- Promote assembly and stablization of microtubules, thus inhibiting cell replication
- may also inhibit angiogenesis
- Example: Docetaxel
- Oncology
Define antimetabolites
- Resemble naturally occurring nuclear structural components
- Incorporate into DNA or RNA -> interfere with function/synthesis
- May also inhibit enzymes involved in synthesis of DNA or proteins
- Example: Fluorourcail (5-FU)
- Oncolgy
Define antitumour antibiotics
- Insert between DNA base pairs -> uncoil DNA helix -> inhibit DNA + RNA synthesis
- May also inhibit polymerase (catalyzes formation of new DNA and RNA from existing strand of DNA or RNA)
- Example: Doxorubicin
- Oncology
Define a druge that is an Alkylating agent + antitumour antibiotic
- Drug: Streptozocin
- Undergoes spontaneous decomposition -> reactive methylcarbonium ions -> alkylate DNA -> interstrand cross links -> inhibits mitosis
- Nitrosurea specific for beta and exocrine cells of pancreas due to an attached suar moiety
- Naturally occurring methylnitrosurea produced from fermentation of Streptomyces archromogenes (Is a natural occuring)
- Oncology
Define Camptothecins
- Bind topoisomerase I, enzyme responsible for reversible, single-strand breaks in DNAA during DNA replication; therefore prevent religation of DNA strand, resulting in cell death
- Example: Irinotecan
Define vinca alkaloids
- Prevent polymerization of tubulin to form microtubules
- induce depolymerization of formed tubules
- inhibit mitosis
- Example: Vincristine
Name and define types of immunotherapy.
**1. Immune Checkpoint inhibitors: Take the ‘brakes’ off of the immune system, which helps it to recognize & attack cancer cells
- T-Cell transfer therapy (Adoptive cell therapy): Boosts T cell ability to fight cancer by taking immune cells from the tumor, selecting, modifying & growing those that are most active against cancer, and infusing them back into the patient
- Monoclonal antibodies: Design antibodies to attack a very specific part of a cancer cell
- Cancer Vaccines: Use vacciens to stimulate teh immune system to prevent or treat cancer
Name different targeted therapy with examples
**1. Monoclonal antibodies: target a receptor
**— Trastuzumab (Herceptin): Anti-HER2
— Rituximab (Rituxan): Anti-CD20
- Proteasome inhibitors:
— Bortezomib (Velcade) - Tyrosine Kinase inhibitors:
— Imatinib (Gleevec): Targets bcr-abl gene found in ALL, CML and gastric stromal tumours..
Name different endocrine therapy with examples
**-Aromatoaseee inhibitors: Lectrozole <- for breast cancer
- Hormone antagonists: taxmoxifen, flutamide, nilutamide, bicalutamide
- Progestins: Medroxyprogesterone, Megesterol acetate
- GnRH analogues: leuprolide, goserelin
- Corticosteroids: prednisone, dexamethasone
What are some common side effects from drugs?
- Febrile neurtropenia: Fever from decreas3ed neutrophile
- Anemia: Decreased red blood cells
- Thrombocytopenia: Decreased platelet
- Mucositis/Stomatitis: inflammation of stomache lining/mouth
- Nausea & vomiting
- Diarrhea/constipation
- weight loss
- Fatigue
- alpecia: loss of hair
- infertility
Caution:
Side effects can arise from drug interactions
What are personalized oncogemonics?
- Cancer contains many diseases that arise from many different outcomes
- Because of this, cancer should be treated uniquely for each person as the “drivers” of the cancer are different.
- We can find the “drivers” through full genome sequencing
Screening tests and the area they screen
Screening area: Test
Colorectal: Colonoscopy
Breast: Mammography
Cervix: Pap Smear
Skin: Dermatology Screening
What is cancer?
- Group of > 100 different diseases
- uncontrolled proliferation & spread of abnormal cells
- A type of cancer is metastasis -> causes cancers at other sites in the body
- Common sites of metastasis: Lymph nodes, bones, liver, brain, lungs
- Classified as solid or hematological cancer
Solid: cancer from one spot
Hematological: blood cancer
Name the causes/etiology of cancers and which type of cancer is caused
Occupational: Asbestos, Chromium, nickel -> lung cancer
Ultraviolet radiation -> Melanoma
Alcohol -> Liver cancer
Tobacco -> Lung cancer
Dietary factors -> colon cancer
Ionizing radiation (uranium deposits) -> leukemia
Viruses (HPV) -> Cervical cancer
Genetics: BRCA1, BRCA2 -> Breast cancer
Drugs: Alkylating agents -> leukemia + bladder cancer
(There are more but don’t need to know)
How can we protect ourselves from cancer?
Avoid potential causes such as …
- Life-style: smoking, alcohol, saturated fat diet
- Carcinogens: asbestos
- Microbes: Human Papillomavirus (HPV) <- HPV vaccine
- Radiation: UV rays
How can you diagnose and determine the stage of the cancer?
- You can only full diagnose a cancer after looking at tissues/cells under the microscope
- Look for signs/symptoms of cancer -> unusual lumps for solid cancer
STAGES
TNM classification for solid tumours
T - Cancer is only at the extent of the primary tumour (size)
N - Cancer is at the extent of regional lymph node metasis
M - Presences of distant meastasis (stage 4 cancer)
What is chemotherapy and how to determine which chemotherapy is right for you? What are precautions of chemotherapy?
Chemotherapy is the use of drug that damage DNA/interfere with DNA synthesis -> cell death of cancer cell. Some drugs are phase-specific (as in what stage the cell is in) while others are not. These drugs work by being absorbed by cells undergoing rapid division (high growth fraction)
- Most people use combination chemotherapy (using more than one chemo)
Pros: Broader coverage against resistant cells
Cons: Is very toxic and can cause the following
— hypersensitivity
— Carcinogenicity
— Mutagenticity
— Infertility
— Pregnancy risk for the fetal
— don’t breastfeed
When choosing combination chemotherapy, keep in mind of the mechanism of action; overlapping toxicities; optimal dose and schedule; and single-agent activity
Precautions: Hypersensitivity, Carcinogenicity, mutagenicity, infertility, risk to fetals during pregnancy -> no breastfeeding
Factors that makes cancers more drug resistant and how they become drug resisitance?
Increasing tumour size will help with drug resistance due to more possiblity of mutation and inheritance of resistance.
Mechanisms of drug resistnance:
- improve DNA repair
- inactivate cancer drug
- decrease cellular uptake of drug
- increase efflux of drug
- Change biochemical pathways
- Change target enzymes
Name the different nervous systems and what they do?
CNS: Control conscious and unconscious functions
— Brain
— Spinal cord
PNS:
— Somatic nervous system: Conscious control
—— Efferent
—— Afferent
— Autonomic nervous system: autonomous control -> Heart rate/contraction, respiration, digestion
—— Parasympathetic: Rest and digest
E.G. Heart rate -> decreased
Brochial constriction (less air)
—— Sympathetic: Fight or flight
E.G. Heart rate -> increased
Bronchial dilation (more air)
** Organs will be under the influence of both the sympathetic and parasympathetic nervous systems but there will be a dominant tone (greater influence) from one of the nervous system. This means that drugs will have varying effects in different organs
What are the major neurotransmitters used in the autonomic nervous system?
Parasympathetic nervous system: Cholinergic responses (Acetylcholine)
(Muscarinic receptors are found in this pathways)
Sympathetic nervous system: Adrenergic responses (adrenaline)
What are some common traits between parasympathetic and sympathetic nervous system?
- Both have ganglia/relay station but the PSNS is further from the spinal cord
- Neurotransmitter released onto receptors at the ganglia is acetylcholine
- The receptors at the ganglia are nicotonic receptors
- Most drugs work at postganglionic receptors on the ORGAN
Neurotransmitters and what releases them?
ACETYLECHOLINE: Synthesized in from acetyl CoA and choline and stored in vesicles in the presynaptic until released
Adrenal medulla in kidney(parasympathetic): Releases 80% EPINEPHRINE and 20% NOREPINEPHRINE
All of these neurotransmitters are catecholamines that are formed from tyrosine.
What receptors are activated in the PSNS and key facts about them?
Muscarinic (M) receptors and has several subtypes (M1-5)
There are fewer drugs that target muscarinic receptors compared to adrenergic receptors but play a big part in side effects.
** Play an important role in the CNS <- role in cognitive function
M1, M3, M5 - excitatory g-protein coupled receptors -> increase contractions in smooth muscles
M2, M4 - inhibitory g-protein coupled receptors -> decrease contractions in smooth muscles
What are the effects of a muscarinic agonsit?
This is parasympathetic response
Heart (M2) - decreased rate, constractions
Lungs - bronchoconstriction (less air)
Sphincters (GI and bladder) - relaxation (allow movement of food)
Walls ([M3]Bladder, GI tract) - contraction (move things to the next compartment)
Secretion (salivary, respiratory, tears) - increased
How can we stimultae muscarinic receptors?
- Using a dircet agonist
- Inhibiting acetylcholinesterase -> increased concentration of acetylcholine -> activate ganglia
What type of chemical reaction can occur when cholinesterase is bound?
- Acetylation (Physiolgocial and fast recovery)
- Carbamylation (slower recovery and reverisble drugs)
- Phosphorylation (No recovery and irreversible drugs)
What would an excessive cholinergic response look like?
Secretions (drooling, tearing, clogged airways) - increased
Lungs - bronchoconstriction (difficulty breathing)
Heart - reduced heart rate (decreased endurance)
GI motility - Increase nausea, vomiting, diarrhea
urinary tract - constraction of bladder, relaxation of sphincters (urination)
What are parasympatholytics and name one.
Parasympatholytics block PSNS responses by antagonism of muscarinic receptors.
Also known as anticholinergics or anti-muscarinics
One parasympatholytic is atropine
What are some uses and side effects of atropine?
Uses
- Open airway
- Dilate pupils to faciliate eye exams
- Dilate bronchioles
- Conteract poisoning by cholinesterase inhibitors
Side effects
Mouth - dry mouth
Heart - tachycardia (increased heart rate)
Gut - constipation
Bladder - diffuclty urinating
What are the different receptor for SNS and what are their functions?
** Liver, kidney and uterus are only stimulated by the SNS
Alpha-1: constriction of smooth muscles (g-protein)
— Sphincters (bladder, GI tract), blood verssels
Alpha-2: inhibition of presynaptic norepinephrine release (on presynaptic)
Beta-1: Stimulate heart -> increased heart rate and contractility (g-protein)
— Stimulate kidney -> release of renin -> increase in blood pressure
Beta-2: relaxtion of smooth muscle in lungs, blood vessels in skeletal muscle, GI tract/bladder/uterus walls; also stimulate liver to release glucose via gluconeogenesis and glycogenolysis (g-protein)
What are sympathomimetics?
Drugs that mimic stimulation of the sympathetic nervous system by
directly stimulating adrenergic receptors
or
increase amount of sympathetic neurotransmitter in the synapse
1. By increasing neurotransmitter release
2. Inhibiting the reputake of neurotransmitter
3. inhibit metabolism of neurotransmitter
What are sympatholytics?
Drugs that block or reduce sympathetic activity.
Done by blocking adrenergic receptors (propanolol) [E.G. beta-1] or decreasing the amount of sympathetic neurotransmitter released into the synapse (clonidine) [E.G. alpha-2]
What muscles are in the eye?
Iris muscle: controls the size of pupil diameter
— Circular muscle (Sphincter) - M3/2 receptors -> contraction constricts pupil
— Radial muscle - alpha-1 receptor -> contraction dilates pupil
Ciliary muscle - shapes lens to focus image on retina and controls production of aqueous humor
What is glaucoma?
Common codition in elderly which results from increased aqueous humor in the eye lens.
-> increase in intraocular pressure (increased production or decreased drainage of aqueous humor)
We can treat glaucoma by increasing drainage (stimulate M2/3 receptors to open trabecular meshwork and canal of schlemm) or decreasing production of aqueous humor (beta-2 receptor antagonist to decrease blood flow and aqueous humor production or alpha-2 agonist)
