Exam 2 Material Flashcards
Releasing agents
Examples
Amphetamine
Tyramine
epigenetics definition
changes gene expression, so the phenotype is changed without affecting the DNA sequence of the gene. The change is in chromatin structure.
these changes are heritable.
The Therapeutic Window
More clinically relevant safety index.
dosage range between the minimum effective therapeutic concentration and the minimum toxic concentration
Contraindications of antimuscarinic agents
Contraindicated in patients with angle-closure glaucoma
Should be used with caution in patients with prostatic hypertrophy and in the elderly
Proto-oncogenes
Produce proteins which promote cell growth or prevent apoptosis
Gain of Function Mutation and/or over- or mis-expression causes cell growth
Mutation in ONE copy sufficient to cause cancer
Bloom syndrome Charactaristics
- smaller than average
- narrow chin, prominent nose and ears
- facial rash (pigment and dilated blood vessels) upon exposure to sun -often get diabetes and have neurological, lung and immune system deficiencies
Virtually all cancer cells show dysregulation of the G1 -S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB. What are these 4 genes?
RB, CDK4, cyclin D gene, and CDKN2A (p16).
Physiological Antagonism
One drug opposes another through different receptors.
Ex. Epinephrine and histamine.
Isochromosomes
There is loss of one arm of a chromosome & duplication of the other arm
X isochromosome: long arms of the X chromosome join to form an isochromosome. Leads to Turner Syndrome.
Typically results in chromosomal and gene dosage imbalance
Isochromosome of an autosome is lethal
Connective Tissue Function
Connective tissue is directly supplied by _________?
support
repair
defense (immune)
nutrition (storage & transport)
blood, lymphatic vessels and nerves.
Turner Syndrome and Isochromosome X
Only one copy of X short arm. Isochromosome usually inactivated.
Haploinsufficiency of genes on the p arm that escape X inactivation thought to give rise to Turner Syndrome phenotype
Bethanechol
Type
Function
Mnemonic?
Direct acting Cholinergic agonist
Decrease urinary retention.
BATHanechol….. It makes you have to go to the BATHroom.
Irreversible Competitive Antagonism
Emax of the agonist is reduced.
This antagonism is insurmountable.
Some authors refer to this type of antagonism as noncompetitive
What happens when an enzyme responsible for metabolism of a certain drug is inhibited?
Drug levels may reach toxic concentrations
O-glycosylation
Individual linkage of activated sugars step by step directly to the protein.
Reticular Fibres
- Type III collagen primarily
- They are short, thin and branching in nature.
- Found in organs with large volume changes (spleen, arteries, intestine, testes, etc)
- Argyrophilic (silver staining) and PAS positive (due to carbohydrate content)
- First type of collagen synthesized during wound healing
M3 Receptor
Locations
Signaling
Effects on each location
Smooth muscle, secretory glands, eye, urinary system, vascular entothelium
incr. Gq activity
SM contraction/bronchoconstriction, secretion, Miosis (pupil constriction), Incr. urinary output, vasodilation
Identify the disease:
FAP
Pharmacokinetics
the study of absorption, distribution, metabolism and excretion of drugs
Label the order and describe:
t(9;22)→Chronic myelogenous leukemia (CML)
Activation of an oncogene→ Cancer Philadelphia chromosome t(9;22)→ Activation of BCR-ABL tyrosine kinase which is a proto-oncogene in hematopoietic cells
Clonidine
Type
Function
Mnemonic?
Direct acting, alpha-2 selective adrenergic agonist
Activates @ presynaptic alpha-2 receptor. Acts as a partial agonist, and decr. BP. Works as an antihypertensive
Clonidine sounds like Klondike. and Klondike is comfort food that makes you relax, lowering BP.
Categories of β -adrenergic blockers
Non-selective β blocker
β 1-selective blocker
Partial β-agonist
Mutagens
increase the frequency of ‘normal’ mutations (mismatches, depurination, etc.)
Tropicamide
Tertiary Amine Muscarinic Antagonist
Copper cofactor
Prolyl hydroxylase
Lysyl hydroxylase
Lysyl oxidase
no
no
yes
Abnormal Homogenously staining regions
amplified oncogenes attached to the chromosome.
N-glycosylation
This […]-rich precursor is linked only to the nitrogen of an […] side chain.
All proteins receive the same oligosaccharide and only later the sugars are individually modified in the […] and […] dependent on the protein.
Complex glycoproteins and high-mannose glycoproteins are formed in the […].
This mannose-rich precursor is linked only to the nitrogen of an asparagine side chain.
All proteins receive the same oligosaccharide and only later the sugars are individually modified in the RER and Golgi dependent on the protein.
Complex glycoproteins and high-mannose glycoproteins are formed in the Golgi.
Two Hit Hypothesis: Familial cancers
- First mutation is inherited, and therefore, present in every cell (1 st hit)
- Second mutation can occur in any cell (2 nd hit)
- Loss of all tumor suppressor activity in that cell
- Cancer/ malignant transformation
Ataxia telangiectasia
defect is in […] gene (11q22-23) (involved in repair of […])
A serine-threonine protein kinase with a number of functions including […] and […].
- […] inheritance
- rare disease (incidence estimated to be 1:50,000)
defect is in ATM gene (11q22-23) (involved in repair of double strand breaks)
A serine-threonine protein kinase with a number of functions including: -detecting DNA damage (i.e. it is a sensor) and activating cell cycle arrest and DNA repair proteins (e.g. p53)
- autosomal recessive inheritance
- rare disease (incidence estimated to be 1:50,000
Clearance
a measure of the body’s ability to eliminate the drug
Collagen Commonly found amino acids
Proline, lysine, hydroxyproline, hydroxylysine
Deamination
- Pretty common form of spontaneous lesion
- loss of amine group from a base
- Example: cytosine (which base pairs with G) deaminates to form uracil (Uracil would like to pair with A). This is easy to fix because Uracil does not belong in DNA.
Bioavailability formula
F = (AUC oral / AUC IV) * 100
Wolf-Hirschhorn syndrome (WHS)
- Deletion of ch 4p
- Seizures
- Skeletal abnormalities and congenital heart defects
- Spectrum of intellectual and developmental delay, mild to severe
- Facial anomalies - widely spaced eyes, high-arched eyebrows, broad & flat nasal bridge, short philtrum, downturned mouth, small chin
Beta-1 receptor
Locations
Signaling
Effects on each location
heart, juxtaglomular cells, adipocytes
incr. cAMP. incr. Gs pathway
incr. HR/force of contraction/AV conduction (Tachybradia), Renin release, incr. lipolysis
2 types of cholinergic antagonists
Muscarinic
Nicotinic
DNA repair mechanisms
Nucleotide Excision
Base Excision- (Same as NER, but much smaller scale)
Mismatch Repair
OPRT and OMP decarboxylase
different activities present on the same polypeptide chain
This enzyme is also known as UMP synthase
Fibroblast / tendon cell / tendinocyte layers of covering
Covering an entire tendon: - Epitendineum
Covering around a group of fascicles: - Peritendineum
Covering around a group of fibers: - Endotendineum
Toxicology
the study of adverse effects of drugs
Ion Channels
- Several classes of drugs act by altering the conductance of ion channels.
- Examples are
- Local anesthetics
- Sedative-hypnotics
- Antiepileptics
CPS II is activated by
ATP and PRPP
Choroid Plexus
Invaginated folds of pia mater containing tufts of fenestrated capillaries covered by simple cuboidal ependymal cell in ventricles of the brain
Identify and describe:
Adipose Connective Tissue
Cells -large
Nucleus -peripheral
Lipid droplet -one
Function -fat storage
Maintenance dose formula
At what stages is gene expression regulated?
This regulation can occur at many different steps of gene expression, including:
– Transcription (most frequently)
–mRNA processing
– Translation
– Regulation of protein half life
Direct acting cholinergic agonists
bind to and activate muscarinic or nicotinic receptors.
Many have effects on both receptors.
Most therapeutically useful drugs preferentially activate muscarinic receptors
Transcription factors may also act as repressors
Three modes of action
Competition
Quenching
Blocking
Describe how efficacy and potency compares here.
Drug A is more potent than Drug B.
Drug A and Drug B have equal efficacy.
Drug C has lower potency and lower efficacy than Drugs A and B.
Repressors
bind to an operator region and prevent RNA polymerase from initiating transcription
The donors of C and N atoms for the pyrimidine ring are
Aspartate, Glutamine and CO2
Beta-2 receptor
Locations
Signaling
Effects on each location
Smooth muscle, skeletal muscle, Pancreatic a cells, Liver, Adipocytes
incr. cAMP
SM relaxation/vasodilation/bronchodilation, incr. glycogenolysis and K+ uptake, incr. glucagon secretion, incr. glycogenolysis and gluconeogenesis, incr. lipolysis
Location (intracellular or extracellular)
Prolyl hydroxylase
Lysyl hydroxylase
Lysyl oxidase
intracellular
intracellular
extracellular
Indications for Cytogenetic or Cytogenomic Testing for a microdeletion syndrome
Unexplained developmental delay or autism spectrum disorder
Congenital anomalies/dysmorphic features
Suspected deletion or duplication syndrome
Induction has important clinical consequences. What are they?
- A drug can increase its own metabolism.
- A drug can increase the metabolism of a coadministered drug.
- This may reduce drug plasma concentrations below therapeutic levels.
47, XXX females may be the result of
meiosis I or II nondisjunction in moms or meiosis II non-disjunction in dad
How do you acheive the proper dose of medication:
Multiply Vd by Target Concentration (TC).
operator
upstream region of regulated genes adjacent to the promoter
a sequence of DNA which is a binding site for specific proteins that help to regulate gene expression
How is the Vd curve liniarized?
by plotting the logarithm of the plasma drug concentration vs time.
Atropine
Prototype of muscarinic antagonists
Reversible competitive antagonist at muscarinic receptors
Tertiary amine: both central and peripheral muscarinic blocker
Methotrexate (folic acid analogue)
Type of inhibition and which enzyme?
Function of enzyme?
Mechanism of action?
End result?
Competitively inhibit dihydrofolate reductase
makes tetrahydrofolic acid
cnacer cells become resistant to MTX by amp. of gene for dihydrofolate reductase.
Anti-Cancer. Treats psoriasis, rheumatoid arthritis, neoplastic disease. LUKEMIA!
Bcr-Abl Translocations in Chronic Myeloid Leukemia
Philadelphia Chromosome t(9;22)(q34;q11)
Quantal Dose-effect Curves
plots the fraction of the population that responds to a given dose of drug as a function of the drug dose.
characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect
dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50).
dose required to cause death in 50% of animals is called the median lethal dose (LD50)
Categories of Indirect acting cholinergic agents
Edrophonium
Carbamates
Organophosphates
Activation of the Ras proto-oncogene
Ras activated by binding GTP
- It initiates a phosphorylation cascade that activates cellular proliferation
- It is quickly inactivated by intrinsic GTPase activity (GTP→GDP)
- A constant stimulation is required to continue to grow
Turner Syndrome (45,X) Features
- X chromosome monosomy - Usually due to nondisjunction during spermatogenesis
- Short stature
- Webbed neck, cystic hygroma at birth (neck swelling)
- Primary amenorrhea
- Gonadal dysgenesis
- ‘Streak ovaries’
- Lymphoedema of hands and feet
What is uric acid??
end product of purine breakdown (adenine, guanine, hypoxanthine)
normally excreted in the urine has a low solubility
When the blood uric acid levels (hyperuricemia) are high, monosodium urate tends to precipitate in the joint (synovial) fluid causing arthritis (gouty arthritis) – ‘Needle shaped crystals’
Renal stones made up of uric acid may also be seen
Neostigmine
Type
Function
Indirect acting cholinergic agonist
Treats urinary retention and myasthenia gravis
topical carbachol
(a cholinergic muscarinic agonist) into the conjunctival sac. This caused exaggerated miosis.
Like what ophthalmologists
Main use of volume distributin
determine the loading dose to quickly achieve a target plasma concentration.
If intermittent doses are given, the maintenance dose is calculated with
Maintenance dose = dosing rate x dosing interval
Carbamates
form a covalent bond with the enzyme
Physostigmine
Neostigmine
Pyridostigmine
Multiple Systems Atrophy
group of disorders characterized by neuronal degeneration
Identify the form of administration
IV bolus injection
Glycosaminoglycans
Hyaluronan,
Chondroitin-4- Sulphate
Chondroitin-6- sulphate
Heparan sulphate
Keratan sulphate
Dermatan sulphate
Inverse Agonists
Some receptors are constitutively active even when there is no agonist. (ex: GBeta) Inverse agonists reverse the constitutive activity of a receptor.
Myasthenia gravis
Autoimmune disease, affecting neuromuscular junction
Ach receptors get attacked by antibodies in the post synaptic membrane
Results in fluctuating weakness and fatigue of skeletal muscles. Ocular, bulbar, limb, and respiratory muscles are all affected.
Microglia
- smallest Central Neuroglia
- phagocytosis of bacteria, injured tissue & debris
- Abundant spikes/ruffled border
Which pathway is involved with smooth muscle?
What 2nd messengers are involved with this pathway?
What is the result?
Gq pathway
Phspholipase C
PIP2
IP3 and DAG
Increase of Ca2+ and activation of PKC
Volume of distribution:
a measure of the apparent space in the body available to contain the drug
the volume that would be required to contain all of the drug in the body at the same concentration as it is in the blood.
alpha-adrenergic types
alpha 1 selective
alpha 2 selective
Potency
a measure of the concentration or amount of drug necessary to produce an effect of any magnitude
The EC50 of a drug is usually used to determine potency.
Two methods of drug removal
Metabolism
Excretion
phytohemagglutinin
It its presence, White blood cells, lymphocytes, divide
Normal APC Pathway: WNT signal present
- Destruction complex inactivated
- β-catenin not degraded
- β-catenin moves to nucleus, forms complex with TCF-4
- Activates growth promoting genes
What are the effects of reciprocal translocation in carriers if the reciprocal translocation is present in the germ line cells?
there is a higher incidence of spontaneous abortions in the carrier
Collagen amino acid composition
1/3 represented by glycine (in each 3 rd position
Identify:
Elastic artery
1) Dnmt3
2) MeCP2
3) HDAC1
4) Dnmt1
Dnmt3 methylates unmethylated DNA
MeCP2 recruites either HDAC1 or Dnmt1
HDAC1 deacetylates histones
Dnmt1 methylates hemimethylated DNA
Α - actinin
Actin binding protein that bundles and helps stabilize thin filaments at Z line
ganglionic blockade and neuromuscular blockade
Effect of pH on drug absorption (liposolubility)
- Most drugs are weak acids or weak bases that are present in solution as both the nonionized and ionized species.
- The protonated form of a weak acid is the more liposoluble form
- The unprotonated form of a weak base is the more liposoluble form.
Adrenergic agonists and antagonists are useful in the treatment of many disorders, such as
Hypertension
Angina
Heart failure
Arrhythmias
Asthma
Migraine
Anaphylactic reactions
G Protein-linked Receptors
- Approximately 60 % of prescription drugs act by binding to G protein linked receptors.
- Examples:
▪ Albuterol, a B2 -agonist, is used for asthma.
▪ Propranolol, a B-antagonist, is used for hypertension.
allosteric antagonism
reduces the action of the agonist.
This type of antagonism is insurmountable.
Emax is decreased.
Does Collagen Synthesis occur in fibroblasts as soluble protein? How?
Yes procollagen helix 3 pro-a-chains
Troponin C
Troponin T
Troponin I
- troponin-C (TnC) binds calcium
- troponin-T (TnT) binds to tropomyosin and anchors troponin complex
- troponin-I (TnI) inhibits actin-myosin interaction
Atropine actions for each of the following
Eye
GI
Urinary
Cardiovascular
Secretions
Eye: Mydriasis & cycloplegia (M3 blockade)
GI: Reduces gastric motility (M3 blockade)
Urinary system: Decreases hypermotility of urinary bladder (M3 blockade)
CV system: Moderate to high therapeutic doses cause tachycardia (Atrial M2 blockade)
Secretions: Salivary, sweat and lachrymal glands are blocked. Inhibition of sweat glands may cause high body temperature (M3 blockade)
Smooth Muscle - contraction
- Contractile myofilaments are oriented obliquely to the long axis of the myocyte
- These are anchored to cytoplasmic and cell membrane densities
- Therefore during contraction there is a net shortening of the cell
- The cell adopts a globular shape and the nucleus adopts a “corkscrew” shape
Tubocurarine
Mechanism of action
Use
Nondepolaizing blockers
Competitive antagonist
As adjuvant drugs in anaesthesia during surgery to relax skeletal muscle
liability in multifactorial genetics
All factors that contribute to the disease = liability produces normal distribution
If: - you have only “good” genes you can have a lot of “bad” environment and still be okay
But - if you start out with some “bad” genes, it does not take much “bad” environment to tip you over the edge
Albuterol
Type
Function
Direct acting beta-2 selective adrenergic agonist
Causes bronchodilation to treat asthma and COPD
Turner Syndrome (45,X)
- X chromosome monosomy - Usually due to nondisjunction during spermatogenesis
- Short stature
- Webbed neck, cystic hygroma at birth (neck swelling)
- Primary amenorrhea
- Gonadal dysgenesis
- ‘Streak ovaries’
- Lymphoedema of hands and feet
- Many TS patients are mosaic • Some of their cells are 45,X • Other cells are 46,XX and 47,XXX (indicate mitotic nondisjunction during embryogenesis)
Tyrosine Kinase Receptors
polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain (tyrosine kinase).
play an important role in cellular growth and differentiation.
Gain-of-function mutations in these receptors can lead to cancer, so inhibitors are used as anti-cancers.
Pharmacominetics
A drug should be able to reach its site of action after administration.
In few situations a drug is directly applied to its target tissue.
Example: topical application of an anti inflammatory agent to inflamed skin.
Cocaine
Type
Function
Indirect acting adrenergic agonist
Blocks monoamine reuptake
Monoamines accumulate in synaptic space.
This results in potentiation and prolongation of their central and peripheral actions.
Anaphylactic Shock and edema
Anaphylactic shock - increased mast cell release of histamine.
Edema - increased tissue fluid
Organ effects of Acetylcholinesterases
amplify the action of endogenous acetylcholine
similar effects (but not always identical) to the effects of the direct acting cholinomimetic agonists
SNS stimulation ONLY in
➢Vascular smooth muscle
➢Sweat glands
➢Piloerector muscles
➢Liver
➢Adipose tissue
➢Kidney
Blood uric acid levels >6.8 mg/dL usually results in precipitation of
monosodium urate crystals in joints and soft tissues – Gout
MicroRNA in Tumorigenesis
- miRNAs act to reduce the expression of genes by targeting specific mRNAs
- Aberrant expression/activity of miRNAs could be tumorigenic
- miRNAs have been shown to undergo changes in expression in cancer cells with frequent amplifications and deletions of miRNA loci
Reduction of miRNA that could have inhibited oncogene RNA. Increase in miRNA that inhibits tumor suppressor RNA
Label the different lines:
Collagen Genes
One or two genes are expressed for triple helix formation
Oral Route
maximum convenience, but absorption may be slower and less complete than with parenteral routes.
Ingested drugs suffer first-pass effect: a fraction of the drug is metabolized in the gut wall and the liver before reaching systemic circulation.
Trisomy 13 (Patau syndrome) Features
- Polydactyly
- Cleft lip and palate
- Microphthalmia
- Microcephaly
- Intellectual disability
- Cardiac anomalies (VSD or ASD)
Familial Adenomatous Polyposis
- Multiple (>100) adenomatous polyps develop throughout distal colon
- Very high penetrance
- ~1% of colorectal cancers
- Tumor suppressor gene (affects B- catenin involved in growth control pathway)
- Autosomal dominant inheritance
Many different mutations of the APC gene (Chrom. 5) are reported (Allelic heterogeneity)
Which chromosomes are acrocentric
13, 14, 15, 21, 22
Muscle Spindle
Encapsulated sensory receptors
Specialized stretch receptor located in the muscle belly
Senses changes in muscle length or stretch
Contains modified muscle fibers or Spindle Cells
Titin
Spring like protein→ keeps thick filament centered between two the Z lines of the sarcomere and prevents excessive stretching
Ion Trapping
- The most important application of this equation is in the manipulation of drug excretion by the kidney.
- If a drug is in a liposoluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion.
Neuromuscular blockers
Competitive Antagonists (Nondepolarizing blockers)
Agonists (depolarizing blockers)
Connective Tissue Classification and Subcategories
Embryonic: Mesenchyma and Mucous
Connective Tissue Proper: Loose, Dense Regular, Dense Irregular
Specialized Connective Tissue: Cartilage, Blood, Bone/Hemopoetic, Adipose, Elastic, Reticular
Rifampin (Rifamycin)
Type?
Treats?
Mechanism of action?
Targets?
Antibiotic
TB
blocks formation of 1st phosphodiester bond inhibiting prok. transctiption initiation.
prok. RNA polymerase
Enteral Routes of administration
Oral
Sublingual
Rectal
Drug liposolubility
a major factor affecting drug distribution, particularly to the brain, where the blood-brain barrier restricts the penetration of polar molecules.
Drug penetration into the brain depends on transcellular rather than paracellular transport.
presence of spare receptors indicates
there is signal amplification
What are the primary types of Proteoglycans in the ground substance?
Aggrecan, Decorin, Versican, Syndecan
can form a bottle-brush structure
maintenance doses usage
To maintain the plasma concentration within a specified range over long periods of therapy
Roles of epigenetics
Gene expression regulation
Stem cell differentiation
Dosage compensation from imprinting. (ex: trisomy rescue)
environmental gene expression modulation
Whole chromosome inactivation. (ex. X inactivation)
Edrophonium
Type
Function
Indirect acting cholinergic antagonist
Dx. Myasthenia gravis by causing a rapid increase in muscle contraction
alpha-1 antitrypsin deficiency
type?
clinical features?
genetic principles?
Autosomal recessive
COPD, emphesyma, lung diseases.
loss of function
Elastin Post-translational hydroxylations, vitamin C
no
What is the therapeutic window?
Determines the range of plasma levels acceptable when designing a dosing regimen
Minimum effective concentration determines the trough plasma concentration.
Minimum toxic concentration determines peak plasma concentration.
Exportin 5
Transports Pre-miRNA to cytoplasm
Transverse tubules
Invaginations of the sarcolemma at the A-I junction.
Have voltage-sensor proteins/ channels activated by membrane depolarization.
Acetylcholinesterases CV effects
In the vascular smooth muscle cholinesterase inhibitors have minimal effects because most vascular beds lack cholinergic innervation
Identify the lines as:
Partial Agonist
Inverse Agonist
Full Agonist
Antagonist
Top-Down:
Full agonist
Partial agonist
Antagonist
Inverse agonist
Propranolol
Type
Function
Non-selective beta adrenergic antagonist
decr. HR (B1), decr. myocardial contractility (B1). decr. glycogenolysis (B2), decr. glucagon secretion (B2).
Contraindicated for patients with Diabetes (masks tachycardia caused by hypoglycemia) and Astham/COPD (causes bronchoconstriction)
Norepinephrine
Type
Function
Direct acting alpha-1, alpha2, and beta-1 adrenergic agonist
Causes peripheral vasoconstriction and cardiac contractility to increase BP and treat shock.
Phenoxybenzamine
Type
Function
Irriversible non-selective alpha-adrenergic antagonist
Used in pheochromocytomas to control hypertension prior to surgical removal of the tumor.
Acetylcholinesterase Neuromuscular junction effects
inhibitors increase strength of contraction
Useful to reverse action of nondepolarizing neuromuscular blockers
Useful in myasthenia gravis
Pheochromocytoma
Description
Clinical Features
Diagnosed
Nonmalignant tumor of adrenal medulla affecting the chromaffin cells. Secretes catecholamines
Episodic hypertension, headaches, palpatations, Tachycardia, Sweating
Elevated serum metanephrine. Increased 24-hour urine metanephrines and vanillylmandelic acid
What is allowed by slow release drug fromulations?
less frequent administration of drugs with short half-lives.
Trisomy 21 (Down syndrome) Features
▪ Intellectual disability
▪ Short stature
▪ Depressed nasal bridge, upslanting palpebral fissures, epicanthal folds
▪ Congenital heart defects
▪ Single palmar crease
▪ Develop changes similar to Alzheimer disease at a relatively young age.
▪ One of the genetic factors responsible for Alzheimer is localized to chromosome 21 (amyloid precursor protein APP)
M1 Receptor
Locations
Signaling
Effects on each location
Ganglia, Vomiting center
Incr. Gq activity.
Galglia depolarization and emesis
Methotrexate side effects
anemia, GI disturbance, scaly skin, hair loss, immune deficiency
Sarin
Type
Function
Indirect acting cholinergic agonist
Nerve agent: poison gas
Rectal Route
partial avoidance of the first-pass effect.
Cardiovascular Effects of ACh
Direct effects
Vasodilation (M3)
Decreased heart rate (M2)
Decrease in rate of conduction in the SA and AV nodes (M2)
Decrease in force of contraction (M2)
Some of these direct effects can be obscured by baroreceptor reflexes
Transverse tubular system Cardiac Muscle
Located at the Z line (compare to skeletal muscle)
T tubules contain voltage-sensor proteins
Plasma Cell function and structure
Phagocytic; produce cytokines
Antigen presenting cells; multinuclear giant cells
Nicotinic Cholinergic antagonists
Ganglion blockers
Neuromuscular blockers
Presynaptic blockers
Collagen Special
Type I-III fibril-forming Type IV for basement membrane
What amino acids are predominent in elastin?
glycine, proline, desmosine and isodesmosine (lysine‐like)
Transverse component of intercalated discs
Fascia Adherens (Adhering junctions) binds cardiac muscle cells at their ends and serves as attachment site for thin filaments
Desmosomes bind individual cells together, reinforce FA. Found in transverse and lateral components
sulfonamides
sulfa drugs
inhibit bacterial folate synthesis
PABA analogs
Muscle cell Mitochondria location
arranged between the myofibrils
Ring Chromosomes
forms when a chromosome loses genetic material at the terminal portions & the ends fuse to form a ring like structure
Phentolamine
Type
Function
Reversible, non-selective alpha-adrenergic antagonist
Used for pheochromocytomas to treat hypertensive crisis resulting from drug overdose
Plasma cells golgi
negative Golgi –slightly acidophilic area close the nucleus
The BMR for young male individuals is set generally as
24 kcal/kg/day body weight (1 kcal/kg/hour).
The synthesis of thymidine requires one-carbon groups as
methylene tetrahydrofolate (THF)
G6PD deficiency
type?
clinical features?
X-linked recessive
hemolytic anemia on ingestion
Fibrous astrocytes
- prevalent in white matter
- straight processes
- GFAP
Pyridostigmine
Type
Function
Indirect acting cholinergic agonist
Does not enter CNS
Long term treatment of myasthenia gravis
Confined germline mosaic
Body cells all the same genotype, but gametes may vary.
imatinib
Tyrosine kinase inhibitor, effective for leukemia.
binds to the active site of the fusion protein, bcr-abl (tyrosine kinase) and prevents its activity
Vitamin C cofactor
Prolyl hydroxylase
Lysyl hydroxylase
Lysyl oxidase
yes
yes
no
Constitutive Prokaryotic Gene Regulation
- Some genes (constitutive genes) are always expressed within a cell
- Constitutive genes are often referred to as “housekeeping” gene.
Burkitt lymphoma
Myc oncogene is fused to immunoglobulin locus (t 8:14)
Level of oncogene expression is increased as myc is now under the regulation of IgH promoter (Active promoter)
Increased myc production
Interstitial fluid
- Small quantity of H2O - for solvation and diffusion
- Edema
Cri-du-chat Syndrome features
- High pitched, cat-like cry
- Micrognathia which influences the cat-like cry and later, speech problems
- Severe intellectual disability
- Microcephaly
- Hypertelorism (widely spaced eyes)
Depurination
- most common form of spontaneous lesion
- breaking of glycosidic bond between base and sugar in purine nucleotides
- sugar-phosphate backbone remains but base is lost
- if it persists through replication then mutation can occur
Trimethoprim
inhibits bacterial dihydrofolate reductase
Ehlers-Danlos syndrome
Abnormal collagen production attributed to mutations in genes encoding the α chains in the various collagens.
Characterized by hyper mobility of joints of digits, pale thin skin, early morbidity and mortality due to rupture of vessels and internal organs.
Succinylcholine
Mechanism of action
Use
Depolarizing blockers
binds to the nicotinic receptor and depolarizes the junction. Persists in the synaptic cleft, stimulating the receptorto desensitize it, leading to flaccid paralysis.
Rapid endotracheal intubation and ECT
Blood-Brain Barrier
- The endothelial cells of the brain capillaries have continuous tight junctions.
- Astrocytic “end feet” surround the outside of capillary endothelial cells.
- The P-glycoprotein actively transports drugs back into the systemic circulation.
47, XXY Klinefelter syndrome may be caused by nondisjunction during
meiosis I or II in the mom, or nondisjunction during meiosis I in dad
Muscle nicotinic receptors are found at the
skeletal neuromuscular junction
Rb protein – Regulator of G1/S phase transition
W/ cyclins E2F not repressed. Cell divides
w/o cyclins, Rb/E2F binds DNA. Recruits methylase and histone deacetylase. Blocks transcription, resulting in G! arrest.
Mycophenolic acid
Type of inhibition and which enzyme?
Function of enzyme?
Mechanism of action?
End result?
Reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase
IMP->xanthosine monophosphate->GMP
deprives rapidly proliferating T and B cells of key components of nucleic acids
prevents graft recognition
What kinds of glycoproteins are formed in the Golgi?
Complex glycoproteins and high-mannose glycoproteins are formed in the Golgi.
Zero order elimination is observed with a small number of drugs
- Aspirin at high doses
- Ethanol
- Phenytoin
Overall result of Drosha->Exportin 5 -> Dicer -> RISC pathway
Inhibition of the ribosome ability to translate protein from mRNA transcript
Oligodendrocytes
One oligodendrocyte for several axons
Identify the type of inversion:
Pericentric
Four Tissue Types
- Epithelium
- Nervous Tissue
- Muscle
- Connective Tissue
Identify and describe:
Endomysium- En
Delicate layer of reticular fibers surrounding an individual muscle fiber
small blood vessels and very fine neuronal branches
alpha-adrenergic blockers
non selective alpha blocker
alpha 1 selective blocker
Describe the membrane of a Plasma cell
Irregular cell membrane / cytoplasmic extensions (pseudopodia)
Atropine
Type
Function
Mnemonic?
Muscarinic Cholinergic Antagonist. Belladonna alkaloid
Blocks respiratory tract secretions prior to surgery. Anti-Cholinergic everything.
hot as a hare, dry as a cracker, red as a beat, mad a a hatter
Malathion
Type
Function
Indirect acting cholinergic agonist
Toxic insecticide
Hydroxyurea
inhibitor of ribonucleotide reductase, which makes ribonucleotides into deoxyribonucleotides
Beckwith-Wiedemann Syndrome (BWS) features
- macroglossia (enlarged tongue)
- birth weight and length greater than 90 percentile
- abdominal wall defects such as umbilical hernia
- ear creases or pits -neonatal hypoglycemia
- increased risk of cancer
IVF increases risk
Immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)
Mutation
Symptoms
mutation in the Dnmt3b gene.
facial dysmorphism, mental retardation, recurrent and prolonged infections, and variable immune deficiency with a constant decrease of IgA
Nicotine uses
Smoking cessation therapy
Monosodium urate can also be deposited in the _________ as ___________
soft tissues
tophi
Cardiac Msucle Sarcoplasmic Reticulum
Single network along the sarcomere extending from Z line to Z line
less developed than the one in skeletal muscle
– Terminal cisterna contain Ca2+ release channels to release Ca2+ into sarcoplasm
siRNA - short interfering RNA
- Derived from
- Method of gene regulation
- Origin
derived from long dsRNAs and ‘random’ processing
regulates expression by mRNA degradation
often exogenous (from outside the cell, i.e. Virus or injected)
Describe Choline Esters
quaternary ammoniums
Poorly absorbed and poorly distributed into the CNS.
differ in their susceptibility to hydrolysis by cholinesterase
Acetylcholine is very rapidly hydrolyzed
Absorption of drugs
Transfer of drug to the bloodstream from administration site.
Rate and efficiency depend on route of administration
For IV delivery, absorption is complete: the total dose reaches systemic circulation
Drug delivery by other routes may result in only partial absorption.
Spina bifida
- Incomplete closure of the spine
- Can be quite variable in severity
- Repair may be done in utero or postnatally but successful outcomes are variable
Bioavailability
the fraction of drug absorbed into the systemic circulation
Allopurinol
Type of inhibition and which enzyme?
Function of enzyme?
Mechanism of action?
End result?
irreversibly inhibits xanthine oxidase
forms uric acid by degrading purines
binds to Molybdenum-sulfide complex in enzyme.
used to limit uric acid production in pts. with gout.
Identify and describe:
Elastic Connective Tissue
- Elastic fibers - yellow colored
- Ligamentum flavum, vocal ligament, suspensory ligament of the penis
N-Glycosylation
Formation of a mannose-rich oligosaccharide bound to the lipid dolichol pyrophosphate.
Physostigmine
Type
Function
Indirect acting cholinergic agonist
Treats Atropine overdose
Identify:
Renal corpuscle and convoluted tubule of the kidney
PAS stain of glycoproteins and proteogylcans
Adipocytes: Unilocular
one large fat droplet ‐ “white” fat
- Typical fat cell ‐ signet ring cell.
- Large fat inclusion; organelles/ nucleus pushed to periphery of the cell.
- Major energy source ‐triglycerides
- Rich blood supply.
Elastin Lysyl oxidase, copper needed
Yes: allysine residues and special: desmosine
Limitations of twin studies
1) May underestimate heritability (only addresses differences between 100% and 50% identical genomes)
2) MZs do have some different genes (e.g. mitochondrial genes) and epigenetic differences
3) Different environmental exposures (in utero and outside)
4) Different genes in different twin pairs (studies between different sets of twins may point to different contributors for same phenotype)
5) Most studies do NOT specify the loci and alleles but how genotype and environment interact
Myosin II
Thick filament
•Motor proteins aggregated tail to tail to form thick myosin filaments
Wilms Tumor
Autosomal Dominant Inheritance
Loss of function in the WT1 gene on Chromosome 11, which encodes a transcription factor important in the control of cell growth and differentiation.
This is a renal cancer.
Adverse effects of Muscarinic Agonists
Salivation
Flushing
Hypotension
Nausea
Abdominal Pain
Diarrhea
Bronchoplasm
Thiopurine and azathioprine
metabolized in vivo into intermediates that inhibit the denovo synthesis of purine nucleotides
Used as anticancer agents (leukemia); also used as immunosuppressive agents in a variety of disorders
Succinylcholine
Type
Function
Mnemonic?
Nicotinic cholinergic antagonist. Depolarizing
Causes flaccid paralysis. Used for rapid endotrachial intubation
Elastin Commonly found amino acids
Alanine, valine, proline, lysine rarely hydroxylated
two main types of regulatory protein in bacteria:
Repressors
Activators
• A given gene (or group of genes) may use either or both types of protein for regulation
Clearence Formula
Methacholine
Type
Function
Mnemonic?
Direct acting Cholinergic Agonist
Used to Diagnose Asthma by causing bronchoconstriction
METHacholine. Meth gets inhaled. this drug relates to breathing.
Prazosin
Type
Function
alpha-1 selective adrenergic antagonist
decr. blood pressure. Used to treat hypertension, DOC for symptom relief, relaxing bladder smooth muscle.
Mixed somatic/germline mosaic
Body cells vary in genotype.
Ex. some cells XXY and some XXXY in kleinfelter’s
detrusor muscle
bladder wall is composed of smooth muscle, innervated by
- sympathetic (B2 receptors)
- parasympathetic (M3 muscarinic receptors)
10 Dietary essential amino acid
Phenylalanine Valine Tryptophan Threonine Isoleucine Methionine Histidine Arginine Lysine Leucine
Golgi tendon organ
Encapsulated proprioceptor located at the myotendinous junction
Senses tension in the muscle
Sensory component of the Golgi tendon reflex
Elastin Special structure
Needs the extracellular protein fibrillin as scaffold
Multilocular Adipocytes
Brown Fat
Characterized by: Many lipid droplets Central nucleus Rich in mitochondria Highly vascular Rich in innervation Lipochrome pigments Main function ‐ heat production Specialized locations in the body neck, abdomen of neonates
2 ways that a person could be mosaic for a Down syndrome
Non-disjunction occurs as a post-zygotic mitotic nondisjunction from normal egg and normal sperm.
Trisomy 21 @ conception. Post-fertilization mitosis evicts one Chrom. 21, so some cells are normal and some are trisomy.
Tumor progression results from _____________followed by _____________
waves of mutation
clonal expansion
Activators
bind to or near an operator region and allow RNA polymerase to initiate transcription
Ganglion blocker medications
Hexamethonium
Nicotine
Dosing rate formula
Identify and describe structure and function:
Loose (areolar) Connective Tissue
- Fills spaces between other tissues - large number of cells
- Flexible, rich blood supply, not resistant to stress
Identify the yellow and blue circles and their components
Yellow: Stroma (Connective tissue) with supportig structures
Blue: Parenchyma (epithelium, nerve, muscle). Functional unit.
Identify what is indicated by the graph:
Multiple oral drug administrations:
The oscillations in plasma concentration are influenced by both rate of drug absorption and rate of drug eliminantion
Whole Mount Preparation
a piece of tissue is removed as a whole -for example like the mesentery - and placed on a slide, stained and the contents visualized through microscope. The cells and the fibers can be visualized.
The cellular component is predominant – loose connective tissue.
Identify and describe:
Epimysium- E
Dense connective tissue
encases multiple fascicles
Contains major blood vessels and nerves
Continues with tendon to attach muscle at the myotendinous junction
Identify and describe:
Brown adipose tissue
Cells -smaller
Nucleus -central
Lipid droplet -many
Function -energy release
Volume of distribution formula
What kind of peak does oral drug administration yield?
more rounded peak
Identify and describe
Perimysium- P
Groups of skeletal myocytes/fibers form a fascicle (F), each of which is surrounded by a layer of connective tissue or perimysium
Contains larger blood vessels and nerves
Embryonic Connective Tissue Identify the following two pictures:
a. Mesenchyme
b. Mucous
Fill in the Chart
Identify and describe:
Dense Irregular Connective Tissue
- Fewer cells, more fibers than loose (areolar) tissue
- No orientation of collagen fibers - resistance to stress in all directions
- Organs capsules, periosteum, dermis
Identify and describe:
Reticular Connective Tissue
- Reticular cells (modified fibroblasts) - cytoplasmic extensions cover reticular fibers
- Framework for myeloid (bone marrow) and lymphoid (lymph nodes, spleen) organs
Label the phases on the graph indicated by arrows.
- The rapid fall is the distribution phase.
- The slower phase is the elimination phase.
What happens when the drug is given repeatedly at regular intervals
Plasma concentration increases until steady state is reached. The pasma concentration fluctuates about a mean.
Neuropil
Meshwork of tissue in grey matter excluding the cell bodies
Comprised of: dendritic and axonal processes, central glial cells
Identify and describe:
Dense Regular Connective Tissue
- Specific orientation of collagen fibers
- Tendons / ligaments
- Imparts tensile strength
Identify the type of inversion:
Paracentric
Identify:
Cerebral Cortex Tissue
t1/2 formula
Label the yellow box and the frequency of administration of each line on the graph:
Loading dose formula
Identify:
Laminin (glycoprotein) in basement membrane
Effects of large IV ACh dose
HR
MAP
PVR
cause vasodilation, a fall in blood pressure (M3 effect) and bradycardia (M2 effect)
Effects of small IV ACh dose
hr
map
pvr
fall in blood pressure due to vasodilation (M3 effect) usually accompanied by reflex tachycardia.
Fill in the right side of the chart:
Identify the disease:
HNPCC
