Pharm 450 Cahill & Cole Lectures

Front 1

3 Types of Pain

Back 1

Transient
Acute
Chronic

Front 2

Transient Pain

Back 2

Only when stimulus is present. Nocireceptor-mediated.
Pain in absence of tissue damage.

Front 3

Acute Pain

Back 3

Physiological pain.
Nocireceptor mediated.
Temporary -> seconds to weeks

Front 4

Chronic Pain

Back 4

Pathological pain.
Not only nocireceptor-mediated.
Lasts at least 6 months.

Front 5

Somatic Pain

Back 5

Caused by nociceptor activation in either cutaneous or deep tissue.
acute = needs rest
chronic = needs exercise
Responds to NSAIDs

Front 6

Visceral Pain

Back 6

Stretching, extension, compression of chest, abdominal, or pelvic viscera.
acute = myocardial infarct
chronic = IBS
Responds to NSAIDs
Exercise NOT helpful

Front 7

Neuropathic Pain

Back 7

PNS/CNS lesion with sensory symptoms and signs

Front 8

Tx Neuropathic Pain

Back 8

Opiods (morphine)
Amitryptyline (TCA)
Anticonvulsants
Carbamazepine
Gapapentin
Pregabalin
Capsaicin

Front 9

Carbamazepine

Back 9

Na channel blocker
Anticonvulsant used for neuropathic pain

Front 10

Gabapentin, Pregabalin

Back 10

Ca channel blockers
Anticonvulsants used for neuropathic pain

Front 11

Amitryptyline

Back 11

TCA used for neuropathic pain

Front 12

Capsaicin receptor

Back 12

TRPB-1

Front 13

Neuroanatomy of nociception superficial dorsal horn

Back 13

Lamina 1 = marginal zone
Lamina 2 = substantia gelatinosa

Part of Rex Lamina (10 laminae total)

Front 14

Spinothalamic Tract

Back 14

Lamina 1 and 5 to thalamus & cortex

Pain, itch, temperature

Front 15

Spinoreticular Tract

Back 15

Lamina 7 and 8 to reticular formaion, then thalamus and cortex.

Integration of pain info contributing to motivational, affective, and aversive responses to pain.

Front 16

Spinomesencephalic Tract

Back 16

Lamina 1, 4, 5, 7 to midbrain.

Affective and aversive behaviours associated with pain.

Front 17

Intensity of pain correlates with

Back 17

Activation of S1 somatosensory cortex

Front 18

Unpleasantness of pain correlates with

Back 18

Activation of anterior cingulate cortex.

Can be activated just by fear of exposure to pain.

Front 19

A-alpha Fibres

Back 19

Proprioception

Myelinated, large diameter

Front 20

A-beta Fibres

Back 20

Light touch, vibration, pressure

Myelinated, large diameter

Front 21

A-delta Fibres

Back 21

All nociception; mediates initial burst of pain using glutamate.

Light myelination
Medium diameter

Front 22

C Fibres

Back 22

Nociception, itch, temperature
Unmyelinated
Small diameter

Mediates later throbbing pain using glutamate AND neuropeptides (substance P, CGRP)

Front 23

Glutamate Receptors

Back 23

NMDA, AMPA, KA, mGluRs

Front 24

Substance P Receptors

Back 24

Neurokinin I receptor

Front 25

ATP Receptors

Back 25

P2X receptors

Front 26

Endogenous Opiod Receptors

Back 26

Mu, delta, kappa

Front 27

GABA Receptors

Back 27

GABA-A, GABA-B

Front 28

Glycine Receptors

Back 28

Glycine receptors

NB. Inhibiting glycine or GABA receptors causes pain!

Front 29

Peripheral Sensitization

Back 29

Inflammatory soup of bradykinins, histamine, 5-HT, ATP, H ions, prostaglandins all decrease afferent neuron activation threshold.

Front 30

Neurogenic Pain Response

Back 30

Substance P and CGRP released by C fibres cause ANTIDROMIC STIMULATION, exacerbating the pain response.
- both cause vasodilation
- substance P activates macrophages

Front 31

Peripheral sensitization shifts the pain response curve...

Back 31

Left

Front 32

Bulbospinal Systems

Back 32

Descending pathways from the brain that also mediate pain.

1. Periaqueductal grey -> raphe magnus in medulla -> Spinal dorsal horn

2. Locus ceruleus & lateral tegmentum in pons -> spinal dorsal horn

Front 33

Locus ceruleus neurons

Back 33

Release noradrenalin

Front 34

Raphe magnus neurons

Back 34

Release serotonin

Front 35

Natura opiod-R agonists

Back 35

Morphine, codeine

Front 36

Semi-synthetic opiod-R agonists

Back 36

Heroin
Hydromorphone
Oxycodone

Front 37

Syntehtic opiod-R agonists

Back 37

Meperidine
Methadone
Fentanyl

Front 38

Mixed Opiod-R agonists/antagonists

Back 38

Pentazocine
Buprenorphine

Front 39

Pure Opiod-R Antagonists

Back 39

Naloxone
Naltrexone

Front 40

Agonist actions by opiod receptor

Back 40

70% mu
20% delta
10% kappa

Front 41

Enkephalins

Back 41

Delta selective

- methionine
- leucine

Front 42

Dynorphins

Back 42

Kappa selective

Front 43

Endorphins

Back 43

Mu, delta selective

Front 44

Endomorphins

Back 44

Mu selective

Front 45

Nociceptin

Back 45

Opiod-like
- not blocked by naloxone

Front 46

Opiod motif

Back 46

Tyr-gly-gly-phe

Front 47

2 opiods with high propensity for addiction

Back 47

Morphine
Oxycodone

Front 48

Opiod Receptors in the CNS

Back 48

Dorsal horn of spinal cord
Thalamus
Periaqueductal gray
Rostral ventral medulla
Limbic system
Hypothalamus
Amygdala

Front 49

Opiod Receptors in the PNS

Back 49

High threshold, primary afferent fibres

eg. Neural plexi in GI tract

Front 50

Coupling of opiod receptors to G proteins starts signalling cascade, resulting in...

Back 50

1. Decrease in Ca channel activation, blocking presynaptic vesicle release.
2. Increase in K channel activation, hyperpolarizing postsynaptic neurons.
3. Decrease adenyl cyclase pre and postsynaptically.

Front 51

Opiod CNS Effects

Back 51

Analgesia, euphoria, sedation, respiratory depression, cough suppression, miosis, nausea, vomiting.

Front 52

Opiod PNS Effects

Back 52

CV: decrease peripheral resistance; inhibits baroreceptor reflex; morphine mediated histamine-release can cause hypotension.

GI: constipation!

Front 53

3 Types of Neurons

Back 53

Motor
Sensory
Interneurons

Front 54

3 Types of Support Cells in CNS

Back 54

Microglia (immune reactions)
Astrocytes (BBB sealing)
Ologdendrocytes ( myelination)

Front 55

Vesicle Release

Back 55

1. AP generated by voltage gated Na channels

2. Ca influx as voltage gated Ca channels open in response to AP

3. Vesicles migrate to synaptic cleft and release NTs

Front 56

Only drugs that are ____ can pass the BBB.

Back 56

1. Uncharged
2. Lipophylic
3. AA of NT precursor like.

Front 57

Lipoic Acid

Back 57

Antioxidant that strengthens BBB

Front 58

3 diseases associated with oxidative stress on BBB

Back 58

1. Epilepsy
2. Meningitis
3 MS

Front 59

Fast Onset Receptors

Back 59

Ionotropic receptors for glutamate and GABA.

Front 60

Slow Onset Receptors

Back 60

Metabotropic receptors for glutamate, GABA, monoamines, and neuropeptides.

Front 61

2 Types of Voltage-gated Ca Channels

Back 61

N and PQ

Front 62

Voltage-gated channels

Back 62

Are metabotrpic

Front 63

Ligand-gated channels

Back 63

eg. GABA-R, NMDA receptors

Are ionotropic.

Front 64

IPSPs are due to

Back 64

K channel activation

Front 65

Vitamin B6 is important in ___

Back 65

Important in monoamine syntehsis

Front 66

Cocaine inhibits ___

Back 66

DA, NE reuptake

Front 67

Amphetamines cause ___

Back 67

Cytosolic NT and monoamine release

Front 68

Barbituates help couple ___

Back 68

GABA and its receptor

Front 69

Vigabatrin blocks

Back 69

GABA breakdown

Front 70

Bicuculline is a ____

Back 70

GABA-A antagonist

Front 71

Muscimol is a ___

Back 71

GABA-A agonist

Front 72

3 Ionotropic Receptors for Acidic AAs

Back 72

Kainate (KA)
AMPA
NMDA

Front 73

NMDA receptors are unique because ___

Back 73

They allow Ca entry

Front 74

Metabotropic acid AA receptors regulate ___

Back 74

Adenylase cyclase activity, causing slow excitation of inhibition.

Front 75

Glutamate reuptake is done by ___

Back 75

Neurons and astrocytes. Astrocytes convert glutamate to glutamine.

Front 76

NMDA receptors need

Back 76

1. Glycine co-binding
2. Slight depolarizaitons to dislodge Mg sitting in the channel

Front 77

Neutral AAs open ___

Back 77

Cl channels to hyperpolarize cells

Front 78

2 Types of GABA receptors

Back 78

GABA-A = ionotropic receptors (mediate Cl channels)

GABA-B = metabotropic receptors

Front 79

Glycine is mostly found in

Back 79

Grey matter of the spinal cord

Front 80

Monoamines

Back 80

Cathecholamines = dopamine, NE
5-HT/serotonin

Front 81

Dopamine receptors

Back 81

D1-like and D2-like

Both metabotropic

Front 82

NE receptors

Back 82

A2 receptors that increase K conductance (causing hyperpolarization)

Metabotropic

Front 83

5-HT Receptors

Back 83

Involved in LSD hallucinations, sleep, temperature, appetite, neuroendocrine levels.

1 ionotropic; rest are metabotropic.

Front 84

Gene therapy is currently used for ___

Back 84

Monogenetic disorders
eg. SCID, HD, PD, CF, thalassemia, sickle cell anemia, hemophilia, cancerous oncogenes

Front 85

2 Types of Gene Therapy

Back 85

1. In vivo: delivering transgene DNA to tissues in the body

2. Ex vivo: remove target cells from body, insert transgene invitro, then put cells back in body

Front 86

Biological DNA delivery systems

Back 86

Viral vectors

Front 87

Non-biological DNA delivery systems

Back 87

Non-viral means:
- electroporation
- CaHPO4 precipitation
- Gene gun
- Cationic lipid liposomes

Front 88

Lipid liposomes enter cells in 2 ways

Back 88

1. Endocytosis
2. Membrane fusion (bypasses lysosome part)

Influenced by choice of lipid

Front 89

Cationic lipids have 3 parts

Back 89

1. Lipid anchor
2. Head group
3. Linker

Front 90

Physical Delivery Limitations

Back 90

LIPID TOXICITY
- insufficient delivery
- ineffcient uptake
- ineffective nuclear targeting
- insufficient transgene release
- need large amounts of DNA

Front 91

Improving nuclear targeting

Back 91

Tagging with DNA/PEG/Lys tag

Front 92

Nuclear pore complex diameter

Back 92

25nm

Front 93

Retoviruses & Lentiviruses as vectors

Back 93

Good: stable, high efficiency

Bad: genes integrate randomly; only infects dividing cells; almost no cell-type specificity.

Front 94

Adenoviruses as vectors

Back 94

Good: large gene capacity; no serious diseases.

Bad: serious immune reactions; may only be transient integration.

Front 95

Herpesvirsuses as vectors

Back 95

Good: broad host range; high effciency & gene expression.

Bad: serious immune reactions; integration issues.

Front 96

Adeno-associated viruses (AAV) are ___

Back 96

Small ssDNA viruses that insert at speciic sites on chromosome 19.

Can transduce non-dividing cells, mediating sustained expression.

BUT can only deliver small genes.

Front 97

Modified AAVs

Back 97

AAV5, AAV2 - target airway epithelia

AAV6 targets cardiac and skeletal muscle

Front 98

Cystic Fibrosis

Back 98

Caused by CFTR gene mutation
- cAMP-dependent chloride channel

Front 99

Most common CFTR mutation

Back 99

delta F508 -> pheylalanine deletion at position 508

causes protein misfolding and failure to localize at apical membrane

Front 100

Antimetabolites

Back 100

Inhibit DNA synthesis

Front 101

Antimicrotubule agents do 1 of 2 things

Back 101

1. Inhibit polymerization
2. Prevent depolymerization

Front 102

Vinca Alkaloids

Back 102

Prevent MT formation

- vincristine, vinblastine

Front 103

Taxanes

Back 103

Prevent MT disassembly

- paclitaxel, docitaxel

Front 104

Paclitaxel

Back 104

Taxane alkaloid; anti MT agent.
- unique mechanism
- obtained from Pacific Yew bark but killed tree in process

Front 105

Mechanism & structure of alkylating agents

Back 105

- Their alkyl groups covalently bind to DNA

- a nitrogen containing 2 halide leaving groups

Front 106

DNA undergoes ___ following alkylation

Back 106

1. Cross-linking to 2nd DNA strang
2. Depurination
3. Cleavage of rings in bases
4. Abnormal base pairing (can be mutagenic)

Front 107

Cysplatin

Back 107

Atypical alkylating agent that uses platinum and is thus inorganic.

Forms DNA adducts with preference for N-7 GUANINE.

IT CURES TESTICULAR CANCER!

Major renal toxicity so must superhydrate patients.

Front 108

Camptothecin

Back 108

Topo I inhibitors

Front 109

Topo II differs from Topo I because

Back 109

1. It cleaves both strands
2. it requires ATP
3. Knocking out topo II is lethal

Front 110

Doxorubicin

Back 110

Topo II inhibitor belonging to the anthracycline family.

Used to cure solid tumours.
Causes cardiotoxicity.
Used by Terry Fox.

Front 111

Etoposide (VP-16)

Back 111

Topo II inhibitor that causes DNA damage, greatly increasing the risk of secondary malignancies later on.

Front 112

Daunorubicin

Back 112

Closely related to doxorubicin -- off by 1 OH group -- but useless for solid tumours. Used in leukemia.

Front 113

Targeted Non-cytotoxic agents

Back 113

Target cell signalling pathways instead of DNA or MTs, especially tyrosine kinases.

Front 114

2 ways of targeting tyrosine kinases

Back 114

1. Monoclonal antibodies target outside portion of its receptor
2. Small molecules target its ATP binding region intracellularly

Front 115

Gefitnib

Back 115

Targets the EGF receptor in lung acncer

Front 116

Sorafenib

Back 116

targets the Ras/Raf tyrosine kinases in mealonmas, renal cell cancers

Front 117

Oncolytic viruses

Back 117

Virsuses that propagate selectively in tumour tissue

Front 118

3 Drug Resistance Mechanisms to Antineopalstics

Back 118

1. Pharmacokinetic
2. Cellular
3. Tumour Microenvironment

Front 119

2 Morphine Metabolities

Back 119

M6G = more potent analgesic

M3G = no analgesic effects; neuroexcitatory effects; morphine-evoked pain at high doses, antgonizing the morphine receptor

Front 120

Morphien metabolsim

Back 120

Hepatic via conjugation with glucouronide

metabolized via P450

Front 121

Codein

Back 121

weak opiod

Front 122

Fentanyl

Back 122

potent, used in patches for constant dosage

Front 123

Parietis

Back 123

side effect of chronic opiod use

skin itching due to histamine release

Front 124

3 Causes of loss of effectiveness following chronic opiod use

Back 124

1. cellular adaptation
2. opiod receptor desensitization
3. adaptive increase in levels of pain transmitters

Front 125

Incomplete cross tolerance

Back 125

occurs between opiods so must decrease dose when switching

Front 126

Opiod tolerance

Back 126

only for certain effects: sedation, analgesia, nausea, euphora

not for constipation, miosis, bradycardia

Front 127

Physical opiod withdrawal

Back 127

dysphoria, diarrhea

Front 128

Pseudo-addiction to opiods

Back 128

severe pain but not prescribed enough to control the pain; patients will exhibit behaviours that look like addiction.

Front 129

Cannabinoid receptors

Back 129

CB-1: most prevalent GPCR in brain; also in spinal cord.

CB-2: in periphery

Front 130

Active Cannabinoid

Back 130

delta-9 THC

Front 131

Cannabinoid drug interactions

Back 131

synergistic with opiods

Front 132

PD neuron loss

Back 132

DA neurons in substantia nigra of basal ganglia

Front 133

HD neuron loss

Back 133

GABA neurons in neostriatum of basal ganglia

Front 134

AG neuron loss

Back 134

Cholinergic neurons in hippocampus & neocortex

Front 135

Incidence rates of neurodegenerative diseases

Back 135

PD: 1% over 65
AD: 10% over 65
HD: rarer but 50% of each generation in families carrying the gene

Front 136

Dieases associated with basal ganglia disease

Back 136

PD
HD
Tourette's

Front 137

Basal Ganglia Functions

Back 137

Controls motor actions by INDIRECTLY acting on descending pathways to the eyes, limbs, and trunk.

Cognition

Emotions & Addiction

Front 138

Gpe

Back 138

Globus pallidus external

Front 139

Gpi

Back 139

Globus pallidus internal

Front 140

SNpc

Back 140

substantia nigra pars compacta

Front 141

SNr

Back 141

substantia nigra pars reticulata

Front 142

STN

Back 142

subthalamic nucleus

Front 143

D1 receptors in caudate putamen mediate ___

Back 143

direct pathway in basal ganglia circuit

promotes voluntary movement via increased thalamic feedback to cortex

Front 144

D2 receptors in caudate putamen mediate ___

Back 144

indirect pathway in basal ganglia circuit

inhibits movement by decreasing thalamic feedback to cortex

Front 145

PD caused by

Back 145

degeneration of dopamine neurons in the substantia nigra pars compacta

- loss of pigmented neurons
- intracellular Lewy bodies appear

Front 146

Amount of DA neuron loss before PD becomes symptomatic

Back 146

70-80%

Front 147

4 Cardinal Clinical Features of PD

Back 147

1. Bradykinesia
2. Muscle Rigidity
3. Tremors at rest
4. Disturbed postural balance

Front 148

Levodopa is usually given with a ___

Back 148

Dopa decarboxylase inhibitrs (together = carbidopa)

Front 149

MAO-B inhibitors treat PD by ___

Back 149

Inhibiting MPTP conversion to MPP, which inhibits mitochondria in neurons, leading to apoptosis.

Front 150

Amantadine

Back 150

Treats PD by promoting DA release.

Early in disease progression and not for elderly.

Front 151

Anticholinergics

Back 151

Increases DA transmission

Early PD treatment and not for elderly

Front 152

Adverse effects of levodopa

Back 152

nausea
hallucinations
psychosis in some
addictions (reward centres in mesolimbic pathway get activated)
excessive sexual arousal

Front 153

DA receptor agonist pros and cons

Back 153

pros: no enzymatic conversion; doesn't need any substantia nigra neurons to be left intact.

cons: insomnia; worse gambling problems than L-dopa; all L-dopa's adverse effects.

Front 154

Prognosis for advanced melanoma, renal carcinomas

Back 154

No treatment available

Front 155

Prognosis for breast, ovarian, colon cancers (advanced)

Back 155

Variable results

Front 156

Prognosis for gestational choriocarinoma, testicular cancer, Hodgkin's lymphoma (advanced)

Back 156

Mostly curable

Front 157

Cells most vulnerable to antineoplastic drug toxicities

Back 157

Those with high turnover rates

Front 158

Bone marrow Toxicity Sx

Back 158

Anemia -> low RBC
Infections -> low WBC
Internal Bleeding -> low platelets

Front 159

Combination chemotherapy ideally combines drugs with

Back 159

1. activity in the same tissue
2. different mechanisms
3. non-overlapping toxicities

Front 160

Methotrexate

Back 160

Folic acid analog. Works like trimethoprim.

Inhibits dihydrofolate reductase enzyme, stopping synthesis of FH4 (purine, ethionine precursor) and folic acid (thymidine precursor)

Front 161

Polyglutamylation

Back 161

Occurs to methotrexate, helping to keep the drug in the cell. More = better prognosis.

Front 162

5-FU

Back 162

pyridimine analog; needs to be activated into FdUMP inside the cell

- inactivated by DPD enzyme outside cell

Front 163

FdUMP

Back 163

active form of 5-FU; inhibits thymidylate synthetase

Front 164

Cytosine arabinoside (AraC)

Back 164

Cytidine analog. 3 fates:
1. inactivated to AraU by cytidine deaminase
2. converted to AraUMP, inhibiting RNA synthesis
3. converted to AraCTP, inhibiting DNA synthesis

Front 165

3 Categories of CNS Stimulants

Back 165

1. Convulsant & Respiratory Stimulants
2. Psychomotor Stimulants
3. Psychotomimetic Drugs

Front 166

Convulsant & Respiratory Stimulants

Back 166

Little effect on mental function.

Effects in spinal cord and brainstem.

Front 167

Psychomotor Stimulants

Back 167

Marked mental & behavioural excitement.
- excitement, euphoria
- reduced sense of fatigue
- increased motor activity

Front 168

Psychotomimetic Drugs

Back 168

Altered thoughts & perceptions
- Psychotic symptoms due to distorted cognition

Front 169

Strychnine

Back 169

Experimental drug

Obtained from seed of Indian tree; used for centuries as poison.

Produces convulsions by blocking glycine receptors (takes away motor neuron inhibition)

Front 170

Bicuculline

Back 170

Experimental drug

GABA-A receptor antagonist

Front 171

Amphetamines

Back 171

Cause monoamine release
- most important 2 are NE and DA

Front 172

Methamphetamine

Back 172

Speed -> used by military, pilots

Front 173

Methylphenidate

Back 173

Ritalin for ADHD

Front 174

Methylenedioxymethamphetamine

Back 174

Ecstasy

Front 175

Amphetamine Effects

Back 175

1. Locomotor Stimulation
2. Euphoria & excitement
3. Stereotype behaviour
4 Anorexia

Increased confidence; hypersocial' hyperactive; increased sex drive.

Improved mental performance.

Peripheral sympathomimetic: increase BP; decreased GI motility.

Front 176

Clinical Amphetamine Uses

Back 176

1. ADHD
2. Narcolepsy
3. Appetite suppression (rare!)

Front 177

Amphetamine Psychosis

Back 177

Repeated use of amphetamines over a few days produces psychosis resembling acute schizophrenia )hallucinations, paranoia, aggression)

Front 178

Physical withdrawal symptoms from amphetamines

Back 178

No clear set of symptoms

Front 179

Cocaine

Back 179

Blocks DA and NE reuptake

Front 180

Effects of Cocaine

Back 180

1. Psychomotor excitation
2. Euphoria

NO STEREOTYPED BEHAVIOUR***

Front 181

Lack of stereotyped behaviour with cocaine due to ___

Back 181

It has no effect on 5-HT like amphetamines do.

Front 182

Cocaine metabolism

Back 182

Deposited in fingernails and hair, even in newborns.

Front 183

Methylxanthines

Back 183

1. Caffeine
2. Theophylline (major methylxanthine in tea)

Front 184

Methylxanthine mechanism

Back 184

Blocks adenosine receptor

Inhibits phosphodiesterase at high concentrations, increasing cAMP within the cell.

Front 185

Caffeine withdrawal symptoms

Back 185

Headache, irritability, lethargy

Front 186

Caffeine effects

Back 186

CNS stimulation
Diuresis
Stimulation of cardiac muscle
Relaxation of smooth muscle, especially brochial SM